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Sample records for her2 positive metastatic

  1. HER-2-positive metastatic breast cancer: new possibilities for therapy

    Directory of Open Access Journals (Sweden)

    E. V. Artamonova

    2013-01-01

    Full Text Available This article is devoted to modern approaches in HER-2-positive metastatic breast cancer therapy. Recently treatment algorithm for this type of cancer included trastuzumab plus cytostatic in first line, continuation of trastuzumab with another chemotherapy regimen in second line, further switch to lapatinib and eventual return to trastuzumab after progression. Nowadays our options are broader owing to new anti-HER-2 agents which are pertruzumab and T-DM1. Now the most effective therapy regimen in first line is double HER-2 blockade (trastuzumab + pertuzumab in combination with docetaxel. Benefit of new agent T-DM1 versus combination of lapatinib and capecitabin is proved in patients progressed on trastuzumab and taxanes. T-DM1 also showed high efficacy as salvage therapy in intensively pretreated patients with meta- static HER-2-positive breast cancer who progressed on taxanes, trastuzumab and lapatinib.

  2. Characterizing Metastatic HER2-Positive Gastric Cancer at the CDH1 Haplotype

    Science.gov (United States)

    Caggiari, Laura; Miolo, Gianmaria; Buonadonna, Angela; Basile, Debora; Santeufemia, Davide A.; De Zorzi, Mariangela; Fornasarig, Mara; Alessandrini, Lara; Lo Re, Giovanni; Puglisi, Fabio; Steffan, Agostino

    2017-01-01

    The CDH1 gene, coding for the E-cadherin protein, is linked to gastric cancer (GC) susceptibility and tumor invasion. The human epidermal growth factor receptor 2 (HER2) is amplified and overexpressed in a portion of GC. HER2 is an established therapeutic target in metastatic GC (mGC). Trastuzumab, in combination with various chemotherapeutic agents, is a standard treatment for these tumors leading to outcome improvement. Unfortunately, the survival benefit is limited to a fraction of patients. The aim of this study was to improve knowledge of the HER2 and the E-cadherin alterations in the context of GC to characterize subtypes of patients that could better benefit from targeted therapy. An association between the P7-CDH1 haplotype, including two polymorphisms (rs16260A-rs1801552T) and a subset of HER2-positive mGC with better prognosis was observed. Results indicated the potential evaluation of CDH1 haplotypes in mGC to stratify patients that will benefit from trastuzumab-based treatments. Moreover, data may have implications to understanding the HER2 and the E-cadherin interactions in vivo and in response to treatments. PMID:29295527

  3. Maintenance Therapy with Trastuzumab in Her2 Positive Metastatic Parotid Ductal Adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Muhammad Shahid Iqbal

    2014-01-01

    Full Text Available Salivary ductal carcinomas (SDCs are extremely rare and aggressive malignancies, accounting for approximately 6% of all salivary gland malignancies. One distinct feature is their resemblance to ductal carcinomas of breast. A significant percentage of SDCs overexpress Her2 and the use of targeted therapy with trastuzumab can be considered in these patients. We report a rare case of long term disease control with trastuzumab in Her2 positive metastatic parotid ductal carcinoma. Our case also highlights that isolated brain metastasis should be managed aggressively to allow optimal local control when systemic disease is under remission with trastuzumab. We have also reviewed the published literature on the use of trastuzumab in SDCs.

  4. High p95HER2/HER2 Ratio Associated With Poor Outcome in Trastuzumab-Treated HER2-Positive Metastatic Breast Cancer NCCTG N0337 and NCCTG 98-32-52 (Alliance).

    Science.gov (United States)

    Chumsri, Saranya; Sperinde, Jeff; Liu, Heshan; Gligorov, Joseph; Spano, Jean-Philippe; Antoine, Martine; Moreno Aspitia, Alvaro; Tan, Winston; Winslow, John; Petropoulos, Christos J; Chenna, Ahmed; Bates, Michael; Weidler, Jodi Marie; Huang, Weidong; Dueck, Amylou; Perez, Edith A

    2018-03-12

    Purpose: p95HER2 is a truncated form of HER2 that confers resistance to trastuzumab in vitro , but clinical results have been conflicting to date. Given that p95HER2 levels correlate with total HER2 expression levels, which confer better outcomes, we sought to evaluate the p95HER2/HER2 ratio in the North Central Cancer Treatment Group N0337 and N98-32-52 trials. Experimental Design: The HERmark assay and VeraTag technology (Monogram Biosciences) were used to measure total HER2 and p95HER2 expression levels in 91 patient samples. Results: In the multivariate model, increasing total HER2 level was significantly associated with longer (OS; HR, 0.33; P = 0.002) and decreasing p95HER2 level was significantly associated with longer OS (HR, 4.2; P = 0.01). Total HER2 expression level was significantly associated with longer progression-free survival (PFS) (HR, 0.57; P = 0.04), whereas p95HER2 level was not (HR, 1.7; P = 0.25). However, there was a positive association between p95HER2 and total HER2 expression levels ( R 2 = 0.48; P < 0.001). Consistent with our hypothesis, the ratio of p95HER2/HER2 was significantly associated with worsening PFS (HR, 1.7; P = 0.04) and OS (HR, 2.8; P = 0.002). Patients with the highest tertile of p95HER2/HER2 values had significantly less favorable PFS (HR, 1.8; P = 0.06) and OS (HR, 2.3; P = 0.02). Conclusions: A high p95HER2/HER2 ratio identified patients with metastatic breast cancer with poor outcomes on trastuzumab-based therapies. Further investigation of the p95HER2/HER2 ratio as a potential prognostic or predictive biomarker for HER2-targeted therapy is warranted. Clin Cancer Res; 1-6. ©2018 AACR. ©2018 American Association for Cancer Research.

  5. Palbociclib: A Review in HR-Positive, HER2-Negative, Advanced or Metastatic Breast Cancer.

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    Kim, Esther S; Scott, Lesley J

    2017-06-01

    Oral palbociclib (Ibrance®) is a first-in-class, highly selective inhibitor of cyclin-dependent kinases 4 and 6 (i.e. a CDK4/6 inhibitor). It is indicated for the treatment of women with HR-positive, HER2-negative advanced or metastatic breast cancer, in combination with an aromatase inhibitor as initial endocrine-based therapy, and in combination with fulvestrant (with or without a luteinizing hormone-releasing hormone agonist) in those previously treated with endocrine therapy. In clinical trials, palbociclib in combination with letrozole as initial endocrine-based therapy in postmenopausal women (PALOMA-1 and PALOMA-2), or in combination with fulvestrant in pre-, peri-, or postmenopausal women with disease progression after endocrine therapy (PALOMA-3), significantly prolonged progression-free survival (PFS) and improved clinical benefit response (CBR) rates. Neutropenia was the most commonly reported any-grade and grade ≥ 3 adverse event. It was infrequently associated with febrile neutropenia (<2%) and generally manageable with a palbociclib dose delay, interruption or reduction, without the routine use of growth factors, and without affecting efficacy. In conclusion, oral palbociclib combination therapy is a valuable emerging option for use in patients with HR-positive, HER2-negative advanced or metastatic breast cancer.

  6. Combination neratinib (HKI-272) and paclitaxel therapy in patients with HER2-positive metastatic breast cancer.

    Science.gov (United States)

    Chow, L W-C; Xu, B; Gupta, S; Freyman, A; Zhao, Y; Abbas, R; Vo Van, M-L; Bondarenko, I

    2013-05-28

    Neratinib is a potent irreversible pan-ErbB tyrosine kinase inhibitor that has demonstrated antitumour activity and an acceptable safety profile in patients with human epidermal growth factor receptor (HER)-2-positive breast cancer and other solid tumours. This was a phase I/II, open-label, two-part study. Part 1 was a dose-escalation study to determine the maximum tolerated dose (MTD) of neratinib plus paclitaxel in patients with solid tumours. Part 2 evaluated the safety, efficacy, and pharmacokinetics of the combination at the MTD in patients with HER2-positive breast cancer. Eight patients were included in the dose-escalation study; no dose-limiting toxicities were observed, and an MTD of oral neratinib 240 mg once daily plus intravenous paclitaxel 80 mg m(-2) on days 1, 8, and 15 of each 28-day cycle was determined. A total of 102 patients with HER2-positive breast cancer were enrolled in part 2. The overall median treatment duration was 47.9 weeks (range: 0.1-147.3 weeks). Common treatment-emergent adverse events (all grades/grade ≥3) included diarrhoea (92%/29%; none grade 4), peripheral sensory neuropathy (51%/3%), neutropenia (50%/20%), alopecia (46%/0%), leukopenia (41%/18%), anaemia (37%/8%), and nausea (34%/1%). Three (3%) patients discontinued treatment due to an adverse event (mouth ulceration, left ventricular ejection fraction reduction, and acute renal failure). Among the 99 evaluable patients in part 2 of the study, the overall response rate (ORR) was 73% (95% confidence interval (CI): 62.9-81.2%), including 7 (7%) patients who achieved a complete response; an additional 9 (9%) patients achieved stable disease for at least 24 weeks. ORR was 71% among patients with 0/1 prior chemotherapy regimen for metastatic disease and no prior lapatinib, and 77% among those with 2/3 prior chemotherapy regimens for metastatic disease with prior lapatinib permitted. Kaplan-Meier median progression-free survival was 57.0 weeks (95% CI: 47.7-81.6 weeks

  7. Functional Imaging of HER2-Positive Metastatic Breast Cancer Using 64Cu-DOTA-Trastuzumab Positron Emission Tomography

    Science.gov (United States)

    Mortimer, Joanne E.; Bading, James R.; Colcher, David M.; Conti, Peter S.; Frankel, Paul H.; Carroll, Mary I.; Tong, Shan; Poku, Erasmus; Miles, Joshua K.; Shively, John E.; Raubitschek, Andrew A.

    2014-01-01

    Women with human epidermal growth factor receptor 2 (HER2)-positive breast cancer are candidates for treatment with the anti-HER2 antibody trastuzumab. Assessment of HER2 status in recurrent disease is usually made by core needle biopsy of a single lesion which may not be representative of the larger tumor mass or other sites of disease. Our long-range goal is to develop positron emission tomography (PET) of radiolabeled trastuzumab for systemically assessing tumor HER2 expression and identifying appropriate use of anti-HER2 therapies. The purpose of this study was to evaluate PET-CT of 64Cu-DOTA-trastuzumab for detecting and measuring tumor uptake of trastuzumab in patients with HER2-positive metastatic breast cancer. Methods Eight women with biopsy-confirmed HER2-positive metastatic breast cancer and no anti-HER2 therapy for ≥ 4 mo underwent complete staging, including 18F-fluorodeoxyglucose (FDG)/PET-CT. For 6 of the 8 patients, 64Cu-DOTA-trastuzumab injection (364-512 MBq, 5 mg trastuzumab) was preceded by trastuzumab infusion (45 mg). PET-CT (PET scan duration 1 h) was performed 21-25 (“Day 1”) and 47-49 (“Day 2”) h after 64Cu-DOTA-trastuzumab injection. Scan fields of view were chosen based on 18F-FDG/PET-CT. Lesions visualized relative to adjacent tissue on PET were considered PET-positive; analysis was limited to lesions identifiable on CT. Radiolabel uptake in prominent lesions was measured as maximum single-voxel standardized uptake value (SUVmax). Results Liver uptake of 64Cu was reduced approximately 75% with the 45 mg trastuzumab pre-dose, without significant effect on tumor uptake. The study included 89 CT-positive lesions; detection sensitivity was 77, 89 and 93% for Day 1, Day 2 and 18F-FDG, respectively. On average, tumor uptake was similar for 64Cu-DOTA-trastuzumab and 18F-FDG [SUVmax (mean, range): Day 1 (8.1, 3.0-22.5, n=48); Day 2 (8.9, 0.9-28.9, n=38); 18F-FDG (9.7, 3.3-25.4, n=56)], but the extent of same-lesion uptake was not

  8. FDA Approval: Palbociclib for the Treatment of Postmenopausal Patients with Estrogen Receptor-Positive, HER2-Negative Metastatic Breast Cancer.

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    Beaver, Julia A; Amiri-Kordestani, Laleh; Charlab, Rosane; Chen, Wei; Palmby, Todd; Tilley, Amy; Zirkelbach, Jeanne Fourie; Yu, Jingyu; Liu, Qi; Zhao, Liang; Crich, Joyce; Chen, Xiao Hong; Hughes, Minerva; Bloomquist, Erik; Tang, Shenghui; Sridhara, Rajeshwari; Kluetz, Paul G; Kim, Geoffrey; Ibrahim, Amna; Pazdur, Richard; Cortazar, Patricia

    2015-11-01

    On February 3, 2015, the FDA granted accelerated approval to palbociclib (IBRANCE, Pfizer Inc.), an inhibitor of cyclin-dependent kinases 4 and 6 (CDK4 and CDK6), for use in combination with letrozole for the treatment of postmenopausal women with estrogen receptor (ER)-positive, HER2-negative advanced breast cancer as initial endocrine-based therapy for their metastatic disease. The approval is based on a randomized, multicenter, open-label phase I/II trial (PALOMA-1) in 165 patients randomized to palbociclib (125 mg orally daily for 21 consecutive days, followed by 7 days off treatment) plus letrozole (2.5 mg orally daily) or letrozole alone. The phase II portion of the trial was divided into two cohorts: cohort 1 enrolled 66 biomarker-unselected patients and cohort 2 enrolled 99 biomarker-positive patients. The major efficacy outcome measure was investigator-assessed progression-free survival (PFS). A large magnitude of improvement in PFS was observed in patients receiving palbociclib plus letrozole compared with patients receiving letrozole alone (HR, 0.488; 95% confidence interval, 0.319-0.748). Multiple sensitivity analyses were supportive of clinical benefit. The most common adverse reaction in patients receiving palbociclib plus letrozole was neutropenia. This article summarizes the FDA thought process and data supporting accelerated approval based on PALOMA-1 that may be contingent upon verification and description of clinical benefit in the ongoing and fully accrued confirmatory trial PALOMA-2. ©2015 American Association for Cancer Research.

  9. Use of trastuzumab for HER2-positive metastatic breast cancer in daily practice : a population-based study focusing on the elderly

    NARCIS (Netherlands)

    van Rooijen, Johan M.; de Munck, Linda; Teeuwen, Guusje M.; de Graaf, Jacques C.; Jansman, Frank G.; Boers, James E.; Siesling, Sabine

    The addition of trastuzumab to chemotherapy in human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) prolongs overall survival (OS) in clinical trials. However, treatment patterns and survival in daily practice are unknown. This study aims to compare trastuzumab use

  10. Use of trastuzumab for HER2-positive metastatic breast cancer in daily practice: a population-based study focusing on the elderly

    NARCIS (Netherlands)

    van Rooijen, Johan M.; de Munck, Linda; Teeuwen, Guusje M.; de Graaf, Jacques C.; Jansman, Frank G.; Boers, James E.; Siesling, Sabine

    2016-01-01

    The addition of trastuzumab to chemotherapy in human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) prolongs overall survival (OS) in clinical trials. However, treatment patterns and survival in daily practice are unknown. This study aims to compare trastuzumab use

  11. Biological Monitoring of HER-2 Positive Patients Using Serum HER-2 and Circulating Tumor Cells

    National Research Council Canada - National Science Library

    Fournier, Marcia

    2002-01-01

    ...: Blood samples were collected from 55 women with HER-2 positive (lHC+++ and/or FlSH+) metastatic breast cancer and 30 healthy female volunteers Blood samples were collected at baseline, during With the first cycle...

  12. A retrospective multicentric observational study of trastuzumab emtansine in HER2 positive metastatic breast cancer: a real-world experience

    Science.gov (United States)

    Vici, Patrizia; Pizzuti, Laura; Michelotti, Andrea; Sperduti, Isabella; Natoli, Clara; Mentuccia, Lucia; Lauro, Luigi Di; Sergi, Domenico; Marchetti, Paolo; Santini, Daniele; Magnolfi, Emanuela; Iezzi, Laura; Moscetti, Luca; Fabbri, Agnese; Cassano, Alessandra; Grassadonia, Antonino; Omarini, Claudia; Piacentini, Federico; Botticelli, Andrea; Bertolini, Ilaria; Scinto, Angelo Fedele; Zampa, Germano; Mauri, Maria; D’Onofrio, Loretta; Sini, Valentina; Barba, Maddalena; Maugeri-Saccà, Marcello; Rossi, Ernesto; Landucci, Elisabetta; Tomao, Silverio; Alberti, Antonio Maria; Giotta, Francesco; Ficorella, Corrado; Adamo, Vincenzo; Russo, Antonio; Lorusso, Vito; Cannita, Katia; Barni, Sandro; Laudadio, Lucio; Greco, Filippo; Garrone, Ornella; Giulia, Marina Della; Marolla, Paolo; Sanguineti, Giuseppe; Cocco, Barbara Di; Ciliberto, Gennaro; Maria, Ruggero De; Gamucci, Teresa

    2017-01-01

    We addressed trastuzumab emtansine (T-DM1) efficacy in HER2+ metastatic breast cancer patients treated in real-world practice, and its activity in pertuzumab-pretreated patients. We conducted a retrospective, observational study involving 23 cancer centres, and 250 patients. Survival data were analyzed by Kaplan Meier curves and log rank test. Factors testing significant in univariate analysis were tested in multivariate models. Median follow-up was 15 months and median T-DM1 treatment-length 4 months. Response rate was 41.6%, clinical benefit 60.9%. Median progression-free and median overall survival were 6 and 20 months, respectively. Overall, no differences emerged by pertuzumab pretreatment, with median progression-free and median overall survival of 4 and 17 months in pertuzumab-pretreated (p=0.13), and 6 and 22 months in pertuzumab-naïve patients (p=0.27). Patients who received second-line T-DM1 had median progression-free and median overall survival of 3 and 12 months (p=0.0001) if pertuzumab-pretreated, and 8 and 26 months if pertuzumab-naïve (p=0.06). In contrast, in third-line and beyond, median progression-free and median overall survival were 16 and 18 months in pertuzumab-pretreated (p=0.05) and 6 and 17 months in pertuzumab-naïve patients (p=0.30). In multivariate analysis, lower ECOG performance status was associated with progression-free survival benefit (p<0.0001), while overall survival was positively affected by lower ECOG PS (p<0.0001), absence of brain metastases (p 0.05), and clinical benefit (p<0.0001). Our results are comparable with those from randomized trials. Further studies are warranted to confirm and interpret our data on apparently lower T-DM1 efficacy when given as second-line treatment after pertuzumab, and on the optimal sequence order. PMID:28915642

  13. In-111-Trastuzumab Scintigraphy in HER2-Positive Metastatic Breast Cancer Patients Remains Feasible during Trastuzumab Treatment

    NARCIS (Netherlands)

    Gaykema, Sietske B. M.; de Jong, Johan R.; Perik, Patrick J.; Brouwers, Adrienne H.; Schroder, Carolien P.; Oude Munnink, Thijs H.; Bongaerts, Alphons H. H.; de Vries, Elisabeth G. E.; Lub-de Hooge, Marjolijn N.

    Human epidermal growth factor receptor (HER)2 imaging with radiolabeled trastuzumab might support HER2-targeted therapy. It is, however, frequently questioned whether HER2 imaging is also possible during trastuzumab treatment as the receptor might be saturated. We studied the effect of trastuzumab

  14. Plasma thymidine kinase-1 activity predicts outcome in patients with hormone receptor positive and HER2 negative metastatic breast cancer treated with endocrine therapy.

    Science.gov (United States)

    Bonechi, Martina; Galardi, Francesca; Biagioni, Chiara; De Luca, Francesca; Bergqvist, Mattias; Neumüller, Magnus; Guarducci, Cristina; Boccalini, Giulia; Gabellini, Stefano; Migliaccio, Ilenia; Di Leo, Angelo; Pestrin, Marta; Malorni, Luca

    2018-03-27

    The aim of this study was to investigate if thymidine kinase-1 (TK1), a well-known proliferation marker, could represent a valid circulating biomarker to identify hormone receptor positive (HR+)/HER2 negative (HER2neg) metastatic breast cancer (MBC) patients most likely to benefit from endocrine therapy (ET). We used the DiviTum™ assay to analyze TK1 activity in cell lysates of three HR+/HER2neg BC cell lines and in plasma of 31 HR+/HER2neg MBC patients receiving ET. Blood samples were collected at treatment initiation, after one month and at disease progression. CTCs count and ESR1 / PIK3CA mutations in circulating tumor DNA were performed and correlated with TK1 activity. TK1 activity was reduced in the two endocrine-sensitive cell lines after 2 days of treatment. In patients, high baseline TK1 activity correlated with CTCs positivity (p-value=0.014). Patients with low baseline levels of TK1 activity had a significantly better PFS compared to those with high baseline TK1 activity (p-value=0.012). Patients with an early drop of TK1 activity after one month of treatment had a significantly better PFS compared to those who experienced an increase (p-value=0.0026). Our study suggests that TK1 could be a potential prognostic, predictive and monitoring marker of early ET response in HR+/HER2neg MBC patients.

  15. The efficacy of lapatinib in metastatic breast cancer with HER2 non-amplified primary tumors and EGFR positive circulating tumor cells: a proof-of-concept study.

    Directory of Open Access Journals (Sweden)

    Justin Stebbing

    Full Text Available Analysis of circulating tumor cells (CTCs provides real-time measures of cancer sub-populations with potential for CTC-directed therapeutics. We examined whether lapatinib which binds both HER2 and EGFR could induce depletion of the EGFR-positive pool of CTCs, which may in turn lead to clinical benefits.Patients with metastatic breast cancer and HER2 non-amplified primary tumors with EGFR-positive CTCs were recruited and lapatinib 1500 mg daily was administered, in a standard two step phase 2 trial.There were no responses leading to termination at the first analysis with 16 patients recruited out of 43 screened. In 6 out of 14 (43% individuals eligible for the efficacy analysis, a decrease in CTCs was observed with most of these having a greater decrease in their EGFR-positive CTC pool.This is one of the first studies of CTC-directed therapeutics and suggests that lapatinib monotherapy is not having any demonstrable clinical effects by reducing the EGFR-positive pool of CTCs in HER2 non-amplified primary tumors. Our attempt to expand the pool of patients eligible for a targeted therapy was unsuccessful; the role of clonal populations in cancer biology and therapeutic strategies to control them will require extensive evaluation in years to come.Clinical trials.gov NCT00820924.

  16. Trastuzumab emtansine in locally advanced or metastatic HER2 positive breast cancer; GENESIS-SEFH drug evaluation report

    Directory of Open Access Journals (Sweden)

    Patricia Miranda Romero

    2015-02-01

    Full Text Available Trastuzumab emtansina (T-DM1 is an antibody-drug conjugate directed against the HER2 for the treatment of HER2+ mestastatic breast cancer (MBC, who has previously received trastuzumab plus a taxane. According to the results of the EMILIA trial versus lapatinib plus capecitabine T-DM1 shows an improvement in progression-free survival (PFS and the overall survival (OS. It has a favorable profile reducing the incidence of grade 3-4 adverse reactions such as hand-foot syndrome and diarrhea. On the contrary increases significantly severe thrombocytopenia; bleeding risk and liver function should also be monitored. With the current import price T-DM1 has a cost per QALY of over 120,000 €. The price of the drug for the Spanish NHS has not yet been established. Drug cost would be the key factor in the sensitivity analysis and a 50% reduction in the price of the drug would place it close to the threshold of cost-effectiveness usually considered in our midst. According to the budget impact model used, a maximum of 1,218 patients / year and the budgetary impact throughout the Spanish state would be at € 70,490,850. In the initial analysis no advantage was found for T-DM1 in those patients without visceral involvement. Although a subsequent re-analysis of the results of PFS in which the definition of visceral involvement was specified a significant benefit was shown in this subgroup. We believe that this approach introduces a high degree of uncertainty, which does not guarantee the benefit achieved for this subgroup of patients

  17. Pharmacodynamics, pharmacokinetics and clinical efficacy of neratinib in HER2-positive breast cancer and breast cancer with HER2 mutations.

    Science.gov (United States)

    Kourie, Hampig Raphael; Chaix, Marie; Gombos, Andrea; Aftimos, Phillippe; Awada, Ahmad

    2016-08-01

    Despite the availability of several potent HER2-directed targeted agents, primary and acquired resistance continues to influence patient outcomes in HER2-positive breast cancer. Neratinib is an irreversible pan-HER tyrosine kinase inhibitor in late-phase clinical development. This review article focuses on neratinib in the treatment of HER2-positive breast cancer - early and metastatic stage - and HER2-mutant breast cancer, with particular emphasis on the pharmacokinetics and pharmacodynamics of the drug. The phase III ExteNET trial shows that neratinib improves 2-year invasive disease-free survival after trastuzumab-based adjuvant therapy in early-stage HER2-positive breast cancer, and in particular HER2+/HR+ tumors. Survival data are awaited. The investigational role of neratinib in high-risk patients or conversely in de-escalation dual regimens with other anti-HER2 therapies and without chemotherapy are of interest. Phase II trials show that neratinib has efficacy, either as monotherapy or in combination with other chemotherapeutic or endocrine agents, in patients with HER2-positive metastatic breast cancer and in tumors harboring HER2 mutations. The role of neratinib in therapeutic algorithms of HER2-positive patients, as well as delaying CNS events, awaits the results of ongoing trials such as NALA. Diarrhea, the main toxicity of neratinib, can be effectively managed with early loperamide prophylaxis.

  18. Neratinib Efficacy and Circulating Tumor DNA Detection of HER2 Mutations in HER2 Nonamplified Metastatic Breast Cancer.

    Science.gov (United States)

    Ma, Cynthia X; Bose, Ron; Gao, Feng; Freedman, Rachel A; Telli, Melinda L; Kimmick, Gretchen; Winer, Eric; Naughton, Michael; Goetz, Matthew P; Russell, Christy; Tripathy, Debu; Cobleigh, Melody; Forero, Andres; Pluard, Timothy J; Anders, Carey; Niravath, Polly Ann; Thomas, Shana; Anderson, Jill; Bumb, Caroline; Banks, Kimberly C; Lanman, Richard B; Bryce, Richard; Lalani, Alshad S; Pfeifer, John; Hayes, Daniel F; Pegram, Mark; Blackwell, Kimberly; Bedard, Philippe L; Al-Kateb, Hussam; Ellis, Matthew J C

    2017-10-01

    Purpose: Based on promising preclinical data, we conducted a single-arm phase II trial to assess the clinical benefit rate (CBR) of neratinib, defined as complete/partial response (CR/PR) or stable disease (SD) ≥24 weeks, in HER2 mut nonamplified metastatic breast cancer (MBC). Secondary endpoints included progression-free survival (PFS), toxicity, and circulating tumor DNA (ctDNA) HER2 mut detection. Experimental Design: Tumor tissue positive for HER2 mut was required for eligibility. Neratinib was administered 240 mg daily with prophylactic loperamide. ctDNA sequencing was performed retrospectively for 54 patients (14 positive and 40 negative for tumor HER2 mut ). Results: Nine of 381 tumors (2.4%) sequenced centrally harbored HER2 mut (lobular 7.8% vs. ductal 1.6%; P = 0.026). Thirteen additional HER2 mut cases were identified locally. Twenty-one of these 22 HER2 mut cases were estrogen receptor positive. Sixteen patients [median age 58 (31-74) years and three (2-10) prior metastatic regimens] received neratinib. The CBR was 31% [90% confidence interval (CI), 13%-55%], including one CR, one PR, and three SD ≥24 weeks. Median PFS was 16 (90% CI, 8-31) weeks. Diarrhea (grade 2, 44%; grade 3, 25%) was the most common adverse event. Baseline ctDNA sequencing identified the same HER2 mut in 11 of 14 tumor-positive cases (sensitivity, 79%; 90% CI, 53%-94%) and correctly assigned 32 of 32 informative negative cases (specificity, 100%; 90% CI, 91%-100%). In addition, ctDNA HER2 mut variant allele frequency decreased in nine of 11 paired samples at week 4, followed by an increase upon progression. Conclusions: Neratinib is active in HER2 mut , nonamplified MBC. ctDNA sequencing offers a noninvasive strategy to identify patients with HER2 mut cancers for clinical trial participation. Clin Cancer Res; 23(19); 5687-95. ©2017 AACR . ©2017 American Association for Cancer Research.

  19. Serum HER 2 extracellular domain level is correlated with tissue HER 2 status in metastatic gastric or gastro-oesophageal junction adenocarcinoma.

    Directory of Open Access Journals (Sweden)

    Shu-Qin Dai

    Full Text Available BACKGROUND: To explore the association between serum human epidermal growth factor receptor 2 (HER 2 extracellular domain (ECD levels and tissue HER 2 status in metastatic gastric cancer. PATIENTS AND METHODS: HER 2 status was retrospectively analyzed in 219 advanced gastric or gastroesophageal junction (GEJ patients. Serum HER 2 ECD was measured by chemiluminescent assay and tissue HER 2 was assessed by fluorescent in situ hybridisation (FISH and immunohistochemistry (IHC assay. RESULTS: Significant associations were found between serum HER 2 ECD levels and tissue HER 2 status. Twenty-four patients had HER 2 ECD levels >16.35 ng/mL, which has a sensitivity of 51.4% and a specificity of 97.3% to predict tissue HER 2 status. When the cut-off value was increased to 22 ng/mL, then all 12 patients with serum HER 2 ECD levels>22 ng/mL were tissue HER 2 positive, corresponding to a specificity of 100% and a sensitivity of 32.4%. High serum HER 2 ECD levels were strongly associated with the intestinal histological type (Lauren's classification, liver metastasis, multiple metastasis (>2 and increased LDH levels, but not with overall survival. CONCLUSIONS: The high specificity of the serum HER 2 ECD assay in predicting tissue HER 2 status suggests its potential as a surrogate marker of the HER 2 status in gastric cancer.

  20. Safety and efficacy of neratinib (HKI-272) plus vinorelbine in the treatment of patients with ErbB2-positive metastatic breast cancer pretreated with anti-HER2 therapy.

    Science.gov (United States)

    Awada, A; Dirix, L; Manso Sanchez, L; Xu, B; Luu, T; Diéras, V; Hershman, D L; Agrapart, V; Ananthakrishnan, R; Staroslawska, E

    2013-01-01

    Neratinib (HKI-272) is a potent irreversible pan-ErbB tyrosine kinase inhibitor with clinical activity in patients with ErbB2/HER2-positive breast cancer. Phase I of this open-label, phase I/II study investigated the maximum tolerated dose (MTD) of oral neratinib (160 or 240 mg/day) plus vinorelbine (25 mg/m2; days 1 and 8 of each 21-day cycle) in patients with solid tumors. Phase II assessed the safety, clinical activity, and pharmacokinetics of the combination in patients with HER2-positive metastatic breast cancer; the primary efficacy end point was objective response (OR). In phase I (n=12), neratinib (240 mg) plus vinorelbine (25 mg/m2) was established as the MTD. In phase II, 79 patients with HER2-positive metastatic breast cancer were treated at the MTD. The most common treatment-related adverse events were diarrhea (96%), neutropenia (54%), and nausea (50%). Three patients discontinued treatment due to diarrhea. No clinically important skin side-effects were observed. The OR rate in assessable phase II patients was 41% (no prior lapatinib) and 8% (prior lapatinib). There was no evidence of pharmacokinetic interaction between neratinib and vinorelbine. Neratinib plus vinorelbine showed promising antitumor activity and no unexpected toxic effects in HER2-positive metastatic breast cancer patients. Trial registration ClinicalTrials.gov #NCT00706030.

  1. Vinorelbine-based salvage therapy in HER2-positive metastatic breast cancer patients progressing during trastuzumab-containing regimens: a retrospective study

    Directory of Open Access Journals (Sweden)

    Viale Giuseppe

    2008-07-01

    Full Text Available Abstract Background The vinka-alkaloyd vinorelbine is a potentially valuable treatment in patients with HER2-positive, trastuzumab-resistant advanced breast cancer. We sought to document the clinical activity of vinorelbine-based salvage treatments in this clinical setting. Methods We analyzed a cohort of 424 consecutive women receiving trastuzumab-based therapy for HER2-positive advanced breast cancer. Of these, 299 were identified as progressing during the initial trastuzumab-based treatment, and 77 received vinorelbine-based therapy as first salvage treatment. Central review of pathological specimens revealed that 70 patients had HER2-amplification detected by FISH. For these patients we determined overall response rate (ORR = complete-CR + partial-PR and clinical benefit (CB = CR+PR+ Stable disease lasting at least 6 months, time to progression (TTP and overall survival (OS from the initiation of vinorelbine-based salvage therapy. Results In 60 patients who were evaluable for tumor response, ORR and CB rates were 28% (95% C.I. 18%-41% and 50% (95% C.I. 38%-62%, respectively. Median follow-up from the initiation of salvage therapy was 15 months (range 1–63 months. Median TTP and OS were 7.1 months (95% C.I. 6.6–7.7 months and 21 months (95% C.I. 14.3–27.7 months, respectively. No differences in clinical outcomes were observed according to whether vinorelbine was administered as a single agent or in combination with other cytostatics, or whether trastuzumab was stopped or continued beyond disease progression. Conclusion our findings suggests that vinorelbine-based combinations are active and should be further evaluated in studies conducted in trastuzumab-resistant patients, including those evaluating newer HER2-targeting agents.

  2. HERMIONE: a randomized Phase 2 trial of MM-302 plus trastuzumab versus chemotherapy of physician’s choice plus trastuzumab in patients with previously treated, anthracycline-naïve, HER2-positive, locally advanced/metastatic breast cancer

    International Nuclear Information System (INIS)

    Miller, Kathy; Cortes, Javier; Hurvitz, Sara A.; Krop, Ian E.; Tripathy, Debu; Verma, Sunil; Riahi, Kaveh; Reynolds, Joseph G.; Wickham, Thomas J.; Molnar, Istvan; Yardley, Denise A.

    2016-01-01

    Human epidermal growth factor receptor 2 (HER2)-positive breast cancer is a particularly aggressive form of the disease, and ultimately progresses in patients with metastases on standard therapies. Anthracyclines, such as doxorubicin, are an effective treatment for HER2-positive breast cancer, particularly when administered in combination with trastuzumab – however, doxorubicin-related cardiotoxicity has limited its use. Many patients are therefore never treated with anthracyclines, even upon disease progression, despite the potential for benefit. MM-302 is a novel, HER2-targeted antibody–liposomal doxorubicin conjugate that specifically targets HER2-overexpressing cells. Preclinical and Phase 1 data suggest that MM-302, as a monotherapy or in combination with trastuzumab, could be effective for managing previously treated, anthracycline-naïve, HER2-positive breast cancer, without the cardiotoxicity observed with free doxorubicin formulations. HERMIONE is an open-label, multicenter, randomized (1:1) Phase 2 trial of MM-302 plus trastuzumab versus chemotherapy of physician’s choice (gemcitabine, capecitabine, or vinorelbine) plus trastuzumab planned to enroll 250 anthracycline-naïve patients with locally advanced/metastatic HER2-positive breast cancer. Key inclusion criteria are: previous treatment with trastuzumab (with or without pertuzumab) in any setting; refractory or intolerant to pertuzumab (refractory to pertuzumab defined as progression in the locally advanced or metastatic setting, or disease recurrence during or within 12 months of completing pertuzumab-containing neoadjuvant and/or adjuvant therapy); and disease progression on, or intolerant to, ado-trastuzumab emtansine for locally advanced or metastatic disease. The trial is currently being conducted at sites in the USA, Canada, and Western Europe. Treatment will be administered in 21-day cycles, and will be continued until disease progression or unacceptable toxicity. The primary endpoint is

  3. Salivary expression of soluble HER2 in breast cancer patients with positive and negative HER2 status

    Directory of Open Access Journals (Sweden)

    Laidi F

    2014-07-01

    Full Text Available Fatna Laidi,1 Amal Bouziane,2 Amina Lakhdar,3 Samira Khabouze,3 Brahim Rhrab,3 Fatima Zaoui1 1Oral Biomechanics and Biotechnology Research Unit, Faculty of Dental Medicine, 2Department of Periodontology, Faculty of Dental Medicine, Biostatistical, Clinical and Epidemiological Research Laboratory, Faculty of Medicine and Pharmacy, 3Department of Obstetrics and Gynecology, Ibn Sina University Hospital, Rabat, Morocco Background: The aim of this study was to investigate the relationship between salivary concentration of the soluble fragment of the HER2 (human epidermal growth factor receptor protein and its status in mammary tissues. Methods: This case-control study was done in 27 breast cancer patients with no visible metastatic disease treated at the gynecology service, Maternity Souissi Hospital, Rabat, Morocco. Two groups were selected, ie, patients with positive and negative HER2 status in mammary tissue. The salivary HER2 protein concentration was assessed by enzyme-linked immunosorbent assay. The salivary HER2 concentration was compared between the HER2-positive and HER2-negative groups using the Mann-Whitney U test. A P-value <0.05 was considered to be statistically significant. Results: No statistically significant difference in salivary HER2 protein expression was found between the case and control groups. There was also no significant difference in clinical characteristics according to positive and negative HER2 status (P>0.05, except for the progesterone hormone receptor which was statistically significant in both the case and control groups (P=0.047. Conclusion: According to our data, salivary expression of the HER2 receptor may not be a reliable alternative to tissue assessment. Keywords: breast cancer, HER2, saliva, diagnosis

  4. HSP90 inhibition is effective in breast cancer: a phase II trial of tanespimycin (17-AAG) plus trastuzumab in patients with HER2-positive metastatic breast cancer progressing on trastuzumab.

    Science.gov (United States)

    Modi, Shanu; Stopeck, Alison; Linden, Hannah; Solit, David; Chandarlapaty, Sarat; Rosen, Neal; D'Andrea, Gabriella; Dickler, Maura; Moynahan, Mary E; Sugarman, Steven; Ma, Weining; Patil, Sujata; Norton, Larry; Hannah, Alison L; Hudis, Clifford

    2011-08-01

    HSP90 is a chaperone protein required for the stability of a variety of client proteins. 17-Demethoxygeldanamycin (17-AAG) is a natural product that binds to HSP90 and inhibits its activity, thereby inducing the degradation of these clients. In preclinical studies, HER2 is one of the most sensitive known client proteins of 17-AAG. On the basis of these data and activity in a phase I study, we conducted a phase II study of 17-AAG (tanespimycin) with trastuzumab in advanced trastuzumab-refractory HER2-positive breast cancer. We enrolled patients with metastatic HER2(+) breast cancer whose disease had previously progressed on trastuzumab. All patients received weekly treatment with tanespimycin at 450 mg/m(2) intravenously and trastuzumab at a conventional dose. Therapy was continued until disease progression. The primary endpoint was response rate by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Thirty-one patients were enrolled with a median age of 53 years and a median Karnofsky performance status (KPS) of 90%. The most common toxicities, largely grade 1, were diarrhea, fatigue, nausea, and headache. The overall response rate was 22%, the clinical benefit rate [complete response + partial response + stable disease] was 59%, the median progression-free survival was 6 months (95% CI: 4-9), and the median overall survival was 17 months (95% CI: 16-28). This is the first phase II study to definitively show RECIST-defined responses for 17-AAG in solid tumors. Tanespimycin plus trastuzumab has significant anticancer activity in patients with HER2-positive, metastatic breast cancer previously progressing on trastuzumab. Further research exploring this therapeutic interaction and the activity of HSP90 inhibitors is clearly warranted. ©2011 AACR.

  5. New developments in the treatment of HER2-positive breast cancer

    Directory of Open Access Journals (Sweden)

    Nahta R

    2012-05-01

    Full Text Available Rita NahtaDepartments of Pharmacology and Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USAAbstract: Approximately 20%–30% of metastatic breast cancers show increased expression of the human epidermal growth factor receptor-2 (HER2 tyrosine kinase. Two HER2-specific therapies are currently approved for clinical treatment of patients with HER2-overexpressing metastatic breast cancer. Trastuzumab is a monoclonal antibody against HER2 and is approved for first-line treatment of HER2-positive metastatic breast cancer. Lapatinib is a small molecule dual inhibitor of epidermal growth factor receptor and HER2 tyrosine kinases, and is approved for trastuzumab-refractory disease. Although trastuzumab is a highly effective therapy for patients with HER2-overexpressing metastatic breast cancer, a significant number of patients in the initial clinical trials of trastuzumab monotherapy showed resistance to trastuzumab-based therapy. Further, among those who did respond, the initial trials indicated that the median time to progression was less than 1 year. Similarly, lapatinib is effective in a subset of trastuzumab-refractory cases, but the majority of patients display resistance. This review discusses the multiple molecular mechanisms of resistance that have been proposed in the literature. In addition, novel agents that are being tested for efficacy against HER2-positive breast cancer, including the antibodies pertuzumab and trastuzumab-DM1 and the immunotoxin affitoxin, are reviewed. The introduction of trastuzumab has revolutionized the clinical care of patients with HER2-positive metastatic breast cancer and has resulted in dramatic reductions in recurrences of early-stage HER2-positive breast cancer. The development and implementation of gene- and protein-based assays that measure potential molecular predictors of trastuzumab resistance will allow individualization of HER2-targeted therapeutic approaches

  6. Safety, pharmacokinetics and efficacy findings in an open-label, single-arm study of weekly paclitaxel plus lapatinib as first-line therapy for Japanese women with HER2-positive metastatic breast cancer.

    Science.gov (United States)

    Inoue, Kenichi; Kuroi, Katsumasa; Shimizu, Satoru; Rai, Yoshiaki; Aogi, Kenjiro; Masuda, Norikazu; Nakayama, Takahiro; Iwata, Hiroji; Nishimura, Yuichiro; Armour, Alison; Sasaki, Yasutsuna

    2015-12-01

    Lapatinib is the human epidermal growth factor receptor 2 (HER2) targeting agent approved globally for HER2-positive metastatic breast cancer (MBC). The efficacy, safety and pharmacokinetics (PK) of lapatinib combined with paclitaxel (L+P) were investigated in this study, to establish clear evidence regarding the combination in Japanese patients. In this two-part, single-arm, open-label study, the tolerability of L+P as first-line treatment in Japanese patients with HER2-positive MBC was evaluated in six patients in the first part, and the safety, efficacy and PK were evaluated in a further six patients (making a total of twelve patients) in the second part. Eligible women were enrolled and received lapatinib 1500 mg once daily and paclitaxel 80 mg/m(2) weekly for at least 6 cycles. The only dose-limiting toxicity reported was Grade 3 diarrhea in one patient. The systemic exposure to maximum plasma concentration and area under the plasma concentration curve (AUC) for lapatinib, as well as the AUC of paclitaxel, were increased when combined. The most common adverse events (AEs) related to the study treatment were alopecia, diarrhea and decreased hemoglobin. The majority of drug-related AEs were Grade 1 or 2. The median overall survival was 35.6 months (95 % confidence interval 23.9, not reached). The response rate and clinical benefit rate were both 83 % (95 % confidence interval 51.6, 97.9). The L+P treatment was well tolerated in Japanese patients with HER2-positive MBC. Although the PK profiles of lapatinib and paclitaxel influenced each other, the magnitudes were not greatly different from those in non-Japanese patients.

  7. HER-2, ER, PR status concordance in primary breast cancer and corresponding metastatic lesion in lymph node in Chinese women.

    Science.gov (United States)

    Li, Min Hua; Hou, Chuan Ling; Wang, Cheng; Sun, Ai Jing

    2016-04-01

    To compare the expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER-2) in the primary site and the metastatic lesion of lymph nodes in invasive breast cancer for investigating whether the expression of these biomarkers in the primary site could act as a surrogate to the lymphatic metastatic lesion in the same patient. In lymphatic metastatic lesion and corresponding primary lesion of 107 cases of invasive breast cancer, ER and PR statuses were assessed by immunohistochemistry (IHC). HER-2 expression level was evaluated by IHC and/or fluorescence in situ hybridization (FISH). In the primary lesions, 43.9% were ER positive; 46.7% were PR positive; 34.6% were HER-2 positive. In corresponding lymphatic metastatic lesions, the HER-2 status was concordant in 90 patients; 9 patients were diagnosed positive in metastatic lesion while negative in primary lesion; 8 patients were negative in metastatic lesion while positive in primary site (agreement, 84.1%; κ=0.647). A change in ER status was observed in 24 cases: 17 cases positive in metastatic site while negative in primary site; 7 cases negative in metastatic site while positive in primary site (agreement, 77.6%; κ=0.534). PR status discordance between the primary lesion and the metastatic regional lymph nodes was reported in 19 cases (agreement, 82.2%; κ=0.640). This study revealed that there was only a moderate concordance of ER, PR and HER-2 status between primary tumors and metastatic lymph nodes. These results indicate that it was inappropriate to predict the status of ER, PR and HER-2 in metastatic lymph nodes based on the results of evaluation of that in primary lesions. Copyright © 2015 Elsevier GmbH. All rights reserved.

  8. Safety and efficacy of neratinib in combination with weekly paclitaxel and trastuzumab in women with metastatic HER2positive breast cancer: an NSABP Foundation Research Program phase I study.

    Science.gov (United States)

    Jankowitz, Rachel C; Abraham, Jame; Tan, Antoinette R; Limentani, Steven A; Tierno, Marni B; Adamson, Laura M; Buyse, Marc; Wolmark, Norman; Jacobs, Samuel A

    2013-12-01

    Neratinib is an oral, small-molecule inhibitor that irreversibly binds to pan-HER (ErbB) receptor tyrosine kinases. Studies suggest that dual anti-HER therapies utilized in breast cancer patients are more efficacious than single agents in both the metastatic and neoadjuvant settings. In this phase I study, neratinib was combined with trastuzumab and paclitaxel in metastatic HER2-positive patients. Twenty-one patients entered this dose-escalation study to determine the maximum-tolerated dose, safety, and efficacy of neratinib (120 up to 240 mg/day) with trastuzumab (4 mg/kg IV loading dose, then 2 mg/kg IV weekly), and paclitaxel (80 mg/m(2) IV days 1, 8, and 15 of a 28-day cycle) in women with HER2-positive metastatic breast cancer previously treated with anti-HER agent(s) and a taxane. The recommended phase II dose of neratinib with trastuzumab and paclitaxel was 200 mg/day. Common grade 3/4 adverse events were diarrhea (38 %), dehydration (14 %), electrolyte imbalance (19 %), and fatigue (19 %). With mandated primary diarrheal prophylaxis, ≥grade 3 diarrhea was not observed. Objective responses, complete (CR) and partial (PR), occurred in eight patients (38 %), with a clinical benefit of CR + PR+ stable disease (SD) ≥24 weeks in 11 patients (52 %). Median time-to-disease progression was 3.7 months. Dual anti-HER blockade with neratinib and trastuzumab resulted in significant clinical benefit despite prior exposure to trastuzumab, lapatinib, T-DM1, a taxane, and multiple lines of chemotherapy. In selected populations, inhibiting multiple ErbB-family receptors may be more advantageous than single-agent inhibition. Based on favorable tolerance and efficacy, this three-drug combination will be further assessed in a randomized phase II neoadjuvant trial (NSABP FB-7:NCT01008150).

  9. Trastuzumab for HER-2-Positive Advanced Salivary Gland Cancer

    Directory of Open Access Journals (Sweden)

    Yi-Tsung Yang

    2014-12-01

    Full Text Available Salivary gland adenocarcinoma is a rare type of head and neck cancer and often has aggressive behavior with propensity to recur and metastasize. Currently, there are no standard treatment guidelines. Surgery is however, the mainstay of treatment in resectable disease and radiation is also considered for most patients after surgery. Systemic chemotherapy is reserved for metastatic cases, but its results are often disappointing. Recent development of molecular biology has shown that salivary gland caner has several molecular changes which may guide potential therapeutic targets. Here, we report a 67 year-old man diagnosed to have metastasized minor salivary gland adenocarcinoma with diffuse human epidermal growth factor receptor-2 (HER-2-positive, by the immunohistochemical (IHC stain. He was treated with a trastuzumab-containing chemotherapeutic regimen with encouraging results.

  10. A virosomal formulated Her-2/neu multi-peptide vaccine induces Her-2/neu-specific immune responses in patients with metastatic breast cancer: a phase I study.

    Science.gov (United States)

    Wiedermann, Ursula; Wiltschke, C; Jasinska, J; Kundi, M; Zurbriggen, R; Garner-Spitzer, E; Bartsch, R; Steger, G; Pehamberger, H; Scheiner, O; Zielinski, C C

    2010-02-01

    We have previously shown in mice that vaccination with three Her-2-peptides representing B-cell epitopes of the extracellular domain of Her-2/neu induces Her-2/neu-specific IgG antibodies with strong anti-tumor activity in vitro and in vivo. We have now finalized a phase I clinical trial with an anti-Her-2/neu vaccine-construct of immunopotentiating reconstituted influenza virosomes with the three peptides in patients with metastatic breast cancer (MBC). Ten MBC patients with low protein overexpression of Her-2/neu of MBC (+ or ++ upon immunohistochemistry, FISH negative) and positive hormone receptor status were enrolled in a single center phase I study. The virosomal formulated vaccine, consisting of 10 microg/peptide, was intramuscularly applied three times on days 1, 28, and 56. The primary endpoint of the study, which lasted 12 weeks, was safety, the secondary endpoint immunogenicity. Local erythema at the injection site was the only vaccine-related side effect occurring in four patients. In 8 of 10 patients an increase in peptide-specific antibody titer measured by ELISA was found. Importantly, the induced antibodies were also directed against the native Her-2/neu protein. Cellular immune responses, as measured by in vitro production of IL-2, IFN-c, and TNF-a of PBMCs showed a marked increase after vaccination in the majority of vaccinees. Notably, the number of CD4+CD25+Foxp3+T regulatory cells, which were significantly increased compared to healthy controls prior to vaccination, was markedly reduced following vaccination. In all, the immunological responses after vaccination indicated that the patients in stage IV of disease were immunocompetent and susceptible to vaccination. The Her-2/neu multipeptide vaccine was safe, well tolerated and effective in overcoming immunological tolerance to Her-2/neu. The induction of anti-Her-2-specific antibodies could result in clinical benefit comparable to passive anti-Her-2 antibody therapy.

  11. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2.

    Science.gov (United States)

    Slamon, D J; Leyland-Jones, B; Shak, S; Fuchs, H; Paton, V; Bajamonde, A; Fleming, T; Eiermann, W; Wolter, J; Pegram, M; Baselga, J; Norton, L

    2001-03-15

    The HER2 gene, which encodes the growth factor receptor HER2, is amplified and HER2 is overexpressed in 25 to 30 percent of breast cancers, increasing the aggressiveness of the tumor. We evaluated the efficacy and safety of trastuzumab, a recombinant monoclonal antibody against HER2, in women with metastatic breast cancer that overexpressed HER2. We randomly assigned 234 patients to receive standard chemotherapy alone and 235 patients to receive standard chemotherapy plus trastuzumab. Patients who had not previously received adjuvant (postoperative) therapy with an anthracycline were treated with doxorubicin (or epirubicin in the case of 36 women) and cyclophosphamide alone (138 women) or with trastuzumab (143 women). Patients who had previously received adjuvant anthracycline were treated with paclitaxel alone (96 women) or paclitaxel with trastuzumab (92 women). The addition of trastuzumab to chemotherapy was associated with a longer time to disease progression (median, 7.4 vs. 4.6 months; P<0.001), a higher rate of objective response (50 percent vs. 32 percent, P<0.001), a longer duration of response (median, 9.1 vs. 6.1 months; P<0.001), a lower rate of death at 1 year (22 percent vs. 33 percent, P=0.008), longer survival (median survival, 25.1 vs. 20.3 months; P=0.01), and a 20 percent reduction in the risk of death. The most important adverse event was cardiac dysfunction of New York Heart Association class III or IV, which occurred in 27 percent of the group given an anthracycline, cyclophosphamide, and trastuzumab; 8 percent of the group given an anthracycline and cyclophosphamide alone; 13 percent of the group given paclitaxel and trastuzumab; and 1 percent of the group given paclitaxel alone. Although the cardiotoxicity was potentially severe and, in some cases, life-threatening, the symptoms generally improved with standard medical management. Trastuzumab increases the clinical benefit of first-line chemotherapy in metastatic breast cancer that

  12. Palbociclib in Combination With Fulvestrant in Women With Hormone Receptor-Positive/HER2-Negative Advanced Metastatic Breast Cancer: Detailed Safety Analysis From a Multicenter, Randomized, Placebo-Controlled, Phase III Study (PALOMA-3).

    Science.gov (United States)

    Verma, Sunil; Bartlett, Cynthia Huang; Schnell, Patrick; DeMichele, Angela M; Loi, Sherene; Ro, Jungsil; Colleoni, Marco; Iwata, Hiroji; Harbeck, Nadia; Cristofanilli, Massimo; Zhang, Ke; Thiele, Alexandra; Turner, Nicholas C; Rugo, Hope S

    2016-10-01

    Palbociclib enhances endocrine therapy and improves clinical outcomes in hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC). Because this is a new target, it is clinically important to understand palbociclib's safety profile to effectively manage toxicity and optimize clinical benefit. Patients with endocrine-resistant, HR-positive/HER2-negative MBC (n = 521) were randomly assigned 2:1 to receive fulvestrant (500 mg intramuscular injection) with or without goserelin with oral palbociclib (125 mg daily; 3 weeks on/1 week off) or placebo. Safety assessments at baseline and day 1 of each cycle included blood counts on day 15 for the first 2 cycles. Hematologic toxicity was assessed by using laboratory data. A total of 517 patients were treated (palbociclib, n = 345; placebo, n = 172); median follow-up was 8.9 months. With palbociclib, neutropenia was the most common grade 3 (55%) and 4 (10%) adverse event; median times to onset and duration of grade ≥3 episodes were 16 and 7 days, respectively. Asian ethnicity and below-median neutrophil counts at baseline were significantly associated with an increased chance of developing grade 3-4 neutropenia with palbociclib. Dose modifications for grade 3-4 neutropenia had no adverse effect on progression-free survival. In the palbociclib arm, febrile neutropenia occurred in 3 (<1%) patients. The percentage of grade 1-2 infections was higher than in the placebo arm. Grade 1 stomatitis occurred in 8% of patients. Palbociclib plus fulvestrant treatment was well-tolerated, and the primary toxicity of asymptomatic neutropenia was effectively managed by dose modification without apparent loss of efficacy. This study appears at ClinicalTrials.gov, NCT01942135. Treatment with palbociclib in combination with fulvestrant was generally safe and well-tolerated in patients with hormone receptor (HR)-positive metastatic breast cancer. Consistent with the drug's proposed

  13. HER-2-PET imaging with Zr-89-trastuzumab in metastatic breast cancer patients

    NARCIS (Netherlands)

    Munnink, T. Oude; Dijkers, E.; Hooge, M. Lub-de; Kosterink, J.; Brouwers, A.; de Jong, J. R.; van Dongen, G.; de Vries, E.

    2009-01-01

    1045 Background: Non-invasive diagnostic tools can optimize and evaluate HER2 directed therapy in HER2 positive breast cancer patients. HER2 imaging with (111)In-trastuzumab SPECT showed promising results (Perik et al, J Clin Oncol. 2006). To further optimize HER2 imaging, we developed

  14. Prognostic value of HER2 gene amplification detected by chromogenic in situ hybridization (CISH) in metastatic breast cancer.

    Science.gov (United States)

    Todorović-Raković, Natasa; Jovanović, Danica; Nesković-Konstantinović, Zora; Nikolić-Vukosavljević, Dragica

    2007-06-01

    After so many years of research, clinical value of HER2 (Human epidermal growth factor receptor 2) is unclear. Perhaps the main reason is variability of testing methods that produce controversial results. There is a lack of studies regarding prognostic value of CISH especially in metastatic breast cancer (MBC) when risk evaluation is based on different parameters than for primary breast cancer. Aim of this study was to compare prognostic relevance of HER2 status in MBC tested by two different methods i.e. immunohistochemistry (IHC) and chromogenic in situ hybridization (CISH). HER2 status of the same group of 107 MBC patients was determined by IHC (protein overexpression) and by CISH (gene amplification). HER2 results obtained by IHC and CISH showed significant correlation, beside the existence of discrepancies. Beside the significant correlation in two methods, there was a difference in prognostic values of compared methods during the course of metastatic disease. There was a significant difference in progression-free interval (PFI) between HER2 non-amplified and HER2 amplified cases determined by CISH, in postmenopausal subgroup and node-positive subgroup, but no significant difference for IHC stratified MBC patients. CISH seems to be accurate and more informative method than IHC regarding prognostic value of HER2 in metastatic breast cancer.

  15. Combination therapies for the treatment of HER2-positive breast cancer: current and future prospects.

    Science.gov (United States)

    Brandão, Mariana; Pondé, Noam F; Poggio, Francesca; Kotecki, Nuria; Salis, Mauren; Lambertini, Matteo; de Azambuja, Evandro

    2018-05-24

    HER2-positive disease is an aggressive subtype of breast cancer that has been revolutionized by anti-HER2 directed therapies. Multiple drugs have been developed and are currently in clinical use, including trastuzumab, lapatinib, pertuzumab, T-DM1, and neratinib, alone or combined in 'dual HER2-blockade' regimens. Areas covered: A comprehensive literature review was performed regarding the current state and the future of combination regimens containing anti-HER2 agents, focusing on their efficacy, toxicity, and cost-effectiveness. Expert commentary: The combination of trastuzumab/pertuzumab is approved in all disease settings, while trastuzumab/neratinib is approved in the adjuvant setting and trastuzumab/lapatinib in metastatic disease. Meanwhile, as breast cancer biology and resistance mechanisms become clearer, combinations with drugs like PI3K/Akt/mTOR inhibitors, CDK4/6 inhibitors, anti-PD(L)1 antibodies, endocrine therapy, and new anti-HER2 agents (panHER and HER2 tyrosine kinase inhibitors, bispecific antibodies, anti-HER3 antibodies, and antibody-drug conjugates) are being extensively tested in clinical trials. More specific strategies for the 'triple-positive' (estrogen receptor-positive/HER2-positive) disease are also being explored. However, there is an urgent need for the development of predictive biomarkers for a better tailoring of anti-HER2 directed therapy. This is the only way to further improve clinical outcomes and quality of life and to decrease costs and toxicities of unnecessary treatments.

  16. Single-cell quantitative HER2 measurement identifies heterogeneity and distinct subgroups within traditionally defined HER2-positive patients.

    Science.gov (United States)

    Onsum, Matthew D; Geretti, Elena; Paragas, Violette; Kudla, Arthur J; Moulis, Sharon P; Luus, Lia; Wickham, Thomas J; McDonagh, Charlotte F; MacBeath, Gavin; Hendriks, Bart S

    2013-11-01

    Human epidermal growth factor receptor 2 (HER2) is an important biomarker for breast and gastric cancer prognosis and patient treatment decisions. HER2 positivity, as defined by IHC or fluorescent in situ hybridization testing, remains an imprecise predictor of patient response to HER2-targeted therapies. Challenges to correct HER2 assessment and patient stratification include intratumoral heterogeneity, lack of quantitative and/or objective assays, and differences between measuring HER2 amplification at the protein versus gene level. We developed a novel immunofluorescence method for quantitation of HER2 protein expression at the single-cell level on FFPE patient samples. Our assay uses automated image analysis to identify and classify tumor versus non-tumor cells, as well as quantitate the HER2 staining for each tumor cell. The HER2 staining level is converted to HER2 protein expression using a standard cell pellet array stained in parallel with the tissue sample. This approach allows assessment of HER2 expression and heterogeneity within a tissue section at the single-cell level. By using this assay, we identified distinct subgroups of HER2 heterogeneity within traditional definitions of HER2 positivity in both breast and gastric cancers. Quantitative assessment of intratumoral HER2 heterogeneity may offer an opportunity to improve the identification of patients likely to respond to HER2-targeted therapies. The broad applicability of the assay was demonstrated by measuring HER2 expression profiles on multiple tumor types, and on normal and diseased heart tissues. Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  17. (64)Cu-DOTA-trastuzumab PET imaging and HER2 specificity of brain metastases in HER2-positive breast cancer patients.

    Science.gov (United States)

    Kurihara, Hiroaki; Hamada, Akinobu; Yoshida, Masayuki; Shimma, Schuichi; Hashimoto, Jun; Yonemori, Kan; Tani, Hitomi; Miyakita, Yasuji; Kanayama, Yousuke; Wada, Yasuhiro; Kodaira, Makoto; Yunokawa, Mayu; Yamamoto, Harukaze; Shimizu, Chikako; Takahashi, Kazuhiro; Watanabe, Yasuyoshi; Fujiwara, Yasuhiro; Tamura, Kenji

    2015-01-01

    The purpose of this study was to determine whether brain metastases from HER2-positive breast cancer could be detected noninvasively using positron emission tomography (PET) with (64)Cu-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-trastuzumab. PET was performed on five patients with brain metastases from HER2-positive breast cancer, at 24 or 48 h after the injection of approximately 130 MBq of the probe (64)Cu-DOTA-trastuzumab. Radioactivity in metastatic brain tumors was evaluated based on PET images in five patients. Autoradiography, immunohistochemistry (IHC), and liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis were performed in one surgical case to confirm HER2 specificity of (64)Cu-DOTA-trastuzumab. Metastatic brain lesions could be visualized by (64)Cu-DOTA-trastuzumab PET in all of five cases, which might indicated that trastuzumab passes through the blood-brain barrier (BBB). The HER2 specificity of (64)Cu-DOTA-trastuzumab was demonstrated in one patient by autoradiography, immunohistochemistry, and LC-MS/MS. Cu-DOTA-trastuzumab PET could be a potential noninvasive procedure for serial identification of metastatic brain lesions in patients with HER2-positive breast cancer. UMIN000004170.

  18. Emerging treatments for HER2-positive early-stage breast cancer: focus on neratinib.

    Science.gov (United States)

    Kourie, Hampig Raphael; El Rassy, Elie; Clatot, Florian; de Azambuja, Evandro; Lambertini, Matteo

    2017-01-01

    Over the last decades, a better understanding of breast cancer heterogeneity provided tools for a biologically based personalization of anticancer treatments. In particular, the overexpression of the human epidermal growth factor receptor 2 (HER2) by tumor cells provided a specific target in these HER2-positive tumors. The development of the monoclonal antibody trastuzumab, and its approval in 1998 for the treatment of patients with metastatic disease, radically changed the natural history of this aggressive subtype of breast cancer. These findings provided strong support for the continuous research in targeting the HER2 pathway and implementing the development of new anti-HER2 targeted agents. Besides trastuzumab, a series of other anti-HER2 agents have been developed and are currently being explored for the treatment of breast cancer patients, including those diagnosed with early-stage disease. Among these agents, neratinib, an oral tyrosine kinase inhibitor that irreversibly inhibits HER1, HER2, and HER4 at the intracellular level, has shown promising results, including when administered to patients previously exposed to trastuzumab-based treatment. This article aims to review the available data on the role of the HER2 pathway in breast cancer and on the different targeted agents that have been studied or are currently under development for the treatment of patients with early-stage HER2-positive disease with a particular focus on neratinib.

  19. PTEN expression as a predictor for the response to trastuzumab-based therapy in Her-2 overexpressing metastatic breast cancer.

    Directory of Open Access Journals (Sweden)

    Daphne Gschwantler-Kaulich

    Full Text Available Even though trastuzumab is an effective therapy in early stage Her-2+ breast cancer, 40-50% of advanced Her-2+ breast cancer patients develop trastuzumab resistance. A potential resistance mechanism is aberrant downstream signal transmission due to loss of phosphatase and tensin homologue (PTEN. This study investigated the relationship between the expression of PTEN and trastuzumab response in Her-2 overexpressing metastatic breast cancer patients.Between 2000 and 2007, 164 patients with Her-2+ metastatic breast cancer received trastuzumab-based therapy in our institution. We analyzed PTEN status by immunohistochemistry of 115 available tumor tissues and analyzed associations with other histopathological parameters, response rate, progression free survival (PFS and overall survival (OS with a median follow-up of 60 months.Eighty patients were PTEN positive (69.6% and 35 patients PTEN negative (30.4%. We found a significant association of the expression of PTEN and p53 (p = 0.041, while there was no association with grading, hormone receptor status, IGFR or MIB. We found significantly more cases with progressive disease under trastuzumab-based therapy in patients with PTEN positive breast cancers (p = 0.018, while there was no significant correlation with PFS or OS.In Her-2-positive metastatic breast cancers, PTEN positivity was significantly associated with progressive disease, but not with PFS or OS.

  20. A systematic review of dual targeting in HER2-positive breast cancer

    DEFF Research Database (Denmark)

    Kümler, Iben; Tuxen, Malgorzata K; Nielsen, Dorte Lisbet

    2014-01-01

    BACKGROUND: Human epidermal growth factor receptor 2 (HER2) is overexpresed in 15-20% of all breast cancers. Treatment with trastuzumab has led to an improved outcome and prolonged survival of HER2-positive breast cancer patients and today the drug is established as standard of care in both...... the adjuvant and metastatic settings. However, trastuzumab resistance is common and a major focus in the treatment of HER2-positive breast cancer has been developing therapeutic agents to either potentiate the effect of trastuzumab or to target cells which have become resistant to trastuzumab. The present...... of lapatinib, pertuzumab or trastuzumab-DM1 in combination with trastuzumab in the (neo)adjuvant and metastatic settings. Furthermore, combinations of trastuzumab and drugs targeting the downstream pathway are described. CONCLUSION: Dual blockade is likely to represent a substantial advance for patients...

  1. Novel HER2 Aptamer Selectively Delivers Cytotoxic Drug to HER2-positive Breast Cancer Cells in Vitro

    Directory of Open Access Journals (Sweden)

    Liu Zhe

    2012-07-01

    Full Text Available Abstract Background Aptamer-based tumor targeted drug delivery system is a promising approach that may increase the efficacy of chemotherapy and reduce the related toxicity. HER2 protein is an attractive target for tumor-specific drug delivery because of its overexpression in multiple malignancies, including breast, gastric, ovarian, and lung cancers. Methods In this paper, we developed a new HER2 aptamer (HB5 by using systematic evolution of ligands by exponential enrichment technology (SELEX and exploited its role as a targeting ligand for delivering doxorubicin (Dox to breast cancer cells in vitro. Results The selected aptamer was an 86-nucleotide DNA molecule that bound to an epitope peptide of HER2 with a Kd of 18.9 nM. The aptamer also bound to the extracellular domain (ECD of HER2 protein with a Kdof 316 nM, and had minimal cross reactivity to albumin or trypsin. In addition, the aptamer was found to preferentially bind to HER2-positive but not HER2-negative breast cancer cells. An aptamer-doxorubicin complex (Apt-Dox was formulated by intercalating Dox into the DNA structure of HB5. The Apt-Dox complex could selectively deliver Dox to HER2-positive breast cancer cells while reducing the drug intake by HER2-negative cells in vitro. Moreover, Apt-Dox retained the cytotoxicity of Dox against HER2-positive breast cancer cells, but reduced the cytotoxicity to HER2-negative cells. Conclusions The results suggest that the selected HER2 aptamer may have application potentials in targeted therapy against HER2-positive breast cancer cells.

  2. Neratinib in HER-2-positive breast cancer: results to date and clinical usefulness.

    Science.gov (United States)

    Chan, Arlene

    2016-09-01

    The management of HER-2-positive breast cancer has improved significantly with the use of targeted agents to the HER-2 signaling pathway. Despite the improved survival achieved with the use of trastuzumab and chemotherapy in both the adjuvant and metastatic setting, patients may still recur or progress; whilst preclinical data demonstrate that these cancer cells remain addicted to the HER-2 oncogene. Neratinib, an oral small molecule tyrosine-kinase inhibitor has efficacy in the metastatic and adjuvant setting of patients who have previously received trastuzumab-based treatment. Diarrhea, being a class effect of tyrosine-kinase inhibitor, is the most common side effect seen following neratinib administration, but recent data suggests that a prophylactic loperamide regimen can reduce the incidence of grade 3 diarrhea. Phase I through to III clinical trials of neratinib will be reviewed, with discussion of the postulated mechanism underlying diarrheal events and its management.

  3. Cytologic assessment of estrogen receptor, progesterone receptor, and HER2 status in metastatic breast carcinoma.

    Science.gov (United States)

    Pareja, Fresia; Murray, Melissa P; Jean, Ryan Des; Konno, Fumiko; Friedlander, Maria; Lin, Oscar; Edelweiss, Marcia

    2017-01-01

    Discordance in the receptor status between primary breast carcinomas (PBC) and corresponding metastasis is well documented. Interrogation of the receptor status of metastatic breast carcinoma (MBC) in cytology material is common practice; however, its utility has not been thoroughly validated. We studied patients with MBC, and evaluated the concordance rates of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) between PBC surgical specimens and corresponding MBC cell blocks (CBs). We correlated the findings with clinicopathologic variables and with the fixation methods used. We searched for patients with MBC diagnosed on cytology from 2007 to 2009 and selected those with ER, PR and HER2 tested in both the PBC surgical specimens and the MBC CBs. We included CBs fixed in formalin and methanol based solution (CytoLyt®). All slides were reevaluated by cytopathologists. Clinical information was retrieved from the medical records. We studied 65 patients with PBC and MBC paired specimens. The concordance rates between PBC and MBC were 78.5%, 58.5% and 96.9%, for ER, PR and HER2, respectively. When discordant, PR status switched from positive (PBC) to negative (MBC) in most cases (23/27). The PR concordance rate was 45.2% for CBs fixed in formalin and 70.6% for those fixed with CytoLyt® (p=0.047). The ER, PR and HER2 concordance rates between the PBC and MBC CBs are similar to those reported in paired surgical specimens. PR status was the most prevalent discordance and was not accompanied by a switch in ER.

  4. Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET)

    DEFF Research Database (Denmark)

    Chan, Arlene; Delaloge, Suzette; Holmes, Frankie A

    2016-01-01

    BACKGROUND: Neratinib, an irreversible tyrosine-kinase inhibitor of HER1, HER2, and HER4, has clinical activity in patients with HER2-positive metastatic breast cancer. We aimed to investigate the efficacy and safety of 12 months of neratinib after trastuzumab-based adjuvant therapy in patients w...

  5. Emerging treatments for HER2-positive early-stage breast cancer: focus on neratinib

    Directory of Open Access Journals (Sweden)

    Kourie HR

    2017-07-01

    Full Text Available Hampig Raphael Kourie,1 Elie El Rassy,1 Florian Clatot,2,3 Evandro de Azambuja,4 Matteo Lambertini3,4 1Department of Oncology, Faculty of Medicine, Saint Joseph University, Beirut, Lebanon; 2Department of Medical Oncology and IRON/U1245, Centre Henri Becquerel, Rouen, France; 3Breast Cancer Translational Research Laboratory, 4Department of Medicine, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium Abstract: Over the last decades, a better understanding of breast cancer heterogeneity provided tools for a biologically based personalization of anticancer treatments. In particular, the overexpression of the human epidermal growth factor receptor 2 (HER2 by tumor cells provided a specific target in these HER2-positive tumors. The development of the monoclonal antibody trastuzumab, and its approval in 1998 for the treatment of patients with metastatic disease, radically changed the natural history of this aggressive subtype of breast cancer. These findings provided strong support for the continuous research in targeting the HER2 pathway and implementing the development of new anti-HER2 targeted agents. Besides trastuzumab, a series of other anti-HER2 agents have been developed and are currently being explored for the treatment of breast cancer patients, including those diagnosed with early-stage disease. Among these agents, neratinib, an oral tyrosine kinase inhibitor that irreversibly inhibits HER1, HER2, and HER4 at the intracellular level, has shown promising results, including when administered to patients previously exposed to trastuzumab-based treatment. This article aims to review the available data on the role of the HER2 pathway in breast cancer and on the different targeted agents that have been studied or are currently under development for the treatment of patients with early-stage HER2-positive disease with a particular focus on neratinib. Keywords: breast cancer, HER2-positive, neratinib, early-stage, targeted

  6. Overview of the trastuzumab (Herceptin) anti-HER2 monoclonal antibody clinical program in HER2-overexpressing metastatic breast cancer. Herceptin Multinational Investigator Study Group.

    Science.gov (United States)

    Shak, S

    1999-08-01

    The recombinant humanized anti-HER2 monoclonal antibody trastuzumab (Herceptin; Genentech, San Francisco, CA) was evaluated in human clinical trials for treatment of women with metastatic breast cancer who have tumors that overexpress HER2. The trastuzumab clinical program consisted of a series of phase I, phase II, and phase III clinical trials. Clinical experience with this novel biologic has been obtained in more than 1,000 women with HER2-overexpressing metastatic breast cancer. Two pivotal trials were performed to evaluate trastuzumab efficacy and safety: (1) trastuzumab in combination with chemotherapy as first-line therapy and (2) trastuzumab as a single agent in second- and third-line chemotherapy. Preliminary results of the pivotal clinical trials that have been presented at national meetings are summarized below. The data suggest that trastuzumab will be an important new treatment option for women with HER2-overexpressing metastatic breast cancer.

  7. Metastatic Breast Cancer Survival according to HER2 and Topo2a Gene Status

    Directory of Open Access Journals (Sweden)

    N. Todorović-Raković

    2009-01-01

    Full Text Available The aim of this study was to determine the relationship between amplification of HER2 (Human epidermal growth factor receptor 2 and Topo2a (topoisomerase 2a and their influence on prognosis in metastatic breast cancer (MBC patients. Amplification of both HER2 and Topo2a genes was determined by chromogenic in situ hybridization (CISH in primary tumor tissue of 71 MBC patients. Starting point for follow-up was the time of diagnosis of metastatic disease. Although there was significant correlation between HER2 amplification and Topo2a alterations, Topo2a amplification was not strictly related to HER2 amplification. Follow-up of patients showed that there was no difference in MBC survival between HER2-nonamplified and HER2-amplified patients for subgroup as whole, but there was significant difference in MBC survival between patients with and without Topo2a amplification. HER2 amplification showed prognostic value in subgroups of patients, as well as Topo2a. Combination of these two genes with different status (nonamplified, amplified, coamplified indicated that they might have additive effect. Also, it has been shown that Topo2a-amplified cases have poorer survival than Topo2a-nonamplified, when treated with CMF therapy.

  8. Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer

    DEFF Research Database (Denmark)

    von Minckwitz, Gunter; Procter, Marion; de Azambuja, Evandro

    2017-01-01

    BACKGROUND: Pertuzumab increases the rate of pathological complete response in the preoperative context and increases overall survival among patients with metastatic disease when it is added to trastuzumab and chemotherapy for the treatment of human epidermal growth factor receptor 2 (HER2......)-positive breast cancer. In this trial, we investigated whether pertuzumab, when added to adjuvant trastuzumab and chemotherapy, improves outcomes among patients with HER2-positive early breast cancer. METHODS: We randomly assigned patients with node-positive or high-risk node-negative HER2-positive......, operable breast cancer to receive either pertuzumab or placebo added to standard adjuvant chemotherapy plus 1 year of treatment with trastuzumab. We assumed a 3-year invasive-disease-free survival rate of 91.8% with pertuzumab and 89.2% with placebo. RESULTS: In the trial population, 63% of the patients...

  9. Quality of life with palbociclib plus fulvestrant in previously treated hormone receptor-positive, HER2-negative metastatic breast cancer: patient-reported outcomes from the PALOMA-3 trial.

    Science.gov (United States)

    Harbeck, N; Iyer, S; Turner, N; Cristofanilli, M; Ro, J; André, F; Loi, S; Verma, S; Iwata, H; Bhattacharyya, H; Puyana Theall, K; Bartlett, C H; Loibl, S

    2016-06-01

    In the PALOMA-3 study, palbociclib plus fulvestrant demonstrated improved progression-free survival compared with fulvestrant plus placebo in hormone receptor-positive, HER2- endocrine-resistant metastatic breast cancer (MBC). This analysis compared patient-reported outcomes (PROs) between the two treatment groups. Patients were randomized 2 : 1 to receive palbociclib 125 mg/day orally for 3 weeks followed by 1 week off (n = 347) plus fulvestrant (500 mg i.m. per standard of care) or placebo plus fulvestrant (n = 174). PROs were assessed on day 1 of cycles 1-4 and of every other subsequent cycle starting with cycle 6 using the EORTC QLQ-C30 and its breast cancer module, QLQ-BR23. High scores (range 0-100) could indicate better functioning/quality of life (QoL) or worse symptom severity. Repeated-measures mixed-effect analyses were carried out to compare on-treatment overall scores and changes from baseline between treatment groups while controlling for baseline. Between-group comparisons of time to deterioration in global QoL and pain were made using an unstratified log-rank test and Cox proportional hazards model. Questionnaire completion rates were high at baseline and during treatment (from baseline to cycle 14, ≥95.8% in each group completed ≥1 question on the EORTC QLQ-C30). On treatment, estimated overall global QoL scores significantly favored the palbociclib plus fulvestrant group [66.1, 95% confidence interval (CI) 64.5-67.7 versus 63.0, 95% CI 60.6-65.3; P = 0.0313]. Significantly greater improvement from baseline in pain was also observed in this group (-3.3, 95% CI -5.1 to -1.5 versus 2.0, 95% CI -0.6 to 4.6; P = 0.0011). No significant differences were observed for other QLQ-BR23 functioning domains, breast or arm symptoms. Treatment with palbociclib plus fulvestrant significantly delayed deterioration in global QoL (P < 0.025) and pain (P < 0.001) compared with fulvestrant alone. Palbociclib plus fulvestrant allowed patients to maintain good Qo

  10. Novel approaches to target HER2-positive breast cancer: trastuzumab emtansine

    International Nuclear Information System (INIS)

    Recondo, Gonzalo Jr; Vega, Maximo de la; Galanternik, Fernando; Díaz-Cantón, Enrique; Leone, Bernardo Amadeo; Leone, José Pablo

    2016-01-01

    The human epidermal growth factor receptor 2 (HER2) is overexpressed in 20% of breast carcinomas. Prior to the development of targeted therapies, HER2-positive breast cancer was associated with more aggressive disease and poor prognosis. Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate that results from the combination of trastuzumab and DM1, a derivative of the antimicrotubule agent maytansine. This molecule has the ability to enhance cytotoxic drug delivery to specifically targeted cells that overexpress HER2, therefore, maximizing efficacy while sparing toxicity. In recent years, T-DM1 has shown to improve outcomes in metastatic HER2-positive breast cancer that is resistant to trastuzumab. In addition, T-DM1 is currently being tested in the neoadjuvant and adjuvant settings to identify patients who may benefit from this therapy. This review focuses on the mechanism of action, early and late-phase clinical trials, and ongoing studies of T-DM1 in HER2-positive breast cancer

  11. Quantitative measurements of tumoral p95HER2 protein expression in metastatic breast cancer patients treated with trastuzumab: independent validation of the p95HER2 clinical cutoff.

    Science.gov (United States)

    Duchnowska, Renata; Sperinde, Jeff; Chenna, Ahmed; Haddad, Mojgan; Paquet, Agnes; Lie, Yolanda; Weidler, Jodi M; Huang, Weidong; Winslow, John; Jankowski, Tomasz; Czartoryska-Arłukowicz, Bogumiła; Wysocki, Piotr J; Foszczyńska-Kłoda, Małgorzata; Radecka, Barbara; Litwiniuk, Maria M; Zok, Jolanta; Wiśniewski, Michał; Zuziak, Dorota; Biernat, Wojciech; Jassem, Jacek

    2014-05-15

    P95HER2 (p95) is a truncated form of the HER2, which lacks the trastuzumab-binding site and contains a hyperactive kinase domain. Previously, an optimal clinical cutoff of p95 expression for progression-free survival (PFS) and overall survival (OS) was defined using a quantitative VeraTag assay (Monogram Biosciences) in a training set of trastuzumab-treated metastatic breast cancer (MBC) patients. In the current study, the predictive value of the p95 VeraTag assay cutoff established in the training set was retrospectively validated for PFS and OS in an independent series of 240 trastuzumab-treated MBC patients from multiple institutions. In the subset of 190 tumors assessed as HER2-total (H2T)-positive using the quantitative HERmark assay (Monogram Biosciences), p95 VeraTag values above the predefined cutoff correlated with shorter PFS (HR = 1.43; P = 0.039) and shorter OS (HR = 1.94; P = 0.0055) where both outcomes were stratified by hormone receptor status and tumor grade. High p95 expression correlated with shorter PFS (HR = 2.41; P = 0.0003) and OS (HR = 2.57; P = 0.0025) in the hormone receptor-positive subgroup of patients (N = 78), but not in the hormone receptor-negative group. In contrast with the quantitative p95 VeraTag measurements, p95 immunohistochemical expression using the same antibody was not significantly correlated with outcomes. The consistency in the p95 VeraTag cutoff across different cohorts of patients with MBC treated with trastuzumab justifies additional studies using blinded analyses in larger series of patients. ©2014 American Association for Cancer Research.

  12. Prevention of everolimus-related stomatitis in women with hormone receptor-positive, HER2-negative metastatic breast cancer using dexamethasone mouthwash (SWISH): a single-arm, phase 2 trial.

    Science.gov (United States)

    Rugo, Hope S; Seneviratne, Lasika; Beck, J Thaddeus; Glaspy, John A; Peguero, Julio A; Pluard, Timothy J; Dhillon, Navneet; Hwang, Leon Christopher; Nangia, Chaitali; Mayer, Ingrid A; Meiller, Timothy F; Chambers, Mark S; Sweetman, Robert W; Sabo, J Randy; Litton, Jennifer K

    2017-05-01

    Stomatitis is a class effect associated with the inhibition of mTOR and is associated with everolimus therapy for breast cancer. Topical steroids might reduce stomatitis incidence and severity, and the need for dose reductions and interruptions of everolimus. Anecdotal use of topical steroid oral prophylaxis has been reported in patients with breast cancer. We aimed to assess dexamethasone-based mouthwash for prevention of stomatitis in patients with breast cancer. This US-based, multicentre, single-arm, phase 2 prevention study enrolled women aged 18 years and older with postmenopausal status who had histologically or cytologically confirmed metastatic hormone receptor-positive, HER2-negative breast cancer. Beginning on day 1 of cycle 1, patients received everolimus 10 mg plus exemestane 25 mg daily, with 10 mL of alcohol-free dexamethasone 0·5 mg per 5 mL oral solution (swish for 2 min and spit, four times daily for 8 weeks). After 8 weeks, dexamethasone mouthwash could be continued for up to eight additional weeks at the discretion of the clinician and patient. The primary endpoint was incidence of grade 2 or worse stomatitis by 8 weeks assessed in the full analysis set (patients who received at least one dose of everolimus and exemestane and at least one confirmed dose of dexamethasone mouthwash) versus historical controls from the BOLERO-2 trial (everolimus and exemestane treatment in patients with hormone receptor-positive advanced breast cancer who were not given dexamethasone mouthwash for prevention of stomatitis). This trial is registered at ClinicalTrials.gov, number NCT02069093. Between May 28, 2014, and Oct 8, 2015, we enrolled 92 women; 85 were evaluable for efficacy. By 8 weeks, the incidence of grade 2 or worse stomatitis was two (2%) of 85 patients (95% CI 0·29-8·24), versus 159 (33%) of 482 patients (95% CI 28·8-37·4) for the duration of the BOLERO-2 study. Overall, 83 (90%) of 92 patients had at least one adverse event. The most frequently

  13. Neratinib for the treatment of HER2-positive early stage breast cancer.

    Science.gov (United States)

    Echavarria, Isabel; López-Tarruella, Sara; Márquez-Rodas, Iván; Jerez, Yolanda; Martin, Miguel

    2017-08-01

    Despite the advances in the treatment of HER2-positive breast cancer, resistance to actual chemotherapeutic regimens eventually occurs. Neratinib, an orally available pan-inhibitor of the ERBB family, represents an interesting new option for early-stage HER2-positive breast cancer. Areas covered: In this article, the development of neratinib, with a special focus on its potential value in the treatment of early-stage HER2-positive breast cancer, has been reviewed. For this purpose, a literature search was conducted, including preclinical studies, early-phase trials in advanced cancer with neratinib in monotherapy and in combination, and phase II and large phase III trials in the early setting. Management of neratinib-induced toxicity, future perspectives for the drug, and ongoing trials are also discussed in this review. Expert commentary: Neratinib is emerging as a promising oral drug for the treatment of HER2-positive breast cancer. Although FDA and EMA approval is derived from the extended adjuvant treatment, this setting may not be the ideal scenario to obtain the beneficial effects of neratinib. Confirmatory data in the neoadjuvant setting and subgroup analysis from the ExTENET trial might bring some light into the best setting for neratinib therapy. Data from confirmatory trials in the metastatic setting are also required.

  14. Effective Treatment of Solitary Pituitary Metastasis with Panhypopituitarism in HER2-Positive Breast Cancer by Lapatinib.

    Science.gov (United States)

    Park, Youngmok; Kim, Hyemin; Kim, Eui-Hyun; Suh, Chang-Ok; Lee, Soohyeon

    2016-01-01

    Brain metastasis affects one third of patients with HER2-positive breast cancer after treatment with trastuzumab. Surgical resection and radiation therapy are often unsuccessful at accomplishing complete control of metastasis. Lapatinib is presumed to cross the blood-brain barrier, and exhibits clinical activities for treatment of HER2-positive breast cancer. A 43-year-old woman was treated for early breast carcinoma with total mastectomy, axillary lymph-node dissection, and adjuvant chemotherapy with cyclophosphamide plus doxorubicin. After the end of adjuvant trastuzumab therapy, she was diagnosed with panhypopituitarism due to pituitary metastasis. Surgical removal and whole brain radiation therapy were performed, but a portion of viable tumor remained. Only taking lapatinib, the size of the metastatic lesion began to shrink. Trastuzumab may have controlled the micro-metastasis of breast cancer, but it was unable to control its progression to the central nervous system. Lapatinib is a possible option for HER2-positive metastatic breast cancer patients with brain metastasis.

  15. Her-2 Positive Gastric Cancer Presented with Thrombocytopenia and Skin Involvement: A Case Report

    Directory of Open Access Journals (Sweden)

    Deniz Arslan

    2014-01-01

    Full Text Available Gastric cancer is the 5th most frequent cancer around the world and the 3rd most frequent reason of deaths due to cancer. Every year, about 1 million new cases are taking place, with varying geographical distribution. Gastric cancer is often metastatic to liver, lungs, and bones in hematogenous way, to peripheral lymph nodes in lymphogenous way, and to peripheral tissues in adjacency way, yet bone marrow (BM and cutaneous metastasis are quite seldom. Pancytopenia is a more frequent finding identified in BM metastasis of solid organ cancers, and isolated thrombocytopenia is less often. The human epidermal growth factor 2 (HER-2 is positive in gastric cancer at a rate of 7–34%. Here, we have presented our HER-2 positive gastric cancer incident which presented with BM and cutaneous metastasis, and has no 18F-fluoro-2-deoxi-D-glucose (FDG involvement except bone metastases.

  16. POSSIBILITIES OF THERAPY OF HER-2-POSITIVE REGIONAL BREAST CANCER

    Directory of Open Access Journals (Sweden)

    A. S. Belokhvostova

    2015-01-01

    Full Text Available Breast cancer heads the list of malignant neoplasms in women. In this connection the regional forms of cancer are diagnosed in one fourth of the patients. The treatment of regional cancer begins with systemic therapy and aimed at gaining of state fit for operation. The choice of modern treatment strategy is based on determination of molecular subtype of the tumor. One of them is referred to HER-2-positive cancer, requiring the administration of additional targeted therapy. This form of cancer is referred to prognostically pejorative tumors, as it’s more aggressive, leads to fast metastasis and early death of the patients. The “golden standard” of systemic chemotherapy is defined as administration of docetaxel and trastuzumab,  and antracyclic drugs, which also prove to be efficient. However concomitant administration of trastuzumab and antracyclines is limited due to their cardiotoxicity. Chemotherapy is not always efficient and, upon recommendations both of Russian and international oncologists, radiotherapy is the next stage of treatment. The question about radiosensibility of HER-2-positive tumors is still open and worth studying. Addition of radiotherapy to regional cancer treatment regimen in combination with the targeted therapy and chemotherapy may contribute to obtaining better survival rate and disease control. There are still no clearly defined standard for the sequence of chemo-radiation therapy. Simultaneous  chemo-radiatiojn  therapy results in  reliably better loco-regional control of tumor and  enables to gain a  higher degree of pathomorphological response on the one hand, and it may result in development of serious adverse effects on the other hand. Striving for improvement of immediate results of antineoplastic therapy, including that of regional cancer, by combining various methods, one should keep in mind the increasing action toxicity, which may have a considerable impact on the patients’ quality of living

  17. Prognostic and predictive values of EGFR overexpression and EGFR copy number alteration in HER2-positive breast cancer.

    Science.gov (United States)

    Lee, H J; Seo, A N; Kim, E J; Jang, M H; Kim, Y J; Kim, J H; Kim, S-W; Ryu, H S; Park, I A; Im, S-A; Gong, G; Jung, K H; Kim, H J; Park, S Y

    2015-01-06

    Epidermal growth factor receptor (EGFR) is overexpressed in a subset of human epidermal growth factor receptor 2 (HER2)-positive breast cancers, and coexpression of HER2 and EGFR has been reported to be associated with poor clinical outcome. Moreover, interaction between HER2 and EGFR has been suggested to be a possible basis for trastuzumab resistance. We analysed the clinical significance of EGFR overexpression and EGFR gene copy number alterations in 242 HER2-positive primary breast cancers. In addition, we examined the correlations between EGFR overexpression, trastuzumab response and clinical outcome in 447 primary, and 112 metastatic HER2-positive breast cancer patients treated by trastuzumab. Of the 242 primary cases, the level of EGFR overexpression was 2+ in 12.7% and 3+ in 11.8%. High EGFR gene copy number was detected in 10.3%. Epidermal growth factor receptor overexpression was associated with hormone receptor negativity and high Ki-67 proliferation index. In survival analyses, EGFR overexpression, but not high EGFR copy number, was associated with poor disease-free survival in all patients, and in the subgroup not receiving adjuvant trastuzumab. In 447 HER2-positive primary breast cancer patients treated with adjuvant trastuzumab, EGFR overexpression was also an independent poor prognostic factor. However, EGFR overexpression was not associated with trastuzumab response, progression-free survival or overall survival in the metastatic setting. Epidermal growth factor receptor overexpression, but not high EGFR copy number, is a poor prognostic factor in HER2-positive primary breast cancer. Epidermal growth factor receptor overexpression is a predictive factor for trastuzumab response in HER2-positive primary breast cancer, but not in metastatic breast cancer.

  18. Real-world effectiveness of everolimus-based therapy versus fulvestrant monotherapy in HR(+)/HER2(-) metastatic breast cancer.

    Science.gov (United States)

    Hao, Yanni; Lin, Peggy L; Xie, Jipan; Li, Nanxin; Koo, Valerie; Ohashi, Erika; Wu, Eric Q; Rogerio, Jaqueline

    2015-08-01

    Assessing real-world effectiveness of everolimus-based therapy (EVE) versus fulvestrant monotherapy (FUL) among postmenopausal women with hormone receptor-positive (HR(+))/HER2(-) metastatic breast cancer (mBC) after progression on nonsteroidal aromatase inhibitor (NSAI). Medical charts of community-based patients who received EVE or FUL for mBC after NSAI were examined. Progression-free survival (PFS), time on treatment and time to chemotherapy were compared using Kaplan-Meier curves and Cox proportional hazards models adjusting for line of therapy and patient characteristics. 192 patients received EVE and 156 FUL. After adjusting for patient characteristics, EVE was associated with significantly longer PFS than FUL (hazard ratio: 0.71; p = 0.045). EVE was associated with better PFS than FUL among NSAI-refractory postmenopausal HR(+)/HER2(-) mBC patients.

  19. Tailoring DNA vaccines: designing strategies against HER2 positive cancers

    Directory of Open Access Journals (Sweden)

    Cristina eMarchini

    2013-05-01

    Full Text Available The crucial role of HER2 in epithelial transformation and its selective overexpression on cancer tissues makes it an ideal target for cancer immunotherapies such as passive immunotherapy with Trastuzumab. There are, however, a number of concerns regarding the use of monoclonal antibodies which include resistance, repeated treatments, considerable costs and side effects that make active immunotherapies against HER2 desirable alternative approaches. The efficacy of anti-HER2 DNA vaccination has been widely demonstrated in transgenic cancer-prone mice, which recapitulate several features of human breast cancers. Nonetheless, the rational design of a cancer vaccine able to trigger a long lasting immunity, and thus prevent tumor recurrence in patients, would require the understanding of how tolerance and immunosuppression regulate antitumor immune responses and, at the same time, the identification of the most immunogenic portions of the target protein. We herein retrace the findings that led to our most promising DNA vaccines that, by encoding human/rat chimeric forms of HER2, are able to circumvent peripheral tolerance. Preclinical data obtained with these chimeric DNA vaccines have provided the rationale for their use in an ongoing phase I clinical trial (EudraCT 2011-001104-34.

  20. Phase II Study of HER-2/neu Intracellular Domain Peptide-Based Vaccine Administered to Stage IV HER2 Positive Breast Cancer Patients Receiving Trastuzumab

    National Research Council Canada - National Science Library

    Disis, Mary L

    2007-01-01

    The primary purpose of this grant is to determine the overall survival benefit in Stage IV HER2 positive breast cancer patients vaccinated with a HER2 ICD peptide-based vaccine while receiving maintenance trastuzumab...

  1. Phase II Study of HER-2/neu Intracellular Domain Peptide-Based Vaccine Administered to Stage IV HER2 Positive Breast Cancer Patients Receiving Trastuzumab

    National Research Council Canada - National Science Library

    Disis, Mary L

    2006-01-01

    The primary purpose of this grant is to determine the overall survival benefit in Stage IV HER2 positive breast cancer patients vaccinated with a HER2 ICD peptide-based vaccine while receiving maintenance trastuzumab...

  2. 64Cu-DOTA-trastuzumab PET imaging in patients with HER2-positive breast cancer.

    Science.gov (United States)

    Tamura, Kenji; Kurihara, Hiroaki; Yonemori, Kan; Tsuda, Hitoshi; Suzuki, Junko; Kono, Yuzuru; Honda, Natsuki; Kodaira, Makoto; Yamamoto, Harukaze; Yunokawa, Mayu; Shimizu, Chikako; Hasegawa, Koki; Kanayama, Yousuke; Nozaki, Satoshi; Kinoshita, Takayuki; Wada, Yasuhiro; Tazawa, Shusaku; Takahashi, Kazuhiro; Watanabe, Yasuyoshi; Fujiwara, Yasuhiro

    2013-11-01

    The purpose of this study was to determine the safety, distribution, internal dosimetry, and initial human epidermal growth factor receptor 2 (HER2)-positive tumor images of (64)Cu-DOTA-trastuzumab in humans. PET was performed on 6 patients with primary or metastatic HER2-positive breast cancer at 1, 24, and 48 h after injection of approximately 130 MBq of the probe (64)Cu-DOTA-trastuzumab. Radioactivity data were collected from the blood, urine, and normal-tissue samples of these 6 patients, and the multiorgan biodistribution and internal dosimetry of the probe were evaluated. Safety data were collected for all the patients after the administration of (64)Cu-DOTA-trastuzumab and during the 1-wk follow-up period. According to our results, the best timing for the assessment of (64)Cu-DOTA-trastuzumab uptake by the tumor was 48 h after injection. Radiation exposure during (64)Cu-DOTA-trastuzumab PET was equivalent to that during conventional (18)F-FDG PET. The radioactivity in the blood was high, but uptake of (64)Cu-DOTA-trastuzumab in normal tissues was low. In 2 patients, (64)Cu-DOTA-trastuzumab PET showed brain metastases, indicative of blood-brain barrier disruptions. In 3 patients, (64)Cu-DOTA-trastuzumab PET imaging also revealed primary breast tumors at the lesion sites initially identified by CT. The findings of this study indicated that (64)Cu-DOTA-trastuzumab PET is feasible for the identification of HER2-positive lesions in patients with primary and metastatic breast cancer. The dosimetry and pharmacologic safety results were acceptable at the dose required for adequate PET imaging.

  3. Targeting HER2-positive cancer using multifunctional nanoparticles

    DEFF Research Database (Denmark)

    Juul, Christian Ammitzbøll

    Advanced delivery of chemotherapeutics to tumor tissue is an active field of research, as it offers several benefits over conventional cancer therapies. In the three introductory chapters of this thesis, the development of liposomes as drug carriers, including novel strategies to improve delivery...... efficiency, is thoroughly reviewed. Chapter 4 encompasses a comprehensive manuscript, which describes the in vitro and in vivo evaluation of a novel liposomal delivery platform designed to target the HER2 receptor on cancer cells and be activated by enzyme activity in the tumor. In Chapter 5, an alternative...... HER2-targeted liposome formulation was assessed in vitro. Rather than being enzyme-sensitive, these liposomes were responsive to reducing conditions. Such conditions are found in several cancers due to hypoxia as well as in endocytic compartments. The progressive in vitro optimization of a complex...

  4. Short term real world safety data of pertuzumab use in HER2 targeted treatment of metastatic breast cancer

    Directory of Open Access Journals (Sweden)

    Ece Esin

    2018-04-01

    ventriculer ejection fraction was measured stable for all of the cases, none of them experienced any significant decrease. Conclusion: According to the results of this retrospective analysis, the use of pertuzumab-trastuzumab-docetaxel in the first line treatment of HER2 expressing metastatic breast cancer had good safety profile and had positive clinical results and paralleled with the results of the pivotal study. Keywords: Human epidermal growth factor, Epidermal growth factor receptor, Pertuzumab, Heterodimerization

  5. Clinical use of S-HER2 in breast cancer for detecting metastatic recurrence and monitoring effect of trastuzumab treatment

    DEFF Research Database (Denmark)

    Kjær, Ina Mathilde; Brandslund, Ivan

    2014-01-01

    % and the positive predictive value was 47% using a cutoff value of 15 μg/L. Further, we have shown that the S-HER2 value reflects the effect of targeted treatment with trastuzumab. An increase in S-HER2 was correlated with progression of disease in 40 out of 44 clinical courses, whereas a decrease in S-HER2...

  6. Brain metastases in patients who receive trastuzumab-containing chemotherapy for HER2-overexpressing metastatic breast cancer

    International Nuclear Information System (INIS)

    Ono, Makiko; Ando, Masashi; Yunokawa, Mayu

    2009-01-01

    Recently, a high rate of brain metastases has been reported among patients with human epidermal growth factor receptor (HER2)-overexpressing metastatic breast cancer who were treated with trastuzumab. The present study examined risk factors for the development of brain metastasis in patients with HER2-overexpressing breast cancer who were treated with trastuzumab. We retrospectively reviewed 204 patients with HER-2-overexpressing breast cancer who were treated with a trastuzumab-containing regimen between 1999 and 2006. Patients with clinical symptoms were diagnosed as having brain metastases when brain magnetic resonance imaging (MRI) or a computed tomography (CT) scan revealed positive findings for brain metastases. The median follow-up time of this cohort was 53.6 months. Among the patients who received a trastuzumab-containing regimen, 74 patients (36.3%) developed brain metastases. The median survival from the diagnosis of brain metastases was 13.5 months (95% confidence interval [CI], 12.2-14.7 months). The median time interval between the beginning of trastuzumab treatment and the diagnosis of brain metastases was 13.6 months (range, 0.0-45.8 months). Among patients with brain metastases, the median overall survival period was 39 months. A multivariate logistic regression analysis showed that age (≤50 years), recurrent breast cancer, and liver metastases were significant risk factors for the development of brain metastases. Patients with HER2-overexpressing breast cancer treated with trastuzumab had a high incidence of brain metastases (36.3%). Routine screening for brain metastases 1 year after the start of trastuzumab treatment, may be warranted in younger patients (≤50 years) who had recurrent breast cancer with liver metastases. (author)

  7. Galectin-7 Expression Potentiates HER-2-Positive Phenotype in Breast Cancer.

    Directory of Open Access Journals (Sweden)

    Andrée-Anne Grosset

    Full Text Available HER-2 positive tumors are among the most aggressive subtypes of breast cancer and are frequently associated with metastasis and poor outcome. As with other aggressive subtypes of breast cancer, these tumors are associated with abnormally high expression of galectin-7 (gal-7, which confers metastatic breast tumor cells with increased invasive behavior. Although previous studies in the rat model of breast tumorigenesis have shown that gal-7 is also increased in primary breast tumor, its contribution to the development of the primary breast tumors remains unclear. In the present work, we have used genetically-engineered gal-7-deficient mice to examine the role of gal-7 in the development of the mammary gland and of breast cancer. Using histological and immunohistological analysis of whole mammary glands at different stages of development, we detected no significant changes between normal and gal-7-deficient mice. To test the involvement of gal-7 in breast cancer, we next examined the effects of loss of gal-7 on mammary tumor development by crossing gal-7-deficient mice with the mammary tumor transgenic mouse strain FVB-Tg(MMTV-Erbb2NK1Mul/J. Finally, assessment of mice survival and tumor volume showed a delay of mammary tumor growth in the absence of systemic gal-7. These data suggest that gal-7 could potentiate the phenotype of HER-2 positive primary breast cancer.

  8. Survival benefit of anti-HER2 therapy after whole-brain radiotherapy in HER2-positive breast cancer patients with brain metastasis.

    Science.gov (United States)

    Zhang, Qian; Chen, Jian; Yu, Xiaoli; Cai, Gang; Yang, Zhaozhi; Cao, Lu; Hu, Chaosu; Guo, Xiaomao; Sun, Jing; Chen, Jiayi

    2016-09-01

    We aimed to assess the survival benefit of epidermal growth factor receptor 2 (HER2)-positive breast cancer patients with brain metastasis (BM) after whole-brain radiotherapy (WBRT) in combination with systemic treatments, especially anti-HER2 therapy. This retrospective study analyzed the overall survival (OS) of 60 HER2-positive breast cancer patients with BM after WBRT in combination with systemic treatments. Among them, 42 patients received chemotherapy while 18 patients did not receive after WBRT. With regard to anti-HER2 therapy, after WBRT, 17 patients received anti-HER2 treatment without prior adjuvant trastuzumab-based therapy, 7 patients received anti-HER2 treatment with prior adjuvant trastuzumab-based therapy, and 36 patients did not receive further anti-HER2 treatment. All patients were followed up regularly until January 23, 2013. The median OS of patients with BM was 12 months. Patients who received anti-HER2 therapy and chemotherapy after WBRT had significantly better survival compared with patients who did not receive further treatment. Patients who received anti-HER2 treatment after WBRT but did not receive adjuvant trastuzumab-based therapy for early breast cancer had better OS, followed by patients who received anti-HER2 agent both in adjuvant treatment and after WBRT and patients who did not receive anti-HER2 treatment. Multivariate analysis showed that Karnofsky Performance Status, control of extracranial metastases, chemotherapy after WBRT, and anti-HER2 therapy combined with WBRT were all independent predictors for OS. Both chemotherapy and anti-HER2 therapy after WBRT could improve OS. Moreover, patients without prior exposure to adjuvant anti-HER2 treatment may have survival benefit superior to those of patients with prior exposure.

  9. Polymer–lipid hybrid anti-HER2 nanoparticles for targeted salinomycin delivery to HER2-positive breast cancer stem cells and cancer cells

    Directory of Open Access Journals (Sweden)

    Li J

    2017-09-01

    Full Text Available Jun Li,1,* Wenqing Xu,2,* Xiaoli Yuan,3,* Huaiwen Chen,3 Hao Song,1,4 Bingquan Wang,5 Jun Han5 1College of Pharmacy, Liaocheng University, Liaocheng, Shandong, 2Railway Police College, Zhengzhou, 3Department of Cadre Health Care, Nanjing General Hospital of Nanjing Military Command, Nanjing, Jiangsu, 4Centre for Stem Cell & Regenerative Medicine, Liaocheng People’s Hospital, 5Institute of Biopharmaceutical Research, Liaocheng University, Liaocheng, Shandong, China *These authors contributed equally to this work Purpose: Breast cancer stem cells (CSCs are responsible for the initiation, recurrence, and metastasis of breast cancer. Sufficient evidence has established that breast cancer cells can spontaneously turn into breast CSCs. Thus, it is essential to simultaneously target breast CSCs and cancer cells to maximize the efficacy of breast cancer therapy. HER2 has been found to be overexpressed in both breast CSCs and cancer cells. We developed salinomycin-loaded polymer–lipid hybrid anti-HER2 nanoparticles (Sali-NP-HER2 to target both HER2-positive breast CSCs and cancer cells.Methods: The antitumor activity of Sali-NP-HER2 constructed by conjugating anti-HER2 antibodies to polymer–lipid salinomycin nanoparticles was evaluated in vitro and in vivo.Results: Sali-NP-HER2 efficiently bound to HER2-positive breast CSCs and cancer cells, resulting in enhanced cytotoxic effects compared with non-targeted nanoparticles or salinomycin. In mice bearing breast cancer xenografts, administration of Sali-NP-HER2 exhibited superior efficacy in inhibiting tumor growth. Sali-NP-HER2 reduced the breast tumorsphere formation rate and the proportion of breast CSCs more effectively than non-targeted nanoparticles or salinomycin alone.Conclusion: Sali-NP-HER2 represents a promising approach in treating HER2-positive breast cancer by targeting both breast CSCs and cancer cells. Keywords: nanoparticles, breast cancer, cancer stem cells, salinomycin, HER2

  10. HER-2 positive and p53 negative breast cancers are associated with poor prognosis.

    LENUS (Irish Health Repository)

    2011-06-01

    p53 and HER-2 coexpression in breast cancer has been controversial. These markers were tested using immunohistochemistry and HercepTest. HER-2 expression is related to reduced breast cancer survival (p = .02) . p53 expression relates to HER-2 expression (p = .029). Coexpression between p53 and HER-2 has no relation to prognosis. On univariate and multivariate analysis, combination of HER-2 positive and p53 negative expression was associated with a poor prognosis (p = .018 and p = .027, respectively), while the combination of HER-2 negative and p53 positive expression was associated with a favorable prognosis (p = .022 and p = .010, respectively). Therefore the expression of these markers should be considered collectively.

  11. HER-2 positive and p53 negative breast cancers are associated with poor prognosis.

    LENUS (Irish Health Repository)

    2012-02-01

    p53 and HER-2 coexpression in breast cancer has been controversial. These markers were tested using immunohistochemistry and HercepTest. HER-2 expression is related to reduced breast cancer survival (p = .02) . p53 expression relates to HER-2 expression (p = .029). Coexpression between p53 and HER-2 has no relation to prognosis. On univariate and multivariate analysis, combination of HER-2 positive and p53 negative expression was associated with a poor prognosis (p = .018 and p = .027, respectively), while the combination of HER-2 negative and p53 positive expression was associated with a favorable prognosis (p = .022 and p = .010, respectively). Therefore the expression of these markers should be considered collectively.

  12. ADAM10 mediates trastuzumab resistance and is correlated with survival in HER2 positive breast cancer

    Science.gov (United States)

    Feldinger, Katharina; Generali, Daniele; Kramer-Marek, Gabriela; Gijsen, Merel; Ng, Tzi Bun; Wong, Jack Ho; Strina, Carla; Cappelletti, Mariarosa; Andreis, Daniele; Li, Ji-Liang; Bridges, Esther; Turley, Helen; Leek, Russell; Roxanis, Ioannis; Capala, Jacek; Murphy, Gillian; Harris, Adrian L.; Kong, Anthony

    2014-01-01

    Trastuzumab prolongs survival in HER2 positive breast cancer patients. However, resistance remains a challenge. We have previously shown that ADAM17 plays a key role in maintaining HER2 phosphorylation during trastuzumab treatment. Beside ADAM17, ADAM10 is the other well characterized ADAM protease responsible for HER ligand shedding. Therefore, we studied the role of ADAM10 in relation to trastuzumab treatment and resistance in HER2 positive breast cancer. ADAM10 expression was assessed in HER2 positive breast cancer cell lines and xenograft mice treated with trastuzumab. Trastuzumab treatment increased ADAM10 levels in HER2 positive breast cancer cells (p≤0.001 in BT474; p≤0.01 in SKBR3) and in vivo (p≤0.0001) compared to control, correlating with a decrease in PKB phosphorylation. ADAM10 inhibition or knockdown enhanced trastuzumab response in naïve and trastuzumab resistant breast cancer cells. Trastuzumab monotherapy upregulated ADAM10 (p≤0.05); and higher pre-treatment ADAM10 levels correlated with decreased clinical response (p≤0.05) at day 21 in HER2 positive breast cancer patients undergoing a trastuzumab treatment window study. Higher ADAM10 levels correlated with poorer relapse-free survival (p≤0.01) in a cohort of HER2 positive breast cancer patients. Our studies implicate a role of ADAM10 in acquired resistance to trastuzumab and establish ADAM10 as a therapeutic target and a potential biomarker for HER2 positive breast cancer patients. PMID:24952873

  13. Systemic therapy for HER2-positive early-stage breast cancer.

    Science.gov (United States)

    Mathew, Aju; Romond, Edward H

    The advent of the targeted monoclonal antbody trastuzumab for treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer marked a revolution in the understanding and management of mammary carcinoma and, in practice, separated this subtype from other kinds of primary breast malignancy. Long term follow-up from the initial large adjuvant trials continue to show remarkably positive results. Currently, at least four additional agents targeting this receptor, using different and complementary mechanisms of action compared with trastuzumab, have been incorporated into clinical trials. The small molecule tyrosine kinase inhibitors lapatinib and neratinib, in addition to the antibody pertuzumab and the antibody-drug conjugate trastuzumab-ematansine, have shown efficacy in metastatic breast cancer and are being evaluated both in neoadjuvant and adjuvant trials for early stage disease. The cytotoxic chemotherapy regimens used in combination with these agents also are evolving and different therapeutic approaches are emerging for patients depending on their relative level of risk from their cancers, thus moving clinical management toward individualized therapy. Much has been learned about managing the toxicities of treatment and pre-operative approaches have provided a means of assessing the sensitivity of individual patients' cancers to specific treatment regimens. This review traces the development of these studies and focuses on improvements in adjuvant and neoadjuvant therapy for patients with HER2-positive disease whose prognosis has changed in the last decade from dire to favorable. A path forward has been set by which the goal of cure is attainable for almost all patients faced with this aggressive form of breast cancer. Copyright © 2016 Elsevier Inc. All rights reserved.

  14. Determination of HER2 phosphorylation at tyrosine 1221/1222 improves prediction of poor survival for breast cancer patients with hormone receptor-positive tumors

    DEFF Research Database (Denmark)

    Frogne, Thomas; Laenkholm, Anne-Vibeke; Lyng, Maria B

    2009-01-01

    INTRODUCTION: High expression of total HER2 protein confers poor prognosis for breast cancer patients. HER2 is a member of the HER family consisting of four receptors, HER1 to HER4. HER receptor activity is regulated by a variety of mechanisms, and phosphorylation of the C-terminal part of the HER...... metastases, by evaluating the expression of phosphorylated HER1, HER2, HER3, Erk, Akt and the total level of HER4 and HER2. METHODS: Immunohistochemical analysis was performed on 268 primary breast tumors and 30 paired metastatic lesions from postmenopausal women with hormone receptor-positive breast tumors...... of Akt and Erk were quite uniformly expressed in the categories; negative, moderate or strong. In univariate analysis, expression of total HER2, pHER1, pHER2 and pHER3 was significantly associated with poor disease-free survival. Strong HER4 expression was associated with prolonged disease-free as well...

  15. Safety and Efficacy of Low-dose Nanoparticle Albumin-bound Paclitaxel for HER2-negative Metastatic Breast Cancer.

    Science.gov (United States)

    Takashima, Tsutomu; Kawajiri, Hidemi; Nishimori, Takeo; Tei, Seika; Nishimura, Shigehiko; Yamagata, Shigehito; Tokunaga, Shinya; Mizuyama, Yoko; Sunami, Takeshi; Tezuka, Kenji; Ikeda, Katsumi; Ogawa, Yoshinari; Kashiwagi, Shinichiro; Noda, Satoru; Onoda, Naoyoshi; Ishikawa, Tetsuro; Kudoh, Shinzoh; Takada, Minoru; Hirakawa, Kosei; Ohira, Masaichi

    2018-01-01

    Nab-paclitaxel (nab-PTX) is an albumin-bound paclitaxel formulation. Although nab-PTX has shown superior efficacy compared to conventional paclitaxel (PTX) in metastatic breast cancer (MBC), chemotherapy-induced peripheral neuropathy (CIPN) was more frequently observed in nab-PTX. In this study, we aimed to estimate the feasibility of the nab-PTX 175 mg/m 2 /3weeks regimen. Patients having metastatic or inoperable HER2-negative breast cancer received 175 mg/m 2 of nab-PTX every three weeks. The primary endpoint was safety and the secondary endpoints were response and survival. Seventeen patients were enrolled with a median age of 64 years. Ten patients had estrogen receptor positive disease and seven had triple-negative disease. CIPN was observed in seven patients (41%) however, grade 3 CIPN was only seen in one patient (6%). Objective response rate was 41% and progression-free survival was 23 weeks. Nab-PTX 175 mg/m 2 /3wks regimen has a good safety profile and less frequent CIPN. This regimen can contribute to the strategy of MBC treatment. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  16. Tyrosine kinase inhibitors for brain metastases in HER2-positive breast cancer.

    Science.gov (United States)

    Duchnowska, Renata; Loibl, Sibylle; Jassem, Jacek

    2018-06-01

    Approximately 30-50% of advanced HER2-positive breast cancer patients will develop central nervous system (CNS) metastases, with an annual risk of around 10%, and a half of them will die from brain progression. An increased risk of brain metastases is also seen in patients with early HER2-positive breast cancer administered curative therapy. Brain metastases in HER2-positive breast cancer patients usually constitute the first site of recurrence. The administration of anti-HER2 monoclonal antibodies, trastuzumab and pertuzumab, considerably delays the onset of symptomatic brain disease: however, the limited penetration of these compounds into the CNS hinders their efficacy. The small-molecule tyrosine kinase inhibitors of epidermal growth factor receptors family have established activity in HER2-positive breast cancer in both advanced disease and neoadjuvant setting. Favorable physico-chemical properties of these compounds allow them for a more efficient penetration through the blood-brain barrier, and hold the promise for more effective prevention and treatment of brain metastases. In this article we review the role of currently available or investigational HER2 tyrosine kinase inhibitors: lapatinib, neratinib, afatinib and tucatinib in the treatment of brain metastases in HER2-positive breast cancer patients. Copyright © 2018 Elsevier Ltd. All rights reserved.

  17. Combination Immunotherapy for the Treatment of High-Risk HER2-Positive Breast Cancer

    Science.gov (United States)

    2017-10-01

    AWARD NUMBER: W81XWH-14-1-0109 TITLE: Combination Immunotherapy for the Treatment of High-Risk HER2-Positive Breast Cancer PRINCIPAL INVESTIGATOR...Elizabeth A. Mittendorf, MD, PhD CONTRACTING ORGANIZATION: University of Texas MD Anderson Cancer Center Houston, TX 77030 REPORT DATE: October...CONTRACT NUMBER Combination Immunotherapy for the Treatment of High-Risk HER2-Positive Breast Cancer 5b. GRANT NUMBER W81XWH-14-1-0109 5c. PROGRAM

  18. Switching addictions between HER2 and FGFR2 in HER2-positive breast tumor cells: FGFR2 as a potential target for salvage after lapatinib failure

    International Nuclear Information System (INIS)

    Azuma, Koichi; Tsurutani, Junji; Sakai, Kazuko; Kaneda, Hiroyasu; Fujisaka, Yasuhito; Takeda, Masayuki; Watatani, Masahiro; Arao, Tokuzo; Satoh, Taroh; Okamoto, Isamu; Kurata, Takayasu; Nishio, Kazuto; Nakagawa, Kazuhiko

    2011-01-01

    Highlights: → A lapatinib-resistant breast cancer cell line, UACC812 (UACC812/LR), was found to harbor amplification of the FGFR2 gene. → Inhibition of the molecule by a specific inhibitor of FGFR dramatically induced growth inhibition accompanied by cell death. → Immunohistochemical analysis of patients with HER2-positive breast cancer demonstrated an association between FGFR2 expression and poor outcome for lapatinib-containing chemotherapy. -- Abstract: Agents that target HER2 have improved the prognosis of patients with HER2-amplified breast cancers. However, patients who initially respond to such targeted therapy eventually develop resistance to the treatment. We have established a line of lapatinib-resistant breast cancer cells (UACC812/LR) by chronic exposure of HER2-amplified and lapatinib-sensitive UACC812 cells to the drug. The mechanism by which UACC812/LR acquired resistance to lapatinib was explored using comprehensive gene hybridization. The FGFR2 gene in UACC812/LR was highly amplified, accompanied by overexpression of FGFR2 and reduced expression of HER2, and a cell proliferation assay showed that the IC 50 of PD173074, a small-molecule inhibitor of FGFR tyrosine kinase, was 10,000 times lower in UACC812/LR than in the parent cells. PD173074 decreased the phosphorylation of FGFR2 and substantially induced apoptosis in UACC812/LR, but not in the parent cells. FGFR2 appeared to be a pivotal molecule for the survival of UACC812/LR as they became independent of the HER2 pathway, suggesting that a switch of addiction from the HER2 to the FGFR2 pathway enabled cancer cells to become resistant to HER2-targeted therapy. The present study is the first to implicate FGFR in the development of resistance to lapatinib in cancer, and suggests that FGFR-targeted therapy might become a promising salvage strategy after lapatinib failure in patients with HER2-positive breast cancer.

  19. Switching addictions between HER2 and FGFR2 in HER2-positive breast tumor cells: FGFR2 as a potential target for salvage after lapatinib failure

    Energy Technology Data Exchange (ETDEWEB)

    Azuma, Koichi [Department of Medical Oncology, Kinki University Faculty of Medicine, 377-2 Ohnohigashi, Osakasayama, Osaka 589-8511 (Japan); Tsurutani, Junji, E-mail: tsurutani_j@dotd.med.kindai.ac.jp [Department of Medical Oncology, Kinki University Faculty of Medicine, 377-2 Ohnohigashi, Osakasayama, Osaka 589-8511 (Japan); Sakai, Kazuko; Kaneda, Hiroyasu [Department of Genome Biology, Kinki University Faculty of Medicine, 377-2 Ohnohigashi, Osakasayama, Osaka 589-8511 (Japan); Fujisaka, Yasuhito; Takeda, Masayuki [Department of Medical Oncology, Kinki University Faculty of Medicine, 377-2 Ohnohigashi, Osakasayama, Osaka 589-8511 (Japan); Watatani, Masahiro [Department of Surgery, Kinki University Faculty of Medicine, 377-2 Ohnohigashi, Osakasayama, Osaka 589-8511 (Japan); Arao, Tokuzo [Department of Genome Biology, Kinki University Faculty of Medicine, 377-2 Ohnohigashi, Osakasayama, Osaka 589-8511 (Japan); Satoh, Taroh; Okamoto, Isamu; Kurata, Takayasu [Department of Medical Oncology, Kinki University Faculty of Medicine, 377-2 Ohnohigashi, Osakasayama, Osaka 589-8511 (Japan); Nishio, Kazuto [Department of Genome Biology, Kinki University Faculty of Medicine, 377-2 Ohnohigashi, Osakasayama, Osaka 589-8511 (Japan); Nakagawa, Kazuhiko [Department of Medical Oncology, Kinki University Faculty of Medicine, 377-2 Ohnohigashi, Osakasayama, Osaka 589-8511 (Japan)

    2011-04-01

    Highlights: {yields} A lapatinib-resistant breast cancer cell line, UACC812 (UACC812/LR), was found to harbor amplification of the FGFR2 gene. {yields} Inhibition of the molecule by a specific inhibitor of FGFR dramatically induced growth inhibition accompanied by cell death. {yields} Immunohistochemical analysis of patients with HER2-positive breast cancer demonstrated an association between FGFR2 expression and poor outcome for lapatinib-containing chemotherapy. -- Abstract: Agents that target HER2 have improved the prognosis of patients with HER2-amplified breast cancers. However, patients who initially respond to such targeted therapy eventually develop resistance to the treatment. We have established a line of lapatinib-resistant breast cancer cells (UACC812/LR) by chronic exposure of HER2-amplified and lapatinib-sensitive UACC812 cells to the drug. The mechanism by which UACC812/LR acquired resistance to lapatinib was explored using comprehensive gene hybridization. The FGFR2 gene in UACC812/LR was highly amplified, accompanied by overexpression of FGFR2 and reduced expression of HER2, and a cell proliferation assay showed that the IC{sub 50} of PD173074, a small-molecule inhibitor of FGFR tyrosine kinase, was 10,000 times lower in UACC812/LR than in the parent cells. PD173074 decreased the phosphorylation of FGFR2 and substantially induced apoptosis in UACC812/LR, but not in the parent cells. FGFR2 appeared to be a pivotal molecule for the survival of UACC812/LR as they became independent of the HER2 pathway, suggesting that a switch of addiction from the HER2 to the FGFR2 pathway enabled cancer cells to become resistant to HER2-targeted therapy. The present study is the first to implicate FGFR in the development of resistance to lapatinib in cancer, and suggests that FGFR-targeted therapy might become a promising salvage strategy after lapatinib failure in patients with HER2-positive breast cancer.

  20. Efficacy of HER2-targeted therapy in metastatic breast cancer. Monoclonal antibodies and tyrosine kinase inhibitors

    DEFF Research Database (Denmark)

    Nielsen, Dorte L; Kümler, Iben; Palshof, Jesper Andreas

    2013-01-01

    to those obtained for capecitabine plus lapatinib (48%), continuing trastuzumab in combination with capecitabine (48%), pertuzumab plus trastuzumab (24%), and neratinib (24%). Strategies combining multiple HER2-directed therapies might yield additive or synergistic effects and lead to improved outcome...

  1. Metastatic hidradenocarcinoma with demonstration of Her-2/neu gene amplification by fluorescence in situ hybridization: potential treatment implications.

    Science.gov (United States)

    Nash, Jason W; Barrett, Terry L; Kies, Merrill; Ross, Merrick I; Sneige, Nour; Diwan, A Hafeez; Lazar, Alexander J F

    2007-01-01

    A 44-year-old man was referred for a right chest nodule of 3 months duration. A 'benign' nodule had been excised from this location 8 years prior. On examination, palpable nodes were noted in the right axilla. Radiographic studies were significant only for right axillary lymphadenopathy. Histologically, a nodular dermal proliferation composed of poorly differentiated epithelioid cells in nests and focally forming ducts with pseudopapillary architecture comprised the primary tumor. Features of a clear cell hidradenoma were noted focally. Immunohistochemical (IHC) analysis revealed reactivity for HMW cytokeratins, CK5 and CK7, p53, p63, CEA (focal), androgen receptor, EGFR, estrogen receptor (ER), MUC5AC, and strong/diffuse membranous staining for Her-2/neu. Negative stains included villin, TTF-1, CDX2, S-100 protein, vimentin, gross cystic disease fluid protein 15 (GCDFP-15), mammoglobulin, and MUC2. A wide local excision and axillary node dissection was performed. Metastatic tumor involved nine of 28 nodes. Interphase fluorescence in situ hybridization (FISH) demonstrated chromosomal amplification of the Her-2/neu locus within the tumor and a nodal metastasis. The patient has completed adjuvant and radiotherapy, including trastuzumab, and is asymptomatic. We believe this to be the first demonstration of Her-2/neu amplification in a malignant skin adnexal tumor. In analogy to breast carcinoma, these findings suggest the applicability of trastuzumab for patients with metastatic adnexal carcinomas demonstrating Her-2/neu amplification.

  2. Large palpable ductal carcinoma in situ is Her-2 positive with high nuclear grade.

    Science.gov (United States)

    Monabati, Ahmad; Sokouti, Ali-Reza; Noori, Sadat Noori; Safaei, Akbar; Talei, Abd-Rasul; Omidvari, Shapoor; Azarpira, Negar

    2015-01-01

    Ductal carcinoma in situ (DCIS) of the breast is a heterogeneous group with variable clinical presentation. The exact molecular mechanism is not known why some ductal carcinomas may reach to such a large size but still remains in situ. Although, molecular classification of DCIS lesions and nuclear grading are important for identification of more aggressive lesions but it is not sufficient. Our aim was to examine the expression pattern of immunohistochemical (IHC) markers of ER, PR, HER-2 in palpable DCIS lesions and compare with clinicopathological findings. Our center is referral hospital from South of Iran. Samples were obtained from fifty four patients with a diagnosis of palpable DCIS. Equivocal (2+) case in HER-2 IHC testing was more characterized by chromogenic in situ hybridization. The positive frequency of HER2, ER, and PR was 92%, 48%, and 37% respectively. Palpable DCIS lesions were significantly more HER-2 positive (92%). The DCIS cases were more likely to be of high nuclear grade (grade III) and Her-2 positive cases were more likely to be of high nuclear grade than intermediate grade. All ER negative tumors had high nuclear grade. The Her-2 positivity is suggested as the most important factor responsible for marked in situ proliferation and production of palpable mass.

  3. PALBOCICLIB IN COMBINATION WITH HORMONE THERAPY FOR LUMINAL HER2-NEGATIVE METASTATIC BREAST CANCER: NEW HIGHLY EFFECTIVE STRATEGY OF DRUG TREATMENT

    Directory of Open Access Journals (Sweden)

    E. V. Artamonova

    2017-01-01

    Full Text Available The review considers a new oral targeted drug palbociclib and its place in treatment of luminal (estrogen receptor-positive HER2metastatic breast cancer. The results of randomized clinical trials have shown that inclusion of palbociclib in various hormone therapy regimens for treatment of HER2metastatic breast cancer with expression of estrogen receptors allows to significantly improve clinical outcomes and increase survival, objective response rate and its duration, as well as clinical benefit rate (CBR. Addition of palbociclib to letrozole in the 1st line hormone therapy or to fulvestrant in patients with progression at/after previous endocrine therapy increased progression-free survival in all groups irrespective of clinical characteristics, tumor progression, or expression of molecular markers mediating development of hormone resistance. The main adverse events associated with palbociclib were neutropenia, leukopenia and thrombocytopenia, but overall hematological toxicity was manageable, and the therapy itself was safe. This strategy received a “breakthrough therapy designation” from the experts and combines proven effectiveness and satisfactory tolerability, allows to maintain high quality of life, and should be prescribed to patients with luminal HER2metastatic breast cancer.

  4. Antitumor activity of pan-HER inhibitors in HER2-positive gastric cancer.

    Science.gov (United States)

    Yoshioka, Takahiro; Shien, Kazuhiko; Namba, Kei; Torigoe, Hidejiro; Sato, Hiroki; Tomida, Shuta; Yamamoto, Hiromasa; Asano, Hiroaki; Soh, Junichi; Tsukuda, Kazunori; Nagasaka, Takeshi; Fujiwara, Toshiyoshi; Toyooka, Shinichi

    2018-04-01

    Molecularly targeted therapy has enabled outstanding advances in cancer treatment. Whereas various anti-human epidermal growth factor receptor 2 (HER2) drugs have been developed, trastuzumab is still the only anti-HER2 drug presently available for gastric cancer. In this study, we propose novel treatment options for patients with HER2-positive gastric cancer. First, we determined the molecular profiles of 12 gastric cancer cell lines, and examined the antitumor effect of the pan-HER inhibitors afatinib and neratinib in those cell lines. Additionally, we analyzed HER2 alteration in 123 primary gastric cancers resected from Japanese patients to clarify possible candidates with the potential to respond to these drugs. In the drug sensitivity analysis, both afatinib and neratinib produced an antitumor effect in most of the HER2-amplified cell lines. However, some cells were not sensitive to the drugs. When the molecular profiles of the cells were compared based on the drug sensitivities, we found that cancer cells with lower mRNA expression levels of IGFBP7, a tumor suppressor gene that inhibits the activation of insulin-like growth factor-1 receptor (IGF-1R), were less sensitive to pan-HER inhibitors. A combination therapy consisting of pan-HER inhibitors and an IGF-1R inhibitor, picropodophyllin, showed a notable synergistic effect. Among 123 clinical samples, we found 19 cases of HER2 amplification and three cases of oncogenic mutations. In conclusion, afatinib and neratinib are promising therapeutic options for the treatment of HER2-amplified gastric cancer. In addition to HER2 amplification, IGFBP7 might be a biomarker of sensitivity to these drugs, and IGF-1R-targeting therapy can overcome drug insensitiveness in HER2-amplified gastric cancer. © 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

  5. Retrospective study of the effect of disease progression on patient reported outcomes in HER-2 negative metastatic breast cancer patients

    Directory of Open Access Journals (Sweden)

    Yu Elaine

    2011-06-01

    Full Text Available Abstract Background This retrospective study evaluated the impact of disease progression and of specific sites of metastasis on patient reported outcomes (PROs that assess symptom burden and health related quality of life (HRQoL in women with metastatic breast cancer (mBC. Methods HER-2 negative mBC patients (n = 102 were enrolled from 7 U.S. community oncology practices. Demographic, disease and treatment characteristics were abstracted from electronic medical records and linked to archived Patient Care Monitor (PCM assessments. The PCM is a self-report measure of symptom burden and HRQoL administered as part of routine care in participating practices. Linear mixed models were used to examine change in PCM scores over time. Results Mean age was 57 years, with 72% of patients Caucasian, and 25% African American. Median time from mBC diagnosis to first disease progression was 8.8 months. Metastasis to bone (60%, lung (28% and liver (26% predominated at initial metastatic diagnosis. Results showed that PCM items assessing fatigue, physical pain and trouble sleeping were sensitive to either general effects of disease progression or to effects associated with specific sites of metastasis. Progression of disease was also associated with modest but significant worsening of General Physical Symptoms, Treatment Side Effects, Acute Distress and Impaired Performance index scores. In addition, there were marked detrimental effects of liver metastasis on Treatment Side Effects, and of brain metastasis on Acute Distress. Conclusions Disease progression has a detrimental impact on cancer-related symptoms. Delaying disease progression may have a positive impact on patients' HRQoL.

  6. NatHER: protocol for systematic evaluation of trends in survival among patients with HER2-positive advanced breast cancer.

    Science.gov (United States)

    Korner, Eli J; Morris, Anne; Allen, Isabel Elaine; Hurvitz, Sara; Beattie, Mary S; Kalesan, Bindu

    2015-10-01

    Human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) is an aggressive form of breast cancer and is historically associated with poor outcomes compared with HER2-negative MBC. Since 1998, four drugs have been globally approved for the targeted treatment of HER2-positive MBC. Additional advances in patient care-such as improved breast cancer screening, HER2 testing, and supportive care-have also occurred. The objective of this systematic review and meta-analysis is to determine whether there has been a cumulative change in survival over time in patients with HER2-positive advanced breast cancer based on results from interventional clinical trials (ICTs) and observational studies and to compare outcomes across these types of studies. A systematic search of Medline, EMBASE, and the Cochrane Central Register of Controlled Trials will be performed. Two investigators will independently assess each abstract for inclusion. English language reports of ICTs and observational studies that include patients with HER2-positive advanced breast cancer from 1987 onwards will be considered. The primary outcome of interest is overall survival; secondary outcomes include progression-free survival and safety. Data on clinical outcomes, as well as on study design, study population, treatment/intervention, methodological quality, and outcomes, will be extracted using a structured codebook developed by the authors for this study. Standard and cumulative random effects meta-analysis will be performed to derive pooled risk estimates, both overall and by study design, controlling for covariates such as aggregate demographic and clinical characteristics of patients, treatment/intervention, and study characteristics. Heterogeneity of studies will be evaluated using the I(2) statistic. Differences in risk estimates by quality characteristics will be performed using meta-regression. This study will evaluate current and evolving trends in survival associated with

  7. Capecitabine and its role in the treatment of advanced HER2 positive breast cancer

    International Nuclear Information System (INIS)

    Barilla, R.; Sycova-Mila, Z.; Andrasina, I.

    2011-01-01

    Metastatic breast cancer is the leading cause of death from cancer among women worldwide. Approximately 20 % women with breast cancer that over express HER2, considered to be strong predictor for disease progression and death, are at greater risk than women whose tumors do not over express HER2. It represents an important therapeutic target in this population. We currently have 2 registered targeted drugs in this setting (trastuzumab and lapatinib) and others are being investigated in clinical trials (pertuzumab, neratinib etc.). (5, 6) The treatment of intensively pretreated breast cancer is essentially palliative with the aim of providing antitumor activity and prolonging survival but without significant deterioration in quality of life. Despite the era of targeted therapies in several cancer types with certainty we cannot omit cytotoxic chemotherapy in these patients. (author)

  8. HER2-positive male breast cancer with thyroid cancer: an institutional report and review of literature.

    Science.gov (United States)

    Bardhan, Pooja; Bui, Marilyn M; Minton, Susan; Loftus, Loretta; Carter, W Bradford; Laronga, Christine; Ismail-Khan, Roohi

    2012-01-01

    We report a rare finding of two male breast cancer patients with HER2-positive breast cancer who also developed thyroid cancer. We reviewed 45 male breast cancer patients treated in our institution from 2003 to 2008. Only five male breast cancer patients were HER2-positive. In reviewing the published data, we found no cases of thyroid cancer and concurrent breast cancer in men. However, breast cancer and thyroid cancer have shown close association in women. This finding therefore provokes speculation as to whether we should investigate whether women with HER2-positive breast cancer are at a higher risk for thyroid cancer. Although this observation seems to be clinically prevalent, publications are sparse in clinical research areas linking thyroid cancer to breast cancer.

  9. The updated network meta-analysis of neoadjuvant therapy for HER2-positive breast cancer.

    Science.gov (United States)

    Nakashoji, Ayako; Hayashida, Tetsu; Yokoe, Takamichi; Maeda, Hinako; Toyota, Tomoka; Kikuchi, Masayuki; Watanuki, Rurina; Nagayama, Aiko; Seki, Tomoko; Takahashi, Maiko; Abe, Takayuki; Kitagawa, Yuko

    2018-01-01

    We previously described a systematic assessment of the neoadjuvant therapies for human epidermal growth factor receptor-2 (HER2) positive breast cancer, using network meta-analysis. Accumulation of new clinical data has compelled us to update the analysis. Randomized trials comparing different anti-HER2 regimens in the neoadjuvant setting were included, and odds ratio for pathologic complete response (pCR) in seven treatment arms were assessed by pooling effect sizes. Direct and indirect comparisons using a Bayesian statistical model were performed. All statistical tests were two-sided. A database search identified 993 articles with 13 studies meeting the eligibility criteria, including three new studies with lapatinib (lpnb). In an indirect comparison, dual anti-HER2 agents with CT achieved a better pCR rate than other arms. The credibility intervals of CT + tzmb + lpnb arm were largely reduced compared to our former report, which we added sufficient clinical evidence by this update. Values of surface under the cumulative ranking (SUCRA) suggested that CT + tzmb + pzmb had the highest probability of being the best treatment arm for pCR, widening the difference between the top two dual-HER2 blockade arms compared to our former report. The overall consistency with our first report enhanced the credibility of the results. Network meta-analysis using new clinical data firmly establish that combining two anti-HER2 agents with CT is most effective against HER2-positive breast cancer in the neoadjuvant setting. New pzmb related trials are required to fully determine the best neoadjuvant dual-HER2 blockade regimen. Copyright © 2017 Elsevier Ltd. All rights reserved.

  10. Radiation binary targeted therapy for HER-2 positive breast cancers: assumptions, theoretical assessment and future directions

    Energy Technology Data Exchange (ETDEWEB)

    Mundy, Daniel W [School of Nuclear Engineering, Purdue University, 400 Central Drive, West Lafayette, IN 47909 (United States); Harb, Wael [Horizon Oncology, The Care Group, Unity Medical Center, Lafayette, IN 47901 (United States); Jevremovic, Tatjana [School of Nuclear Engineering, Purdue University, 400 Central Drive, West Lafayette, IN 47909 (United States)

    2006-03-21

    A novel radiation targeted therapy is investigated for HER-2 positive breast cancers. The proposed concept combines two known approaches, but never used together for the treatment of advanced, relapsed or metastasized HER-2 positive breast cancers. The proposed radiation binary targeted concept is based on the anti HER-2 monoclonal antibodies (MABs) that would be used as vehicles to transport the nontoxic agent to cancer cells. The anti HER-2 MABs have been successful in targeting HER-2 positive breast cancers with high affinity. The proposed concept would utilize a neutral nontoxic boron-10 predicting that anti HER-2 MABs would assure its selective delivery to cancer cells. MABs against HER-2 have been a widely researched strategy in the clinical setting. The most promising antibody is Trastuzumab (Herceptin (registered) ). Targeting HER-2 with the MAB Trastuzumab has been proven to be a successful strategy in inducing tumour regression and improving patient survival. Unfortunately, these tumours become resistant and afflicted women succumb to breast cancer. In the proposed concept, when the tumour region is loaded with boron-10 it is irradiated with neutrons (treatment used for head and neck cancers, melanoma and glioblastoma for over 40 years in Japan and Europe). The irradiation process takes less than an hour producing minimal side effects. This paper summarizes our recent theoretical assessments of radiation binary targeted therapy for HER-2 positive breast cancers on: the effective drug delivery mechanism, the numerical model to evaluate the targeted radiation delivery and the survey study to find the neutron facility in the world that might be capable of producing the radiation effect as needed. A novel method of drug delivery utilizing Trastuzumab is described, followed by the description of a computational Monte Carlo based breast model used to determine radiation dose distributions. The total flux and neutron energy spectra of five currently available

  11. Development of a Targeted anti-HER2 scFv Chimeric Peptide for Gene Delivery into HER2-Positive Breast Cancer Cells.

    Science.gov (United States)

    Cheraghi, Roya; Nazari, Mahboobeh; Alipour, Mohsen; Majidi, Asia; Hosseinkhani, Saman

    2016-12-30

    Chimeric polymers are known as suitable carriers for gene delivery. Certain properties are critical for a polymer to be used as a gene delivery vector. A new polymer was designed for the targeted delivery of genes into breast cancer cell lines, based on MPG peptide. It is composed of different functional domains, including HIV gp41, nuclear localization sequence of SV40 T-antigen, two C-terminus repeats of histone H1, and the scFv of anti-HER2 antibody. The results demonstrated that the vector can effectively condense plasmid DNA into nanoparticles with an average size of 250nm. Moreover, fusion of the scFv portion to the carrier brought about the specific recognition of HER2. Overall, the transfection efficiency of the vector demonstrated that it could deliver the desired gene into BT-474 HER2-positive breast cancer cells. Copyright © 2016 Elsevier B.V. All rights reserved.

  12. Prolyl isomerase Pin1 is highly expressed in Her2-positive breast cancer and regulates erbB2 protein stability

    Directory of Open Access Journals (Sweden)

    Lu Kun

    2008-12-01

    Full Text Available Abstract Overexpression of HER-2/Neu occurs in about 25–30% of breast cancer patients and is indicative of poor prognosis. While Her2/Neu overexpression is primarily a result of erbB2 amplification, it has recently been recognized that erbB2 levels are also regulated on the protein level. However, factors that regulate Her2/Neu protein stability are less well understood. The prolyl isomerase Pin1 catalyzes the isomerization of specific pSer/Thr-Pro motifs that have been phosphorylated in response to mitogenic signaling. We have previously reported that Pin1-catalyzed post-phosphorylational modification of signal transduction modulates the oncogenic pathways downstream from c-neu. The goal of this study was to examine the expression of prolyl isomerase Pin1 in human Her2+ breast cancer, and to study if Pin1 affects the expression of Her2/Neu itself. Methods Immunohistochemistry for Her2 and Pin1 were performed on two hundred twenty-three human breast cancers, with 59% of the specimen from primary cancers and 41% from metastatic sites. Pin1 inhibition was achieved using siRNA in Her2+ breast cancer cell lines, and its effects were studied using cell viability assays, immunoblotting and immunofluorescence. Results Sixty-four samples (28.7% stained positive for Her2 (IHC 3+, and 54% (122/223 of all breast cancers stained positive for Pin1. Of the Her2-positive cancers 40 (62.5% were also Pin1-positive, based on strong nuclear or nuclear and cytoplasmic staining. Inhibition of Pin1 via RNAi resulted in significant suppression of Her2-positive tumor cell growth in BT474, SKBR3 and AU565 cells. Pin1 inhibition greatly increased the sensitivity of Her2-positive breast cancer cells to the mTOR inhibitor Rapamycin, while it did not increase their sensitivity to Trastuzumab, suggesting that Pin1 might act on Her2 signaling. We found that Pin1 interacted with the protein complex that contains ubiquitinated erbB2 and that Pin1 inhibition accelerated erbB2

  13. Targeting Chromosomal Instability and Tumour Heterogeneity in HER2-Positive Breast Cancer

    DEFF Research Database (Denmark)

    Burrell, Rebecca A.; Birkbak, Nicolai Juul; Johnston, Stephen R.

    2010-01-01

    Chromosomal instability (CIN) is a common cause of tumour heterogeneity and poor prognosis in solid tumours and describes cell-cell variation in chromosome structure or number across a tumour population. In this article we consider evidence suggesting that CIN may be targeted and may influence...... response to distinct chemotherapy regimens, using HER2-positive breast cancer as an example. Pre-clinical models have indicated a role for HER2 signalling in initiating CIN and defective cell-cycle control, and evidence suggests that HER2-targeting may attenuate this process. Anthracyclines and platinum...... agents may target tumours with distinct patterns of karyotypic complexity, whereas taxanes may have preferential activity in tumours with relative chromosomal stability. A greater understanding of karyotypic complexity and identification of methods to directly examine and target CIN may support novel...

  14. Trastuzumab after Chemotherapy Is Effective in HER2-Positive Breast Cancer

    Science.gov (United States)

    Treatment with trastuzumab for 1 year following standard chemotherapy improved disease-free survival in women with HER2-positive early breast cancer, according to 4-year follow-up results of the Herceptin Adjuvant (HERA) trial reported February 25, 2011,

  15. In vivo tracking of genetically engineered, anti-HER2/neu directed natural killer cells to HER2/neu positive mammary tumors with magnetic resonance imaging

    International Nuclear Information System (INIS)

    Daldrup-Link, Heike E.; Meier, Reinhardt; Metz, Stephan; Settles, Marcus; Rummeny, Ernst J.; Rudelius, Martina; Piontek, Guido; Schlegel, Juergen; Piert, Morand; Uherek, Christoph; Wels, Winfried

    2005-01-01

    The purpose of this study is to optimize labeling of the human natural killer (NK) cell line NK-92 with iron-oxide-based contrast agents and to monitor the in vivo distribution of genetically engineered NK-92 cells, which are directed against HER2/neu receptors, to HER2/neu positive mammary tumors with magnetic resonance (MR) imaging. Parental NK-92 cells and genetically modified HER2/neu specific NK-92-scFv(FRP5)-zeta cells, expressing a chimeric antigen receptor specific to the tumor-associated ErbB2 (HER2/neu) antigen, were labeled with ferumoxides and ferucarbotran using simple incubation, lipofection and electroporation techniques. Labeling efficiency was evaluated by MR imaging, Prussian blue stains and spectrometry. Subsequently, ferucarbotran-labeled NK-92-scFv(FRP5)-zeta (n=3) or parental NK-92 cells were intravenously injected into the tail vein of six mice with HER2/neu-positive NIH 3T3 mammary tumors, implanted in the mammary fat pad. The accumulation of the cells in the tumors was monitored by MR imaging before and 12 and 24 h after cell injection (p.i.). MR data were correlated with histopathology. Both the parental NK-92 and the genetically modified NK-92-scFv(FRP5)-zeta cells could be labeled with ferucarbotran and ferumoxides by lipofection and electroporation, but not by simple incubation. The intracellular cytoplasmatic iron-oxide uptake was significantly higher after labeling with ferucarbotran than ferumoxides (P 6 NK-92-scFv(FRP5)-zeta cells into tumor-bearing mice, MR showed a progressive signal decline in HER2/neu-positive mammary tumors at 12 and 24 h (p.i.). Conversely, injection of 5 x 10 6 parental NK-92 control cells, not directed against HER2/neu receptors, did not cause significant signal intensity changes of the tumors. Histopathology confirmed an accumulation of the former, but not the latter cells in tumor tissue. The human natural killer cell line NK-92 can be efficiently labeled with clinically applicable iron-oxide contrast

  16. In vivo tracking of genetically engineered, anti-HER2/neu directed natural killer cells to HER2/neu positive mammary tumors with magnetic resonance imaging

    Energy Technology Data Exchange (ETDEWEB)

    Daldrup-Link, Heike E. [UCSF Medical Center, Department of Radiology, San Francisco, CA (United States); Meier, Reinhardt; Metz, Stephan; Settles, Marcus; Rummeny, Ernst J. [Technical University Munich, Department of Radiology, Munich (Germany); Rudelius, Martina; Piontek, Guido; Schlegel, Juergen [Technical University Munich, Institute of Pathology, Division of Neuropathology, Munich (Germany); Piert, Morand [Technical University Munich, Department of Nuclear Medicine, Munich (Germany); Uherek, Christoph; Wels, Winfried [University of Frankfurt, Georg Speyer House, Frankfurt (Germany)

    2005-01-01

    The purpose of this study is to optimize labeling of the human natural killer (NK) cell line NK-92 with iron-oxide-based contrast agents and to monitor the in vivo distribution of genetically engineered NK-92 cells, which are directed against HER2/neu receptors, to HER2/neu positive mammary tumors with magnetic resonance (MR) imaging. Parental NK-92 cells and genetically modified HER2/neu specific NK-92-scFv(FRP5)-zeta cells, expressing a chimeric antigen receptor specific to the tumor-associated ErbB2 (HER2/neu) antigen, were labeled with ferumoxides and ferucarbotran using simple incubation, lipofection and electroporation techniques. Labeling efficiency was evaluated by MR imaging, Prussian blue stains and spectrometry. Subsequently, ferucarbotran-labeled NK-92-scFv(FRP5)-zeta (n=3) or parental NK-92 cells were intravenously injected into the tail vein of six mice with HER2/neu-positive NIH 3T3 mammary tumors, implanted in the mammary fat pad. The accumulation of the cells in the tumors was monitored by MR imaging before and 12 and 24 h after cell injection (p.i.). MR data were correlated with histopathology. Both the parental NK-92 and the genetically modified NK-92-scFv(FRP5)-zeta cells could be labeled with ferucarbotran and ferumoxides by lipofection and electroporation, but not by simple incubation. The intracellular cytoplasmatic iron-oxide uptake was significantly higher after labeling with ferucarbotran than ferumoxides (P<0.05). After intravenous injection of 5 x 10{sup 6} NK-92-scFv(FRP5)-zeta cells into tumor-bearing mice, MR showed a progressive signal decline in HER2/neu-positive mammary tumors at 12 and 24 h (p.i.). Conversely, injection of 5 x 10{sup 6} parental NK-92 control cells, not directed against HER2/neu receptors, did not cause significant signal intensity changes of the tumors. Histopathology confirmed an accumulation of the former, but not the latter cells in tumor tissue. The human natural killer cell line NK-92 can be efficiently

  17. Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial.

    Science.gov (United States)

    Cristofanilli, Massimo; Turner, Nicholas C; Bondarenko, Igor; Ro, Jungsil; Im, Seock-Ah; Masuda, Norikazu; Colleoni, Marco; DeMichele, Angela; Loi, Sherene; Verma, Sunil; Iwata, Hiroji; Harbeck, Nadia; Zhang, Ke; Theall, Kathy Puyana; Jiang, Yuqiu; Bartlett, Cynthia Huang; Koehler, Maria; Slamon, Dennis

    2016-04-01

    In the PALOMA-3 study, the combination of the CDK4 and CDK6 inhibitor palbociclib and fulvestrant was associated with significant improvements in progression-free survival compared with fulvestrant plus placebo in patients with metastatic breast cancer. Identification of patients most suitable for the addition of palbociclib to endocrine therapy after tumour recurrence is crucial for treatment optimisation in metastatic breast cancer. We aimed to confirm our earlier findings with this extended follow-up and show our results for subgroup and biomarker analyses. In this multicentre, double-blind, randomised phase 3 study, women aged 18 years or older with hormone-receptor-positive, HER2-negative metastatic breast cancer that had progressed on previous endocrine therapy were stratified by sensitivity to previous hormonal therapy, menopausal status, and presence of visceral metastasis at 144 centres in 17 countries. Eligible patients-ie, any menopausal status, Eastern Cooperative Oncology Group performance status 0-1, measurable disease or bone disease only, and disease relapse or progression after previous endocrine therapy for advanced disease during treatment or within 12 months of completion of adjuvant therapy-were randomly assigned (2:1) via a centralised interactive web-based and voice-based randomisation system to receive oral palbociclib (125 mg daily for 3 weeks followed by a week off over 28-day cycles) plus 500 mg fulvestrant (intramuscular injection on days 1 and 15 of cycle 1; then on day 1 of subsequent 28-day cycles) or placebo plus fulvestrant. The primary endpoint was investigator-assessed progression-free survival. Analysis was by intention to treat. We also assessed endocrine therapy resistance by clinical parameters, quantitative hormone-receptor expression, and tumour PIK3CA mutational status in circulating DNA at baseline. This study is registered with ClinicalTrials.gov, NCT01942135. Between Oct 7, 2013, and Aug 26, 2014, 521 patients were

  18. ABO and Rh blood groups frequency in women with HER2 positive breast cancer.

    Science.gov (United States)

    Urun, Y; Utkan, G; Altundag, K; Arslan, O; Onur, H; Arslan, U Y; Kocer, M; Dogan, I; Senler, F C; Yalcin, B; Demirkazik, A; Akbulut, H; Icli, F

    2012-01-01

    The role of genetic factors in the development of cancer is widely accepted. Data on the role of ABO blood group and Rh factor in breast cancer is inconclusive. The aim of this study was to investigate the presence of a possible association between HER2 (+) breast cancer in Turkish women and ABO blood groups and Rh factor. In 294 female patients with HER2 (+) breast cancer, ABO blood groups and Rh factor were examined. The relationship of blood groups with age, menopausal status, and family history of cancer, estrogen receptor (ER), progesterone receptor (PR) and HER2 status of these patients was evaluated. Blood groups distribution of 22,821 healthy blood donors was also assessed and compared with the patients' blood groups distribution. The median patient age was 47 years (range 20-80) and 56% of the patients were premenopausal. ER and PR were positive in 50 and 60% of the patients, respectively. Overall, the ABO blood group distribution of the 294 HER2 (+) breast cancer patients was similar to that of the healthy blood donors (p=0.36). Likewise there was no correlation between blood type and ER, PR and menopausal status. Rh (-) patients had more frequent family cancer history and this difference was significant for patients with blood group B Rh (-) and O Rh (-) (p = 0.04). In the present study we didn't find any relationship between HER2 status and ABO blood group and Rh factor. However, further studies with larger number of patients are needed to establish the role (if any) of blood groups in patients with breast cancer.

  19. TNFα-Induced Mucin 4 Expression Elicits Trastuzumab Resistance in HER2-Positive Breast Cancer.

    Science.gov (United States)

    Mercogliano, María F; De Martino, Mara; Venturutti, Leandro; Rivas, Martín A; Proietti, Cecilia J; Inurrigarro, Gloria; Frahm, Isabel; Allemand, Daniel H; Deza, Ernesto Gil; Ares, Sandra; Gercovich, Felipe G; Guzmán, Pablo; Roa, Juan C; Elizalde, Patricia V; Schillaci, Roxana

    2017-02-01

    Although trastuzumab administration improved the outcome of HER2-positive breast cancer patients, resistance events hamper its clinical benefits. We demonstrated that TNFα stimulation in vitro induces trastuzumab resistance in HER2-positive breast cancer cell lines. Here, we explored the mechanism of TNFα-induced trastuzumab resistance and the therapeutic strategies to overcome it. Trastuzumab-sensitive breast cancer cells, genetically engineered to stably overexpress TNFα, and de novo trastuzumab-resistant tumors, were used to evaluate trastuzumab response and TNFα-blocking antibodies effectiveness respectively. Immunohistochemistry and antibody-dependent cell cytotoxicity (ADCC), together with siRNA strategy, were used to explore TNFα influence on the expression and function of its downstream target, mucin 4 (MUC4). The clinical relevance of MUC4 expression was studied in a cohort of 78 HER2-positive breast cancer patients treated with adjuvant trastuzumab. TNFα overexpression turned trastuzumab-sensitive cells and tumors into resistant ones. Histopathologic findings revealed mucin foci in TNFα-producing tumors. TNFα induced upregulation of MUC4 that reduced trastuzumab binding to its epitope and impaired ADCC. Silencing MUC4 enhanced trastuzumab binding, increased ADCC, and overcame trastuzumab and trastuzumab-emtansine antiproliferative effects in TNFα-overexpressing cells. Accordingly, administration of TNFα-blocking antibodies downregulated MUC4 and sensitized de novo trastuzumab-resistant breast cancer cells and tumors to trastuzumab. In HER2-positive breast cancer samples, MUC4 expression was found to be an independent predictor of poor disease-free survival (P = 0.008). We identified TNFα-induced MUC4 expression as a novel trastuzumab resistance mechanism. We propose MUC4 expression as a predictive biomarker of trastuzumab efficacy and a guide to combination therapy of TNFα-blocking antibodies with trastuzumab. Clin Cancer Res; 23(3); 636-48.

  20. Emerging technologies for HER2 testing

    NARCIS (Netherlands)

    van de Vijver, Marc

    2002-01-01

    HER2-positive status is the sole criterion for identifying patients with breast cancer for Herceptin therapy, which has known efficacy in women with metastatic breast cancer (MBC). Immunohistochemistry (IHC) and fluorescence in-situ hybridization (FISH), which measure the HER2 protein and gene,

  1. CD147 knockdown improves the antitumor efficacy of trastuzumab in HER2-positive breast cancer cells.

    Science.gov (United States)

    Xiong, Lijuan; Ding, Li; Ning, Haoyong; Wu, Chenglin; Fu, Kaifei; Wang, Yuxiao; Zhang, Yan; Liu, Yan; Zhou, Lijun

    2016-09-06

    Trastuzumab is widely used in the clinical treatment of human epidermal growth factor receptor-2 (HER2)-positive breast cancer, but the patient response rate is low. CD147 stimulates cancer cell proliferation, migration, metastasis and differentiation and is involved in chemoresistance in many types of cancer cells. Whether CD147 alters the effect of trastuzumab on HER2-positive breast cancer cells has not been previously reported. Our study confirmed that CD147 suppression enhances the effects of trastuzumab both in vitro and in vivo. CD147 suppression increased the inhibitory rate of trastuzumab and cell apoptosis in SKBR3, BT474, HCC1954 and MDA-MB453 cells compared with the controls. Furthermore, CD147 knockdown increased expression of cleaved Caspase-3/9 and poly (ADP-ribose) polymerase (PARP) and decreased both mitogen-activated protein kinase (MAPK) and Akt phosphorylation in the four cell lines. In an HCC1954 xenograft model, trastuzumab achieved greater suppression of tumor growth in the CD147-knockdown group than in the shRNA negative control (NC) group. These data indicated that enhancement of the effect of trastuzumab on HER2-positive cells following CD147 knockdown might be attributed to increased apoptosis and decreased phosphorylation of signaling proteins. CD147 may be a key protein for enhancing the clinical efficacy of trastuzumab.

  2. [Advanced luminal breast cancer (hormone receptor-positive, HER2 negative): New therapeutic options in 2015].

    Science.gov (United States)

    Vanacker, Hélène; Bally, Olivia; Kassem, Loay; Tredan, Olivier; Heudel, Pierre; Bachelot, Thomas

    2015-06-01

    Despite improvements in early detection, surgery and systemic therapy, metastatic breast cancer remains a major cause of death. Luminal type breast cancers expressing hormone estrogen receptor (ER) or progesterone (PR) and without HER2 overexpression are generally sensitive to endocrine therapy, but raise the issue of the occurrence of resistance to treatment, particularly at metastatic stage. A better understanding of hormone resistance may guide the development of new therapeutics. New strategies aim at enhancing and prolonging of endocrine sensitivity, by optimizing existing schemes, or by combining an endocrine therapy with a targeted therapies specific to hormone resistance pathways: ER signaling, PI3K/AKT/mTOR and Cyclin Dependent Kinase (CDK). Key corners of 2014 include confirmation of benefit of high dose fulvestrant, and commercialization of everolimus as the first mTOR inhibitor in this indication. Other strategies are being tested dealing with new endocrine therapies or new molecular targets such as PI3K inhibitors, insulin-like growth factor receptor (IGF-R) and histone deacetylase (HDAC) inhibitors. Coming years may be fruitful and might radically change our way to treat these patients. Copyright © 2015 Société Françise du Cancer. Publié par Elsevier Masson SAS. Tous droits réservés. Published by Elsevier Masson SAS. All rights reserved.

  3. Positive HER-2 protein expression in circulating prostate cells and micro-metastasis, resistant to androgen blockage but not diethylstilbestrol

    Directory of Open Access Journals (Sweden)

    Nigel P Murray

    2011-01-01

    Full Text Available Introduction : HER-2 expression in prostate cancer is associated with a worse prognosis and is suggested to play a role in androgen resistance. We present a study of HER-2 expression in circulating tumor cells and micrometastasis in bone marrow and the effect of androgen blockage or DES in the presence of HER-2 expressing cells. Patients and Methods : A multicenter study of men with prostate cancer, treated with surgery, radiotherapy, or observation, and with or without hormone therapy. Mononuclear cells were separated from blood and bone marrow aspirate by differential centrifugation, touch preps were made from bone marrow biopsy samples. Prostate cells were detected using anti-PSA monoclonal antibody and standard immunocytochemistry. Positive samples were processed using Herceptest® to determine HER-2 expression. After 1 year, patients were re-evaluated and the findings of HER-2 expression and PSA change compared with treatment. Results : Total 199 men participated, and 97 had a second evaluation 1 year later, frequency of HER-2 expression in circulating tumor cells and micrometastasis was 18% and 21%, respectively. There was no significant difference in HER-2 expression in the pretreatment group, after radical surgery or radiotherapy or with biochemical failure. Men with androgen blockade had a significantly higher expression of HER-2 (58% (P =0.001. Of the 97 men with a second evaluation, 56 were in the observation arm, 27 androgen blockade, and 14 DES. Use of androgen blockade or DES significantly reduced serum PSA levels in comparison with observation (P =0.001. However, there was a significant increase in HER-2 expression in patients with androgen blockade (P =0.05 en comparison with observation or DES treatment. No patient with observation or DES became HER-2 positive, en comparison 4/22 patients initially HER-2 negative became HER-2 positive with androgen blockade. Conclusions : The results suggest that HER-2 positive cells are

  4. ABP 980: promising trastuzumab biosimilar for HER2-positive breast cancer.

    Science.gov (United States)

    Paplomata, Elisavet; Nahta, Rita

    2018-03-01

    Approval of the HER2-targeted antibody trastuzumab dramatically improved outcomes for patients with HER2-positive breast cancer. Multiple trastuzumab biosimilars, including ABP 980, are in clinical development. Biosimilars are not identical to the reference biologic, but exhibit equivalence and safety in analytical and clinical studies. Areas covered: A brief introduction to trastuzumab, overview of trastuzumab biosimilars, and detailed review of ABP 980 preclinical and clinical studies are included. We searched PubMed and 2016-2017 ASCO and ESMO conference proceedings for 'ABP 980' or 'trastuzumab biosimilar'. 'ABP 980 and breast cancer' or 'trastuzumab biosimilar and breast cancer' were used to search clinicaltrials.gov for phase III trials. Analytical studies of ABP 980 pharmacokinetics (PK) or pharmacodynamics (PD), phase I studies of ABP 980 safety and PK/PD, and phase III studies of clinical efficacy vs trastuzumab are included. Expert opinion: Questions remain regarding long-term impact of biosimilars on overall healthcare costs, insurance coverage of multiple approved biosimilars, and extensive clinical safety and efficacy follow-up. By producing a competitive market, trastuzumab biosimilars are anticipated to improve access to standard of care therapies, although real-world evidence remains to be obtained. Increased global access to HER2-targeted therapy may eventually alter the landscape of breast cancer and survival rates.

  5. A phase I clinical trial of bavituximab and paclitaxel in patients with HER2 negative metastatic breast cancer

    International Nuclear Information System (INIS)

    Chalasani, Pavani; Marron, Marilyn; Roe, Denise; Clarke, Kathryn; Iannone, Maria; Livingston, Robert B; Shan, Joseph S; Stopeck, Alison T

    2015-01-01

    Bavituximab is a chimeric monoclonal antibody that targets phosphatidylserine (PS). PS is externalized on cells in the tumor microenvironment when exposed to hypoxia and/or other physiological stressors. On attaching to PS, bavituximab is thought to promote antitumor immunity through its effects on PS receptors in monocytes, and myeloid-derived suppressor cells, as well as trigger antitumor effects by inducing an antibody-dependent cellular cytotoxicity on tumor-associated endothelial cells. We conducted a phase I clinical trial of bavituximab in combination with paclitaxel in patients with HER2-negative metastatic breast cancer. Patients were treated with weekly paclitaxel (80 mg/m 2 for 3/4 weeks) and weekly bavituximab (3 mg/kg for 4/4 weeks). Correlative studies included the measurement of circulating microparticles, endothelial cells, and apoptotic tumor cells by flow cytometry. Fourteen patients with metastatic breast cancer were enrolled; all were evaluable for toxicity and 13 were evaluable for response. Treatment resulted in an overall response rate (RR) of 85% with a median progression-free survival (PFS) of 7.3 months. Bone pain, fatigue, headache, and neutropenia were the most common adverse effects. Infusion-related reactions were the most common adverse event related to bavituximab therapy. Correlative studies showed an increase in the PS-expressing apoptotic circulating tumor cells in response to bavituximab, but not with paclitaxel. No changes in the number of circulating endothelial cells or apoptotic endothelial cells were observed with therapy. Platelet and monocyte-derived microparticles decreased after initiation of bavituximab. Bavituximab in combination with paclitaxel is well tolerated for treatment of patients with metastatic breast cancer with promising results observed in terms of clinical RRs and PFS. The toxicity profile of bavituximab is notable for manageable infusion-related reactions with no evidence for increased thrombogenicity

  6. Prognostic factors of HER2-positive breast cancer patients who develop brain metastasis: a multicenter retrospective analysis.

    Science.gov (United States)

    Hayashi, Naoki; Niikura, Naoki; Masuda, Norikazu; Takashima, Seiki; Nakamura, Rikiya; Watanabe, Ken-ichi; Kanbayashi, Chizuko; Ishida, Mayumi; Hozumi, Yasuo; Tsuneizumi, Michiko; Kondo, Naoto; Naito, Yoichi; Honda, Yayoi; Matsui, Akira; Fujisawa, Tomomi; Oshitanai, Risa; Yasojima, Hiroyuki; Yamauchi, Hideko; Saji, Shigehira; Iwata, Hiroji

    2015-01-01

    The clinical course and prognostic factors of HER2-positive breast cancer patients with brain metastases are not well known because of the relatively small population. The aim of this study was to determine prognostic factors associated with HER2-positive patients who develop brain metastases. This retrospective study assessed the largest dataset to date of 432 HER2-positive patients who were diagnosed with brain metastases from 24 institutions of the Japan Clinical Oncology Group, Breast Cancer Study Group. The median age of the 432 patients was 54 years (range, 20-86 years). Of the patients, 162 patients (37.5 %) had ER-positive/HER2-positive (ER+HER2+) breast cancer, and 270 (62.5 %) had ER-negative/HER2-positive (ER-HER2+) breast cancer. The median brain metastasis-free survival period from primary breast cancer was 33.5 months in both groups. The median survival after developing brain metastasis was 16.5 and 11.5 months in the ER+HER2+ and ER-HER2+ groups, respectively, (p = 0.117). Patients with >3 brain metastases had significantly shorter overall survival in both ER+HER2+ (p developing brain metastases was not associated with survival duration after developing brain metastases (p = 0.571). However, patients treated with both trastuzumab and lapatinib after developing metastasis had significantly longer survival than patients treated with trastuzumab alone, lapatinib alone, or no HER2-targeting agent (p brain metastases, regardless of the use of trastuzumab before developing brain metastasis, treatment with both trastuzumab and lapatinib might improve survival.

  7. Patient-reported Quality of Life and Treatment Satisfaction in Patients With HR+/HER2- Advanced/Metastatic Breast Cancer.

    Science.gov (United States)

    Wood, Robert; Mitra, Debanjali; de Courcy, Jonathan; Iyer, Shrividya

    2017-08-01

    Globally, around 1.67 million new cases of breast cancer are diagnosed each year, with advanced breast cancer (ABC-Stage III) and metastatic breast cancer (MBC-Stage IV) together accounting for up to 22% of incident cases. Hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR + /HER2 - ) breast cancer comprises 66% of ABC/MBC. Understanding disease-specific health-related quality of life and patient satisfaction with treatments currently available for HR + /HER2 - ABC/MBC in clinical practice is essential for assessing potential unmet need in this patient population. Data on treatment patterns in patients with HR + /HER2 - ABC/MBC were collected from oncology practices across the United States and Europe in a cross-sectional study in a clinical practice setting, the Adelphi Real World Advanced Breast Cancer Disease Specific Programme. A subset of patients included in the study completed several self-reported tools, including the Functional Assessment of Cancer Therapy-Breast and the Cancer Therapy Satisfaction Questionnaire. Analyses were conducted using data from the overall cohort and stratified by current treatment, metastatic sites, and number of prior therapy lines. Overall, 739 patients were recruited by 173 oncologists; 83% of patients had MBC, with the balance having ABC. The majority of patients with MBC had visceral metastases without bone metastases, and similar percentages of the total study population (≈40%) were receiving chemotherapy and endocrine therapy. Patients receiving only endocrine therapy had significantly better cancer-specific quality of life than did those receiving chemotherapy. Endocrine therapy also associated with fewer concerns about side effects and higher treatment satisfaction than chemotherapy. Statistically lower scores, indicating poorer well-being, were observed in patients with both bone and visceral metastases compared with those with either bone-only or visceral-only metastases for all but the

  8. Selective anti-proliferation of HER2-positive breast cancer cells by anthocyanins identified by high-throughput screening.

    Directory of Open Access Journals (Sweden)

    Weihua Liu

    Full Text Available Overexpressed Human epidermal growth factor receptor 2 (HER2 drives the biology of 20% breast cancer and is a prediction of a poor prognosis for patients. HER2-targeted therapies significantly improve outcomes for HER2-positive patients. Traditional Chinese herbs/medicines have been used to treat breast cancer patients including HER2-positive patients in Asia for decades. Although the traditional medicines demonstrate efficacy in clinics for HER2-positive patients, the mechanism is largely unknown. In this article, we screened a 10,000 natural product library in 6 different cell lines representing breast cancer, and assessed the ability of each drug to cause cytotoxicity through a high-throughput screening approach. We have identified eight natural compounds that selectively inhibit the proliferation of HER2-positive cells. Two of the hit compounds, peonidin-3-glucoside and cyaniding-3-glucoside, are both extracts from black rice. They inhibit the phospho-HER2 and phospho-AKT and were confirmed to induce HER2-psotive breast cancer cells apoptosis both in vitro and in vivo. Peonidin-3-glucoside and cyaniding-3-glucoside treatments significantly reduced the tumor size and volume in vivo compared to the control group. There is no significant difference of antitumorgenic effects between peonidin-3-glucoside and cyaniding-3-glucoside treatments.

  9. Physician experiences and preferences in the treatment of HR+/HER2metastatic breast cancer in the United States: a physician survey

    International Nuclear Information System (INIS)

    Lin, Peggy L.; Hao, Yanni; Xie, Jipan; Li, Nanxin; Zhong, Yichen; Zhou, Zhou; Signorovitch, James E.; Wu, Eric Q.

    2015-01-01

    Sequential endocrine therapy (ET) is recommended for postmenopausal women with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2−) metastatic breast cancer (mBC) and without visceral symptoms. Chemotherapy (CT) can be considered after sequential ETs, but is associated with adverse side effects. We assessed physicians' preferences and self-reported prescribing patterns for ET and CT in the treatment of HR+/HER2− mBC at community practices in the United States. Community-based oncologists/hematologists from a nationwide online panel who treated postmenopausal women with HR+/HER2− mBC were invited to complete a survey, blinded to the identity of study sponsor. Treatment preferences were collected by treatment class of ET-based regimens versus CT and by agent for postmenopausal HR+/HER2− mBC patients after prior nonsteroidal aromatase inhibitor use in the adjuvant or mBC setting. Among 213 physicians who completed the survey, 78% were male, 71% were based in small/intermediate practices (2–9 oncologists/subspecialists), 55% had >10 years of experience, and 58% referred to the National Comprehensive Cancer Network Guidelines when treating mBC. Among first-line ETs, anastrozole was the most frequently used treatment (35%), followed by everolimus-based (EVE, 34%) and fulvestrant-based (FUL, 15%) therapy. After first-line ET, the most preferred second- and third-line treatments were ET monotherapy (48% and 39%), ET combination therapy (31% and 19%), and CT monotherapy (13% and 30%). Comparing EVE versus FUL, physicians preferred EVE in all lines but first line. Efficacy was the most important consideration for treatment choice. Physicians prescribed CT in early lines mainly because of visceral symptoms. This survey of treatment patterns for HR+/HER2− mBC in community practice suggested that after first-line ET, ET mono- or combination therapy was commonly used for the second- and third-line treatments and CT

  10. Tumour 18 F-FDG Uptake on preoperative PET/CT may predict axillary lymph node metastasis in ER-positive/HER2-negative and HER2-positive breast cancer subtypes

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Jin You; Lee, Suck Hong; Kim, Suk [Pusan National University Hospital, Pusan National University School of Medicine and Medical Research Institute, Department of Radiology, Seo-gu, Busan (Korea, Republic of); Kang, Taewoo [Pusan National University Hospital, Busan Cancer Center, Busan (Korea, Republic of); Bae, Young Tae [Pusan National University Hospital, Department of Surgery, Busan (Korea, Republic of)

    2015-04-01

    To evaluate the association between tumour FDG uptake on preoperative PET/CT and axillary lymph node metastasis (ALNM) according to breast cancer subtype. The records of 671 patients with invasive breast cancer who underwent {sup 18} F-FDG PET/CT and surgery were reviewed. Using immunohistochemistry, tumours were divided into three subtypes: oestrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative, HER2-positive, and triple-negative. Tumour FDG uptake, expressed as maximum standardized uptake value (SUV{sub max}), and clinicopathological variables were analysed. ALNM was present in 187 of 461 ER-positive/HER2-negative, 54 of 97 HER2-positive, and 38 of 113 triple-negative tumours. On multivariate analysis, high tumour SUV{sub max} (≥4.25) (P < 0.001), large tumour size (>2 cm) (P = 0.003) and presence of lymphovascular invasion (P < 0.001) were independent variables associated with ALNM. On subset analyses, tumour SUV{sub max} maintained independent significance for predicting ALNM in ER-positive/HER2-negative (adjusted odds ratio: 3.277, P < 0.001) and HER2-positive tumours (adjusted odds ratio: 14.637, P = 0.004). No association was found for triple-negative tumours (P = 0.161). Tumour SUV{sub max} may be an independent prognostic factor for ALNM in patients with invasive breast cancer, especially in ER-positive/HER2-negative and HER2-positive subtypes, but not in those with triple-negative subtype. (orig.)

  11. Trastuzumab mediates antibody-dependent cell-mediated cytotoxicity and phagocytosis to the same extent in both adjuvant and metastatic HER2/neu breast cancer patients.

    Science.gov (United States)

    Petricevic, Branka; Laengle, Johannes; Singer, Josef; Sachet, Monika; Fazekas, Judit; Steger, Guenther; Bartsch, Rupert; Jensen-Jarolim, Erika; Bergmann, Michael

    2013-12-12

    Monoclonal antibodies (mAb), such as trastuzumab are a valuable addition to breast cancer therapy. Data obtained from neoadjuvant settings revealed that antibody-dependent cell-mediated cytotoxicity (ADCC) is a major mechanism of action for the mAb trastuzumab. Conflicting results still call into question whether disease progression, prolonged treatment or concomitant chemotherapy influences ADCC and related immunological phenomena. We analyzed the activity of ADCC and antibody-dependent cell-mediated phagocytosis (ADCP) of peripheral blood mononuclear cells (PBMCs) from human epidermal growth factor receptor 2 (HER2/neu) positive breast cancer patients receiving trastuzumab therapy either in an adjuvant (n = 13) or metastatic (n = 15) setting as well as from trastuzumab treatment-naive (t-naive) HER2/neu negative patients (n = 15). PBMCs from healthy volunteers (n = 24) were used as controls. ADCC and ADCP activity was correlated with the expression of antibody binding Fc-gamma receptor (FcγR)I (CD64), FcγRII (CD32) and FcγRIII (CD16) on CD14+ (monocytes) and CD56+ (NK) cells, as well as the expression of CD107a+ (LAMP-1) on CD56+ cells and the total amount of CD4+CD25+FOXP3+ (Treg) cells. In metastatic patients, markers were correlated with progression-free survival (PFS). ADCC activity was significantly down regulated in metastatic, adjuvant and t-naive patient cohorts as compared to healthy controls. Reduced ADCC activity was inversely correlated with the expression of CD107a on CD56+ cells in adjuvant patients. ADCC and ADCP activity of the patient cohorts were similar, regardless of treatment duration or additional chemotherapy. PFS in metastatic patients inversely correlated with the number of peripheral Treg cells. The reduction of ADCC in patients as compared to healthy controls calls for adjuvant strategies, such as immune-enhancing agents, to improve the activity of trastuzumab. However, efficacy of trastuzumab-specific ADCC and ADCP appears not to

  12. Palmitate-induced ER stress increases trastuzumab sensitivity in HER2/neu-positive breast cancer cells

    International Nuclear Information System (INIS)

    Baumann, Jan; Wong, Jason; Sun, Yan; Conklin, Douglas S.

    2016-01-01

    HER2/neu-positive breast cancer cells have recently been shown to use a unique Warburg-like metabolism for survival and aggressive behavior. These cells exhibit increased fatty acid synthesis and storage compared to normal breast cells or other tumor cells. Disruption of this synthetic process results in apoptosis. Since the addition of physiological doses of exogenous palmitate induces cell death in HER2/neu-positive breast cancer cells, the pathway is likely operating at its limits in these cells. We have studied the response of HER2/neu-positive breast cancer cells to physiological concentrations of exogenous palmitate to identify lipotoxicity-associated consequences of this physiology. Since epidemiological data show that a diet rich in saturated fatty acids is negatively associated with the development of HER2/neu-positive cancer, this cellular physiology may be relevant to the etiology and treatment of the disease. We sought to identify signaling pathways that are regulated by physiological concentrations of exogenous palmitate specifically in HER2/neu-positive breast cancer cells and gain insights into the molecular mechanism and its relevance to disease prevention and treatment. Transcriptional profiling was performed to assess programs that are regulated in HER2-normal MCF7 and HER2/neu-positive SKBR3 breast cancer cells in response to exogenous palmitate. Computational analyses were used to define and predict functional relationships and identify networks that are differentially regulated in the two cell lines. These predictions were tested using reporter assays, fluorescence-based high content microscopy, flow cytometry and immunoblotting. Physiological effects were confirmed in HER2/neu-positive BT474 and HCC1569 breast cancer cell lines. Exogenous palmitate induces functionally distinct transcriptional programs in HER2/neu-positive breast cancer cells. In the lipogenic HER2/neu-positive SKBR3 cell line, palmitate induces a G2 phase cell cycle delay and

  13. Upregulation of ER signaling as an adaptive mechanism of cell survival in HER2-positive breast tumors treated with anti-HER2 therapy

    Science.gov (United States)

    Giuliano, Mario; Hu, Huizhong; Wang, Yen-Chao; Fu, Xiaoyong; Nardone, Agostina; Herrera, Sabrina; Mao, Sufeng; Contreras, Alejandro; Gutierrez, Carolina; Wang, Tao; Hilsenbeck, Susan G.; De Angelis, Carmine; Wang, Nicholas J.; Heiser, Laura M.; Gray, Joe W.; Lopez-Tarruella, Sara; Pavlick, Anne C.; Trivedi, Meghana V.; Chamness, Gary C.; Chang, Jenny C.; Osborne, C. Kent; Rimawi, Mothaffar F.; Schiff, Rachel

    2015-01-01

    Purpose To investigate the direct effect and therapeutic consequences of epidermal growth factor receptor 2 (HER2)-targeting therapy on expression of estrogen receptor (ER) and Bcl2 in preclinical models and clinical tumor samples. Experimental design Archived xenograft tumors from two preclinical models (UACC812 and MCF7/HER2-18) treated with ER and HER2-targeting therapies, and also HER2+ clinical breast cancer specimens collected in a lapatinib neoadjuvant trial (baseline and week 2 post treatment), were used. Expression levels of ER and Bcl2 were evaluated by immunohistochemistry and western blot. The effects of Bcl2 and ER inhibition, by ABT-737 and fulvestrant respectively, were tested in parental versus lapatinib-resistant UACC812 cells in vitro. Results Expression of ER and Bcl2 was significantly increased in xenograft tumors with acquired resistance to anti-HER2 therapy, compared with untreated tumors, in both preclinical models (UACC812: ER p=0.0014; Bcl2 p<0.001. MCF7/HER2-18: ER p=0.0007; Bcl2 p=0.0306). In the neoadjuvant clinical study, lapatinib treatment for two weeks was associated with parallel upregulation of ER and Bcl2 (Spearman’s coefficient: 0.70; p=0.0002). Importantly, 18% of tumors originally ER-negative (ER−) converted to ER+ upon anti-HER2 therapy. In ER−/HER2+ MCF7/HER2-18 xenografts, ER re-expression was primarily observed in tumors responding to potent combination of anti-HER2 drugs. Estrogen deprivation added to this anti-HER2 regimen significantly delayed tumor progression (p=0.018). In the UACC812 cells, fulvestrant, but not ABT-737, was able to completely inhibit anti-HER2-resistant growth (p<0.0001). Conclusion HER2 inhibition can enhance or restore ER expression with parallel Bcl2 upregulation, representing an ER-dependent survival mechanism potentially leading to anti-HER2 resistance. PMID:26015514

  14. Dual PI3K/mTOR inhibitor BEZ235 exerts extensive antitumor activity in HER2-positive gastric cancer

    International Nuclear Information System (INIS)

    Zhu, Yan; Tian, Tiantian; Zou, Jianling; Wang, Qiwei; Li, Zhongwu; Li, Yanyan; Liu, Xijuan; Dong, Bin; Li, Na; Gao, Jing; Shen, Lin

    2015-01-01

    To investigate the in vitro and in vivo antitumor activity of dual PI3K/mTOR inhibitor BEZ235 (NVP-BEZ235) in HER2-positive gastric cancer. HER2-positive breast cancer cell line (BT474), HER2-positive (NCI-N87 and SNU216), and HER2-negative (MKN45) gastric cancer cell lines were used in this study. Cell viability, cell cycle, and HER2 downstream signaling pathways were analyzed using the MTS assay, flow cytometry, and western blotting, respectively. For the in vivo experiments, HER2-positive gastric cancer patient-derived xenografts were treated with BEZ235 to assess its antitumor activity. The sensitivity of trastuzumab in BT474 cells was higher than that for NCI-N87 and SNU216 cells, which may be partially attributed to continuously active HER2 downstream signaling pathway. BEZ235 inhibited the proliferation of NCI-N87 and SNU216 cells in vitro in a dose-dependent manner by inducing the cell cycle arrest at the G1 phase. BEZ235 demonstrated greater inhibitory effects than trastuzumab, a unique targeted drug, in both the in vitro and in vivo set of experiments. Additionally, our results indicate that BEZ235 displayed some synergism with trastuzumab. BEZ235 exhibited its antitumor activity in gastric cancer by inhibiting important HER2 downstream signaling pathways, as indicated by the inhibition of phosphorylated AKT and S6. The present study has demonstrated, for the first time, the antitumor activity of BEZ235 against HER2-positive gastric cancer in patient-derived xenografts, as well its synergistic interaction with trastuzumab. These important findings can be utilized to facilitate the design of future clinical trials. The online version of this article (doi:10.1186/s12885-015-1900-y) contains supplementary material, which is available to authorized users

  15. Is progression-free survival a more relevant endpoint than overall survival in first-line HR+/HER2metastatic breast cancer?

    Directory of Open Access Journals (Sweden)

    Forsythe A

    2018-05-01

    Full Text Available Anna Forsythe,1 David Chandiwana,2 Janina Barth,3 Marroon Thabane,4 Johan Baeck,5 Anastasiya Shor,1 Gabriel Tremblay6 1Health Technology Assessment Evidence, Purple Squirrel Economics, New York, NY, USA; 2Global Value and Access, Novartis Pharmaceutical Corporation, East Hanover, NJ, USA; 3German Market Access, Novartis Pharma GmbH, Nuremberg, Germany; 4Health Policy and Patient Access, Novartis Pharmaceuticals Incorporated, Dorval, QC, Canada; 5Global Medical Affairs (Oncology Business Unit, Novartis Pharmaceutical Corporation, East Hanover, NJ, USA; 6Health Economics, Purple Squirrel Economics, New York, NY, USA Background: Hormone receptor-positive (HR+, human epidermal growth factor receptor 2- negative (HER2−, metastatic breast cancer (MBC accounts for 73% of all MBCs. Endocrine therapy (ET is the basis of first-line (1L therapy for patients with HR+/HER2− MBC. Novel therapies have demonstrated improvements in progression-free survival (PFS compared to ET. The clinical relevance of PFS is being debated, as there is no proven direct correlation with overall survival (OS benefit to date. We reviewed studies of HR+/HER2− MBC to assess PFS and other factors that influence OS and treatment response, and health-related quality of life (HRQoL. Methods: The Embase®, Medline®, and Cochrane databases were systematically searched to identify studies in adult women with HR+/HER2− MBC, published between January 2006 and January 2017, and written in English. Phase II and III randomized controlled trials (RCTs, observational, and retrospective studies were included. Results: Seventy-nine RCTs were identified: 58 (73% in the 1L+ setting and 21 (27% in second-line or greater settings. PFS hazard ratios (HRs were reported in 61 (77% studies; 31 (39% reported significant PFS improvements. OS was reported in 44 (41% studies; 12 (15% reported significant OS improvements. Significant improvements in both PFS and OS were reported in only 6 (8% studies

  16. Preference for subcutaneous or intravenous administration of trastuzumab in patients with HER2-positive early breast cancer (PrefHer)

    DEFF Research Database (Denmark)

    Pivot, Xavier; Gligorov, Joseph; Müller, Volkmar

    2013-01-01

    Subcutaneous trastuzumab has shown non-inferior efficacy and a similar pharmacokinetic and safety profile when compared with intravenous trastuzumab in patients with HER2-positive early breast cancer. We assessed patient preference for either subcutaneous or intravenous trastuzumab...

  17. CPT-11/bevacizumab for the treatment of refractory brain metastases in patients with HER2-neu-positive breast cancer.

    Science.gov (United States)

    Sengupta, S; Rojas, R; Mahadevan, A; Kasper, E; Jeyapalan, S

    2015-04-01

    Nervous system relapse of patients with advanced HER2-neu-positive breast cancer is an increasing problem, with one-third of women developing brain metastases. Standard therapies using steroids, surgery and radiotherapy do not provide a lasting response. We evaluated CPT-11 and bevacizumab, which can both cross the blood-brain barrier, as combination therapy to treat HER2-neu-positive breast cancer with brain metastases.

  18. Progression-free survival/time to progression as a potential surrogate for overall survival in HR+, HER2metastatic breast cancer

    Directory of Open Access Journals (Sweden)

    Forsythe A

    2018-05-01

    Full Text Available Anna Forsythe,1 David Chandiwana,2 Janina Barth,3 Marroon Thabane,4 Johan Baeck,2 Gabriel Tremblay1 1Purple Squirrel Economics, New York, NY, 2Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA; 3Novartis Pharma GmbH, Nuremberg, Germany; 4Novartis Pharmaceuticals Incorporated, Dorval, QC, Canada Background: Several recent randomized controlled trials (RCTs in hormone receptor-positive (HR+, human epidermal growth factor receptor 2-negative (HER2metastatic breast cancer (MBC have demonstrated significant improvements in progression-free survival (PFS; however, few have reported improvement in overall survival (OS. The surrogacy of PFS or time to progression (TTP for OS has not been formally investigated in HR+, HER2– MBC.Methods: A systematic literature review of RCTs in HR+, HER2– MBC was conducted to identify studies that reported both median PFS/TTP and OS. The correlation between PFS/TTP and OS was evaluated using Pearson’s product–moment correlation and Spearman’s rank correlation. Subgroup analyses were performed to explore possible reasons for heterogeneity. Errors-in-variables weighted least squares regression (LSR was used to model incremental OS months as a function of incremental PFS/TTP months. An exploratory analysis investigated the impact of three covariates (chemotherapy vs hormonal/targeted therapy, PFS vs TTP, and first-line therapy vs second-line therapy or greater on OS prediction. The lower 95% prediction band was used to determine the minimum incremental PFS/TTP months required to predict OS benefit (surrogate threshold effect [STE].Results: Forty studies were identified. There was a statistically significant correlation between median PFS/TTP and OS (Pearson =0.741, P=0.000; Spearman =0.650, P=0.000. These results proved consistent for chemotherapy and hormonal/targeted therapy. Univariate LSR analysis yielded an R2 of 0.354 with 1 incremental PFS/TTP month corresponding to 1.13 incremental OS months

  19. Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer.

    Science.gov (United States)

    Vogel, Charles L; Cobleigh, Melody A; Tripathy, Debu; Gutheil, John C; Harris, Lyndsay N; Fehrenbacher, Louis; Slamon, Dennis J; Murphy, Maureen; Novotny, William F; Burchmore, Michael; Shak, Steven; Stewart, Stanford J; Press, Michael

    2002-02-01

    To evaluate the efficacy and safety of first-line, single-agent trastuzumab in women with HER2-overexpressing metastatic breast cancer. One hundred fourteen women with HER2-overexpressing metastatic breast cancer were randomized to receive first-line treatment with trastuzumab 4 mg/kg loading dose, followed by 2 mg/kg weekly, or a higher 8 mg/kg loading dose, followed by 4 mg/kg weekly. The objective response rate was 26% (95% confidence interval [CI], 18.2% to 34.4%), with seven complete and 23 partial responses. Response rates in 111 assessable patients with 3+ and 2+ HER2 overexpression by immunohistochemistry (IHC) were 35% (95% CI, 24.4% to 44.7%) and none (95% CI, 0% to 15.5%), respectively. The clinical benefit rates in assessable patients with 3+ and 2+ HER2 overexpression were 48% and 7%, respectively. The response rates in 108 assessable patients with and without HER2 gene amplification by fluorescence in situ hybridization (FISH) analysis were 34% (95% CI, 23.9% to 45.7%) and 7% (95% CI, 0.8% to 22.8%), respectively. Seventeen (57%) of 30 patients with an objective response and 22 (51%) of 43 patients with clinical benefit had not experienced disease progression at follow-up at 12 months or later. The most common treatment-related adverse events were chills (25% of patients), asthenia (23%), fever (22%), pain (18%), and nausea (14%). Cardiac dysfunction occurred in two patients (2%); both had histories of cardiac disease and did not require additional intervention after discontinuation of trastuzumab. There was no clear evidence of a dose-response relationship for response, survival, or adverse events. Single-agent trastuzumab is active and well tolerated as first-line treatment of women with metastatic breast cancer with HER2 3+ overexpression by IHC or gene amplification by FISH.

  20. mRNA profiling reveals determinants of trastuzumab efficiency in HER2-positive breast cancer.

    Directory of Open Access Journals (Sweden)

    Silvia von der Heyde

    Full Text Available Intrinsic and acquired resistance to the monoclonal antibody drug trastuzumab is a major problem in the treatment of HER2-positive breast cancer. A deeper understanding of the underlying mechanisms could help to develop new agents. Our intention was to detect genes and single nucleotide polymorphisms (SNPs affecting trastuzumab efficiency in cell culture. Three HER2-positive breast cancer cell lines with different resistance phenotypes were analyzed. We chose BT474 as model of trastuzumab sensitivity, HCC1954 as model of intrinsic resistance, and BTR50, derived from BT474, as model of acquired resistance. Based on RNA-Seq data, we performed differential expression analyses on these cell lines with and without trastuzumab treatment. Differentially expressed genes between the resistant cell lines and BT474 are expected to contribute to resistance. Differentially expressed genes between untreated and trastuzumab treated BT474 are expected to contribute to drug efficacy. To exclude false positives from the candidate gene set, we removed genes that were also differentially expressed between untreated and trastuzumab treated BTR50. We further searched for SNPs in the untreated cell lines which could contribute to trastuzumab resistance. The analysis resulted in 54 differentially expressed candidate genes that might be connected to trastuzumab efficiency. 90% of 40 selected candidates were validated by RT-qPCR. ALPP, CALCOCO1, CAV1, CYP1A2 and IGFBP3 were significantly higher expressed in the trastuzumab treated than in the untreated BT474 cell line. GDF15, IL8, LCN2, PTGS2 and 20 other genes were significantly higher expressed in HCC1954 than in BT474, while NCAM2, COLEC12, AFF3, TFF3, NRCAM, GREB1 and TFF1 were significantly lower expressed. Additionally, we inferred SNPs in HCC1954 for CAV1, PTGS2, IL8 and IGFBP3. The latter also had a variation in BTR50. 20% of the validated subset have already been mentioned in literature. For half of them we

  1. Tumor containing fragment number influences immunohistochemistry positive rate of HER2 in biopsy specimens of gastric cancer.

    Science.gov (United States)

    Xu, Chen; Liu, Yalan; Ge, Xiaowen; Jiang, Dongxian; Zhang, Ying; Ji, Yuan; Hou, Jun; Huang, Jie; Su, Jieakesu; Zeng, Haiying; Qin, Jing; Hou, Yingyong

    2017-05-26

    HER2 assessment in biopsy specimens of gastric cancer (GC) is challenging because of the intratumoral heterogeneity. False negative results may be get because of limited biopsy material. The aim of this study is to explore how tumor-containing fragment number and biopsy specimen number affect HER2 immunohistochemistry (IHC) positive rate. Eight hundred and ninety biopsy specimens and 459 paired resected specimens were collected. IHC staining of HER2 was performed. HER2 IHC positive (scored 3+) rate was compared based on tumor-containing fragment number, biopsy specimen number, average size and tumor tissue proportion of tumor-containing fragments. The positive predictability of biopsy specimens to resected specimens was analyzed based on tumor fragment number. HER2 IHC positive rates were 2.0, 3.5, 7.0, 13.2, 17.1, and 15.9% when tumor fragment numbers were 1, 2, 3, 4, 5 and 6 respectively. The rate rose with the increase of tumor fragment number (P = 0.004). ROC curve analysis showed that biopsy specimens exhibited positive predictability when tumor fragment number reached 3, but showed better performance when the number was ≥4 (P fragment number reached 4, no statistic differences were reached in either HER2 IHC positive rate or positive predictability with further increase of the number (P > 0.05). HER2 IHC positive rate was not associated with biopsy number (P = 0.127), average size of tumor fragments (P = 0.397), and tumor tissue proportion of tumor fragments (P = 0.825) directly. The number of tumor-containing fragments influences HER2 IHC positive (scored 3+) rate. Greater than or equal to 4 (≥4) tumor fragments give better results in the positive rate as well as positive predictability. We recommend the number of tumor containing fragments be described in the HER2 IHC pathology reports for clinical reference in endoscopic biopsy specimens of GC.

  2. Efficacy of weekly trastuzumab and paclitaxel in the treatment of women with HER-2/neu overexpressing metastatic breast cancer. The impact of taxane free interval on treatment outcomes

    International Nuclear Information System (INIS)

    Janku, P.; Petruzelka, L.; Pribylova, O.; Honova, H.; Pecen, L.; Zimovjanova, M.; Pazdrova, G.; Safanda, M.; Konopasek, B.; Zemanova, M.; Vedralova, J.

    2002-01-01

    Purpose. Trastuzumab is known as an active agent in HER2/neu overexpressing metastatic breast cancer. In the prospective study we investigated efficacy, safety and toxicity of trastuzumab and paclitaxel in metastatic breast cancer progressing on previous therapy. Patients and methods. We accrued 17 patients with histologically confirmed breast cancer, Karnofsky performance status at least 60 %, median age 50 (36-66), pretreated with at least two regimens. HER-2/neu expression was tested by HercepTest (r) (DAKO) in all 17 patients. Fifteen specimens were 3+ positive and 2 specimens 2+ positive. All patients except one were pretreated with taxanes. Taxane free interval (TFI) was defined as a time from last taxane administration until the beginning of the study for every enrolled patient. TFI longer than 1 year was found in 7 patients. TFI shorter than 1 year was observed in 9 patients. Trastuzumab was given 4 mg/kg i.v. as a loading dose followed by 2 mg/kg i.v. weekly. Paclitaxel was given 80 mg/m 2 i.v. weekly until disease progression or unacceptable toxicity. We assessed the response rate (RR), the time to progression (TTP), the survival (OS) and toxicity. Results. In the intent to treat population we found objective response in 10 patients (59 %), including 2 complete responses (CR). In the subset with TFI > 1 year we observed response in 4 cases including 1 CR (RR 57 %). In TFI ≤ 1 year subgroup we observed response in 6 cases also with 1 CR (RR 67 %). TFI was not statistically significant for response (p 1 year tend to have longer TTP (p = 0,0201). Median OS has not been reached with 10 patients surviving. We administered 599 cycles including 473 cycles of trastuzumab and paclitaxel with no dose adjustment. One patient developed hypersensitivity reaction on the first trastuzumab infusion and was excluded from study. The most common toxicity was trastuzumab infusion related pyretic reaction observed in 6 patients. Dose limiting adverse effect which led to the

  3. Nuclear HER4 mediates acquired resistance to trastuzumab and is associated with poor outcome in HER2 positive breast cancer

    Science.gov (United States)

    Nafi, Siti Norasikin Mohd; Generali, Daniele; Kramer-Marek, Gabriela; Gijsen, Merel; Strina, Carla; Cappelletti, Mariarosa; Andreis, Daniele; Haider, Syed; Li, Ji-Liang; Bridges, Esther; Capala, Jacek; Ioannis, Roxanis; Harris, Adrian L; Kong, Anthony

    2014-01-01

    The role of HER4 in breast cancer is controversial and its role in relation to trastuzumab resistance remains unclear. We showed that trastuzumab treatment and its acquired resistance induced HER4 upregulation, cleavage and nuclear translocation. However, knockdown of HER4 by specific siRNAs increased trastuzumab sensitivity and reversed its resistance in HER2 positive breast cancer cells. Preventing HER4 cleavage by a γ-secretase inhibitor and inhibiting HER4 tyrosine kinase activity by neratinib decreased trastuzumab-induced HER4 nuclear translocation and enhanced trastuzumab response. There was also increased nuclear HER4 staining in the tumours from BT474 xenograft mice and human patients treated with trastuzumab. Furthermore, nuclear HER4 predicted poor clinical response to trastuzumab monotherapy in patients undergoing a window study and was shown to be an independent poor prognostic factor in HER2 positive breast cancer. Our data suggest that HER4 plays a key role in relation to trastuzumab resistance in HER2 positive breast cancer. Therefore, our study provides novel findings that HER4 activation, cleavage and nuclear translocation influence trastuzumab sensitivity and resistance in HER2 positive breast cancer. Nuclear HER4 could be a potential prognostic and predictive biomarker and understanding the role of HER4 may provide strategies to overcome trastuzumab resistance in HER2 positive breast cancer. PMID:25153719

  4. COX-2 activation is associated with Akt phosphorylation and poor survival in ER-negative, HER2-positive breast cancer

    International Nuclear Information System (INIS)

    Glynn, Sharon A; Ambs, Stefan; Prueitt, Robyn L; Ridnour, Lisa A; Boersma, Brenda J; Dorsey, Tiffany M; Wink, David A; Goodman, Julie E; Yfantis, Harris G; Lee, Dong H

    2010-01-01

    Inducible cyclooxgenase-2 (COX-2) is commonly overexpressed in breast tumors and is a target for cancer therapy. Here, we studied the association of COX-2 with breast cancer survival and how this association is influenced by tumor estrogen and HER2 receptor status and Akt pathway activation. Tumor COX-2, HER2 and estrogen receptor α (ER) expression and phosphorylation of Akt, BAD, and caspase-9 were analyzed immunohistochemically in 248 cases of breast cancer. Spearman's correlation and multivariable logistic regression analyses were used to examine the relationship between COX-2 and tumor characteristics. Kaplan-Meier survival and multivariable Cox proportional hazards regression analyses were used to examine the relationship between COX-2 and disease-specific survival. COX-2 was significantly associated with breast cancer outcome in ER-negative [Hazard ratio (HR) = 2.72; 95% confidence interval (CI), 1.36-5.41; comparing high versus low COX-2] and HER2 overexpressing breast cancer (HR = 2.84; 95% CI, 1.07-7.52). However, the hazard of poor survival associated with increased COX-2 was highest among patients who were both ER-negative and HER2-positive (HR = 5.95; 95% CI, 1.01-34.9). Notably, COX-2 expression in the ER-negative and HER2-positive tumors correlated significantly with increased phosphorylation of Akt and of the two Akt targets, BAD at Ser136 and caspase-9 at Ser196. Up-regulation of COX-2 in ER-negative and HER2-positive breast tumors is associated with Akt pathway activation and is a marker of poor outcome. The findings suggest that COX-2-specific inhibitors and inhibitors of the Akt pathway may act synergistically as anticancer drugs in the ER-negative and HER2-positive breast cancer subtype

  5. Antiproliferative effects of γ-tocotrienol are associated with lipid raft disruption in HER2-positive human breast cancer cells.

    Science.gov (United States)

    Alawin, Osama A; Ahmed, Rayan A; Ibrahim, Baher A; Briski, Karen P; Sylvester, Paul W

    2016-01-01

    A large percentage of human breast cancers are characterized by excessive or aberrant HER2 activity. Lipid rafts are specialized microdomains within the plasma membrane that are required for HER2 activation and signal transduction. Since the anticancer activity of γ-tocotrienol is associated with suppression in HER2 signaling, studies were conducted to examine the effects of γ-tocotrienol on HER2 activation within the lipid raft microdomain in HER2-positive SKBR3 and BT474 human breast cancer cells. Treatment with 0-5μM γ-tocotrienol induced a significant dose-dependent inhibition in cancer cell growth after a 5-day culture period, and these growth inhibitory effects were associated with a reduction in HER2 dimerization and phosphorylation (activation). Phosphorylated HER2 was found to be primarily located in the lipid raft microdomain of the plasma membrane in vehicle-treated control groups, whereas γ-tocotrienol treatment significantly inhibited this effect. Assay of plasma membrane subcellular fractions showed that γ-tocotrienol also accumulates exclusively within the lipid raft microdomain. Hydroxypropyl-β-cyclodextrin (HPβCD) is an agent that disrupts lipid raft integrity. Acute exposure to 3mM HPβCD alone had no effect, whereas an acute 24-h exposure to 20μM γ-tocotrienol alone significantly decreased SKBR3 and BT474 cell viability. However, combined treatment with these agents greatly reduced γ-tocotrienol accumulation in the lipid raft microdomain and cytotoxicity. In summary, these findings demonstrate that the anticancer effects of γ-tocotrienol are associated with its accumulation in the lipid raft microdomain and subsequent interference with HER2 dimerization and activation in SKBR3 and BT474 human breast cancer cells. Copyright © 2015 Elsevier Inc. All rights reserved.

  6. Intrinsic Subtype and Therapeutic Response Among HER2-Positive Breast Tumors from the NCCTG (Alliance) N9831 Trial

    Science.gov (United States)

    Perez, Edith A.; Ballman, Karla V.; Mashadi-Hossein, Afshin; Tenner, Kathleen S.; Kachergus, Jennifer M.; Norton, Nadine; Necela, Brian M.; Carr, Jennifer M.; Ferree, Sean; Perou, Charles M.; Baehner, Frederick; Cheang, Maggie Chon U.

    2017-01-01

    Background: Genomic data from human epidermal growth factor receptor 2–positive (HER2+) tumors were analyzed to assess the association between intrinsic subtype and clinical outcome in a large, well-annotated patient cohort. Methods: Samples from the NCCTG (Alliance) N9831 trial were analyzed using the Prosigna algorithm on the NanoString platform to define intrinsic subtype, risk of recurrence scores, and risk categories for 1392 HER2+ tumors. Subtypes were evaluated for recurrence-free survival (RFS) using Kaplan-Meier and Cox model analysis following adjuvant chemotherapy (n = 484) or chemotherapy plus trastuzumab (n = 908). All statistical tests were two-sided. Results: Patients with HER2+ tumors from N9831 were primarily scored as HER2-enriched (72.1%). These individuals received statistically significant benefit from trastuzumab (hazard ratio [HR] = 0.68, 95% confidence interval [CI] = 0.52 to 0.89, P = .005), as did the patients (291 of 1392) with luminal-type tumors (HR = 0.52, 95% CI = 0.32 to 0.85, P = .01). Patients with basal-like tumors (97 of 1392) did not have statistically significantly better RFS when treated with trastuzumab and chemotherapy compared with chemotherapy alone (HR = 1.06, 95% CI = 0.53 to 2.13, P = .87). Conclusions: The majority of clinically defined HER2-positive tumors were classified as HER2-enriched or luminal using the Prosigna algorithm. Intrinsic subtype alone cannot replace conventional histopathological evaluation of HER2 status because many tumors that are classified as luminal A or luminal B will benefit from adjuvant trastuzumab if that subtype is accompanied by HER2 overexpression. However, among tumors that overexpress HER2, we speculate that assessment of intrinsic subtype may influence treatment, particularly with respect to evaluating alternative therapeutic approaches for that subset of HER2-positive tumors of the basal-like subtype. PMID:27794124

  7. Intrinsic Subtype and Therapeutic Response Among HER2-Positive Breaty st Tumors from the NCCTG (Alliance) N9831 Trial.

    Science.gov (United States)

    Perez, Edith A; Ballman, Karla V; Mashadi-Hossein, Afshin; Tenner, Kathleen S; Kachergus, Jennifer M; Norton, Nadine; Necela, Brian M; Carr, Jennifer M; Ferree, Sean; Perou, Charles M; Baehner, Frederick; Cheang, Maggie Chon U; Thompson, E Aubrey

    2017-02-01

    Genomic data from human epidermal growth factor receptor 2-positive (HER2+) tumors were analyzed to assess the association between intrinsic subtype and clinical outcome in a large, well-annotated patient cohort. Samples from the NCCTG (Alliance) N9831 trial were analyzed using the Prosigna algorithm on the NanoString platform to define intrinsic subtype, risk of recurrence scores, and risk categories for 1392 HER2+ tumors. Subtypes were evaluated for recurrence-free survival (RFS) using Kaplan-Meier and Cox model analysis following adjuvant chemotherapy (n = 484) or chemotherapy plus trastuzumab (n = 908). All statistical tests were two-sided. Patients with HER2+ tumors from N9831 were primarily scored as HER2-enriched (72.1%). These individuals received statistically significant benefit from trastuzumab (hazard ratio [HR] = 0.68, 95% confidence interval [CI] = 0.52 to 0.89, P = .005), as did the patients (291 of 1392) with luminal-type tumors (HR = 0.52, 95% CI = 0.32 to 0.85, P = .01). Patients with basal-like tumors (97 of 1392) did not have statistically significantly better RFS when treated with trastuzumab and chemotherapy compared with chemotherapy alone (HR = 1.06, 95% CI = 0.53 to 2.13, P = .87). The majority of clinically defined HER2-positive tumors were classified as HER2-enriched or luminal using the Prosigna algorithm. Intrinsic subtype alone cannot replace conventional histopathological evaluation of HER2 status because many tumors that are classified as luminal A or luminal B will benefit from adjuvant trastuzumab if that subtype is accompanied by HER2 overexpression. However, among tumors that overexpress HER2, we speculate that assessment of intrinsic subtype may influence treatment, particularly with respect to evaluating alternative therapeutic approaches for that subset of HER2-positive tumors of the basal-like subtype. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions

  8. HER2-positive breast cancer, how far away from the cure?-on the current situation of anti-HER2 therapy in breast cancer treatment and survival of patients.

    Science.gov (United States)

    Liao, Ning

    2016-06-01

    With the diagnosis and treatment of tumor enter into the area of precision medical, based on selected targeted molecular typing of patients with individualized diagnosis and treatment play an important role. HER gene encoded epidermal growth factor receptor 2 (HER2) leading to increased early distant metastasis of breast cancer in patients and poor prognosis. However, a number of clinical studies provided evidence-based anti-HER2 targeted therapy and confirmed the benefit of anti-HER2 targeted therapy in patient survival. In recent years, through the tireless efforts of scholars in the field of breast cancer in our country, the whole diagnosis and treatment of breast cancer has accomplished an international standard. But based on a variety of factors, the anti-HER2 targeted therapy between China and the developed countries, and between different areas in China still exists certain gaps, is now a problem need to be solved. This article will analyzing the diagnostic and treatment on HER2-positive breast cancer in the United States and China, exploring reasons and looking for answers to narrow down the gap in the treatment of HER2-positive breast cancer between China and the United States. Improve the anti-HER2 targeted therapy in our country, let the patients get maximum benefit from anti-HER2 targeted therapy.

  9. Prognostic Impact of VEGFA Germline Polymorphisms in Patients with HER2-positive Primary Breast Cancer

    DEFF Research Database (Denmark)

    Maae, Else; Andersen, Rikke Fredslund; Dahl Steffensen, Karina

    2012-01-01

    Background: Vascular endothelial growth factor A (VEGFA) is essential in tumour angiogenesis, and polymorphisms in the VEGFA gene have been associated with breast cancer prognosis. The human epidermal growth factor receptor 2 (HER2) is overexpressed in breast tumours and is also associated with a...

  10. [{sup 177}Lu]pertuzumab: experimental studies on targeting of HER-2 positive tumour cells

    Energy Technology Data Exchange (ETDEWEB)

    Persson, Mikael; Gedda, Lars [Uppsala University, Biomedical Radiation Sciences, Rudbeck Laboratory, Uppsala (Sweden); Uppsala University, Experimental Urology, Rudbeck Laboratory, Uppsala (Sweden); Tolmachev, Vladimir; Andersson, Karl; Carlsson, Joergen [Uppsala University, Biomedical Radiation Sciences, Rudbeck Laboratory, Uppsala (Sweden); Sandstroem, Mattias [Uppsala University, Medical Radiation Physics, Uppsala University Hospital, Uppsala (Sweden)

    2005-12-01

    The new antibody pertuzumab (Omnitarg) targets the dimerisation subdomain of HER-2. The purpose of this study was to analyse whether pertuzumab retains HER-2 targeting capacity after labelling with the therapeutically interesting beta emitter {sup 177}Lu and to make initial characterisations in vitro and in vivo. Pertuzumab was conjugated with isothiocyanate-benzyl-CHX-A{sup ''}-DTPA and chelated to {sup 177}Lu. Immunoreactivity, affinity, cellular retention and internalisation were analysed using SKOV-3 cells. The affinity of non-radioactive pertuzumab was measured using a surface plasmon resonance biosensor. In vivo targeting and specific binding were assessed in Balb/c (nu/nu) mice carrying SKOV-3 xenografts. The biodistribution of {sup 177}Lu was determined 1, 3 and 7 days after [{sup 177}Lu]pertuzumab administration. Gamma camera images were taken after 3 days. The immunoreactivity of [{sup 177}Lu]pertuzumab was 85.8{+-}1.3%. The affinity of non-radioactive pertuzumab was 1.8{+-}1.1 nM, and that of [{sup 177}Lu]pertuzumab, 4.1{+-}0.7 nM. The cellular retention after 5 h pre-incubation was 90{+-}2% at 20 h. The targeting was HER-2 specific both in vitro and in vivo, since excess amounts of non-labelled antibody inhibited the uptake of labelled antibody (p<0.0001 and p<0.01, respectively). The biodistribution and gamma camera images of {sup 177}Lu showed extensive tumour uptake. Normal tissues had a surprisingly low uptake. Pertuzumab was efficiently labelled with {sup 177}Lu and showed good intracellular retention and HER-2 specific binding both in vitro and in vivo. The gamma camera images and the biodistribution study gave excellent tumour targeting results. Thus, [{sup 177}Lu]pertuzumab is of interest for further studies aimed at radionuclide therapy. (orig.)

  11. 2 years versus 1 year of adjuvant trastuzumab for HER2-positive breast cancer (HERA)

    DEFF Research Database (Denmark)

    Goldhirsch, Aron; Gelber, Richard D; Piccart-Gebhart, Martine J

    2013-01-01

    Trastuzumab has established efficacy against breast cancer with overexpression or amplification of the HER2 oncogene. The standard of care is 1 year of adjuvant trastuzumab, but the optimum duration of treatment is unknown. We compared 2 years of treatment with trastuzumab with 1 year of treatment......, and updated the comparison of 1 year of trastuzumab versus observation at a median follow-up of 8 years, for patients enrolled in the HERceptin Adjuvant (HERA) trial....

  12. A gene expression signature of Retinoblastoma loss-of-function predicts resistance to neoadjuvant chemotherapy in ER-positive/HER2-positive breast cancer patients.

    Science.gov (United States)

    Risi, Emanuela; Grilli, Andrea; Migliaccio, Ilenia; Biagioni, Chiara; McCartney, Amelia; Guarducci, Cristina; Bonechi, Martina; Benelli, Matteo; Vitale, Stefania; Biganzoli, Laura; Bicciato, Silvio; Di Leo, Angelo; Malorni, Luca

    2018-07-01

    HER2-positive (HER2+) breast cancers show heterogeneous response to chemotherapy, with the ER-positive (ER+) subgroup deriving less benefit. Loss of retinoblastoma tumor suppressor gene (RB1) function has been suggested as a cardinal feature of breast cancers that are more sensitive to chemotherapy and conversely resistant to CDK4/6 inhibitors. We performed a retrospective analysis exploring RBsig, a gene signature of RB loss, as a potential predictive marker of response to neoadjuvant chemotherapy in ER+/HER2+ breast cancer patients. We selected clinical trials of neoadjuvant chemotherapy ± anti-HER2 therapy in HER2+ breast cancer patients with available information on gene expression data, hormone receptor status, and pathological complete response (pCR) rates. RBsig expression was computed in silico and correlated with pCR. Ten studies fulfilled the inclusion criteria and were included in the analysis (514 patients). Overall, of 211 ER+/HER2+ breast cancer patients, 49 achieved pCR (23%). The pCR rate following chemotherapy ± anti-HER2 drugs in patients with RBsig low expression was significantly lower compared to patients with RBsig high expression (16% vs. 30%, respectively; Fisher's exact test p = 0.015). The area under the ROC curve (AUC) was 0.62 (p = 0.005). In the 303 ER-negative (ER-)/HER2+ patients treated with chemotherapy ± anti-HER2 drugs, the pCR rate was 43%. No correlation was found between RBsig expression and pCR rate in this group. Low expression of RBsig identifies a subset of ER+/HER2+ patients with low pCR rates following neoadjuvant chemotherapy ± anti-HER2 therapy. These patients may potentially be spared chemotherapy in favor of anti-HER2, endocrine therapy, and CDK 4/6 inhibitor combinations.

  13. Assessing the real-world cost-effectiveness of adjuvant trastuzumab in HER-2/neu positive breast cancer.

    LENUS (Irish Health Repository)

    Hedden, Lindsay

    2012-01-01

    Among women with surgically removed, high-risk HER-2\\/neu-positive breast cancer, trastuzumab has demonstrated significant improvements in disease-free and overall survival. The objective of this study is to evaluate the cost-effectiveness of the currently recommended 12-month adjuvant protocol of trastuzumab using a Markov modeling approach and real-world cost data.

  14. Survival is associated with complete response on MRI after neoadjuvant chemotherapy in ER-positive HER2-negative breast cancer

    NARCIS (Netherlands)

    Loo, Claudette E; Rigter, Lisanne S; Pengel, Kenneth E; Wesseling, Jelle; Rodenhuis, Sjoerd; Peeters, Marie-Jeanne T F D Vrancken; Sikorska, Karolina; Gilhuijs, Kenneth G A

    2016-01-01

    BACKGROUND: Pathological complete remission (pCR) of estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer is rarely achieved after neoadjuvant chemotherapy (NAC). In addition, the prognostic value of pCR for this breast cancer subtype is limited. We

  15. Sanctuary site leptomeningeal metastases in HER-2 positive breast cancer: A review in the era of trastuzumab.

    Science.gov (United States)

    Kordbacheh, T; Law, W Y; Smith, I E

    2016-04-01

    The development of trastuzumab and other targeted systemic therapies has transformed the management of HER-2 positive breast cancers. However, as patients live longer and systemic therapies may not cross the blood brain barrier a rising number of patients are developing leptomeningeal metastases and brain metastases as a sanctuary site of disease. Intrathecal trastuzumab has been reported to treat these. We describe a breast cancer patient with HER-2 positive leptomeningeal disease in the spinal cord successfully treated with intrathecal trastuzumab and methotrexate, alongside systemic anti-HER-2 therapy and radiotherapy. We also review the literature to date on the efficacy and safety of intrathecal trastuzumab, and recent evidence suggesting that intrathecal trastuzumab passes via the blood brain barrier into the serum to achieve intravenous concentrations similar to that seen with systemic therapy alone. Overall, intrathecal trastuzumab appears to be a safe and often effective treatment for leptomeningeal metastases in HER-2 positive breast cancer. Ongoing phase I and II studies are required to determine optimum dosing schedules, validate CSF and CSF-to-serum pharmacokinetics, determine efficacy, and to assess the added benefits or disadvantages of prior radiotherapy and concomitant systemic therapy. Copyright © 2016 Elsevier Ltd. All rights reserved.

  16. The dynamics of HER2 status in esophageal adenocarcinoma.

    Science.gov (United States)

    Creemers, Aafke; Ebbing, Eva A; Hooijer, Gerrit K J; Stap, Lisanne; Jibodh-Mulder, Rajni A; Gisbertz, Susanne S; van Berge Henegouwen, Mark I; van Montfoort, Maurits L; Hulshof, Maarten C C M; Krishnadath, Kausilia K; van Oijen, Martijn G H; Bijlsma, Maarten F; Meijer, Sybren L; van Laarhoven, Hanneke W M

    2018-06-01

    Trastuzumab, a monoclonal antibody against HER2, has become standard of care for metastatic HER2-overexpressing esophagogastric adenocarcinoma and is currently investigated as (neo)adjuvant treatment option in HER2-positive esophagogastric adenocarcinoma. The HER2 status is commonly determined on archived material of the primary tumor. However, this status may change over the course of treatment or disease progression. The aim of this study was to assess the dynamics of HER2 status in esophageal adenocarcinoma (EAC) in patients with resectable and recurrent disease, and to determine the associations of these changes with clinical outcome. Discordance, defined as any change in HER2 status between matched biopsy and post-neoadjuvant chemoradiation therapy resection specimen ( N = 170), or between matched resection specimen and recurrence of patients not eligible for curative treatment ( N = 61), was determined using the standardized HER2 status scoring system. Clinically relevant positive discordance was defined as a change to HER2 positive status, as this would imply eligibility for HER2-targeted therapy. A difference in HER2 status between biopsy and resection specimen and resection specimen and metachronous recurrence was observed in 2.1% ( n = 3) and 3.3% ( n = 2) of the paired cases, respectively. Clinically relevant discordance was detected in 1.4% ( n = 2) of the resectable patients and 1.6% ( n = 1) of the patients with recurrent disease. Patients with HER2-positive status tumors before start of neoadjuvant treatment showed better overall survival, but not statistically significant. No association between HER2 status discordance and survival was found. Clinically relevant HER2 status discordance was observed and in order to prevent under-treatment of patients, the assessment of HER2 status in the metastatic setting should preferably be performed on the most recently developed lesions if the previous HER2 assessment on archival material of the primary tumor

  17. Tracking of [{sup 18}F]FDG-labeled natural killer cells to HER2/neu-positive tumors

    Energy Technology Data Exchange (ETDEWEB)

    Meier, Reinhard [Department of Radiology, University of California San Francisco (United States)], E-mail: reinhardt.meier@gmail.com; Piert, Morand [Department of Radiology, Division of Nuclear Medicine, University of Michigan (United States); Piontek, Guido; Rudelius, Martina [Institute of Pathology, Klinikum rechts der Isar, Technische Universitaet Muenchen (Germany); Oostendorp, Robert A. [3rd Department of Internal Medicine, Klinikum rechts der Isar, Technische Universitaet Muenchen (Germany); Senekowitsch-Schmidtke, Reingard [Department of Nuclear Medicine, Klinikum rechts der Isar, Technische Universitaet Muenchen (Germany); Henning, Tobias D. [Department of Radiology, University of California San Francisco (United States); Wels, Winfried S.; Uherek, Christoph [Chemotherapeutisches Forschungsinstitut, Georg-Speyer-Haus, Frankfurt am Main (Germany); Rummeny, Ernst J. [Department of Radiology, Klinikum rechts der Isar, Technische Universitaet Muenchen (Germany); Daldrup-Link, Heike E. [Department of Radiology, University of California San Francisco (United States)

    2008-07-15

    Introduction: The objective of this study was to label the human natural killer (NK) cell line NK-92 with [{sup 18}F]fluoro-deoxy-glucose (FDG) for subsequent in vivo tracking to HER2/neu-positive tumors. Methods: NK-92 cells were genetically modified to NK-92-scFv(FRP5)-zeta cells, which express a chimeric antigen receptor that is specific to the tumor-associated ErbB2 (HER2/neu) antigen. NK-92 and NK-92-scFv(FRP5)-zeta cells were labeled with [{sup 18}F]FDG by simple incubation at different settings. Labeling efficiency was evaluated by a gamma counter. Subsequently, [{sup 18}F]FDG-labeled parental NK-92 or NK-92-scFv(FRP5)-zeta cells were intravenously injected into mice with implanted HER2/neu-positive NIH/3T3 tumors. Radioactivity in tumors was quantified by digital autoradiography and correlated with histopathology. Results: The NK-92 and NK-92-scFv(FRP5)-zeta cells could be efficiently labeled with [{sup 18}F]FDG by simple incubation. Optimal labeling efficiencies (80%) were achieved using an incubation period of 60 min and additional insulin (10 IU/ml). After injection of 5x10{sup 6} [{sup 18}F]FDG-labeled NK-92-scFv(FRP5)-zeta cells into tumor-bearing mice, digital autoradiography showed an increased uptake of radioactivity in HER2/neu-positive tumors at 60 min postinjection. Conversely, injection of 5x10{sup 6} NK-92 cells not directed against HER2/neu receptors did not result in increased uptake of radioactivity in the tumors. Histopathology confirmed an accumulation of the NK-92-scFv(FRP5)-zeta cells, but not the parental NK cells, in tumor tissues. Conclusion: The human NK cell line NK-92 can be directed against HER2/neu antigens by genetic modification. The genetically modified NK cells can be efficiently labeled with [{sup 18}F]FDG, and the accumulation of these labeled NK cells in HER2/neu-positive tumors can be monitored with autoradiography.

  18. Tracking of [18F]FDG-labeled natural killer cells to HER2/neu-positive tumors

    International Nuclear Information System (INIS)

    Meier, Reinhard; Piert, Morand; Piontek, Guido; Rudelius, Martina; Oostendorp, Robert A.; Senekowitsch-Schmidtke, Reingard; Henning, Tobias D.; Wels, Winfried S.; Uherek, Christoph; Rummeny, Ernst J.; Daldrup-Link, Heike E.

    2008-01-01

    Introduction: The objective of this study was to label the human natural killer (NK) cell line NK-92 with [ 18 F]fluoro-deoxy-glucose (FDG) for subsequent in vivo tracking to HER2/neu-positive tumors. Methods: NK-92 cells were genetically modified to NK-92-scFv(FRP5)-zeta cells, which express a chimeric antigen receptor that is specific to the tumor-associated ErbB2 (HER2/neu) antigen. NK-92 and NK-92-scFv(FRP5)-zeta cells were labeled with [ 18 F]FDG by simple incubation at different settings. Labeling efficiency was evaluated by a gamma counter. Subsequently, [ 18 F]FDG-labeled parental NK-92 or NK-92-scFv(FRP5)-zeta cells were intravenously injected into mice with implanted HER2/neu-positive NIH/3T3 tumors. Radioactivity in tumors was quantified by digital autoradiography and correlated with histopathology. Results: The NK-92 and NK-92-scFv(FRP5)-zeta cells could be efficiently labeled with [ 18 F]FDG by simple incubation. Optimal labeling efficiencies (80%) were achieved using an incubation period of 60 min and additional insulin (10 IU/ml). After injection of 5x10 6 [ 18 F]FDG-labeled NK-92-scFv(FRP5)-zeta cells into tumor-bearing mice, digital autoradiography showed an increased uptake of radioactivity in HER2/neu-positive tumors at 60 min postinjection. Conversely, injection of 5x10 6 NK-92 cells not directed against HER2/neu receptors did not result in increased uptake of radioactivity in the tumors. Histopathology confirmed an accumulation of the NK-92-scFv(FRP5)-zeta cells, but not the parental NK cells, in tumor tissues. Conclusion: The human NK cell line NK-92 can be directed against HER2/neu antigens by genetic modification. The genetically modified NK cells can be efficiently labeled with [ 18 F]FDG, and the accumulation of these labeled NK cells in HER2/neu-positive tumors can be monitored with autoradiography

  19. Selective internalization of self-assembled artificial oil bodies by HER2/neu-positive cells

    International Nuclear Information System (INIS)

    Chiang, Chung-Jen; Lin, Che-Chin; Lin, Li-Jen; Chang, Chih-Hsiang; Chao, Yun-Peng

    2011-01-01

    A novel delivery carrier was developed using artificial oil bodies (AOBs). Plant seed oil bodies (OBs) consist of a triacylglycerol matrix surrounded by a monolayer of phospholipids embedded with the storage protein oleosin (Ole). Ole consists of a central hydrophobic domain with two amphiphatic arms that extrude from the surface of OBs. In this study, a bivalent anti-HER2/neu affibody domain (ZH2) was fused with Ole at the C terminus. After overproduction in Escherichia coli, the fusion protein (Ole-ZH2) was recovered to assemble AOBs. The size of self-assembled AOBs was tailored by varying the oil/Ole-ZH2 ratio and pH to reach a nanoscale. Upon co-incubation with tumor cells, the nanoscale AOBs encapsulated with a hydrophobic fluorescence dye were selectively internalized by HER2/neu-overexpressing cells and displayed biocompatibility with the cells. In addition, the ZH2-mediated endosomal entry of AOBs occurred in a time- and AOB dose-dependent manner. The internalization efficiency was as high as 90%. The internalized AOBs disintegrated at the non-permissive pH (e.g. in acidic endosomes) and the cargo dye was released. Results of in vitro study revealed a sustained and prolonged release profile. Taken together, our findings indicate the potential of AOBs as a delivery carrier.

  20. Prospective Biomarker Analysis of the Randomized CHER-LOB Study Evaluating the Dual Anti-HER2 Treatment With Trastuzumab and Lapatinib Plus Chemotherapy as Neoadjuvant Therapy for HER2-Positive Breast Cancer.

    Science.gov (United States)

    Guarneri, Valentina; Dieci, Maria Vittoria; Frassoldati, Antonio; Maiorana, Antonino; Ficarra, Guido; Bettelli, Stefania; Tagliafico, Enrico; Bicciato, Silvio; Generali, Daniele Giulio; Cagossi, Katia; Bisagni, Giancarlo; Sarti, Samanta; Musolino, Antonino; Ellis, Catherine; Crescenzo, Rocco; Conte, PierFranco

    2015-09-01

    The CHER-LOB randomized phase II study showed that the combination of lapatinib and trastuzumab plus chemotherapy increases the pathologic complete remission (pCR) rate compared with chemotherapy plus either trastuzumab or lapatinib. A biomarker program was prospectively planned to identify potential predictors of sensitivity to different treatments and to evaluate treatment effect on tumor biomarkers. Overall, 121 breast cancer patients positive for human epidermal growth factor 2 (HER2) were randomly assigned to neoadjuvant chemotherapy plus trastuzumab, lapatinib, or both trastuzumab and lapatinib. Pre- and post-treatment samples were centrally evaluated for HER2, p95-HER2, phosphorylated AKT (pAKT), phosphatase and tensin homolog, Ki67, apoptosis, and PIK3CA mutations. Fresh-frozen tissue samples were collected for genomic analyses. A mutation in PIK3CA exon 20 or 9 was documented in 20% of cases. Overall, the pCR rates were similar in PIK3CA wild-type and PIK3CA-mutated patients (33.3% vs. 22.7%; p = .323). For patients receiving trastuzumab plus lapatinib, the probability of pCR was higher in PIK3CA wild-type tumors (48.4% vs. 12.5%; p = .06). Ki67, pAKT, and apoptosis measured on the residual disease were significantly reduced from baseline. The degree of Ki67 inhibition was significantly higher in patients receiving the dual anti-HER2 blockade. The integrated analysis of gene expression and copy number data demonstrated that a 50-gene signature specifically predicted the lapatinib-induced pCR. PIK3CA mutations seem to identify patients who are less likely to benefit from dual anti-HER2 inhibition. p95-HER2 and markers of phosphoinositide 3-kinase pathway deregulation are not confirmed as markers of different sensitivity to trastuzumab or lapatinib. HER2 is currently the only validated marker to select breast cancer patients for anti-HER2 treatment; however, it is becoming evident that HER2-positive breast cancer is a heterogeneous disease. In addition, more

  1. Targeted Delivery of Deoxycytidine Kinase to Her2-Positive Cells Enhances the Efficacy of the Nucleoside Analog Fludarabine.

    Directory of Open Access Journals (Sweden)

    Sujatha P Koduvayur

    Full Text Available Cytotoxic drugs, such as nucleoside analogs and toxins, commonly suffer from off-target effects. One approach to mitigate this problem is to deliver the cytotoxic drug selectively to the intended site. While for toxins this can be achieved by conjugating the cell-killing moiety to a targeting moiety, it is not an option for nucleoside analogs, which rely on intracellular enzymes to convert them to their active triphosphorylated form. To overcome this limitation, and achieve site-targeted activation of nucleoside analogs, we fused the coding region of a prodrug-activating enzyme, deoxycytidine kinase (dCK, to affinity reagents that bind to the Her2 cell surface protein. We evaluated dCK fusions to an anti-Her2 affibody and Designed Ankyrin Repeat Protein (DARPin for their ability to kill cancer cells by promoting the activation of the nucleoside analog fludarabine. Cell staining and flow cytometry experiments with three Her2 positive cancer cell lines (BT-474-JB, JIMT-1 and SK-OV-3 indicate dCK fusions binding and cellular internalization. In contrast, these reagents bind only weakly to the Her2 negative cell line, MCF-7. Cell proliferation assays indicate that SK-OV-3 and BT-474-JB cell lines exhibit significantly reduced proliferation rates when treated with targeting-module fused dCK and fludarabine, compared to fludarabine alone. These findings demonstrate that we have succeeded in delivering active dCK into the Her2-positive cells, thereby increasing the activation of fludarabine, which ultimately reduces the dose of nucleoside analog needed for cell killing. This strategy may help establish the therapeutic index required to differentiate between healthy tissues and cancer cells.

  2. Prognostic value of E-cadherin, beta-catenin, CD44v6, and HER2/neu in metastatic cutaneous adenocarcinoma.

    Science.gov (United States)

    Pozdnyakova, Olga; Hoang, Mai M P; Dresser, Karen A; Mahalingam, Meera

    2009-08-01

    Our recent experience with a patient developing cutaneous metastases within 3 months of diagnosis of esophageal adenocarcinoma suggests that altered expression of the cellular adhesion molecules, E-cadherin and CD44v6, may have had a role to play in the rapid onset of metastases. To corroborate these findings, we designed a cross-sectional study to investigate the expression of select molecules involved in the metastatic cascade. E-cadherin, beta-catenin, CD44v6, and HER2/neu immunohistochemical stains were performed on archival materials of metastatic adenocarcinoma to the skin from 27 patients and the available corresponding primary tumors in 10 patients. The primary sites included breast (n = 10; 37%), gastrointestinal tract (n = 10; 37%), ovary (n = 1; 4%), thyroid (n = 2; 7%), lung (n = 1; 4%), and unknown primary (n = 3; 11%). Expression of all markers was noted with the most significant increases observed in beta-catenin (26 of 27 cases; 96%), followed by CD44v6 (24 of 27 cases; 89%), E-cadherin (22 of 27 cases; 82%), and HER2/neu (11 of 27 cases; 41%). Contrasting expression of these molecules in the primary versus the metastatic tumors, enhanced expression of CD44v6 was observed in the cutaneous metastases relative to the primary in 6 of 10 (60%) cases. Of interest, 2 of these 6 cases (33%) also showed reduction in E-cadherin--a member of the cadherin family functioning as an invasion suppressor molecule. These findings reinforce the complexities of the metastatic cascade and imply that the variation in adhesive properties of tumor cells is, perhaps, a consequence of the difference in density of the molecules mediating this process.

  3. Adjuvant trastuzumab with chemotherapy is effective in women with small, node-negative, HER2-positive breast cancer.

    Science.gov (United States)

    McArthur, Heather L; Mahoney, Kathleen M; Morris, Patrick G; Patil, Sujata; Jacks, Lindsay M; Howard, Jane; Norton, Larry; Hudis, Clifford A

    2011-12-15

    Several large, randomized trials established the benefits of adjuvant trastuzumab with chemotherapy. However, the benefit for women with small, node-negative HER2-positive (HER2+) disease is unknown, as these patients were largely excluded from these trials. Therefore, a retrospective, single-institution, sequential cohort study of women with small, node-negative, HER2+ breast cancer who did or did not receive adjuvant trastuzumab was conducted. Women with ≤ 2 cm, node-negative, HER2+ (immunohistochemistry 3+ or fluorescence in situ hybridization ≥ 2) breast cancer were identified through an institutional database. A "no-trastuzumab" cohort of 106 trastuzumab-untreated women diagnosed between January 1, 2002 and May 14, 2004 and a "trastuzumab" cohort of 155 trastuzumab-treated women diagnosed between May 16, 2005 and December 31, 2008 were described. Survival and recurrence outcomes were estimated by Kaplan-Meier methods. The cohorts were similar in age, median tumor size, histology, hormone receptor status, hormone therapy, and locoregional therapy. Chemotherapy was administered in 66% and 100% of the "no trastuzumab" and "trastuzumab" cohorts, respectively. The median recurrence-free and survival follow-up was: 6.5 years (0.7-8.5) and 6.8 years (0.7-8.5), respectively, for the "no trastuzumab" cohort and 3.0 years (0.5-5.2) and 3.0 years (0.6-5.2), respectively, for the "trastuzumab" cohort. The 3-year locoregional invasive recurrence-free, distant recurrence-free, invasive disease-free, and overall survival were 92% versus 98% (P = .0137), 95% versus 100% (P = .0072), 82% versus 97% (P < .0001), and 97% versus 99% (P = .18) for the "no trastuzumab" and "trastuzumab" cohorts, respectively. Women with small, node-negative, HER2+ primary breast cancers likely derive significant benefit from adjuvant trastuzumab with chemotherapy. Copyright © 2011 American Cancer Society.

  4. First-line treatment disruption among post-menopausal women with HR+/HER2- metastatic breast cancer: a retrospective US claims study.

    Science.gov (United States)

    Tang, Derek H; Li, Nanxin; Du, Ella X; Peeples, Miranda; Chu, Lihao; Xie, Jipan; Barghout, Victoria

    2017-12-01

    This study assessed disruption of first-line treatments initiated after the approval of the first CDK 4/6 inhibitor, palbociclib, among post-menopausal women with HR+/HER2- metastatic breast cancer (mBC) in the US. Post-menopausal women with HR+/HER2- mBC who initiated first-line endocrine therapy or chemotherapy (index therapy) between February 3, 2015 (palbociclib approval date) and February 29, 2016 (end of data) were identified from the Symphony Source Lx database. Patients were required to have continuous quarterly activity (defined as ≥1 pharmacy or medical claim) for 12 months prior to and 1 month after the initiation of the index therapy (index date). Treatment disruption was defined as a treatment gap of ≥60 days or adding an agent after the original therapy. Kaplan-Meier analyses were conducted to estimate treatment disruption rates during the 6 months following the index date. Patients without treatment disruption were censored at the end of continuous quarterly activity or end of data. A total of 8,160 and 2,153 eligible patients initiated endocrine therapy or chemotherapy as their first-line mBC treatment, with a median follow-up of 6.7 and 7.6 months, respectively. The three most prevalent metastatic sites were bone (28.1-42.2%), liver (8.8-17.3%), and lung (8.6-9.5%). Overall, 37.7% (n = 3,074) of patients receiving endocrine therapy and 86.1% (n = 1,852) of patients receiving chemotherapy encountered treatment disruption at 6 months (log-rank test p disruption rates of first-line therapies were sub-optimal among post-menopausal women with HR+/HER2- mBC, primarily driven by chemotherapy users. New therapies or interventions are needed to reduce treatment disruption in this patient population.

  5. Serum HER2 levels are increased in patients with chronic heart failure.

    NARCIS (Netherlands)

    Perik, P.J.; Vries, E.G.F. de; Gietema, J.A.; Graaf, W.T.A. van der; Smilde, T.D.; Sleijfer, D.Th.; Veldhuisen, D.J. van

    2007-01-01

    BACKGROUND: The use of trastuzumab, an antibody against the human epidermal growth factor receptor 2 (HER2), in patients with HER2 positive metastatic breast cancer, is related to cardiotoxicity. AIMS: To investigate whether serum HER2 is increased in heart failure patients and related to disease

  6. Integrating molecular mechanisms and clinical evidence in the management of trastuzumab resistant or refractory HER-2metastatic breast cancer.

    Science.gov (United States)

    Wong, Hilda; Leung, Roland; Kwong, Ava; Chiu, Joanne; Liang, Raymond; Swanton, Charles; Yau, Thomas

    2011-01-01

    Human epidermal growth factor receptor (HER)-2(+) breast cancer is a distinct molecular and clinical entity, the prognosis of which is improved by trastuzumab. However, primary resistance to trastuzumab is observed in >50% of patients with HER-2(+) advanced breast cancer, and the majority of patients who initially respond to treatment eventually develop disease progression. To facilitate crosstrial comparisons and the understanding of resistance mechanisms, we propose a unifying definition of trastuzumab resistance as progression at first radiological reassessment at 8-12 weeks or within 3 months after first-line trastuzumab in the metastatic setting or new recurrences diagnosed during or within 12 months after adjuvant trastuzumab. In contrast, we define trastuzumab-refractory breast cancer as disease progression after two or more lines of trastuzumab-containing regimens that initially achieved disease response or stabilization at first radiological assessment. We review mechanisms of trastuzumab resistance mediated by p95HER-2 overexpression, phosphoinositide 3-kinase pathway activation, and signaling pathway activation driven by HER-3, epidermal growth factor receptor, and insulin-like growth factor 1 receptor. We distinguish in vitro from in vivo evidence, highlighting that most data describing trastuzumab resistance are derived from preclinical studies or small retrospective patient cohorts, and discuss targeted therapeutic approaches to overcome resistance. Prospective analysis through clinical trials with robust tissue collection procedures, prior to and following acquisition of resistance, integrated with next-generation tumor genome sequencing technologies, is identified as a priority area for development. The identification of predictive biomarkers is of paramount importance to optimize health economic costs and enhance stratification of anti-HER-2 targeted therapies.

  7. The prognostic value of Her4 receptor isoform expression in triple-negative and Her2 positive breast cancer patients

    International Nuclear Information System (INIS)

    Machleidt, Anna; Buchholz, Stefan; Diermeier-Daucher, Simone; Zeman, Florian; Ortmann, Olaf; Brockhoff, Gero

    2013-01-01

    Not only four but rather seven different human epidermal growth factor receptor related (Her) receptor tyrosine kinases (RTKs) have been described to be expressed in a variety of normal and neoplastic tissues: Her1, Her2, Her3, and additionally four Her4 isoforms have been identified. A differential expression of Her4 isoforms does not, however, play any role in either the molecular diagnostics or treatment decision for breast cancer patients. The prognostic and predictive impact of Her4 expression in breast cancer is basically unclear. We quantified the Her4 variants JM-a/CYT1, JM-a/CYT2, JM-b/CYT1, and JM-b/CYT2 by isoform-specific polymerase chain reaction (qPCR) in (i) triple-negative, (ii) Her2 positive breast cancer tissues and (iii) in benign breast tissues. In all three tissue collectives we never found the JM-b/CYT1 or the JM-b/CYT2 isoform expressed. In contrast, the two JM-a/CYT1 and JM-a/CYT2 isoforms were always simultaneously expressed but at different ratios. We identified a positive prognostic impact on overall survival (OS) in triple-negative and event-free survival (EFS) in Her2 positive patients. This finding is independent of the absolute JM-a/CYT1 to JM-a/CYT2 expression ratio. In Her2 positive patients, Her4 expression only has a favorable effect in estrogen-receptor (ER)-positive but not in ER-negative individuals. In summary, JM-a/CYT1 and JM-a/CYT2 but not JM-b isoforms of the Her4 receptor are simultaneously expressed in both triple-negative and Her2 positive breast cancer tissues. Although different expression ratios of the two JM-a isoforms did not reveal any additional information, Her4 expression basically indicates a prolonged EFS and OFS. An extended expression analysis that takes all Her receptor homologs, including the Her4 isoforms, into account might render more precisely the molecular diagnostics required for the development of optimized targeted therapies

  8. Cardiotoxicity of novel HER2-targeted therapies.

    Science.gov (United States)

    Sendur, Mehmet A N; Aksoy, Sercan; Altundag, Kadri

    2013-08-01

    Trastuzumab, an anti-HER2 humanized monoclonal antibody, is the standard treatment for both early and metastatic HER2-positive breast cancer. In addition to other chemotherapeutic agents, trastuzumab significantly improves response rate and survival in HER2-positive early and metastatic breast cancer. Although it is well known that trastuzumab therapy is closely associated with both symptomatic and asymptomatic cardiotoxicity, less is known about novel HER2-targeted therapies. The aim of this review is to discuss the cardiac safety data from recent studies of novel anti-HER2 drugs other than trastuzumab. Novel HER2-targeted therapies showed favorable results in HER2 positive metastatic breast cancer patients. Pubmed database, ASCO and San Antonio Breast Cancer Symposium Meeting abstracts were searched until January 2013 using the following search keywords; 'trastuzumab, trastuzumab cardiotoxicity, HER-2 targeted therapies, lapatinib, pertuzumab, trastuzumab emtansine, afatinib and neratinib'; papers which were considered relevant for the aim of this review were selected by the authors. Lapatinib, pertuzumab, T-DM1, neratinib and afatinib molecules are evaluated in the study. In a comprehensive analysis, 3689 lapatinib treated patients enrolled in 49 trials; asymptomatic cardiac events were reported in 53 patients (1.4%) and symptomatic grade III and IV systolic dysfunction was observed only in 7 patients (0.2%) treated with lapatinib. In phase I-III trials of pertuzumab, cardiac dysfunction was seen in 4.5-14.5% of patients with pertuzumab treatment and cardiac dysfunction was usually grade I and II. Cardiotoxicity of pertuzumab was usually reported with the trastuzumab combination and no additive cardiotoxicity was reported with addition of pertuzumab to trastuzumab. T-DM1 had a better safety profile compared to trastuzumab, no significant cardiotoxicity was observed with T-DM1 in heavily pre-treated patients. In the EMILIA study, only in 1.7% of patients in the T

  9. Medico-economic impact of MSKCC non-sentinel node prediction nomogram for ER-positive HER2-negative breast cancers.

    Directory of Open Access Journals (Sweden)

    Hélène Bonsang-Kitzis

    Full Text Available Avoiding axillary lymph node dissection (ALND for invasive breast cancers with isolated tumor cells or micrometastatic sentinel node biopsy (SNB could decrease morbidity with minimal clinical significance.The aim of this study is to simulate the medico-economic impact of the routine use of the MSKCC non-sentinel node (NSN prediction nomogram for ER+ HER2- breast cancer patients.We studied 1036 ER+ HER2- breast cancer patients with a metastatic SNB. All had a complementary ALND. For each patient, we calculated the probability of the NSN positivity using the MSKCC nomogram. After validation of this nomogram in the population, we described how the patients' characteristics spread as the threshold value changed. Then, we performed an economic simulation study to estimate the total cost of caring for patients treated according to the MSKCC predictive nomogram results.A 0.3 threshold discriminate the type of sentinel node (SN metastases: 98.8% of patients with pN0(i+ and 91.6% of patients with pN1(mic had a MSKCC score under 0.3 (false negative rate = 6.4%. If we use the 0.3 threshold for economic simulation, 43% of ALND could be avoided, reducing the costs of caring by 1 051 980 EUROS among the 1036 patients.We demonstrated the cost-effectiveness of using the MSKCC NSN prediction nomogram by avoiding ALND for the pN0(i+ or pN1(mic ER+ HER2- breast cancer patients with a MSKCC score of less than or equal to 0.3.

  10. The Lifetime Economic Burden of Inaccurate HER2 Testing: Estimating the Costs of False-Positive and False-Negative HER2 Test Results in US Patients with Early-Stage Breast Cancer.

    Science.gov (United States)

    Garrison, Louis P; Babigumira, Joseph B; Masaquel, Anthony; Wang, Bruce C M; Lalla, Deepa; Brammer, Melissa

    2015-06-01

    Patients with breast cancer whose tumors test positive for human epidermal growth factor receptor 2 (HER2) are treated with HER2-targeted therapies such as trastuzumab, but limitations with HER2 testing may lead to false-positive (FP) or false-negative (FN) results. To develop a US-level model to estimate the effect of tumor misclassification on health care costs and patient quality-adjusted life-years (QALYs). Decision analysis was used to estimate the number of patients with early-stage breast cancer (EBC) whose HER2 status was misclassified in 2012. FP results were assumed to generate unnecessary trastuzumab costs and unnecessary cases of trastuzumab-related cardiotoxicity. FN results were assumed to save money on trastuzumab, but with a loss of QALYs and greater risk of disease recurrence and its associated costs. QALYs were valued at $100,000 under a net monetary benefit approach. Among 226,870 women diagnosed with EBC in 2012, 3.12% (n = 7,070) and 2.18% (n = 4,955) were estimated to have had FP and FN test results, respectively. Approximately 8400 QALYs (discounted, lifetime) were lost among women not receiving trastuzumab because of FN results. The estimated incremental per-patient lifetime burden of FP or FN results was $58,900 and $116,000, respectively. The implied incremental losses to society were $417 million and $575 million, respectively. HER2 tests result in misclassification and nonoptimal treatment of approximately 12,025 US patients with EBC annually. The total economic societal loss of nearly $1 billion suggests that improvements in HER2 testing accuracy are needed and that further clinical and economic studies are warranted. Copyright © 2015 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.

  11. A single-domain antibody-linked Fab bispecific antibody Her2-S-Fab has potent cytotoxicity against Her2-expressing tumor cells.

    Science.gov (United States)

    Li, Aifen; Xing, Jieyu; Li, Li; Zhou, Changhua; Dong, Bin; He, Ping; Li, Qing; Wang, Zhong

    2016-12-01

    Her2, which is frequently overexpressed in breast cancer, is one of the most studied tumor-associated antigens for cancer therapy. Anti-HER2 monoclonal antibody, trastuzumab, has achieved significant clinical benefits in metastatic breast cancer. In this study, we describe a novel bispecific antibody Her2-S-Fab targeting Her2 by linking a single domain anti-CD16 VHH to the trastuzumab Fab. The Her2-S-Fab antibody can be efficiently expressed and purified from Escherichia coli, and drive potent cancer cell killing in HER2-overexpressing cancer cells. In xenograft model, the Her2-S-Fab suppresses tumor growth in the presence of human immune cells. Our results suggest that the bispecific Her2-S-Fab may provide a valid alternative to Her2 positive cancer therapy.

  12. {sup 18}F-FDG-PET/CT for systemic staging of patients with newly diagnosed ER-positive and HER2-positive breast cancer

    Energy Technology Data Exchange (ETDEWEB)

    Ulaner, Gary A.; Castillo, Raychel [Memorial Sloan Kettering Cancer Center, Department of Radiology, New York, NY (United States); Weill Cornell Medical College, Department of Radiology, New York, NY (United States); Wills, Jonathan [Memorial Sloan Kettering Cancer Center, Department of Information Systems, New York, NY (United States); Goenen, Mithat; Goldman, Debra A. [Memorial Sloan Kettering Cancer Center, Department of Epidemiology and Biostatistics, New York, NY (United States)

    2017-08-15

    This study assesses {sup 18}F-FDG-PET/CT for patients with newly diagnosed estrogen receptor-positive/human epidermal growth factor receptor-negative (ER+/HER2-) and human epidermal growth factor receptor-positive (HER2+) breast cancer. In this Institutional Review Board-approved retrospective study, our Healthcare Information System was screened for patients with ER+/HER2- and HER2+ breast cancer who underwent {sup 18}F-FDG-PET/CT prior to systemic or radiation therapy. The initial stage was determined from mammography, ultrasound, magnetic resonance imaging, and/or surgery.{sup 18}F-FDG-PET/CT was evaluated to identify unsuspected extra-axillary regional nodal and distant metastases. The proportion of patients upstaged overall and stratified by stage and receptor phenotypes was calculated along with confidence intervals (CI). A total of 238 patients with ER+/HER2- and 245 patients with HER2+ who met inclusion criteria were evaluated. For patients with ER+/HER2-breast cancer, {sup 18}F-FDG-PET/CT revealed unsuspected distant metastases in 3/71 (4%) initial stage IIA, 13/95 (14%) stage IIB, and 15/57 (26%) stage III. For patients with HER2+ breast cancer, {sup 18}F-FDG-PET/CT revealed unsuspected distant metastases in 3/72 (4%) initial stage IIA, 13/93 (14%) stage IIB, and 13/59 (22%) stage III. The overall upstaging rate for IIB was 14% (95% confidence interval (CI): 9-20%). {sup 18}F-FDG-PET/CT revealed distant metastases in 14% (95% CI: 9-20%) of patients with stage IIB ER+/HER2- and HER2+ breast cancer, which is similar to upstaging rates previously seen in patients with stage IIB triple-negative breast cancer (15%, 95% CI: 9-24%). The detection of unsuspected distant metastases in these patients alters treatment and prognosis. NCCN guidelines should consider adding patients with stage IIB breast cancer for consideration of systemic staging with {sup 18}F-FDG-PET/CT at the time of initial diagnosis. (orig.)

  13. A systematic review of trastuzumab and lapatinib in the treatment of women with brain metastases from HER2-positive breast cancer

    DEFF Research Database (Denmark)

    Larsen, Pia Bükmann; Kümler, Iben; Nielsen, Dorte Lisbet

    2013-01-01

    Patients with HER2-positive breast cancer are living still longer and increasingly experiencing brain metastases. Current HER2-targeted therapies have limited potential to cross the blood-brain-barrier. We performed a systematic review to investigate data on HER2-targeting therapies in the treatm......, it is still not evident which HER2-targeting agent should be preferred when brain metastases occur. The choice of chemotherapy to accompany the blockade is not obvious and we do not know if dual is better than single blockade. Further clinical trials are urgently needed....

  14. Phase 2 Study of a HER-2/neu Intracellular Domain Peptide-Based Vaccine Administered to Stage IV HER2 Positive Breast Cancer Patients Receiving Trastuzumab

    Science.gov (United States)

    2010-12-01

    Leukocytes 14 4 11 4 Headache 10 3 7 3 Hypocalcemia 9 2 7 3 General rash 9 2 5 2 Renal – positive leukocytes 8 2 8 3...in the prevention of tumor relapse. Th17 is a subset of CD4 Th cytokine recently reported and has been found to have anti-tumor effects in tumor...decrease serum TGF-ß indicate that traf- ficking T cells may also be effectively modulating the tumor micro- environment. Theoretically, a decrease in

  15. The Effect of Early Detection of Occult Brain Metastases in HER2-Positive Breast Cancer Patients on Survival and Cause of Death

    International Nuclear Information System (INIS)

    Niwinska, Anna; Tacikowska, Malgorzata; Murawska, Magdalena

    2010-01-01

    Purpose: The aim of the study is to evaluate disease-free survival, survival from the detection of brain metastases, overall survival, and cause of death in patients with occult brain metastases (Group I) vs. patients with symptomatic brain metastases (Group II). Methods and Materials: In 80 HER2-positive breast cancer patients, treated with trastuzumab and cytostatic agents for metastatic disease, magnetic resonance imaging screening of the brain was performed, and in 29 patients (36%) occult brain metastasis was detected (Group I). Whole-brain radiotherapy was delivered to Group I. This first group was compared with 52 patients who had symptomatic brain metastases (Group II) and was treated the same way, at the same clinic, during the same time period. Results: Median disease-free survival was 17 months in Group I and 19.9 months in Group II (p = 0.58). The median time interval between the dissemination of the disease and the detection of occult or symptomatic brain metastases was 9 and 15 months, respectively (p = 0.11). When the brain metastases were detected, the median survival was 9 and 8.78 months, respectively (p = 0.80). The median overall survival was 53 and 51 months, respectively (p = 0.94). In the group with occult brain metastases (Group I) 16% of patients died because of progression within the brain. In the group with symptomatic brain metastases (Group II) the rate of cerebral death was 48% (p = 0.009). Conclusions: Whole-brain radiotherapy of occult brain metastases in HER2-positive breast cancer patients with visceral dissemination produces a three-fold decrease in cerebral deaths but does not prolong survival.

  16. PIK3CA mutations, PTEN, and pHER2 expression and impact on outcome in HER2-positive early-stage breast cancer patients treated with adjuvant chemotherapy and trastuzumab

    DEFF Research Database (Denmark)

    Jensen, J D; Knoop, Ann; Laenkholm, A V

    2012-01-01

    -stage breast cancer patients treated with adjuvant chemotherapy and trastuzumab. PATIENTS AND METHODS: Two hundred and forty HER2-positive early-stage breast cancer patients receiving adjuvant treatment (cyclophosphamide 600 mg/m(2), epirubicin 60 mg/m(2), and fluorouracil 600 mg/m(2)) before administration...... of 1 year trastuzumab were assessable. PTEN and pHER2 expression were assessed by immunohistochemistry. PIK3CA mutations (exons 9 and 20) were determined by pyrosequencing. RESULTS: Five-year overall survival (OS) and invasive disease-free survival were 87.8% and 81.0%, respectively. Twenty-six percent...... activity had a significantly poorer survival despite adequate treatment with adjuvant chemotherapy and trastuzumab....

  17. Impact of somatic PI3K pathway and ERBB family mutations on pathological complete response (pCR) in HER2-positive breast cancer patients who received neoadjuvant HER2-targeted therapies.

    LENUS (Irish Health Repository)

    Toomey, Sinead

    2017-07-27

    The Cancer Genome Atlas analysis revealed that somatic EGFR, receptor tyrosine-protein kinase erbB-2 (ERBB2), Erb-B2 receptor tyrosine kinase 3 (ERBB3) and Erb-B2 receptor tyrosine kinase 4 (ERBB4) gene mutations (ERBB family mutations) occur alone or co-occur with somatic mutations in the gene encoding the phosphatidylinositol 3-kinase (PI3K) catalytic subunit (PIK3CA) in 19% of human epidermal growth factor receptor 2 (HER2)-positive breast cancers. Because ERBB family mutations can activate the PI3K\\/AKT pathway and likely have similar canonical signalling effects to PI3K pathway mutations, we investigated their combined impact on response to neoadjuvant HER2-targeted therapies.

  18. A time and motion study of subcutaneous versus intravenous trastuzumab in patients with HER2-positive early breast cancer

    DEFF Research Database (Denmark)

    De Cock, Erwin; Pivot, Xavier; Hauser, Nik

    2016-01-01

    Within PrefHer (NCT01401166), patients and healthcare professionals (HCPs) preferred subcutaneous (SC) over intravenous (IV) trastuzumab. We undertook a prospective, observational time and motion study to quantify patients' time in infusion chairs and active HCP time in PrefHer. Patients with HER2......-positive early breast cancer received four adjuvant cycles of SC trastuzumab (600 mg fixed dose via SC single-use injection device [SID, Cohort 1] or SC handheld syringe [HHS, Cohort 2]) then four cycles of standard IV trastuzumab or the reverse sequence. Generic case report forms for IV and SC management...... (range across countries: 4-16; P trastuzumab, delivered via SID or HHS, saved patient chair and active HCP times versus IV infusion, supporting a transition to either SC method....

  19. The efficacy and safety of the targeted drug combined with adriamycin liposome solution for HER-2-positive breast cancer

    Directory of Open Access Journals (Sweden)

    Zi-Ping Zhou

    2017-05-01

    Full Text Available Objective: To study the efficacy and safety of the targeted drug trastuzumab combined with adriamycin liposome solution for HER-2-positive breast cancer. Methods: A total of 112 patients with breast cancer who received chemotherapy in Department of Cardiothoracic Breast Surgery, Guangdong TongJiang Hospital between May 2014 and April 2016 were selected as the research subjects and divided into two groups by random number table, liposome group received trastuzumab + adriamycin liposome chemotherapy, and the control group received trastuzumab + adriamycin chemotherapy. Before chemotherapy as well as 4 weeks and 8 weeks after chemotherapy, serum levels of tumor markers, cytokines and myocardial injury indexes were detected, the electrocardiography was conducted and the degree of myocardial injury was determined. Results: 4 weeks and 8 weeks after chemotherapy, serum CEA, CA15-3, TPS, CTGF, TGF-β, TSGF, VEGF and MK levels of both groups were significantly lower than those before chemotherapy, serum CK-MB and cTnI levels were significantly higher than those before chemotherapy, limb leads QRS amplitudes and chest leads QRS amplitudes were significantly lower than those before chemotherapy, serum CEA, CA15-3, TPS, CTGF, TGF-β, TSGF, VEGF, MK, CK-MB and cTnI levels of liposome group were significantly lower than those of control group, and the limb leads QRS amplitudes and chest lead QRS amplitudes were significantly higher than those of control group. Conclusion: Targeted drug combined with adriamycin liposome therapy for HER-2-positive breast cancer can improve the curative effect and reduce the cardiotoxicity.

  20. Neoadjuvant chemotherapy with trastuzumab in HER2-positive breast cancer: pathologic complete response rate, predictive and prognostic factors

    Directory of Open Access Journals (Sweden)

    I.P.C. Buzatto

    Full Text Available The purpose of this study was to retrospectively review the pathologic complete response (pCR rate from patients (n=86 with stage II and III HER2-positive breast cancer treated with neoadjuvant chemotherapy at our institution from 2008 to 2013 and to determine possible predictive and prognostic factors. Immunohistochemistry for hormone receptors and Ki-67 was carried out. Clinical and pathological features were analyzed as predictive factors of response to therapy. For survival analysis, we used Kaplan-Meier curves to estimate 5-year survival rates and the log-rank test to compare the curves. The addition of trastuzumab to neoadjuvant chemotherapy significantly improved pCR rate from 4.8 to 46.8%, regardless of the number of preoperative trastuzumab cycles (P=0.0012. Stage II patients achieved a higher response rate compared to stage III (P=0.03. The disease-free and overall survivals were not significantly different between the group of patients that received trastuzumab in the neoadjuvant setting (56.3 and 70% at 5 years, respectively and the group that initiated it post-operatively (75.8 and 88.7% at 5 years, respectively. Axillary pCR post neoadjuvant chemotherapy with trastuzumab was associated with reduced risk of recurrence (HR=0.34; P=0.03 and death (HR=0.21; P=0.02. In conclusion, we confirmed that trastuzumab improves pCR rates and verified that this improvement occurs even with less than four cycles of the drug. Hormone receptors and Ki-67 expressions were not predictive of response in this subset of patients. Axillary pCR clearly denotes prognosis after neoadjuvant target therapy and should be considered to be a marker of resistance, providing an opportunity to investigate new strategies for HER2-positive treatment.

  1. Efficacy of Anti-HER2 Agents in Combination With Adjuvant or Neoadjuvant Chemotherapy for Early and Locally Advanced HER2-Positive Breast Cancer Patients: A Network Meta-Analysis

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    Márcio Debiasi

    2018-05-01

    Full Text Available BackgroundSeveral (neoadjuvant treatments for patients with HER2-positive breast cancer have been compared in different randomized clinical trials. Since it is not feasible to conduct adequate pairwise comparative trials of all these therapeutic options, network meta-analysis offers an opportunity for more detailed inference for evidence-based therapy.MethodsPhase II/III randomized clinical trials comparing two or more different (neoadjuvant treatments for HER2-positive breast cancer patients were included. Relative treatment effects were pooled in two separate network meta-analyses for overall survival (OS and disease-free survival (DFS.Results17 clinical trials met our eligibility criteria. Two different networks of trials were created based on the availability of the outcomes: OS network (15 trials: 37,837 patients; and DFS network (17 trials: 40,992 patients. Two studies—the ExteNET and the NeoSphere trials—were included only in this DFS network because OS data have not yet been reported. The concept of the dual anti-HER2 blockade proved to be the best option in terms of OS and DFS. Chemotherapy (CT plus trastuzumab (T and lapatinib (L and CT + T + Pertuzumab (P are probably the best treatment options in terms of OS, with 62.47% and 22.06%, respectively. In the DFS network, CT + T + Neratinib (N was the best treatment option with 50.55%, followed by CT + T + P (26.59% and CT + T + L (20.62%.ConclusionThis network meta-analysis suggests that dual anti-HER2 blockade with trastuzumab plus either lapatinib or pertuzumab are probably the best treatment options in the (neoadjuvant setting for HER2-positive breast cancer patients in terms of OS gain. Mature OS results are still expected for the Aphinity trial and for the sequential use of trastuzumab followed by neratinib, the treatment that showed the best performance in terms of DFS in our analysis.

  2. HER-2 protein concentrations in breast cancer cells increase before immunohistochemical and fluorescence in situ hybridization analysis turn positive

    DEFF Research Database (Denmark)

    Olsen, Dorte A; Østergaard, Birthe; Bokmand, Susanne

    2007-01-01

    BACKGROUND: The level of HER-2/neu in breast cancer cells is normally measured by immunohistochemistry (IHC) and/or fluorescence in situ hybridization (FISH). It determines whether patients should be treated with trastuzumab (Herceptin). In this study, HER-2 protein in breast cancer tissue...

  3. Predicting for activity of second-line trastuzumab-based therapy in her2-positive advanced breast cancer

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    Rottenfusser Andrea

    2009-10-01

    Full Text Available Abstract Background In Her2-positive advanced breast cancer, the upfront use of trastuzumab is well established. Upon progression on first-line therapy, patients may be switched to lapatinib. Others however remain candidates for continued antibody treatment (treatment beyond progression. Here, we aimed to identify factors predicting for activity of second-line trastuzumab-based therapy. Methods Ninety-seven patients treated with > 1 line of trastuzumab-containing therapy were available for this analysis. Her2-status was determined by immunohistochemistry and re-analyzed by FISH if a score of 2+ was gained. Time to progression (TTP on second-line therapy was defined as primary study endpoint. TTP and overall survival (OS were estimated using the Kaplan-Meier product limit method. Multivariate analyses (Cox proportional hazards model, multinomial logistic regression were applied in order to identify factors associated with TTP, response, OS, and incidence of brain metastases. p values Results Median TTP on second-line trastuzumab-based therapy was 7 months (95% CI 5.74-8.26, and 8 months (95% CI 6.25-9.74 on first-line, respectively (n.s.. In the multivariate models, none of the clinical or histopthological features could reliably predict for activity of second-line trastuzumab-based treatment. OS was 43 months suggesting improved survival in patients treated with trastuzumab in multiple-lines. A significant deterioration of cardiac function was observed in three patients; 40.2% developed brain metastases while on second-line trastuzumab or thereafter. Conclusion Trastuzumab beyond progression showed considerable activity. None of the variables investigated correlated with activity of second-line therapy. In order to predict for activity of second-line trastuzumab, it appears necessary to evaluate factors known to confer trastuzumab-resistance.

  4. Positive Association of Fibroadenomatoid Change with HER2-Negative Invasive Breast Cancer: A Co-Occurrence Study.

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    Yaqin Chen

    Full Text Available Risk assessment of a benign breast disease/lesion (BBD for invasive breast cancer (IBC is typically done through a longitudinal study. For an infrequently-reported BBD, the shortage of occurrence data alone is a limiting factor to conducting such a study. Here we present an approach based on co-occurrence analysis, to help address this issue. We focus on fibroadenomatoid change (FAC, an under-studied BBD, as our preliminary analysis has suggested its previously unknown significant co-occurrence with IBC.A cohort of 1667 female patients enrolled in the Clinical Breast Care Project was identified. A single experienced breast pathologist reviewed all pathology slides for each case and recorded all observed lesions, including FAC. Fibroadenoma (FA was studied for comparison since FAC had been speculated to be an immature FA. FA and Fibrocystic Changes (FCC were used for method validation since they have been comprehensively studied. Six common IBC and BBD risk/protective factors were also studied. Co-occurrence analyses were performed using logistic regression models.Common risk/protective factors were associated with FA, FCC, and IBC in ways consistent with the literature in general, and they were associated with FAC, FA, and FCC in distinct patterns. Age was associated with FAC in a bell-shape curve so that middle-aged women were more likely to have FAC. We report for the first time that FAC is positively associated with IBC with odds ratio (OR depending on BMI (OR = 6.78, 95%CI = 3.43-13.42 at BMI25 kg/m2. This association is only significant with HER2-negative IBC subtypes.We conclude that FAC is a candidate risk factor for HER2-negative IBCs, and it is a distinct disease from FA. Co-occurrence analysis can be used for initial assessment of the risk for IBC from a BBD, which is vital to the study of infrequently-reported BBDs.

  5. Positive Association of Fibroadenomatoid Change with HER2-Negative Invasive Breast Cancer: A Co-Occurrence Study

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    Kovatich, Albert J.; Hooke, Jeffrey A.; Liu, Jianfang; Kvecher, Leonid; Fantacone-Campbell, J. Leigh; Mitchell, Edith P.; Rui, Hallgeir; Shriver, Craig D.; Hu, Hai

    2015-01-01

    Background Risk assessment of a benign breast disease/lesion (BBD) for invasive breast cancer (IBC) is typically done through a longitudinal study. For an infrequently-reported BBD, the shortage of occurrence data alone is a limiting factor to conducting such a study. Here we present an approach based on co-occurrence analysis, to help address this issue. We focus on fibroadenomatoid change (FAC), an under-studied BBD, as our preliminary analysis has suggested its previously unknown significant co-occurrence with IBC. Methods A cohort of 1667 female patients enrolled in the Clinical Breast Care Project was identified. A single experienced breast pathologist reviewed all pathology slides for each case and recorded all observed lesions, including FAC. Fibroadenoma (FA) was studied for comparison since FAC had been speculated to be an immature FA. FA and Fibrocystic Changes (FCC) were used for method validation since they have been comprehensively studied. Six common IBC and BBD risk/protective factors were also studied. Co-occurrence analyses were performed using logistic regression models. Results Common risk/protective factors were associated with FA, FCC, and IBC in ways consistent with the literature in general, and they were associated with FAC, FA, and FCC in distinct patterns. Age was associated with FAC in a bell-shape curve so that middle-aged women were more likely to have FAC. We report for the first time that FAC is positively associated with IBC with odds ratio (OR) depending on BMI (OR = 6.78, 95%CI = 3.43-13.42 at BMI25 kg/m2). This association is only significant with HER2-negative IBC subtypes. Conclusions We conclude that FAC is a candidate risk factor for HER2-negative IBCs, and it is a distinct disease from FA. Co-occurrence analysis can be used for initial assessment of the risk for IBC from a BBD, which is vital to the study of infrequently-reported BBDs. PMID:26098961

  6. CPT-11/bevacizumab for the treatment of refractory brain metastases in patients with HER2–neu-positive breast cancer

    Science.gov (United States)

    Sengupta, S.; Rojas, R.; Mahadevan, A.; Kasper, E.; Jeyapalan, S.

    2015-01-01

    Nervous system relapse of patients with advanced HER2–neu-positive breast cancer is an increasing problem, with one-third of women developing brain metastases. Standard therapies using steroids, surgery and radiotherapy do not provide a lasting response. We evaluated CPT-11 and bevacizumab, which can both cross the blood–brain barrier, as combination therapy to treat HER2–neu-positive breast cancer with brain metastases. PMID:26634139

  7. Coping with uncertainty: T1a,bN0M0 HER2-positive breast cancer, do we have a treatment threshold?

    LENUS (Irish Health Repository)

    Kelly, C M

    2012-02-01

    BACKGROUND: Recent retrospective studies have suggested that patients with T1a,bN0M0 human epidermal growth factor receptor 2 (HER2)-positive breast cancer are at a higher risk for recurrence and might benefit from adjuvant trastuzumab. The absolute benefits associated with treating this subgroup are uncertain. Design: We reviewed recent studies examining the prognostic value of HER2 in patients with node-negative T1a,b HER2-positive breast cancer. We calculated the number needed to treat (NNT) using baseline risk estimates for untreated T1a,bN0M0 breast cancer and the number needed to harm (NNH) using the incidence of cardiac events in each of the adjuvant trastuzumab clinical trials. RESULTS: Several studies were identified, each with limitations inherent to retrospective database analyses: small cohort sizes, lack of systematic HER2 testing in older specimens, variations in the use of adjuvant therapy and definitions of study end points, and lack of information relating to comorbidities. The 5-year disease-free survival in the pre-trastuzumab era ranged from 77% to 95%. Comparisons between small HER2 -positive and small HER2 -negative cancers showed numerically worse outcome for the HER2-positive cohort in some but not all studies. In many instances, the NNH was larger (26-250) than the NNT (13-35); however, in a subset of patients, the NNH was lower (6) than the NNT (13-35). CONCLUSIONS: Better prediction tools to estimate more precisely the risk for death due to comorbid illness versus breast cancer are needed. In some patients, the risks of therapy could outweigh the benefits. Treatment selection for T1a,bN0 HER2-positive cancers remains in the transition area between evidence- and subjective judgment-based medicine.

  8. Understanding Heterogeneity and Permeability of Brain Metastases in Murine Models of HER2-Positive Breast Cancer Through Magnetic Resonance Imaging: Implications for Detection and Therapy

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    Donna H. Murrell

    2015-06-01

    Full Text Available OBJECTIVES: Brain metastases due to breast cancer are increasing, and the prognosis is poor. Lack of effective therapy is attributed to heterogeneity of breast cancers and their resulting metastases, as well as impermeability of the blood–brain barrier (BBB, which hinders delivery of therapeutics to the brain. This work investigates three experimental models of HER2+ breast cancer brain metastasis to better understand the inherent heterogeneity of the disease. We use magnetic resonance imaging (MRI to quantify brain metastatic growth and explore its relationship with BBB permeability. DESIGN: Brain metastases due to breast cancer cells (SUM190-BR3, JIMT-1-BR3, or MDA-MB-231-BR-HER2 were imaged at 3 T using balanced steady-state free precession and contrast-enhanced T1-weighted spin echo sequences. The histology and immunohistochemistry corresponding to MRI were also analyzed. RESULTS: There were differences in metastatic tumor appearance by MRI, histology, and immunohistochemistry (Ki67, CD31, CD105 across the three models. The mean volume of an MDA-MB-231-BR-HER2 tumor was significantly larger compared to other models (F2,12 = 5.845, P < .05; interestingly, this model also had a significantly higher proportion of Gd-impermeable tumors (F2,12 = 22.18, P < .0001. Ki67 staining indicated that Gd-impermeable tumors had significantly more proliferative nuclei compared to Gd-permeable tumors (t[24] = 2.389, P < .05 in the MDA-MB-231-BR-HER2 model. CD31 and CD105 staining suggested no difference in new vasculature patterns between permeable and impermeable tumors in any model. CONCLUSION: Significant heterogeneity is present in these models of brain metastases from HER2+ breast cancer. Understanding this heterogeneity, especially as it relates to BBB permeability, is important for improvement in brain metastasis detection and treatment delivery.

  9. Adjuvant Trastuzumab in HER2-Positive Early Breast Cancer by Age and Hormone Receptor Status: A Cost-Utility Analysis.

    Science.gov (United States)

    Leung, William; Kvizhinadze, Giorgi; Nair, Nisha; Blakely, Tony

    2016-08-01

    The anti-human epidermal growth factor receptor 2 (HER2) monoclonal antibody trastuzumab improves outcomes in patients with node-positive HER2+ early breast cancer. Given trastuzumab's high cost, we aimed to estimate its cost-effectiveness by heterogeneity in age and estrogen receptor (ER) and progesterone receptor (PR) status, which has previously been unexplored, to assist prioritisation. A cost-utility analysis was performed using a Markov macro-simulation model, with a lifetime horizon, comparing a 12-mo regimen of trastuzumab with chemotherapy alone using the latest (2014) effectiveness measures from landmark randomised trials. A New Zealand (NZ) health system perspective was adopted, employing high-quality national administrative data. Incremental quality-adjusted life-years for trastuzumab versus chemotherapy alone are two times higher (2.33 times for the age group 50-54 y; 95% CI 2.29-2.37) for the worst prognosis (ER-/PR-) subtype compared to the best prognosis (ER+/PR+) subtype, causing incremental cost-effectiveness ratios (ICERs) for the former to be less than half those of the latter for the age groups from 25-29 to 90-94 y (0.44 times for the age group 50-54 y; 95% CI 0.43-0.45). If we were to strictly apply an arbitrary cost-effectiveness threshold equal to the NZ gross domestic product per capita (2011 purchasing power parity [PPP]-adjusted: US$30,300; €23,700; £21,200), our study suggests that trastuzumab (2011 PPP-adjusted US$45,400/€35,900/£21,900 for 1 y at formulary prices) may not be cost-effective for ER+ (which are 61% of all) node-positive HER2+ early breast cancer patients but cost-effective for ER-/PR- subtypes (37% of all cases) to age 69 y. Market entry of trastuzumab biosimilars will likely reduce the ICER to below this threshold for premenopausal ER+/PR- cancer but not for ER+/PR+ cancer. Sensitivity analysis using the best-case effectiveness measure for ER+ cancer had the same result. A key limitation was a lack of treatment

  10. Adjuvant Trastuzumab in HER2-Positive Early Breast Cancer by Age and Hormone Receptor Status: A Cost-Utility Analysis.

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    William Leung

    2016-08-01

    Full Text Available The anti-human epidermal growth factor receptor 2 (HER2 monoclonal antibody trastuzumab improves outcomes in patients with node-positive HER2+ early breast cancer. Given trastuzumab's high cost, we aimed to estimate its cost-effectiveness by heterogeneity in age and estrogen receptor (ER and progesterone receptor (PR status, which has previously been unexplored, to assist prioritisation.A cost-utility analysis was performed using a Markov macro-simulation model, with a lifetime horizon, comparing a 12-mo regimen of trastuzumab with chemotherapy alone using the latest (2014 effectiveness measures from landmark randomised trials. A New Zealand (NZ health system perspective was adopted, employing high-quality national administrative data. Incremental quality-adjusted life-years for trastuzumab versus chemotherapy alone are two times higher (2.33 times for the age group 50-54 y; 95% CI 2.29-2.37 for the worst prognosis (ER-/PR- subtype compared to the best prognosis (ER+/PR+ subtype, causing incremental cost-effectiveness ratios (ICERs for the former to be less than half those of the latter for the age groups from 25-29 to 90-94 y (0.44 times for the age group 50-54 y; 95% CI 0.43-0.45. If we were to strictly apply an arbitrary cost-effectiveness threshold equal to the NZ gross domestic product per capita (2011 purchasing power parity [PPP]-adjusted: US$30,300; €23,700; £21,200, our study suggests that trastuzumab (2011 PPP-adjusted US$45,400/€35,900/£21,900 for 1 y at formulary prices may not be cost-effective for ER+ (which are 61% of all node-positive HER2+ early breast cancer patients but cost-effective for ER-/PR- subtypes (37% of all cases to age 69 y. Market entry of trastuzumab biosimilars will likely reduce the ICER to below this threshold for premenopausal ER+/PR- cancer but not for ER+/PR+ cancer. Sensitivity analysis using the best-case effectiveness measure for ER+ cancer had the same result. A key limitation was a lack of

  11. Treatment patterns and real world clinical outcomes in ER+/HER2- post-menopausal metastatic breast cancer patients in the United States.

    Science.gov (United States)

    Zanotti, Giovanni; Hunger, Matthias; Perkins, Julia J; Horblyuk, Ruslan; Martin, Monique

    2017-06-02

    With several new therapies becoming available, treatment of metastatic breast cancer (mBC) is evolving. The objective of this study is to describe patient characteristics, treatment patterns and real-world clinical outcomes in post-menopausal women with ER+, HER2- mBC and to obtain insight into patient outcomes and potential unmet needs with current therapies. The current study is a physician survey followed by a retrospective chart review of patient medical records by physicians in the US between March and April 2015. One hundred three physicians were asked to complete an online survey aiming to understand their satisfaction and expectations with current available treatments and potential areas of unmet need for mBC patients. Medical records from 178 females were extracted for the chart review. Using these data from medical records, patient characteristics and treatment patterns were analyzed descriptively. Time to progression (TTP) on first line, and progression-free survival (PFS) on second and third line of therapy were analyzed using the Kaplan-Meier method. Sixty-seven percent (n = 119) of patients had metastatic disease at initial diagnosis of breast cancer. Mean age at chart data extraction was 65.8 (SD: 9.4) years. Aromatase inhibitors (AIs) were prescribed for 58% and around 13% of patients in first line and second line, respectively. Chemotherapy was prescribed to 14% in first line and 31% in second line. Median TTP on first line therapy was 12 months for patients receiving AIs as compared to 7.9 months for patients receiving chemotherapy. Across all treatment lines, bone pain and fatigue were reported as the main symptoms associated with disease progression which had an impact on patient quality of life. Physicians expressed that prolonging life was deemed the most important treatment goal, followed by preservation or improvement of quality of life. In this study the majority of patients received endocrine therapy as first line treatment and current

  12. Clinical efficacy and safety of T-DM1 for patients with HER2-positive breast cancer

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    Ma B

    2016-02-01

    Full Text Available Bo Ma,1 Qianqian Ma,2 Hongqiang Wang,3 Guolei Zhang,1 Huiying Zhang,1 Xiaohong Wang1 1Affiliated Central Hospital of Huzhou Teachers College, Huzhou, Zhejiang, People’s Republic of China; 2University Hospital of Tuebingen, Tuebingen, Germany; 3Department of Oncology, Hospital of Zhoushan, Zhoushan, Zhejiang, People’s Republic of China Purpose: The aim of this study was to evaluate the therapeutic efficacy and safety of trastuzumab emtansine (T-DM1 for the treatment of patients with human epidermal growth factor receptor 2-positive breast cancer.  Methods: We performed a systemic review and meta-analysis of the relevant published clinical studies. A computerized search was performed for controlled clinical trials of T-DM1 in targeted treatment. Overall survival, progression-free survival, objective response rate, symptom progression free, and adverse events (AEs were evaluated.  Results: Eight eligible trials with a total of 2,016 patients with breast cancer were included in the present meta-analysis. The treatment of patients with breast cancer with T-DM1 was associated with significantly increased overall and progression-free survival when compared with controls (P<0.0001. An analysis of the objective response rate and symptom progression free also demonstrated favorable results for T-DM1 treatment (P≤0.0001. There was no significant difference between the T-DM1 and control groups with respect to nonhematologic or hematologic AEs (P=0.99 and P=0.30, respectively.  Conclusion: Overall, T-DM1 is efficacious in the treatment of patients with human epidermal growth factor receptor 2-positive breast cancer and low rates of AEs compared with controls. Keywords: breast cancer, meta-analysis, HER2, T-DM1, efficacy

  13. Interaction of CDCP1 with HER2 Enhances HER2-Driven Tumorigenesis and Promotes Trastuzumab Resistance in Breast Cancer

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    Abdullah Alajati

    2015-04-01

    Full Text Available Understanding the molecular pathways that contribute to the aggressive behavior of HER2-positive breast cancers may aid in the development of novel therapeutic interventions. Here, we show that CDCP1 and HER2 are frequently co-overexpressed in metastatic breast tumors and associated with poor patient prognosis. HER2 and CDCP1 co-overexpression leads to increased transformation ability, cell migration, and tumor formation in vivo, and enhanced HER2 activation and downstream signaling in different breast cancer cell lines. Mechanistically, we demonstrate that CDCP1 binds to HER2 through its intracellular domain, thereby increasing HER2 interaction with the non-receptor tyrosine kinase c-SRC (SRC, leading to trastuzumab resistance. Taken together, our findings establish that CDCP1 is a modulator of HER2 signaling and a biomarker for the stratification of breast cancer patients with poor prognosis. Our results also provide a rationale for therapeutic targeting of CDCP1 in HER2-positive breast cancer patients.

  14. Cost-effectiveness analysis of trastuzumab in the adjuvant setting for treatment of HER2-positive breast cancer.

    Science.gov (United States)

    Garrison, Louis P; Lubeck, Deborah; Lalla, Deepa; Paton, Virginia; Dueck, Amylou; Perez, Edith A

    2007-08-01

    Adding trastuzumab to adjuvant chemotherapy provides significant clinical benefit in patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer. A cost-effectiveness analysis was performed to assess clinical and economic implications of adding trastuzumab to adjuvant chemotherapy, based upon joint analysis of NSABP B-31 and NCCTG N9831 trials. A Markov model with 4 health states was used to estimate the cost utility for a 50-year-old woman on the basis of trial results through 4 years and estimates of long-term recurrence and death based on a meta-analysis of trials. From 6 years onward, rates of recurrence and death were assumed to be the same in both trastuzumab and chemotherapy-only arms. Incremental costs were estimated for diagnostic and treatment-related costs. Analyses were from payer and societal perspectives, and these analyses were projected to lifetime and 20-year horizons. Over a lifetime, the projected cost of trastuzumab per quality-adjusted life year (QALY; discount rate 3%) gained was 26,417 dollars (range 9,104 dollars-69,340 dollars under multiway sensitivity analysis). Discounted incremental lifetime cost was 44,923 dollars, and projected life expectancy was 3 years longer for patients who received trastuzumab (19.4 years vs 16.4 years). During a 20-year horizon, the projected cost of adding trastuzumab to chemotherapy was 34,201 dollars per QALY gained. Key cost-effectiveness drivers were discount rate, trastuzumab price, and probability of metastasis. The cost-effectiveness result was robust to sensitivity analysis. Trastuzumab for adjuvant treatment of early stage breast cancer was projected to be cost effective over a lifetime horizon, achieving a cost-effectiveness ratio below that of many widely accepted oncology treatments. (c) 2007 American Cancer Society.

  15. Anti-HER2 CD4(+) T-helper type 1 response is a novel immune correlate to pathologic response following neoadjuvant therapy in HER2-positive breast cancer.

    Science.gov (United States)

    Datta, Jashodeep; Berk, Erik; Xu, Shuwen; Fitzpatrick, Elizabeth; Rosemblit, Cinthia; Lowenfeld, Lea; Goodman, Noah; Lewis, David A; Zhang, Paul J; Fisher, Carla; Roses, Robert E; DeMichele, Angela; Czerniecki, Brian J

    2015-05-23

    A progressive loss of circulating anti-human epidermal growth factor receptor-2/neu (HER2) CD4(+) T-helper type 1 (Th1) immune responses is observed in HER2(pos)-invasive breast cancer (IBC) patients relative to healthy controls. Pathologic complete response (pCR) following neoadjuvant trastuzumab and chemotherapy (T + C) is associated with decreased recurrence and improved prognosis. We examined differences in anti-HER2 Th1 responses between pCR and non-pCR patients to identify modifiable immune correlates to pathologic response following neoadjuvant T + C. Anti-HER2 Th1 responses in 87 HER2(pos)-IBC patients were examined using peripheral blood mononuclear cells pulsed with 6 HER2-derived class II peptides via IFN-γ ELISPOT. Th1 response metrics were anti-HER2 responsivity, repertoire (number of reactive peptides), and cumulative response across 6 peptides (spot-forming cells [SFC]/10(6) cells). Anti-HER2 Th1 responses of non-pCR patients (n = 4) receiving adjuvant HER2-pulsed type 1-polarized dendritic cell (DC1) vaccination were analyzed pre- and post-immunization. Depressed anti-HER2 Th1 responses observed in treatment-naïve HER2(pos)-IBC patients (n = 22) did not improve globally in T + C-treated HER2(pos)-IBC patients (n = 65). Compared with adjuvant T + C receipt, neoadjuvant T + C - utilized in 61.5 % - was associated with higher anti-HER2 Th1 repertoire (p = 0.048). While pCR (n = 16) and non-pCR (n = 24) patients did not differ substantially in demographic/clinical characteristics, pCR patients demonstrated dramatically higher anti-HER2 Th1 responsivity (94 % vs. 33 %, p = 0.0002), repertoire (3.3 vs. 0.3 peptides, p vs. 22.4 SFC/10(6), p non-pCR patients. After controlling for potential confounders, anti-HER2 Th1 responsivity remained independently associated with pathologic response (odds ratio 8.82, p = 0.016). This IFN-γ(+) immune disparity was mediated by anti-HER2 CD4(+)T-bet(+)IFN-γ(+) (i.e., Th1) - not CD4(+)GATA-3(+)IFN-γ(+) (i.e., Th2

  16. Efficacy and mechanism of action of the tyrosine kinase inhibitors gefitinib, lapatinib and neratinib in the treatment of HER2-positive breast cancer: preclinical and clinical evidence.

    Science.gov (United States)

    Segovia-Mendoza, Mariana; González-González, María E; Barrera, David; Díaz, Lorenza; García-Becerra, Rocío

    2015-01-01

    An increasing number of tumors, including breast cancer, overexpress proteins of the epidermal growth factor receptor (EGFR) family. The interaction between family members activates signaling pathways that promote tumor progression and resistance to treatment. Human epidermal growth factor receptor type II (HER2) positive breast cancer represents a clinical challenge for current therapy. It has motivated the development of novel and more effective therapeutic EGFR family target drugs, such as tyrosine kinase inhibitors (TKIs). This review focuses on the effects of three TKIs mostly studied in HER2- positive breast cancer, lapatinib, gefitinib and neratinib. Herein, we discuss the mechanism of action, therapeutic advantages and clinical applications of these TKIs. To date, TKIs seem to be promising therapeutic agents for the treatment of HER2-overexpressing breast tumors, either as monotherapy or combined with other pharmacological agents.

  17. Comparison of medical costs and healthcare resource utilization of post-menopausal women with HR+/HER2- metastatic breast cancer receiving everolimus-based therapy or chemotherapy: a retrospective claims database analysis.

    Science.gov (United States)

    Li, Nanxin; Hao, Yanni; Koo, Valerie; Fang, Anna; Peeples, Miranda; Kageleiry, Andrew; Wu, Eric Q; Guérin, Annie

    2016-01-01

    To analyze medical costs and healthcare resource utilization (HRU) associated with everolimus-based therapy or chemotherapy among post-menopausal women with hormone-receptor-positive, human-epidermal-growth-factor-receptor-2-negative (HR+/HER2-) metastatic breast cancer (mBC). Patients with HR+/HER2- mBC who discontinued a non-steroidal aromatase inhibitor and began a new line of treatment with everolimus-based therapy or chemotherapy (index therapy/index date) between July 20, 2012 and April 30, 2014 were identified from two large claims databases. All-cause, BC-related, and adverse event (AE)-related medical costs (in 2014 USD) and all-cause HRU per patient per month (PPPM) were analyzed for both treatment groups across patients' first four lines of therapies for mBC. Adjusted differences in costs and HRU between the everolimus and chemotherapy treatment group were estimated pooling all lines and using multivariable generalized linear models, accounting for difference in patient characteristics. A total of 3298 patients were included: 902 everolimus-treated patients and 2636 chemotherapy-treated patients. Compared to chemotherapy, everolimus was associated with significantly lower all-cause (adjusted mean difference = $3455, p well as significantly lower HRU (emergency room incidence rate ratio [IRR] = 0.83; inpatient IRR = 0.74; inpatient days IRR = 0.65; outpatient IRR = 0.71; BC-related outpatient IRR = 0.57; all p chemotherapy.

  18. HER2-targeted therapy in breast cancer. Monoclonal antibodies and tyrosine kinase inhibitors

    DEFF Research Database (Denmark)

    Nielsen, Dorte Lisbet; Andersson, Michael; Kamby, Claus

    2008-01-01

    There is strong clinical evidence that trastuzumab, a monoclonal antibody targeting the human epidermal growth factor receptor (HER) two tyrosine kinase receptor, is an important component of first-line treatment of patients with HER2-positive metastatic breast cancer. In particular the combination...... of trastuzumab to chemotherapy improves disease-free and overall survival. The use of lapatinib, a dual tyrosine kinase inhibitor of both HER1 and HER2, in combination with capecitabine in the second-line treatment of HER2-positive patients with metastatic breast cancer previously treated with trastuzumab has...

  19. Effect of PREDICT on chemotherapy/trastuzumab recommendations in HER2-positive patients with early-stage breast cancer

    OpenAIRE

    DOWN, SUE K.; LUCAS, OLIVIA; BENSON, JOHN R.; WISHART, GORDON C.

    2014-01-01

    PREDICT is an online prognostication tool for early-stage breast cancer, which incorporates human epidermal growth factor 2 (HER2) status and stratifies absolute treatment benefits for hormone therapy, chemotherapy and trastuzumab. The present study compared historical multidisciplinary team (MDT) decisions regarding adjuvant treatment with PREDICT estimates, to determine whether certain patients are being over- or undertreated, particularly when stratified by age and oestrogen-receptor (ER) ...

  20. RUNX1 positively regulates the ErbB2/HER2 signaling pathway through modulating SOS1 expression in gastric cancer cells.

    Science.gov (United States)

    Mitsuda, Yoshihide; Morita, Ken; Kashiwazaki, Gengo; Taniguchi, Junichi; Bando, Toshikazu; Obara, Moeka; Hirata, Masahiro; Kataoka, Tatsuki R; Muto, Manabu; Kaneda, Yasufumi; Nakahata, Tatsutoshi; Liu, Pu Paul; Adachi, Souichi; Sugiyama, Hiroshi; Kamikubo, Yasuhiko

    2018-04-23

    The dual function of runt-related transcriptional factor 1 (RUNX1) as an oncogene or oncosuppressor has been extensively studied in various malignancies, yet its role in gastric cancer remains elusive. Up-regulation of the ErbB2/HER2 signaling pathway is frequently-encountered in gastric cancer and contributes to the maintenance of these cancer cells. This signaling cascade is partly mediated by son of sevenless homolog (SOS) family, which function as adaptor proteins in the RTK cascades. Herein we report that RUNX1 regulates the ErbB2/HER2 signaling pathway in gastric cancer cells through transactivating SOS1 expression, rendering itself an ideal target in anti-tumor strategy toward this cancer. Mechanistically, RUNX1 interacts with the RUNX1 binding DNA sequence located in SOS1 promoter and positively regulates it. Knockdown of RUNX1 led to the decreased expression of SOS1 as well as dephosphorylation of ErbB2/HER2, subsequently suppressed the proliferation of gastric cancer cells. We also found that our novel RUNX inhibitor (Chb-M') consistently led to the deactivation of the ErbB2/HER2 signaling pathway and was effective against several gastric cancer cell lines. Taken together, our work identified a novel interaction of RUNX1 and the ErbB2/HER2 signaling pathway in gastric cancer, which can potentially be exploited in the management of this malignancy.

  1. Comparative effectiveness of everolimus-based therapy versus endocrine monotherapy among postmenopausal women with HR+/HER2- metastatic breast cancer: a retrospective chart review in community oncology practices in the US.

    Science.gov (United States)

    Xie, Jipan; Hao, Yanni; Li, Nanxin; Lin, Peggy L; Ohashi, Erika; Koo, Valerie; Signorovitch, James E; Wu, Eric Q; Yardley, Denise A

    2015-06-01

    Everolimus-based therapy and endocrine monotherapy are used among postmenopausal women with hormone receptor-positive human epidermal growth factor receptor-2 negative (HR+/HER2-) metastatic breast cancer (mBC) whose disease progressed or recurred on a non-steroidal aromatase inhibitor (NSAI). However, limited evidence exists regarding the real-world comparative effectiveness of these agents. This retrospective chart review examined postmenopausal HR+/HER2- mBC patients in community-based oncology practices who received everolimus-based therapy or endocrine monotherapy (index therapy) as any line of therapy for mBC between 1 July 2012 and 15 April 2013 after NSAI failure. Time on treatment (TOT), progression-free survival (PFS), and time to chemotherapy (TTC) from index therapy initiation were compared using Kaplan-Meier analyses and Cox proportional hazards models adjusting for baseline characteristics. A total of 243 and 270 patients received everolimus-based therapy or endocrine monotherapy in a quota-based sample. Patients treated with everolimus-based therapy had a higher proportion of visceral metastases, high tumor burden, and use of prior chemotherapies for mBC. After adjusting for baseline characteristics, everolimus-based therapy was associated with significantly longer TOT (HR = 0.67, 95% CI: 0.51-0.87) and PFS (HR = 0.75, 95% CI: 0.57-0.98) than endocrine monotherapy. No significant difference was found between everolimus-based therapy and endocrine monotherapy in TTC (HR = 0.81, 95% CI: 0.52-1.27). Results stratified by line of therapy were generally consistent with the overall results. Limitations include recall and information bias with potentially absent or erroneous chart data, unobserved factors due to non-randomization, inability to measure outcome assessments paired with measuring outcomes prior to exposures, and potential patient selection bias associated with chart review. Among a nationwide sample of postmenopausal HR+/HER2- m

  2. HER3 protein expression in relation to HER2 positivity in patients with primary colorectal cancer: clinical relevance and prognostic value.

    Science.gov (United States)

    Seo, An Na; Kwak, Yoonjin; Kim, Woo Ho; Kim, Duck-Woo; Kang, Sung-Bum; Choe, Gheeyoung; Lee, Hye Seung

    2015-06-01

    The clinical and prognostic significance of HER3 expression and its relation to HER2 status in primary colorectal cancer (pCRC) were investigated. We retrospectively analysed 365 consecutive cases of pCRC that had been previously evaluated for HER2 status and included their 143 matched lymph node metastases. Immunohistochemistry (IHC) was performed to assess HER3 expression using tissue array methods. Of 364 eligible patients, HER3 overexpression was detected in 251 cases (69 %) (IHC 2+, n = 186 and IHC 3+, n = 65). HER3 overexpression was inversely correlated with histologic grade (p = 0.006), tumour size (p < 0.001), tumour depth (p < 0.001), TNM stage (p = 0.002), lymphatic invasion (p = 0.004), lymph node metastasis (p = 0.013) and distant metastasis (p = 0.039). Moreover, it positively correlated with both HER2 overexpression (p = 0.007) and HER2 gene amplification (p = 0.006). Although HER3 overexpression was associated with longer survival in univariate analysis (p = 0.026), it was not an independent prognostic factor in multivariate analysis (p = 0.359). Moreover, co-alteration of HER3 and HER2 was associated with neither survival nor any clinicopathologic parameter except tumour location in the rectum. Although not an independent prognostic factor for overall survival, HER3 overexpression was associated with several favourable prognostic clinicopathologic parameters. Additionally, HER3 overexpression strongly correlated with HER2 positivity in this cohort of patients.

  3. Trastuzumab beyond progression: overall survival analysis of the GBG 26/BIG 3-05 phase III study in HER2-positive breast cancer

    DEFF Research Database (Denmark)

    von Minckwitz, Gunter; Schwedler, Kathrin; Schmidt, Marcus

    2011-01-01

    Continuation of trastuzumab plus capecitabine (XH) showed a significantly improved overall response rate and time to progression compared with capecitabine (X) alone in women with HER2-positive breast cancer progressing during trastuzumab treatment. Here, we report the final analysis on overall...

  4. Adjuvant Trastuzumab Therapy for Early HER2-Positive Breast Cancer in Iran: A Cost-Effectiveness and Scenario Analysis for an Optimal Treatment Strategy

    NARCIS (Netherlands)

    A. Ansaripour (Amir); C.A. Uyl-de Groot (Carin); W.K. Redekop (Ken)

    2017-01-01

    textabstractIntroduction: Clinical guidelines have recommended a 1-year trastuzumab regimen as standard care for early human epidermal growth factor receptor 2 (HER2)-positive breast cancer; however, this recommendation can have a dramatic impact on total drug expenditures in middle-income countries

  5. Invasive micropapillary carcinoma of the breast overexpresses MUC4 and is associated with poor outcome to adjuvant trastuzumab in HER2-positive breast cancer.

    Science.gov (United States)

    Mercogliano, María F; Inurrigarro, Gloria; De Martino, Mara; Venturutti, Leandro; Rivas, Martín A; Cordo-Russo, Rosalía; Proietti, Cecilia J; Fernández, Elmer A; Frahm, Isabel; Barchuk, Sabrina; Allemand, Daniel H; Figurelli, Silvina; Deza, Ernesto Gil; Ares, Sandra; Gercovich, Felipe G; Cortese, Eduardo; Amasino, Matías; Guzmán, Pablo; Roa, Juan C; Elizalde, Patricia V; Schillaci, Roxana

    2017-12-28

    Invasive micropapillary carcinoma of the breast (IMPC) is a histological tumor variant that occurs with low frequency characterized by an inside-out formation of tumor clusters with a pseudopapillary arrangement. IMPC is an aggressive tumor with poor clinical outcome. In addition, this histological subtype usually expresses human epidermal growth factor receptor 2 (HER2) which also correlates with a more aggressive tumor. In this work we studied the clinical significance of IMPC in HER2-positive breast cancer patients treated with adjuvant trastuzumab. We also analyzed mucin 4 (MUC4) expression as a novel biomarker to identify IMPC. We retrospectively studied 86 HER2-positive breast cancer patients treated with trastuzumab and chemotherapy in the adjuvant setting. We explored the association of the IMPC component with clinicopathological parameters at diagnosis and its prognostic value. We compared MUC4 expression in IMPC with respect to other histological breast cancer subtypes by immunohistochemistry. IMPC, either as a pure entity or associated with invasive ductal carcinoma (IDC), was present in 18.6% of HER2-positive cases. It was positively correlated with estrogen receptor expression and tumor size and inversely correlated with patient's age. Disease-free survival was significantly lower in patients with IMPC (hazard ratio = 2.6; 95%, confidence interval 1.1-6.1, P = 0.0340). MUC4, a glycoprotein associated with metastasis, was strongly expressed in all IMPC cases tested. IMPC appeared as the histological breast cancer subtype with the highest MUC4 expression compared to IDC, lobular and mucinous carcinoma. In HER2-positive breast cancer, the presence of IMPC should be carefully examined. As it is often not informed, because it is relatively difficult to identify or altogether overlooked, we propose MUC4 expression as a useful biomarker to highlight IMPC presence. Patients with MUC4-positive tumors with IMPC component should be more frequently

  6. HER2 Genetic Link to Breast Cancer

    Science.gov (United States)

    When researchers discovered the HER2 gene's importance to breast cancer growth, this led to the development of trastuzumab and other treatments that have improved survival for women with HER2-positive breast cancer.

  7. Regional Nodal Irradiation After Breast Conserving Surgery for Early HER2-Positive Breast Cancer: Results of a Subanalysis From the ALTTO Trial.

    Science.gov (United States)

    Gingras, Isabelle; Holmes, Eileen; De Azambuja, Evandro; Nguyen, David H A; Izquierdo, Miguel; Anne Zujewski, Jo; Inbar, Moshe; Naume, Bjorn; Tomasello, Gianluca; Gralow, Julie R; Wolff, Antonio C; Harris, Lyndsay; Gnant, Michael; Moreno-Aspitia, Alvaro; Piccart, Martine J; Azim, Hatem A

    2017-08-01

    Two randomized trials recently demonstrated that regional nodal irradiation (RNI) could reduce the risk of recurrence in early breast cancer; however, these trials were conducted in the pretrastuzumab era. Whether these results are applicable to human epidermal growth factor receptor 2 (HER2)-positive breast cancer patients treated with anti-HER2-targeted therapy is unknown. This retrospective analysis was performed on patients with node-positive breast cancer who were enrolled in the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization phase III adjuvant trial and subjected to BCS. The primary objective of the present study was to examine the effect of RNI on disease-free survival (DFS). A multivariable cox regression analysis adjusted for number of positive lymph nodes, tumor size, grade, age, hormone receptors status, presence of macrometastatis, treatment arm, and chemotherapy timing was carried out to investigate the relationship between RNI and DFS. One thousand six hundred sixty-four HER2-positive breast cancer patients were included, of whom 878 (52.8%) had received RNI to the axillary, supraclavicular, and/or internal mammary lymph nodes. Patients in the RNI group had higher nodal burden and more frequently had tumors larger than 2 cm. At a median follow-up of 4.5 years, DFS was 84.3% in the RNI group and 88.3% in the non-RNI group. No differences in regional recurrence (0.9 % vs 0.6 %) or in overall survival (93.6% vs 95.3%) were observed between the two groups. After adjustment in multivariable analysis, there was no statistically significant association between RNI and DFS (hazard ratio = 0.96, 95% confidence interval = 0.71 to 1.29). Our analysis did not demonstrate a DFS benefit of RNI in HER2-positive, node-positive patients treated with adjuvant HER2-targeted therapy. The benefit of RNI in HER2-positive breast cancer needs further testing within randomized clinical trials. © The Author 2017. Published by Oxford University Press. All

  8. Molecular essence and endocrine responsiveness of estrogen receptor-negative, progesterone receptor-positive, and HER2-negative breast cancer.

    Science.gov (United States)

    Yu, Ke-Da; Jiang, Yi-Zhou; Hao, Shuang; Shao, Zhi-Ming

    2015-10-05

    The clinical significance of progesterone receptor (PgR) expression in estrogen receptor-negative (ER-) breast cancer is controversial. Herein, we systemically investigate the clinicopathologic features, molecular essence, and endocrine responsiveness of ER-/PgR+/HER2- phenotype. Four study cohorts were included. The first and second cohorts were from the Surveillance, Epidemiology, and End Results database (n = 67,932) and Fudan University Shanghai Cancer Center (n = 2,338), respectively, for clinicopathologic and survival analysis. The third and fourth cohorts were from two independent publicly available microarray datasets including 837 operable cases and 483 cases undergoing neoadjuvant chemotherapy, respectively, for clinicopathologic and gene-expression analysis. Characterized genes defining subgroups within the ER-/PgR+/HER2- phenotype were determined and further validated. Clinicopathologic features and survival outcomes of the ER-/PgR+ phenotype fell in between the ER+/PgR+ and ER-/PgR- phenotypes, but were more similar to ER-/PgR-. Among the ER-/PgR+ phenotype, 30% (95% confidence interval [CI] 17-42%, pooled by a fixed-effects method) were luminal-like and 59% (95% CI 45-72%, pooled by a fixed-effects method) were basal-like. We further refined the characterized genes for subtypes within the ER-/PgR+ phenotype and developed an immunohistochemistry-based method that could determine the molecular essence of ER-/PgR+ using three markers, TFF1, CK5, and EGFR. Either PAM50-defined or immunohistochemistry-defined basal-like ER-/PgR+ cases have a lower endocrine therapy sensitivity score compared with luminal-like ER-/PgR+ cases (P defined basal-like ER-/PgR+ cases might not benefit from adjuvant endocrine therapy (log-rank P = 0.61 for sufficient versus insufficient endocrine therapy). The majority of ER-/PgR+/HER2- phenotype breast cancers are basal-like and associated with a lower endocrine therapy sensitivity score. Additional studies are needed

  9. Quantification of Cell-Free HER-2 DNA in Plasma from Breast Cancer Patients

    DEFF Research Database (Denmark)

    Sørensen, Patricia Diana; Andersen, Rikke Fredslund; Pallisgaard, Niels

    2015-01-01

    The purpose of this study was to quantify the free-circulating plasma HER-2 DNA (cfHER-2 DNA) and to assess the ability of analysis to discriminate between patients with primary breast cancer and healthy controls in order to detect metastatic recurrence in comparison with serum HER-2 protein...... and also HER-2 gene amplification. The study population consisted of 100 patients with primary breast cancer and 50 healthy female donors. An additional 22 patients with metastases were subsequently included. cfHER-2 DNA was quantified with a quantitative PCR method together with a reference gene. RESULTS......: Using a cut-off of 2.5 for the ratio of the cfHER-2 DNA/reference gene, three (of 15) tissue HER-2-positive patients had a ratio >2.5 prior to the detection of metastatic disease. In the post-metastatic/pre-chemotherapy setting, 11 (of 23) tissue HER-2-positive patients with metastases had a ratio >2...

  10. Is there any advantage to combined trastuzumab and chemotherapy in perioperative setting her 2neu positive localized gastric adenocarcinoma?

    Directory of Open Access Journals (Sweden)

    Albouzidi Abderrahmane

    2011-09-01

    Full Text Available Abstract We report here a 44-year-old Moroccan man with resectable gastric adenocarcinoma with overexpression of human epidermal growth factor receptor 2 (HER2 by immunohistochemistry who was treated with trastuzumab in combination with chemotherapy in perioperative setting. He received 3 cycles of neoadjuvant chemotherapy consisting of trastuzumab, oxaliplatin, and capecitabine. Afterwards, he received total gastrectomy with extended D2 lymphadenectomy without spleno-pancreatectomy. A pathologic complete response was obtained with a combination of trastuzumab and oxaliplatin and capecitabine. He received 3 more cycles of trastuzumab containing regimen postoperatively. We conclude that resectable gastric carcinoma with overexpression of the c-erbB-2 protein should ideally be managed with perioperative combination of trastuzumab with chemotherapy. Further research to evaluate trastuzumab in combination with chemotherapy regimens in the perioperative and adjuvant setting is urgently needed.

  11. A phase 1 study evaluating the combination of an allosteric AKT inhibitor (MK-2206) and trastuzumab in patients with HER2-positive solid tumors.

    Science.gov (United States)

    Hudis, Clifford; Swanton, Charles; Janjigian, Yelena Y; Lee, Ray; Sutherland, Stephanie; Lehman, Robert; Chandarlapaty, Sarat; Hamilton, Nicola; Gajria, Devika; Knowles, James; Shah, Jigna; Shannon, Keith; Tetteh, Ernestina; Sullivan, Daniel M; Moreno, Carolina; Yan, Li; Han, Hyo Sook

    2013-11-19

    Trastuzumab is effective in human epidermal growth factor receptor 2 (HER2)-over-expressing breast and gastric cancers. However, patients may develop resistance through downstream signaling via the phosphatidylinositol 3-kinase (PI3K)/AKT pathway. This phase 1 trial was conducted to determine the safety and tolerability of the investigational AKT inhibitor MK-2206, to prepare for future studies to determine whether the combination with trastuzumab could inhibit compensatory signaling. Patients with HER2+ treatment-refractory breast and gastroesophageal cancer were enrolled. Treatment consisted of standard doses of intravenous trastuzumab and escalating dose levels of oral MK-2206 using either an every-other-day (45 mg and 60 mg QOD) or once-weekly (135 mg and 200 mg QW) schedule. A total of 34 patients with HER2+ disease were enrolled; 31 received study-drug. The maximum tolerated dose (MTD) for MK-2206 in combination with trastuzumab was 60 mg for the QOD schedule and 135 mg for the QW schedule, although a true MTD was not established due to early termination of the trial. The most common treatment-emergent toxicities included fatigue, hyperglycemia, and dermatologic rash, consistent with prior experience; one death unrelated to treatment was reported. There was one complete response in a patient with metastatic breast cancer, one patient achieved a partial response, and 5 patients had stable disease for at least 4 months, despite progression on multiple prior trastuzumab- and lapatinib-based therapies. Results also indicate that trastuzumab does not affect the pharmacokinetics of MK-2206. Results suggest the AKT inhibitor MK-2206 can be safely combined with trastuzumab, and is associated with clinical activity, supporting further investigation. ClinicalTrials.gov; identifier: NCT00963547.

  12. Quantifying HER-2 expression on circulating tumor cells by ACCEPT.

    Directory of Open Access Journals (Sweden)

    Leonie Zeune

    Full Text Available Circulating tumor cells (CTCs isolated from blood can be probed for the expression of treatment targets. Immunofluorescence is often used for both the enumeration of CTC and the determination of protein expression levels related to treatment targets. Accurate and reproducible assessment of such treatment target expression levels is essential for their use in the clinic. To enable this, an open source image analysis program named ACCEPT was developed in the EU-FP7 CTCTrap and CANCER-ID programs. Here its application is shown on a retrospective cohort of 132 metastatic breast cancer patients from which blood samples were processed by CellSearch® and stained for HER-2 expression as additional marker. Images were digitally stored and reviewers identified a total of 4084 CTCs. CTC's HER-2 expression was determined in the thumbnail images by ACCEPT. 150 of these images were selected and sent to six independent investigators to score the HER-2 expression with and without ACCEPT. Concordance rate of the operators' scoring results for HER-2 on CTCs was 30% and could be increased using the ACCEPT tool to 51%. Automated assessment of HER-2 expression by ACCEPT on 4084 CTCs of 132 patients showed 8 (6.1% patients with all CTCs expressing HER-2, 14 (10.6% patients with no CTC expressing HER-2 and 110 (83.3% patients with CTCs showing a varying HER-2 expression level. In total 1576 CTCs were determined HER-2 positive. We conclude that the use of image analysis enables a more reproducible quantification of treatment targets on CTCs and leads the way to fully automated and reproducible approaches.

  13. Quantifying HER-2 expression on circulating tumor cells by ACCEPT.

    Science.gov (United States)

    Zeune, Leonie; van Dalum, Guus; Decraene, Charles; Proudhon, Charlotte; Fehm, Tanja; Neubauer, Hans; Rack, Brigitte; Alunni-Fabbroni, Marianna; Terstappen, Leon W M M; van Gils, Stephan A; Brune, Christoph

    2017-01-01

    Circulating tumor cells (CTCs) isolated from blood can be probed for the expression of treatment targets. Immunofluorescence is often used for both the enumeration of CTC and the determination of protein expression levels related to treatment targets. Accurate and reproducible assessment of such treatment target expression levels is essential for their use in the clinic. To enable this, an open source image analysis program named ACCEPT was developed in the EU-FP7 CTCTrap and CANCER-ID programs. Here its application is shown on a retrospective cohort of 132 metastatic breast cancer patients from which blood samples were processed by CellSearch® and stained for HER-2 expression as additional marker. Images were digitally stored and reviewers identified a total of 4084 CTCs. CTC's HER-2 expression was determined in the thumbnail images by ACCEPT. 150 of these images were selected and sent to six independent investigators to score the HER-2 expression with and without ACCEPT. Concordance rate of the operators' scoring results for HER-2 on CTCs was 30% and could be increased using the ACCEPT tool to 51%. Automated assessment of HER-2 expression by ACCEPT on 4084 CTCs of 132 patients showed 8 (6.1%) patients with all CTCs expressing HER-2, 14 (10.6%) patients with no CTC expressing HER-2 and 110 (83.3%) patients with CTCs showing a varying HER-2 expression level. In total 1576 CTCs were determined HER-2 positive. We conclude that the use of image analysis enables a more reproducible quantification of treatment targets on CTCs and leads the way to fully automated and reproducible approaches.

  14. Neoadjuvant letrozole for postmenopausal estrogen receptor-positive, HER2-negative breast cancer patients, a study from the Danish Breast Cancer Cooperative Group (DBCG)

    DEFF Research Database (Denmark)

    Skriver, Signe Korsgaard; Laenkholm, Anne-Vibeke; Rasmussen, Birgitte Bruun

    2018-01-01

    response and 55% of patients had partial pathological response. ER at 100%, ductal subtype, tumor size below 2 cm and lymph node-negative status was significantly associated with a better response to NET and malignancy grade 3 with a poorer response to NET. One patient progressed during treatment......INTRODUCTION: Neoadjuvant endocrine treatment (NET) is a low-toxicity approach to achieve operability in locally advanced breast cancer, and to facilitate breast conservation in early breast cancer, particular in patients with highly estrogen receptor (ER) positive and HER2-negative disease. Here......, we report the results obtained by neoadjuvant letrozole in patients with early breast cancer in a phase-II design. MATERIAL AND METHODS: A total of 119 postmenopausal women with ER-positive, HER2-negative operable breast cancer were assigned to four months of neoadjuvant letrozole before definitive...

  15. A definition for aggressive disease in patients with HER-2 negative metastatic breast cancer: an expert consensus of the Spanish Society of Medical Oncology (SEOM).

    Science.gov (United States)

    González, A; Lluch, A; Aba, E; Albanell, J; Antón, A; Álvarez, I; Ayala, F; Barnadas, A; Calvo, L; Ciruelos, E; Cortés, J; de la Haba, J; López-Vega, J M; Martínez, E; Muñoz, M; Peláez, I; Redondo, A; Rodríguez, Á; Rodríguez, C A; Ruíz, A; Llombart, A

    2017-05-01

    To converge on an expert opinion to define aggressive disease in patients with HER2-negative mBC using a modified Delphi methodology. A panel of 21 breast cancer experts from the Spanish Society of Medical Oncology agreed upon a survey which comprised 47 questions that were grouped into three sections: relevance for defining aggressive disease, aggressive disease criteria and therapeutic goals. Answers were rated using a 9-point Likert scale of relevance or agreement. Among the 88 oncologists that were invited to participate, 81 answered the first round (92%), 70 answered the second round (80%), and 67 answered the third round (76%) of the survey. There was strong agreement regarding the fact that identifying patients with aggressive disease needs to be adequately addressed to help practitioners to decide the best treatment options for patients with HER2-negative mBC. The factors that were considered to be strongly relevant to classifying patients with aggressive HER2-negative mBC were a high tumor burden, a disease-free interval of less than 12-24 months after surgery, the presence of progressive disease during adjuvant or neoadjuvant chemotherapy and having a triple-negative phenotype. The main therapeutic goals were controlling symptoms, improving quality of life and increasing the time to progression and overall survival. High tumor burden, time to recurrence after prior therapy and having a triple-negative phenotype were the prognostic factors for which the greatest consensus was found for identifying patients with aggressive HER2-negative mBC. Identifying patients with aggressive disease leads to different therapeutic approaches.

  16. Phase I clinical trial of HER2-specific immunotherapy with concomitant HER2 kinase inhibtion

    Directory of Open Access Journals (Sweden)

    Hamilton Erika

    2012-02-01

    Full Text Available Abstract Background Patients with HER2-overexpressing metastatic breast cancer, despite initially benefiting from the monoclonal antibody trastuzumab and the EGFR/HER2 tyrosine kinase inhibitor lapatinib, will eventually have progressive disease. HER2-based vaccines induce polyclonal antibody responses against HER2 that demonstrate enhanced anti-tumor activity when combined with lapatinib in murine models. We wished to test the clinical safety, immunogenicity, and activity of a HER2-based cancer vaccine, when combined with lapatinib. Methods We immunized women (n = 12 with metastatic, trastuzumab-refractory, HER2-overexpressing breast cancer with dHER2, a recombinant protein consisting of extracellular domain (ECD and a portion of the intracellular domain (ICD of HER2 combined with the adjuvant AS15, containing MPL, QS21, CpG and liposome. Lapatinib (1250 mg/day was administered concurrently. Peripheral blood antibody and T cell responses were measured. Results This regimen was well tolerated, with no cardiotoxicity. Anti-HER2-specific antibody was induced in all patients whereas HER2-specific T cells were detected in one patient. Preliminary analyses of patient serum demonstrated downstream signaling inhibition in HER2 expressing tumor cells. The median time to progression was 55 days, with the majority of patients progressing prior to induction of peak anti-HER2 immune responses; however, 300-day overall survival was 92% (95% CI: 77-100%. Conclusions dHER2 combined with lapatinib was safe and immunogenic with promising long term survival in those with HER2-overexpressing breast cancers refractory to trastuzumab. Further studies to define the anticancer activity of the antibodies induced by HER2 vaccines along with lapatinib are underway. Trial registry ClinicalTrials.gov NCT00952692

  17. Assessment of the tumor load as well as toxic and side effects after herceptin combined with doxorubicin liposome treatment of HER-2 positive breast cance

    Directory of Open Access Journals (Sweden)

    Guo-Quan Wen

    2016-12-01

    Full Text Available Objective: To study the effect of herceptin combined with doxorubicin liposome treatment on tumor load as well as toxic and side effects of HER-2 positive breast cancer. Methods: A total of 138 patients with HER-2 positive breast cancer who received chemotherapy in our hospital between July 2014 and December 2015 were selected as the research subjects and randomly divided into two groups, liposome group received herceptin combined with doxorubicin liposome treatment and control group received herceptin combined with doxorubicin treatment. After 8 weeks of treatment, the content of tumor markers, active molecules and myocardial injury markers in serum as well as the expression levels of immune marker molecules in peripheral blood mononuclear cells were detected. Results: After 8 weeks of treatment, CEA, CA199, CA153, CA125, VEGF, nectin-4, TK-1, PF-4, TSGF, CK, CK-MB, cTnI and cTnT content in serum of liposome group were significantly lower than those of control group, and the fluorescence intensity of CD3, CD4, CD8, CD16, CD19 and CD25 on peripheral blood mononuclear cell surface were significantly higher than those of control group. Conclusions: Herceptin combined with doxorubicin liposome treatment of HER-2 positive breast cancer can more effectively reduce the tumor load and cause less toxic and side effects on the heart and the immune system.

  18. Kit for the preparation of 111In-labeled pertuzumab injection for imaging response of HER2-positive breast cancer to trastuzumab (Herceptin)

    International Nuclear Information System (INIS)

    Lam, Karen; Scollard, Deborah A.; Chan, Conrad; Levine, Mark N.; Reilly, Raymond M.

    2015-01-01

    We previously reported that 111 In-labeled pertuzumab imaged trastuzumab (Herceptin)-mediated changes in HER2 expression preclinically in breast cancer tumors. To advance 111 In-labeled pertuzumab to a Phase I/II clinical trial, a kit was designed for preparing this agent in a form suitable for human administration. Unit-dose kits containing pertuzumab modified with 2-(4-isothiocyanatobenzyl)-diethylenetriaminepentaacetic acid (BzDTPA) were prepared that labeled to high efficiency (>90%) with 111 In and met specifications for pharmaceutical quality. The kits were stable for 4 months and the final radiopharmaceutical was stable for 24 h. Imaging studies demonstrated high and specific uptake in HER2-positive tumors in mice using this clinical kit formulation. - Highlights: • Kits for preparing 111 In-BzDTPA-pertuzumab were prepared which met specifications for pharmaceutical quality. • The kits were stable for at least 4 months and the final radiopharmaceutical was stable for 24 h when stored at 2–8 °C. • High labeling efficiency (>90%) of the kits was achieved with 111 In. • 111 In-BzDTPA-pertuzumab exhibited stability in human plasma. • Biodistribution and microSPECT imaging showed specific targeting of HER2-positive tumors in mice using the kit formulation

  19. Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial

    DEFF Research Database (Denmark)

    Martin, Miguel; Holmes, Frankie A; Ejlertsen, Bent

    2017-01-01

    BACKGROUND: ExteNET showed that 1 year of neratinib, an irreversible pan-HER tyrosine kinase inhibitor, significantly improves 2-year invasive disease-free survival after trastuzumab-based adjuvant therapy in women with HER2-positive breast cancer. We report updated efficacy outcomes from...... cancer, who had completed neoadjuvant and adjuvant chemotherapy plus trastuzumab with no evidence of disease recurrence or metastatic disease at study entry. Patients who were eligible patients were randomly assigned (1:1) via permuted blocks stratified according to hormone receptor status (hormone....../day or matching placebo. Treatment was given continuously for 1 year, unless disease recurrence or new breast cancer, intolerable adverse events, or consent withdrawal occurred. Patients, investigators, and trial funder were masked to treatment allocation. The predefined endpoint of the 5-year analysis...

  20. Tumor-Targeting Salmonella typhimurium A1-R in Combination with Trastuzumab Eradicates HER-2-Positive Cervical Cancer Cells in Patient-Derived Mouse Models.

    Directory of Open Access Journals (Sweden)

    Yukihiko Hiroshima

    Full Text Available We have previously developed mouse models of HER-2-positive cervical cancer. Tumors in nude mice had histological structures similar to the original tumor and were stained by anti-HER-2 antibody in the same pattern as the patient's cancer. We have also previously developed tumor-targeting Salmonella typhimurium A1-R and have demonstrated its efficacy against patient-derived tumor mouse models, both alone and in combination. In the current study, we determined the efficacy of S. typhimurium A1-R in combination with trastuzumab on a patient-cancer nude-mouse model of HER-2 positive cervical cancer. Mice were randomized to 5 groups and treated as follows: (1 no treatment; (2 carboplatinum (30 mg/kg, ip, weekly, 5 weeks; (3 trastuzumab (20 mg/kg, ip, weekly, 5 weeks; (4 S. typhimurium A1-R (5 × 107 CFU/body, ip, weekly, 5 weeks; (5 S. typhimurium A1-R (5 × 107 CFU/body, ip, weekly, 5 weeks + trastuzumab (20 mg/kg, ip, weekly, 5 weeks. All regimens had significant efficacy compared to the untreated mice. The relative tumor volume of S. typhimurium A1-R + trastuzumab-treated mice was smaller compared to trastuzumab alone (p = 0.007 and S. typhimurium A1-R alone (p = 0.039. No significant body weight loss was found compared to the no treatment group except for carboplatinum-treated mice (p = 0.021. Upon histological examination, viable tumor cells were not detected, and replaced by stromal cells in the tumors treated with S. typhimurium A1-R + trastuzumab. The results of the present study suggest that S. typhimurium A1-R and trastuzumab in combination are highly effective against HER-2-expressing cervical cancer.

  1. Standard Pathologic Features Can Be Used to Identify a Subset of Estrogen Receptor-Positive, HER2 Negative Patients Likely to Benefit from Neoadjuvant Chemotherapy.

    Science.gov (United States)

    Petruolo, Oriana A; Pilewskie, Melissa; Patil, Sujata; Barrio, Andrea V; Stempel, Michelle; Wen, Hannah Y; Morrow, Monica

    2017-09-01

    The benefit of neoadjuvant chemotherapy (NAC) in patients with estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancers and in invasive lobular carcinoma (ILC) is uncertain due to the low rates of pathologic complete response (pCR). The aim of this study was to determine if pathologic features can identify subsets likely to benefit from NAC. Patients with stage I-III ER+, HER2- breast cancer receiving NAC were retrospectively reviewed. Endpoints were downstaging to breast-conserving surgery (BCS) and nodal pCR after NAC. Patients were grouped by progesterone receptor (PR) status and grade/differentiation (high grade or poor [HP] vs. non-HP). From 2007 to 2016, 402 ER+/HER2- cancers in patients receiving NAC were identified. Median age was 50 years, 98% were clinical stage II-III, and 75% were cN+. Overall pCR rate was 5%; breast pCR in 7% and nodal pCR in 15% of cN+ patients (p benefit from NAC are those with PR- and HP tumors. Patients with ILC are unlikely to downstage in the breast or axilla compared with IDC. The use of these criteria can assist in defining the initial treatment approach.

  2. Limitations in predicting PAM50 intrinsic subtype and risk of relapse score with Ki67 in estrogen receptor-positive HER2-negative breast cancer

    Science.gov (United States)

    Fernand ez-Martinez, Aranzazu; Pascual, Tomás; Perrone, Giuseppe; Morales, Serafin; de la Haba, Juan; González-Rivera, Milagros; Galván, Patricia; Zalfa, Francesca; Amato, Michela; Gonzalez, Lucia; Prats, Miquel; Rojo, Federico; Manso, Luis; Paré, Laia; Alonso, Immaculada; Albanell, Joan; Vivancos, Ana; González, Antonio; Matito, Judit; González, Sonia; Fernandez, Pedro; Adamo, Barbara; Muñoz, Montserrat; Viladot, Margarita; Font, Carme; Aya, Francisco; Vidal, Maria; Caballero, Rosalía; Carrasco, Eva; Altomare, Vittorio; Tonini, Giuseppe; Prat, Aleix; Martin, Miguel

    2017-01-01

    PAM50/Prosigna gene expression-based assay identifies three categorical risk of relapse groups (ROR-low, ROR-intermediate and ROR-high) in post-menopausal patients with estrogen receptor estrogen receptor-positive (ER+)/ HER2-negative (HER2-) early breast cancer. Low risk patients might not need adjuvant chemotherapy since their risk of distant relapse at 10-years is below 10% with endocrine therapy only. In this study, 517 consecutive patients with ER+/HER2- and node-negative disease were evaluated for Ki67 and Prosigna. Most of Luminal A tumors (65.6%) and ROR-low tumors (70.9%) had low Ki67 values (0-10%); however, the percentage of patients with ROR-medium or ROR-high disease within the Ki67 0-10% group was 42.7% (with tumor sizes ≤2 cm) and 33.9% (with tumor sizes > 2 cm). Finally, we found that the optimal Ki67 cutoff for identifying Luminal A or ROR-low tumors was 14%. Ki67 as a surrogate biomarker in identifying Prosigna low-risk outcome patients or Luminal A disease in the clinical setting is unreliable. In the absence of a well-validated prognostic gene expression-based assay, the optimal Ki67 cutoff for identifying low-risk outcome patients or Luminal A disease remains at 14%. PMID:28423537

  3. Positive response to neoadjuvant cyclophosphamide and doxorubicin in topoisomerase II nonamplified/HER2/neu negative/polysomy 17 absent breast cancer patients

    Directory of Open Access Journals (Sweden)

    Henry G Kaplan

    2010-08-01

    Full Text Available Henry G Kaplan1, Judith A Malmgren2,3, Mary Atwood1, Lynn C Goldstein41Swedish Cancer Institute at Swedish Medical Center, Seattle, Washington, USA; 2HealthStat Consulting Inc., Seattle, Washington, USA; 3School of Public Health and Community Medicine, Department of Epidemiology, University of Washington, Seattle, Washington, USA; 4PhenoPath Laboratories, Seattle, Washington, USAPurpose: Human epidermal growth factor receptor 2 (HER2/neu, topoisomerase II alpha (TOP2A, and polysomy 17 may predict tumor responsiveness to doxorubicin (DOX therapy.Methods: We identified neoadjuvant DOX/cyclophosphamide treated breast cancer patients in our registry from 1997 to 2008 with sufficient tissue for testing (n = 34. Fluorescence in situ hybridization (FISH testing was done on deparaffinized tissue sections pretreated using vendor’s standard protocol modification, and incubated with US Food and Drug Administration approved Abbott Diagnostics Vysis PathVysion™ probe set, including Spectrum-Green-conjugated probe to a-satellite DNA located at the centromere of chromosome 17 (17p11.1–q11.1 and a Spectrum-Orange-conjugated probe to the TOP2A gene. Morphometric analysis was performed using a MetaSystems image analysis system. Manual counting was performed on all samples in which autofluorescence and/or artifact prevented the counting of sufficient numbers of cells. A ratio >2.0 was considered positive for TOP2A amplification. Polysomy 17 (PS17 presence was defined as signals of ≥2.5. Outcomes were pathological complete response (pCR, partial response (PR, and nonresponse (NR.Results: Of 34 patients tested, one was TOP2A amplified (hormone receptor negative/HER2 ­negative, partial responder. The subset of TOP2A nonamplified, HER2 negative, and PS17 absent (n = 23 patients had treatment response: pCR = 2 (9%, PR = 14 (61%, and NR = 7 (30%. Including the two PS17 present and HER2-positive patients (n = 33, 76% of TOP2A nonamplified patients had pCR or PR

  4. Peripheral position of CCND1 and HER-2/neu oncogenes within chromosome territories in esophageal and gastric cancers non-related to amplification and overexpression

    Directory of Open Access Journals (Sweden)

    Lucimari Bizari

    2009-01-01

    Full Text Available Interphase chromosomes have been shown to occupy discrete regions of the nucleus denominated chromosome territories (CTs, their active genes being preferentially positioned on the surfaces of these CTs, where they are accessible to transcriptional machinery. By means of FISH (Fluorescence in situ Hybridization, we analyzed the CCND1 and HER-2/neu gene positions within the CTs and their relationship with gene amplification and protein over-expression in esophageal and gastric cancers. The CCND1 and HER-2/Neu genes were more often positioned at the periphery (mean frequency of 60%-83% of the CTs in tumor tissues of the esophagus and stomach. Moreover, this positioning revealed no association with either gene amplification or the protein over-expression status of these genes, although, in esophageal carcinoma, Kappa statistics showed a moderate agreement between amplification of the CCND1 gene (Kappa = 0.400 and its location within the CT, as well as with over-expression of the corresponding protein (Kappa = 0.444. Thus, our results suggest that gene positioning in interphase chromosomes does not follow a definitive pattern neither does it depend only on gene transcriptional activity. Apparently, this positioning could be both gene- and tissue-specific, and depends on other factors acting together, such as dense-gene, chromosome size, chromatin structure, and the level and stability of its expression.

  5. Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

    Science.gov (United States)

    Chan, Arlene; Delaloge, Suzette; Holmes, Frankie A; Moy, Beverly; Iwata, Hiroji; Harvey, Vernon J; Robert, Nicholas J; Silovski, Tajana; Gokmen, Erhan; von Minckwitz, Gunter; Ejlertsen, Bent; Chia, Stephen K L; Mansi, Janine; Barrios, Carlos H; Gnant, Michael; Buyse, Marc; Gore, Ira; Smith, John; Harker, Graydon; Masuda, Norikazu; Petrakova, Katarina; Zotano, Angel Guerrero; Iannotti, Nicholas; Rodriguez, Gladys; Tassone, Pierfrancesco; Wong, Alvin; Bryce, Richard; Ye, Yining; Yao, Bin; Martin, Miguel

    2016-03-01

    Neratinib, an irreversible tyrosine-kinase inhibitor of HER1, HER2, and HER4, has clinical activity in patients with HER2-positive metastatic breast cancer. We aimed to investigate the efficacy and safety of 12 months of neratinib after trastuzumab-based adjuvant therapy in patients with early-stage HER2-positive breast cancer. We did this multicentre, randomised, double-blind, placebo-controlled, phase 3 trial at 495 centres in Europe, Asia, Australia, New Zealand, and North and South America. Eligible women (aged ≥18 years, or ≥20 years in Japan) had stage 1-3 HER2-positive breast cancer and had completed neoadjuvant and adjuvant trastuzumab therapy up to 2 years before randomisation. Inclusion criteria were amended on Feb 25, 2010, to include patients with stage 2-3 HER2-positive breast cancer who had completed trastuzumab therapy up to 1 year previously. Patients were randomly assigned (1:1) to receive oral neratinib 240 mg per day or matching placebo. The randomisation sequence was generated with permuted blocks stratified by hormone receptor status (hormone receptor-positive [oestrogen or progesterone receptor-positive or both] vs hormone receptor-negative [oestrogen and progesterone receptor-negative]), nodal status (0, 1-3, or ≥4), and trastuzumab adjuvant regimen (sequentially vs concurrently with chemotherapy), then implemented centrally via an interactive voice and web-response system. Patients, investigators, and trial sponsors were masked to treatment allocation. The primary outcome was invasive disease-free survival, as defined in the original protocol, at 2 years after randomisation. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00878709. Between July 9, 2009, and Oct 24, 2011, we randomly assigned 2840 women to receive neratinib (n=1420) or placebo (n=1420). Median follow-up time was 24 months (IQR 20-25) in the neratinib group and 24 months (22-25) in the placebo group. At 2 year follow-up, 70

  6. Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) as second-line chemotherapy in HER2-negative, taxane-pretreated metastatic breast cancer patients: prospective evaluation of activity, safety, and quality of life.

    Science.gov (United States)

    Palumbo, Raffaella; Sottotetti, Federico; Trifirò, Giuseppe; Piazza, Elena; Ferzi, Antonella; Gambaro, Anna; Spinapolice, Elena Giulia; Pozzi, Emma; Tagliaferri, Barbara; Teragni, Cristina; Bernardo, Antonio

    2015-01-01

    A prospective, multicenter trial was undertaken to assess the activity, safety, and quality of life of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) as second-line chemotherapy in HER2-negative, taxane-pretreated metastatic breast cancer (MBC). Fifty-two women with HER2-negative MBC who were candidates for second-line chemotherapy for the metastatic disease were enrolled and treated at three centers in Northern Italy. All patients had previously received taxane-based chemotherapy in the adjuvant or first-line metastatic setting. Single-agent nab-paclitaxel was given at the dose of 260 mg/m(2) as a 30-minute intravenous infusion on day 1 each treatment cycle, which lasted 3 weeks, in the outpatient setting. No steroid or antihistamine premedication was provided. Treatment was stopped for documented disease progression, unacceptable toxicity, or patient refusal. All of the enrolled patients were evaluable for the study endpoints. The objective response rate was 48% (95% CI, 31.5%-61.3%) and included complete responses from 13.5%. Disease stabilization was obtained in 19 patients and lasted >6 months in 15 of them; the overall clinical benefit rate was 77%. The median time to response was 70 days (range 52-86 days). The median progression-free survival time was 8.9 months (95% CI, 8.0-11.6 months, range 5-21+ months). The median overall survival point has not yet been reached. Toxicities were expected and manageable with good patient compliance and preserved quality of life in patients given long-term treatment. Our results showed that single-agent nab-paclitaxel 260 mg/m(2) every 3 weeks is an effective and well tolerated regimen as second-line chemotherapy in HER2-negative, taxane-pretreated MBC patients, and that it produced interesting values of objective response rate and progression-free survival without the concern of significant toxicity. Specifically, the present study shows that such a regimen is a valid therapeutic option for that 'difficult to

  7. Trastuzumab in the adjuvant treatment of HER2-positive early breast cancer patients: a meta-analysis of published randomized controlled trials.

    Directory of Open Access Journals (Sweden)

    Wenjin Yin

    Full Text Available BACKGROUND: Adjuvant trastuzumab therapy has yielded conflicting results for overall survival, concerns about central nervous system (CNS metastasis, and questions about optimal schedule. Therefore, we carried out a meta-analysis to assess the benefits of concurrent or sequential trastuzumab with adjuvant chemotherapy for early breast cancer patients with HER2-positive tumors. METHODS: Computerized and manual searches were performed to identify randomized clinical trials comparing adjuvant chemotherapy with or without trastuzumab in HER2-positive early breast cancer patients. Odds ratios were used to estimate the association between the addition of trastuzumab to adjuvant chemotherapy and various survival outcomes. The fixed-effects or random-effects model was used to combine data. FINDINGS: With six eligible studies identified, this analysis demonstrated that patients with HER2-positive breast cancer derived benefit in disease-free survival, overall survival, locoregional recurrence and distant recurrence (all P<0.001 from the addition of trastuzumab to adjuvant chemotherapy, whereas trastuzumab did worse in CNS recurrence as compared to the control group (P = 0.018. Furthermore, concomitant use of trastuzumab significantly lowered the hazard of death (P<0.001 but bore a higher incidence of CNS recurrence (P = 0.010, while statistical significance failed to be discerned for either overall survival (P = 0.069 or CNS metastasis (P = 0.374 between the sequential and observation arms. CONCLUSION: This analysis verifies the efficacy of trastuzumab in the adjuvant setting. Additionally, our findings indirectly corroborate the superiority of concurrent trastuzumab to sequential use and also illuminate that prolonged survival is the possible reason for the higher incidence of CNS with trastuzumab versus observation.

  8. Decreased background parenchymal enhancement of the contralateral breast after two cycles of neoadjuvant chemotherapy is associated with tumor response in HER2-positive breast cancer.

    Science.gov (United States)

    You, Chao; Gu, Yajia; Peng, Wen; Li, Jianwei; Shen, Xuxia; Liu, Guangyu; Peng, Weijun

    2018-07-01

    Background Several recent studies have focused on the association between background parenchymal enhancement (BPE) and tumor response to neoadjuvant chemotherapy (NAC), but early prediction of tumor response based on BPE has yet not been investigated. Purpose To retrospectively investigate whether changes in the BPE of the contralateral breast following NAC could help predict tumor response in early stage HER2-positive breast cancer. Material and Methods Data from 71 patients who were diagnosed with unilateral HER2 positive breast cancer and then underwent NAC with trastuzumab before surgery were analyzed retrospectively. Two experienced radiologists independently categorized the patients' levels of BPE of the contralateral breast into four categories (1 = minimal, 2 = mild, 3 = moderate, 4 = marked) at baseline and after the second cycle of NAC. After undergoing surgery, 34 patients achieved pathologic complete response (pCR) and 37 patients had residual disease (non-pCR). The association between BPE and histopathologic tumor response was analyzed. Result The level of BPE was higher in premenopausal than post-menopausal women both at baseline and after the second cycle of NAC ( P < 0.005). A significant reduction in BPE ( P < 0.001) was observed after the second NAC cycle; however, a more obvious decrease in BPE was identified in premenopausal relative to post-menopausal women ( P = 0.041). No significant association was identified between pCR and baseline BPE ( P = 0.287). However, after the second NAC cycle, decreased BPE was significantly associated with pCR ( P = 0.003). Conclusion For HER2-positive patients, changes in BPE may serve as an additional imaging biomarker of treatment response at an early stage.

  9. Constitutional variants are not associated with HER2-positive breast cancer: results from the SIGNAL/PHARE clinical cohort

    OpenAIRE

    Pivot, Xavier; Romieu, Gilles; Fumoleau, Pierre; Rios, Maria; Bonnefoi, Herv?; Bachelot, Thomas; Souli?, Patrick; Jouannaud, Christelle; Bourgeois, Hugues; Petit, Thierry; Tennevet, Isabelle; Assouline, David; Mathieu, Marie-Christine; Jacquin, Jean-Philippe; Lavau-Denes, Sandrine

    2017-01-01

    Human epidermal growth factor receptor 2-positive breast cancer is a subtype of interest regarding its outcome and the impressive impact of human epidermal growth factor receptor 2 targeted therapy. Constitutional variants may be involved in the aetiology of human epidermal growth factor receptor 2-positive breast cancer, and we propose a case?case study to test the hypothesis that single nucleotide polymorphisms may be associated with human epidermal growth factor receptor 2 status. A Genome...

  10. Prevalence of Circulating Tumor Cells After Adjuvant Chemotherapy With or Without Anthracyclines in Patients With HER2-negative, Hormone Receptor-positive Early Breast Cancer.

    Science.gov (United States)

    Schramm, Amelie; Schochter, Fabienne; Friedl, Thomas W P; de Gregorio, Nikolaus; Andergassen, Ulrich; Alunni-Fabbroni, Marianna; Trapp, Elisabeth; Jaeger, Bernadette; Heinrich, Georg; Camara, Oumar; Decker, Thomas; Ober, Angelika; Mahner, Sven; Fehm, Tanja N; Pantel, Klaus; Fasching, Peter A; Schneeweiss, Andreas; Janni, Wolfgang; Rack, Brigitte K

    2017-07-01

    Use of anthracycline-based chemotherapy in patients with early breast cancer (EBC) has been well-established but is often associated with cardiotoxicity. Based on data suggesting a limited benefit of anthracyclines in human epidermal growth factor receptor 2 (HER2)-negative patients, the Simultaneous Study of Docetaxel Based Anthracycline Free Adjuvant Treatment Evaluation, as well as Life Style Intervention Strategies (SUCCESS) C study randomized patients to either anthracycline-containing or anthracycline-free chemotherapy. Given the proven prognostic value of circulating tumor cells (CTCs) in EBC, we compared the prevalence of CTCs after chemotherapy between both treatment arms for a preliminary efficacy assessment. The SUCCESS C trial (NCT00847444) is an open-label, phase III study randomizing 3547 patients with HER2-negative EBC to either 3 cycles of epirubicin, 5-fluorouracil, and cyclophosphamide followed by 3 cycles of docetaxel (FEC-DOC) or 6 cycles of docetaxel and cyclophosphamide (DOC-C). CTC status was prospectively evaluated in hormone receptor-positive patients at the time of last chemotherapy cycle using the US Food and Drug Administration-approved CellSearch System (Janssen Diagnostics). Data on CTC status were available for 1766 patients. Overall, CTCs were found in 221 (12.5%) patients. Univariate analyses revealed that presence of CTCs at time of last chemotherapy cycle was not significantly associated with tumor or patient characteristics (all P > .1). There was no significant difference with respect to presence of CTCs between patients randomized to FEC-DOC or DOC-C (11.5% vs. 13.6%; P = .18). The comparable prevalence of CTCs at the time of last chemotherapy cycle may indicate that anthracycline-free chemotherapy is equally effective to anthracycline-containing chemotherapy in HER2-negative, hormone receptor-positive EBC. However, efficacy data from the final survival analysis of SUCCESS C have to be awaited to confirm these preliminary

  11. The efficiency and safety of trastuzumab and lapatinib added to neoadjuvant chemotherapy in Her2-positive breast cancer patients: a randomized meta-analysis

    Directory of Open Access Journals (Sweden)

    Chen ZL

    2016-05-01

    Full Text Available Zhe-Ling Chen, Yan-Wei Shen, Shu-Ting Li, Chun-Li Li, Ling-Xiao Zhang, Jiao Yang, Meng Lv, Ya-Yun Lin, Xin Wang, Jin Yang Department of Medical Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China Background: The addition of human epidermal growth factor receptor 2 (Her2 therapies to neoadjuvant chemotherapy (NAC during treatment of Her2-positive breast cancer has been proposed as an effective way to improve the prognosis. However, the treatment outcomes of adding trastuzumab, lapatinib, or both to NAC were not unequivocal in randomized clinical trials. Based on these data, a meta-analysis was performed. Objective: The main objective was to evaluate the efficiency and safety of trastuzumab and lapatinib added to NAC for treatment of Her2-positive breast cancer. Methods: ClinicalTrials.gov and PubMed were searched for randomized clinical trials that compared trastuzumab, lapatinib, or both, added to NAC. The main endpoint was a pathologically complete response (pCR rate, in breast only or in breast and lymph nodes. The drug safety and the influence of hormone-receptor status, comparing the clinical response and the rate of breast conservation, were evaluated. Results: A total of eight publications were included in the primary analysis, designed as two or three subgroups. The cumulative cases were 2,349 and the analyses of all the clinical trials showed that the pCR rate was significantly higher in the group receiving trastuzumab than that in the group with lapatinib, either in breast only (P=0.001 or in breast and lymph nodes (P=0.0001. Similar results could be seen in comparisons of the combination versus trastuzumab group. Further studies of subgroups divided into hormone receptor-positive or-negative patients showed that the addition of trastuzumab or dual Her2-targeted therapy significantly improved the pCR rate in patients who were hormone-insensitive. Regarding the toxic

  12. Association between partial-volume corrected SUVmax and Oncotype DX recurrence score in early-stage, ER-positive/HER2-negative invasive breast cancer.

    Science.gov (United States)

    Lee, Su Hyun; Ha, Seunggyun; An, Hyun Joon; Lee, Jae Sung; Han, Wonshik; Im, Seock-Ah; Ryu, Han Suk; Kim, Won Hwa; Chang, Jung Min; Cho, Nariya; Moon, Woo Kyung; Cheon, Gi Jeong

    2016-08-01

    Oncotype DX, a 21-gene expression assay, provides a recurrence score (RS) which predicts prognosis and the benefit from adjuvant chemotherapy in patients with early-stage, estrogen receptor-positive (ER-positive), and human epidermal growth factor receptor 2-negative (HER2-negative) invasive breast cancer. However, Oncotype DX tests are expensive and not readily available in all institutions. The purpose of this study was to investigate whether metabolic parameters on (18)F-FDG PET/CT are associated with the Oncotype DX RS and whether (18)F-FDG PET/CT can be used to predict the Oncotype DX RS. The study group comprised 38 women with stage I/II, ER-positive/HER2-negative invasive breast cancer who underwent pretreatment (18)F-FDG PET/CT and Oncotype DX testing. On PET/CT, maximum (SUVmax) and average standardized uptake values, metabolic tumor volume, and total lesion glycolysis were measured. Partial volume-corrected SUVmax (PVC-SUVmax) determined using the recovery coefficient method was also evaluated. Oncotype DX RS (0 - 100) was categorized as low (negative breast cancer.

  13. mTOR inhibitors, a new era for metastatic luminal HER2-negative breast cancer? A systematic review and a meta-analysis of randomized trials.

    Science.gov (United States)

    Rotundo, Maria Saveria; Galeano, Teresa; Tassone, Pierfrancesco; Tagliaferri, Pierosandro

    2016-05-10

    We evaluated if standard hormonal therapy (HT) could be improved by the addition of mammalian target of rapamycin inhibitors (mTOR-I) in metastatic luminal breast cancer. A meta-analysis on 4 phase II-III randomized clinical trials was performed. Pooled hazard ratio (HR) for progression free survival (PFS)/ time to progression (TTP) was 0.62 in favor of mTOR-I+HT arm (95% confidence interval [CI] 0.55-0.70; p<0.0001). There was significant heterogeneity for PFS/TTP (Cochran's Q 32, p<0.0001, I2 index 90.6%). Pooled HR for overall survival (OS) was 0.84 in favor of the combination arm (95% CI 0.71-0.99; p=0.04). Heterogeneity was not significant (Cochran's Q 4.47, p=0.1, I2 index 55.3%). Pooled risk ratio (RR) for objective response rate (ORR) was 0.88 in favor of experimental arm (95% CI 0.85-0.91; p<0.0001). Heterogeneity was not significant (Cochran's Q 2.11, p=0.3, I2 index 5.2%). Adverse events (AEs), in particular those of grade 3-4, mostly occurred in mTOR-I+HT arm. Combination therapy of HT plus mTOR-I improves the outcome of metastatic luminal breast cancer patients. Our results provide evidence of a class-effect of these targeting molecules.

  14. Adjuvant Chemotherapy and Trastuzumab Is Safe and Effective in Older Women With Small, Node-Negative, HER2-Positive Early-Stage Breast Cancer.

    Science.gov (United States)

    Cadoo, Karen A; Morris, Patrick G; Cowell, Elizabeth P; Patil, Sujata; Hudis, Clifford A; McArthur, Heather L

    2016-12-01

    The benefit of adjuvant trastuzumab with chemotherapy is well established for women with higher risk human epidermal growth factor receptor 2-positive (HER2 + ) breast cancer. However, its role in older patients with smaller, node-negative tumors is less clear. We conducted a retrospective, sequential cohort study of this population to describe the impact of trastuzumab on breast cancer outcomes and cardiac safety. Women ≥ 55 years with ≤ 2 cm, node-negative, HER2 + breast cancer were identified and electronic medical records reviewed. A no-trastuzumab cohort of 116 women diagnosed between January 1, 1999 and May 14, 2004 and a trastuzumab cohort of 128 women diagnosed between May 16, 2006 and December 31, 2010 were identified. Overall survival and distant relapse-free survival were estimated by Kaplan-Meier methods. The median ages of the trastuzumab and no-trastuzumab cohorts were 62 and 64 years, respectively. More patients in the trastuzumab cohort had grade III (P = .001), lymphovascular invasion (P = .001), or estrogen receptor-negative (P cancers. The majority of the trastuzumab cohort received chemotherapy versus one-half of the no-trastuzumab cohort (98% vs. 53%; P women in the trastuzumab cohort and 1 in the no-trastuzumab cohort developed symptomatic heart failure. There were no cardiac-related deaths in either arm. Following adjuvant trastuzumab with chemotherapy, selected older women with small, node-negative, HER2 + breast cancers have excellent disease control. The rate of cardiac events is low. Copyright © 2016 Elsevier Inc. All rights reserved.

  15. Imaging of HER2/neu-positive BT-474 human breast cancer xenografts in athymic mice using 111In-trastuzumab (Herceptin) Fab fragments

    International Nuclear Information System (INIS)

    Tang Ying; Wang, Judy; Scollard, Deborah A.; Mondal, Hridya; Holloway, Claire; Kahn, Harriette J.; Reilly, Raymond M.

    2005-01-01

    Trastuzumab (Herceptin) Fab were prepared by digestion of intact IgG with immobilized papain, derivatized with diethylenetriaminepentaacetic acid (DTPA) and radiolabeled with 111 In. The dissociation constant (K d ) for binding of Fab to HER2/neu-positive SK-BR-3 human breast cancer cells was two- to threefold higher than for intact IgG (14-36 vs. 8-14 nM). The binding affinity was not significantly decreased after DTPA derivatization (K d =47 nM). 111 In-trastuzumab Fab localized specifically in HER2/neu-positive BT-474 human breast cancer xenografts in athymic mice with tumor uptake of 7.8±0.7% injected dose (ID)/g and tumor/blood ratio of 25.2±1.6 at 72 h postinjection compared with 2.7±0.7% ID/g and 7.0±0.9 for 111 In-HuM195 anti-CD33 Fab (significantly different, P 111 In-trastuzumab Fab as early as 24 h postinjection

  16. Imaging of HER2/neu-positive BT-474 human breast cancer xenografts in athymic mice using {sup 111}In-trastuzumab (Herceptin) Fab fragments

    Energy Technology Data Exchange (ETDEWEB)

    Tang Ying [Division of Nuclear Medicine, University Health Network, Toronto, Ontario, M5G 2C4 (Canada); Department of Pharmaceutical Sciences, University of Toronto, Toronto, Ontario, M5S 2S2 (Canada); Wang, Judy [Division of Nuclear Medicine, University Health Network, Toronto, Ontario, M5G 2C4 (Canada); Scollard, Deborah A. [Division of Nuclear Medicine, University Health Network, Toronto, Ontario, M5G 2C4 (Canada); Mondal, Hridya [Division of Nuclear Medicine, University Health Network, Toronto, Ontario, M5G 2C4 (Canada); Holloway, Claire [Sunnybrook and Women' s College Health Sciences Center, Toronto, Ontario, M4N 3M5 (Canada); Kahn, Harriette J. [Sunnybrook and Women' s College Health Sciences Center, Toronto, Ontario, M4N 3M5 (Canada); Reilly, Raymond M. [Division of Nuclear Medicine, University Health Network, Toronto, Ontario, M5G 2C4 (Canada) and Department of Pharmaceutical Sciences, University of Toronto, Toronto, Ontario, M5S 2S2 (Canada) and Department of Medical Imaging, University of Toronto, Toronto, Ontario, M5S 3E2 (Canada)]. E-mail: raymond.reilly@utoronto.ca

    2005-01-01

    Trastuzumab (Herceptin) Fab were prepared by digestion of intact IgG with immobilized papain, derivatized with diethylenetriaminepentaacetic acid (DTPA) and radiolabeled with {sup 111}In. The dissociation constant (K{sub d}) for binding of Fab to HER2/neu-positive SK-BR-3 human breast cancer cells was two- to threefold higher than for intact IgG (14-36 vs. 8-14 nM). The binding affinity was not significantly decreased after DTPA derivatization (K{sub d}=47 nM). {sup 111}In-trastuzumab Fab localized specifically in HER2/neu-positive BT-474 human breast cancer xenografts in athymic mice with tumor uptake of 7.8{+-}0.7% injected dose (ID)/g and tumor/blood ratio of 25.2{+-}1.6 at 72 h postinjection compared with 2.7{+-}0.7% ID/g and 7.0{+-}0.9 for {sup 111}In-HuM195 anti-CD33 Fab (significantly different, P<.001). Small (3-5 mm in diameter) BT-474 tumors were imaged with {sup 111}In-trastuzumab Fab as early as 24 h postinjection.

  17. Final Results of the Randomized Phase II NorCap-CA223 Trial Comparing First-Line All-Oral Versus Taxane-Based Chemotherapy for HER2-Negative Metastatic Breast Cancer.

    Science.gov (United States)

    Cinieri, Saverio; Chan, Arlene; Altundag, Kadri; Vandebroek, An; Tubiana-Mathieu, Nicole; Barnadas, Agusti; Dodyk, Patricia; Lazzarelli, Silvia; Botha, Michiel; Rauch, Daniel; Villanova, Gustavo; Coskun, Ugur

    2017-04-01

    The purpose of this study was to evaluate the efficacy of 3 first-line chemotherapy combination regimens for HER2-negative metastatic breast cancer (mBC). In this open-label, 3-arm, randomized phase II trial, patients were randomized to all-oral NORCAP (vinorelbine/capecitabine), GEMPAC (gemcitabine/paclitaxel), or GEMDOC (gemcitabine/docetaxel) as first-line chemotherapy for HER2-negative mBC. Stratification factors were center, previous (neo)adjuvant anthracycline, and age. The primary end point was disease control rate (DCR; complete or partial response, or stable disease for ≥3 months). The DCR was 73% (95% confidence interval [CI], 59-85) with NORCAP (36 of 49 patients), 78% (95% CI, 64-88) with GEMPAC (39 of 50 patients), and 80% (95% CI, 66-90) with GEMDOC (40 of 50 patients). Objective response rates were 33% (16 of 49 patients), 24% (12 of 50 patients), and 50% (25 of 50 patients), respectively; median progression-free survival was 7.6, 9.0, and 11.4 months, respectively. Median overall survival was 30 to 31 months with all regimens. The most common Grade ≥3 adverse event with each regimen was neutropenia (24 patients [50%], 23 patients [46%], and 43 patients [86%], respectively). The most common nonhematological Grade ≥3 adverse event was fatigue. Grade 2 alopecia occurred in 36 patients (72%) who received GEMPAC and 38 patients (76%) who received GEMDOC, but only 4 patients (8%) who received NORCAP. There was no evidence of a detrimental effect of NORCAP on quality of life. All-oral NORCAP is an active first-line chemotherapy regimen and might be offered as an alternative to first-line taxane-based therapy for HER2-negative mBC, particularly if patients wish to avoid alopecia or frequent intravenous administrations. Copyright © 2016 Elsevier Inc. All rights reserved.

  18. HER2-positive breast cancer: {sup 18}F-FDG PET for early prediction of response to trastuzumab plus taxane-based neoadjuvant chemotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Humbert, Olivier; Brunotte, Francois [Centre GF Leclerc, Department of Nuclear Medicine, Dijon (France); CHU Le Bocage, Imaging Department, Dijon (France); Universite de Bourgogne, UMR CNRS 5158, Dijon (France); Cochet, Alexandre [Centre GF Leclerc, Department of Nuclear Medicine, Dijon (France); Universite de Bourgogne, UMR CNRS 5158, Dijon (France); Riedinger, Jean-Marc [Centre GF Leclerc, Department of Nuclear Medicine, Dijon (France); Centre GF Leclerc, Department of Biology and Pathology, Dijon (France); Berriolo-Riedinger, Alina; Toubeau, Michel; Dygai-Cochet, Inna [Centre GF Leclerc, Department of Nuclear Medicine, Dijon (France); Arnould, Laurent [Centre GF Leclerc, Department of Biology and Pathology, Dijon (France); Coudert, Bruno; Desmoulins, Isabelle; Guiu, Severine; Fumoleau, Pierre [Centre GF Leclerc, Department of Medical Oncology, Dijon (France); Coutant, Charles [Centre GF Leclerc, Department of Surgery, Dijon (France)

    2014-08-15

    To investigate the value of {sup 18}F-fluorodeoxyglucose positron emission tomography ({sup 18}F-FDG PET/CT) to predict a pathological complete response (pCR) after neoadjuvant chemotherapy (NAC) in women with human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Fifty-seven consecutive women with HER2-positive breast cancer, treated with trastuzumab plus taxane-based NAC, were prospectively included. Maximum Standardized Uptake Value of the primary tumor and axillary nodes were measured at baseline (PET{sub 1}.SUV{sub max}) and after the first course of NAC (PET{sub 2}.SUV{sub max}). Tumor metabolic volumes were assessed to determine Total Lesion Glycolysis (TLG). The tumor metabolic response (ΔSUV{sub max} and ΔTLG) was calculated. In univariate analysis, negative hormonal receptor status (p = 0.04), high tumor grade (p = 0.03), and low tumor PET{sub 2}.SUV{sub max} (p = 0.001) were predictive of pCR. Tumor ΔSUV{sub max} correlated with pCR (p = 0.03), provided that tumors with low metabolic activity at baseline were excluded. ΔTLG did not correlate with pCR. In multivariate analysis, tumor PET{sub 2}.SUV{sub max} < 2.1 was the best independent predictive factor (Odds ratio =14.3; p = 0.004) with both negative and positive predictive values of 76 %. Although the metabolic features of the primary tumor did not depend on hormonal receptor status, both the baseline metabolism and early response of axillary nodes were higher if estrogen receptors were not expressed (p = 0.01 and p = 0.03, respectively). In HER2-positive breast cancer, very low tumor residual metabolism after the first cycle of NAC (SUV{sub max} < 2.1) was the main predictor of pCR. These results should be further explored in multicenter studies and incorporated into the design of clinical trials. (orig.)

  19. Real-world and trial-based cost-effectiveness analysis of bevacizumab in HER2-negative metastatic breast cancer patients: a study of the Southeast Netherlands Breast Cancer Consortium.

    Science.gov (United States)

    van Kampen, R J W; Ramaekers, B L T; Lobbezoo, D J A; de Boer, M; Dercksen, M W; van den Berkmortel, F; Smilde, T J; van de Wouw, A J; Peters, F P J; van Riel, J M G; Peters, N A J B; Tjan-Heijnen, V C G; Joore, M A

    2017-07-01

    The aim of our analysis was to assess the real-world cost-effectiveness of bevacizumab in addition to taxane treatment versus taxane monotherapy for HER2-negative metastatic breast cancer compared with the cost-effectiveness based on the efficacy results from a trial. A state transition model was built to estimate costs, life years (LYs) and quality-adjusted life years (QALYs) for both treatments. Two scenarios were examined: a real-world scenario and a trial-based scenario in which transition probabilities were primarily based on a real-world cohort study and the E2100 trial, respectively. In both scenarios, costs and utility parameter estimates were extracted from the real-world cohort study. Moreover, the Dutch health care perspective was adopted. In both the real-world and trial scenarios, bevacizumab-taxane is more expensive (incremental costs of €56,213 and €52,750, respectively) and more effective (incremental QALYs of 0.362 and 0.189, respectively) than taxane monotherapy. In the real-world scenario, bevacizumab-taxane compared to taxane monotherapy led to an incremental cost-effectiveness ratio (ICER) of €155,261 per QALY gained. In the trial scenario, the ICER amounted to €278,711 per QALY gained. According to the Dutch informal threshold, bevacizumab in addition to taxane treatment was not considered cost-effective for HER2-negative metastatic breast cancer both in a real-world and in a trial scenario. Copyright © 2017 Elsevier Ltd. All rights reserved.

  20. Four cycles of adriamycin and cyclophosphamide followed by four cycles of docetaxel (NSABP-B27 with concomitant trastuzumab as neoadjuvant therapy for high-risk, early-stage, HER2-positive breast cancer patients

    Directory of Open Access Journals (Sweden)

    Abdel-Razeq H

    2018-04-01

    Full Text Available Hikmat Abdel-Razeq,1,2 Salwa S Saadeh,1 Mahmoud Abu-Nasser,1 Hazem Abdulelah,1 Lina Marie,1 Murad Salam,1 Basel Al-Haj Ali,1 Mohammad Ibrahim,1 Dalia Rimawi3 1Department of Internal Medicine, Section of Hematology and Medical Oncology, King Hussein Cancer Center, Amman, Jordan; 2School of Medicine, University of Jordan, Amman, Jordan; 3Office of Scientific Affairs and Research, King Hussein Cancer Center, Amman, Jordan Background: The majority of breast cancer patients in Jordan are diagnosed at a young age and present with metastatic or locally advanced disease. The National Surgical Adjuvant Breast and Bowel Project Protocol B27 (NSABP-B27 (four cycles of adriamycin and cyclophosphamide [AC] followed by four cycles of docetaxel is a standard neoadjuvant regimen in our institution. In this study, we report the efficacy of adding trastuzumab to docetaxel in this regimen for high-risk human epidermal growth factor receptor 2 (HER2-positive early-stage disease. Patients and methods: Consecutive HER2-positive breast cancer patients treated with this regimen were included. Treatment was given at standard doses and schedules as reported in NSABP-B27. Trastuzumab was given with docetaxel and then continued for 1 year. Results: A total of 121 patients (mean age 45.4 years were included. The majority had high-risk features including large tumor size, positive axillary lymph nodes, and grade III disease. Three patients did not complete the planned cycles of AC due to a lack of response. Eight (6.6% patients missed at least one cycle of docetaxel. Following neoadjuvant therapy, 119 patients underwent surgery, of whom 59 (49.6% patients achieved pathological complete response. The response was higher in node-negative patients (64.0 vs 45.7%; P=0.03 and in hormone receptor-negative disease patients (69.7 vs 41.9%; P=0.018. Breast-conserving surgery was performed in 21.5% of the patients. The median disease-free survival (DFS for the whole group was not

  1. The extracellular domain of Her2 in serum as a biomarker of breast cancer.

    Science.gov (United States)

    Perrier, Alexandre; Gligorov, Joseph; Lefèvre, Guillaume; Boissan, Mathieu

    2018-02-28

    Breast cancer is a major health problem worldwide. In ~15% of breast cancers, the epidermal growth factor receptor HER2, a transmembrane protein, is overexpressed. This HER2 overexpression is associated with an aggressive form of the disease and a poor clinical prognosis. The extracellular domain (ECD) of HER2 is released into the blood by a proteolytic mechanism known as "ECD shedding". This proteolytic shedding leaves a constitutively active truncated receptor in the membrane that is 10-100-fold more oncogenic than the full-length receptor and promotes the growth and survival of cancer cells. Shedding of the HER2 ECD is increased during metastasis: whereas 15% of primary breast cancer patients have elevated levels of serum HER2 ECD (sHER2 ECD), the levels reach 45% in patients with metastatic disease. Thus, sHER2 ECD has been proposed as a promising biomarker for cancer recurrence and for monitoring the disease status of patients overexpressing HER2. Nevertheless, in 2016, the American Society of Clinical Oncology advises clinicians not to use soluble HER2 levels to guide their choice of adjuvant therapy for patients with HER2-positive breast cancer, because the evidence was considered not strong enough. Currently, biomarkers such as carcinoembryonic antigen and cancer antigen 15-3 are widely used to monitor metastatic breast cancer disease even if the level of evidence of clinical impact of this monitoring is poor. In this article, we review the evidence that sHER2 ECD might be used in some situations as a biomarker for breast cancer. Although this serum biomarker will not replace the direct measurement of tumor HER2 status for diagnosis of early-stage tumors; it might be especially useful in metastatic disease for prognosis, as an indicator of cancer progression and of therapy response, particularly to anti-HER2 therapies. Owing to these data, sHER2 ECD should be considered as a promising biomarker to detect cancer recurrence and metastasis.

  2. A kit to prepare {sup 111}In-DTPA-trastuzumab (Herceptin) Fab fragments injection under GMP conditions for imaging or radioimmunoguided surgery of HER2-positive breast cancer

    Energy Technology Data Exchange (ETDEWEB)

    Scollard, Deborah A.; Chan, Conrad [Department of Pharmaceutical Sciences, University of Toronto, Toronto, ON, M5S 3M2 (Canada); Holloway, Claire M.B. [Department of Surgery, Sunnybrook Health Sciences Centre, Toronto, ON, M4N 1H1 (Canada); Reilly, Raymond M., E-mail: raymond.reilly@utoronto.c [Department of Pharmaceutical Sciences, University of Toronto, Toronto, ON, M5S 3M2 (Canada); Department of Medical Imaging, University of Toronto, Toronto, ON, M5S 3E2 (Canada); Toronto General Research Institute, University Health Network, Toronto, ON, M5G 2M9 (Canada)

    2011-01-15

    Introduction: The human epidermal growth factor receptor-2 (HER2) gene is amplified in 25% of invasive breast cancers, and receptor overexpression has been noted in up to 60% of early stages of the disease [ductal carcinoma in situ (DCIS)]. Preclinical studies have revealed high tumor/blood ratios (>27:1) for {sup 111}In-labeled Fab fragments of the HER2 monoclonal antibody, trastuzumab (Herceptin) ({sup 111}In-DTPA-trastuzumab Fab) at 72 h pi in athymic mice bearing subcutaneous human breast cancer xenografts. Our aim in this study was to formulate a kit for preparation of {sup 111}In-DTPA-trastuzumab Fab injection under good manufacturing practice (GMP) conditions suitable for human administration in a Phase I clinical trial of imaging and radioimmunoguided surgery (RIGS) of HER2-positive breast cancer. Methods: Fab fragments were produced by digestion of trastuzumab IgG (Herceptin) with immobilized papain for 20 h at 37{sup o}C. Fab fragments were purified by ultrafiltration, then reacted with a 10-fold molar excess of diethylenetriaminepentaacetic acid (DTPA) dianhydride. DTPA-Fab fragments were purified, then sterilized by filtration into unit dose glass vials (kits). Kits were tested against specifications for volume (0.9-1.1 ml), protein concentration (0.45-0.55 mg/ml), pH (5.5-6.5), DTPA substitution (0.5-4.0 mol DTPA/mol Fab), appearance (clear, colorless and particle free), labeling efficiency ({>=}85%), and sterility and apyrogenicity (USP XXXII). Immunoreactivity of {sup 111}In-DTPA-trastuzumab Fab towards HER2 was measured by saturation radioligand binding assays using SKBR-3 human breast cancer cells (specifications: K{sub a}=0.6-9.6x10{sup 7} L/mol; B{sub max}=0.6-10.4x10{sup 6} sites/cell). {sup 111}In-DTPA-trastuzumab Fab injection was prepared by adding 80-100 MBq of {sup 111}InCl{sub 3} to a single kit vial and incubating for 30 min at room temperature. {sup 111}In-DTPA-trastuzumab Fab was assayed for the amount of radioactivity and tested for p

  3. CORRELATION BETWEEN SERUM HER-2 ONCOPROTEIN AND PATIENTS WITH BREAST CANCER

    Institute of Scientific and Technical Information of China (English)

    Peng Yuan; Bing-he Xu; Da-tong Chu

    2004-01-01

    Objective To detect serum HER-2 oncoprotein levels in patients with operable and metastatic breast cancers, and to study the correlations between serum HER-2 level and lymph node status as well as other clinical parameters.Methods A total of 120 women were studied consisting of 10 healthy volunteers, 31 benign breast disease, 53 operable breast cancer, and 26 metastatic breast cancer patients. The levels of serum HER-2 were measured using an enzyme-liked immunosorbent assay (ELISA).Results The mean serum HER-2 levels were 9.6 + 1.5 ng/mL in healthy volunteers, 11.9 + 1.6 ng/mL in benign breast disease, 13.2 + 4.2 ng/mL in operable breast cancer, and 30.5 + 30.8 ng/mL in metastatic breast cancer patients. The former is much lower than the latter three (P=0.02, 0.001, 0.03, respectively). If using 15 ng/mL as a normal baseline, elevated serum HER-2 levels were observed in none of the healthy volunteers as well as patients with benign disease, but in 18.9% (10/53)operable breast cancer patients and 61.5% (16/26) metastatic patients. In patients with operable breast cancer, there was a positive correlation between serum concentrations of HER-2 and the size of primary rumor (P < 0.05), whereas there was no correlation between serum concentration and axillary lymph node or estrogen receptor status. In patients with metastatic disease, there was no correlation with site of metastases (P > 0.05).Conclusion Serum HER-2 level was strongly correlated with rumor loads and clinical stages, thus acting as a promising predictor of cancer recurrence in breast cancer patients.

  4. Treatment of HER2-positive breast carcinomatous meningitis with intrathecal administration of {alpha}-particle-emitting {sup 211}At-labeled trastuzumab

    Energy Technology Data Exchange (ETDEWEB)

    Boskovitz, Abraham; McLendon, Roger E.; Okamura, Tatsunori [Department of Pathology, Duke University Medical Center, Durham, NC 27710 (United States); Sampson, John H. [Department of Surgery, Duke University Medical Center, Durham, NC 27710 (United States); Bigner, Darell D. [Department of Pathology, Duke University Medical Center, Durham, NC 27710 (United States); Zalutsky, Michael R. [Department of Radiology, Duke University Medical Center, Durham, NC 27710 (United States)], E-mail: zalut001@mc.duke.edu

    2009-08-15

    Introduction: Carcinomatous meningitis (CM) is a devastating disease characterized by the dissemination of malignant tumor cells into the subarachnoid space along the brain and spine. Systemic treatment with monoclonal antibody (mAb) trastuzumab can be effective against HER2-positive systemic breast carcinoma but, like other therapies, is ineffective against CM. The goal of this study was to evaluate the therapeutic effect of {alpha}-particle emitting {sup 211}At-labeled trastuzumab following intrathecal administration in a rat model of breast carcinoma CM. Methods: Athymic rats were injected intrathecally with MCF-7/HER2-18 breast carcinoma cells through a surgically implanted indwelling intrathecal catheter. In Experiment 1, animals received 33 or 66 {mu}Ci {sup 211}At-labeled trastuzumab, cold trastuzumab or saline. In Experiment 2, animals were inoculated with a lower tumor burden and received 46 or 92 {mu}Ci {sup 211}At-labeled trastuzumab or saline. In Experiment 3, animals received 28 {mu}Ci {sup 211}At-labeled trastuzumab, 30 {mu}Ci {sup 211}At-labeled TPS3.2 control mAb or saline. Histopathological analysis of the neuroaxis was performed at the end of the study. Results: In Experiment 1, median survival increased from 21 days for the saline and cold trastuzumab groups to 45 and 48 days for 33 and 66 {mu}Ci {sup 211}At-labeled trastuzumab, respectively. In Experiment 2, median survival increased from 23 days for saline controls to 68 and 92 days for 46 and 92 {mu}Ci {sup 211}At-labeled trastuzumab, respectively. In Experiment 3, median survival increased from 20 days to 29 and 36 days for animals treated with {sup 211}At-labeled TPS3.2 and {sup 211}At-labeled trastuzumab, respectively. Long-term survivors were observed exclusively in the {sup 211}At-trastuzumab-treated groups. Conclusion: Intrathecal {sup 211}At-labeled trastuzumab shows promise as a treatment for patients with HER2-positive breast CM.

  5. Activating HER2 mutations in HER2 gene amplification negative breast cancer.

    Science.gov (United States)

    Bose, Ron; Kavuri, Shyam M; Searleman, Adam C; Shen, Wei; Shen, Dong; Koboldt, Daniel C; Monsey, John; Goel, Nicholas; Aronson, Adam B; Li, Shunqiang; Ma, Cynthia X; Ding, Li; Mardis, Elaine R; Ellis, Matthew J

    2013-02-01

    Data from 8 breast cancer genome-sequencing projects identified 25 patients with HER2 somatic mutations in cancers lacking HER2 gene amplification. To determine the phenotype of these mutations, we functionally characterized 13 HER2 mutations using in vitro kinase assays, protein structure analysis, cell culture, and xenograft experiments. Seven of these mutations are activating mutations, including G309A, D769H, D769Y, V777L, P780ins, V842I, and R896C. HER2 in-frame deletion 755-759, which is homologous to EGF receptor (EGFR) exon 19 in-frame deletions, had a neomorphic phenotype with increased phosphorylation of EGFR or HER3. L755S produced lapatinib resistance, but was not an activating mutation in our experimental systems. All of these mutations were sensitive to the irreversible kinase inhibitor, neratinib. These findings show that HER2 somatic mutation is an alternative mechanism to activate HER2 in breast cancer and they validate HER2 somatic mutations as drug targets for breast cancer treatment. We show that the majority of HER2 somatic mutations in breast cancer patients are activating mutations that likely drive tumorigenesis. Several patients had mutations that are resistant to the reversible HER2 inhibitor lapatinib, but are sensitive to the irreversible HER2 inhibitor, neratinib. Our results suggest that patients with HER2 mutation–positive breast cancers could benefit from existing HER2-targeted drugs.

  6. Endocrine therapy for postmenopausal women with hormone receptor-positive her2-negative advanced breast cancer after progression or recurrence on nonsteroidal aromatase inhibitor therapy: a Canadian consensus statement.

    Science.gov (United States)

    Pritchard, K I; Gelmon, K A; Rayson, D; Provencher, L; Webster, M; McLeod, D; Verma, S

    2013-02-01

    Approximately 22,700 Canadian women were expected to be diagnosed with breast cancer in 2012. Despite improvements in screening and adjuvant treatment options, a substantial number of postmenopausal women with hormone receptor positive (hr+) breast cancer will continue to develop metastatic disease during or after adjuvant endocrine therapy. Guidance on the selection of endocrine therapy for patients with hr+ disease that is negative for the human epidermal growth factor receptor 2 (her2-) and that has relapsed or progressed on earlier nonsteroidal aromatase inhibitor (nsai) therapy is of increasing clinical importance. Exemestane, fulvestrant, and tamoxifen are approved therapeutic options in this context. Four phase iii trials involving 2876 patients-efect, sofea, confirm, and bolero-2-have assessed the efficacy of various treatment options in this clinical setting. Data from those trials suggest that standard-dose fulvestrant (250 mg monthly) and exemestane are of comparable efficacy, that doubling the dose of fulvestrant from 250 mg to 500 mg monthly results in a 15% reduction in the risk of progression, and that adding everolimus to exemestane (compared with exemestane alone) results in a 57% reduction in the risk of progression, albeit with increased toxicity. Multiple treatment options are now available to women with hr+ her2- advanced breast cancer recurring or progressing on earlier nsai therapy, although current clinical trial data suggest more robust clinical efficacy with everolimus plus exemestane. Consideration should be given to the patient's age, functional status, and comorbidities during selection of an endocrine therapy, and use of a proactive everolimus safety management strategy is encouraged.

  7. Endocrine therapy for postmenopausal women with hormone receptor–positive her2–negative advanced breast cancer after progression or recurrence on nonsteroidal aromatase inhibitor therapy: a Canadian consensus statement

    Science.gov (United States)

    Pritchard, K.I.; Gelmon, K.A.; Rayson, D.; Provencher, L.; Webster, M.; McLeod, D.; Verma, S.

    2013-01-01

    Approximately 22,700 Canadian women were expected to be diagnosed with breast cancer in 2012. Despite improvements in screening and adjuvant treatment options, a substantial number of postmenopausal women with hormone receptor positive (hr+) breast cancer will continue to develop metastatic disease during or after adjuvant endocrine therapy. Guidance on the selection of endocrine therapy for patients with hr+ disease that is negative for the human epidermal growth factor receptor 2 (her2–) and that has relapsed or progressed on earlier nonsteroidal aromatase inhibitor (nsai) therapy is of increasing clinical importance. Exemestane, fulvestrant, and tamoxifen are approved therapeutic options in this context. Four phase iii trials involving 2876 patients—efect, sofea, confirm, and bolero-2—have assessed the efficacy of various treatment options in this clinical setting. Data from those trials suggest that standard-dose fulvestrant (250 mg monthly) and exemestane are of comparable efficacy, that doubling the dose of fulvestrant from 250 mg to 500 mg monthly results in a 15% reduction in the risk of progression, and that adding everolimus to exemestane (compared with exemestane alone) results in a 57% reduction in the risk of progression, albeit with increased toxicity. Multiple treatment options are now available to women with hr+ her2– advanced breast cancer recurring or progressing on earlier nsai therapy, although current clinical trial data suggest more robust clinical efficacy with everolimus plus exemestane. Consideration should be given to the patient’s age, functional status, and comorbidities during selection of an endocrine therapy, and use of a proactive everolimus safety management strategy is encouraged. PMID:23443928

  8. HER2 activating mutations are targets for colorectal cancer treatment.

    Science.gov (United States)

    Kavuri, Shyam M; Jain, Naveen; Galimi, Francesco; Cottino, Francesca; Leto, Simonetta M; Migliardi, Giorgia; Searleman, Adam C; Shen, Wei; Monsey, John; Trusolino, Livio; Jacobs, Samuel A; Bertotti, Andrea; Bose, Ron

    2015-08-01

    The Cancer Genome Atlas project identified HER2 somatic mutations and gene amplification in 7% of patients with colorectal cancer. Introduction of the HER2 mutations S310F, L755S, V777L, V842I, and L866M into colon epithelial cells increased signaling pathways and anchorage-independent cell growth, indicating that they are activating mutations. Introduction of these HER2 activating mutations into colorectal cancer cell lines produced resistance to cetuximab and panitumumab by sustaining MAPK phosphorylation. HER2 mutants are potently inhibited by low nanomolar doses of the irreversible tyrosine kinase inhibitors neratinib and afatinib. HER2 gene sequencing of 48 cetuximab-resistant, quadruple (KRAS, NRAS, BRAF, and PIK3CA) wild-type (WT) colorectal cancer patient-derived xenografts (PDX) identified 4 PDXs with HER2 mutations. HER2-targeted therapies were tested on two PDXs. Treatment with a single HER2-targeted drug (trastuzumab, neratinib, or lapatinib) delayed tumor growth, but dual HER2-targeted therapy with trastuzumab plus tyrosine kinase inhibitors produced regression of these HER2-mutated PDXs. HER2 activating mutations cause EGFR antibody resistance in colorectal cell lines, and PDXs with HER2 mutations show durable tumor regression when treated with dual HER2-targeted therapy. These data provide a strong preclinical rationale for clinical trials targeting HER2 activating mutations in metastatic colorectal cancer. ©2015 American Association for Cancer Research.

  9. Budget impact analysis of everolimus for the treatment of hormone receptor positive, human epidermal growth factor receptor-2 negative (HER2-) advanced breast cancer in the United States.

    Science.gov (United States)

    Xie, Jipan; Diener, Melissa; De, Gourab; Yang, Hongbo; Wu, Eric Q; Namjoshi, Madhav

    2013-01-01

    To estimate the budget impact of everolimus as the first and second treatment option after letrozole or anastrozole (L/A) failure for post-menopausal women with hormone receptor positive (HR+), human epidermal growth factor receptor-2 negative (HER2-) advanced breast cancer (ABC). Pharmacy and medical budget impacts (2011 USD) were estimated over the first year of everolimus use in HR+, HER2- ABC from a US payer perspective. Epidemiology data were used to estimate target population size. Pre-everolimus entry treatment options included exemestane, fulvestrant, and tamoxifen. Pre- and post-everolimus entry market shares were estimated based on market research and assumptions. Drug costs were based on wholesale acquisition cost. Patients were assumed to be on treatment until progression or death. Annual medical costs were calculated as the average of pre- and post-progression medical costs weighted by the time in each period, adjusted for survival. One-way and two-way sensitivity analyses were conducted to assess the model robustness. In a hypothetical 1,000,000 member plan, 72 and 159 patients were expected to be candidates for everolimus treatment as first and second treatment option, respectively, after L/A failure. The total budget impact for the first year post-everolimus entry was $0.044 per member per month [PMPM] (pharmacy budget: $0.058 PMPM; medical budget: -$0.014 PMPM), assuming 10% of the target population would receive everolimus. The total budget impacts for the first and second treatment options after L/A failure were $0.014 PMPM (pharmacy budget: $0.018; medical budget: -$0.004) and $0.030 PMPM (pharmacy budget: $0.040; medical budget: -$0.010), respectively. Results remained robust in sensitivity analyses. Assumptions about some model input parameters were necessary and may impact results. Increased pharmacy costs for HR+, HER2- ABC following everolimus entry are expected to be partially offset by reduced medical service costs. Pharmacy and total

  10. H2Mab-77 is a Sensitive and Specific Anti-HER2 Monoclonal Antibody Against Breast Cancer.

    Science.gov (United States)

    Itai, Shunsuke; Fujii, Yuki; Kaneko, Mika K; Yamada, Shinji; Nakamura, Takuro; Yanaka, Miyuki; Saidoh, Noriko; Chang, Yao-Wen; Handa, Saori; Takahashi, Maki; Suzuki, Hiroyoshi; Harada, Hiroyuki; Kato, Yukinari

    2017-08-01

    Human epidermal growth factor receptor 2 (HER2) plays a critical role in the progression of breast cancers, and HER2 overexpression is associated with poor clinical outcomes. Trastuzumab is an anti-HER2 humanized antibody that leads to significant survival benefits in patients with HER2-positive metastatic breast cancers. In this study, we developed novel anti-HER2 monoclonal antibodies (mAbs) and characterized their efficacy in flow cytometry, Western blot, and immunohistochemical analyses. Initially, we expressed the full length or ectodomain of HER2 in LN229 glioblastoma cells and then immunized mice with ectodomain of HER2 or LN229/HER2, and performed the first screening by enzyme-linked immunosorbent assays using ectodomain of HER2. Subsequently, we selected mAbs according to their efficacy in flow cytometry (second screening), Western blot (third screening), and immunohistochemical analyses (fourth screening). Among 100 mAb clones, only three mAbs reacted with HER2 in Western blot, and clone H 2 Mab-77 (IgG 1 , kappa) was selected. Finally, immunohistochemical analyses with H 2 Mab-77 showed sensitive and specific reactions against breast cancer cells, warranting the use of H 2 Mab-77 to detect HER2 in pathological analyses of breast cancers.

  11. U.S. Food and Drug Administration Approval: Neratinib for the Extended Adjuvant Treatment of Early Stage HER2-Positive Breast Cancer.

    Science.gov (United States)

    Singh, Harpreet; Walker, Amanda J; Amiri-Kordestani, Laleh; Cheng, Joyce; Tang, Shenghui; Balcazar, Pamela; Barnett-Ringgold, Kimberly; Palmby, Todd R; Cao, Xianhua; Zheng, Nan; Liu, Qi; Yu, Jingyu; Pierce, William F; Daniels, Selena R; Sridhara, Rajeshwari; Ibrahim, Amna; Kluetz, Paul G; Blumenthal, Gideon M; Beaver, Julia A; Pazdur, Richard

    2018-03-09

    On July 17, 2017, the Food and Drug Administration (FDA) approved neratinib (NERLYNX, Puma Biotechnology, Inc) for the extended adjuvant treatment of adult patients with early-stage HER2-overexpressed/amplified breast cancer, to follow adjuvant trastuzumab-based therapy. Approval was based on data from ExteNET, a randomized, double-blind, placebo-controlled multicenter trial. Women with early-stage HER2-positive breast cancer and within two years of completing adjuvant trastuzumab were randomized to neratinib (n=1420) or placebo (n=1420) for one year. The primary endpoint was invasive disease-free survival (iDFS) defined as the time between randomization date to first occurrence of invasive recurrence (local/regional, ipsilateral or contralateral breast cancer), distance recurrence, or death from any cause, with two years and 28 days of follow up. The trial showed a statistically significant treatment effect favoring neratinib with a stratified hazard ratio of 0.66 (95% CI: 0.49, 0.90, p=0.008). Estimated iDFS rate at 2-years was 94.2% (95% CI: 92.6%, 95.4%) in patients treated with neratinib vs. 91.9% (95% CI: 90.2%, 93.2%) in those receiving placebo. Diarrhea was the most common adverse event (AE) with a 40% incidence of Grade 3 or 4 diarrhea and represents the most common AE leading to treatment discontinuation. Other frequent AEs (>10% incidence) were nausea, abdominal pain, fatigue, vomiting, rash, stomatitis, decreased appetite, and muscle spasms. Other than diarrhea, neratinib is associated with a low incidence of severe AEs; toxicities are generally reversible and manageable with dose interruptions, dose reductions, and/or standard medical care. This article summarizes FDA decision-making and data supporting the neratinib approval. Copyright ©2018, American Association for Cancer Research.

  12. The role of neratinib in HER2-driven breast cancer.

    Science.gov (United States)

    Cherian, Mathew A; Ma, Cynthia X

    2017-06-30

    Up to 25% of patients with early-stage HER2+ breast cancer relapse despite adjuvant trastuzumab-based regimens and virtually all patients with metastatic disease eventually die from resistance to existing treatment options. In addition, recent studies indicate that activating HER2 mutations without gene amplification could drive tumor growth in a subset of HER2-ve breast cancer that is not currently eligible for HER2-targeted agents. Neratinib is an irreversible HER kinase inhibitor with activity as extended adjuvant therapy following standard trastuzumab-based adjuvant treatment in a Phase III trial. Phase II trials of neratinib demonstrate promising activity in combination with cytotoxic agents in trastuzumab resistant metastatic HER2+ breast cancer, and either as monotherapy or in combination with fulvestrant for HER2-mutated breast cancers. We anticipate a potential role for neratinib in the therapy of these patient populations.

  13. Phase I Study of 68Ga-HER2-Nanobody for PET/CT Assessment of HER2 Expression in Breast Carcinoma.

    Science.gov (United States)

    Keyaerts, Marleen; Xavier, Catarina; Heemskerk, Johannes; Devoogdt, Nick; Everaert, Hendrik; Ackaert, Chloé; Vanhoeij, Marian; Duhoux, Francois P; Gevaert, Thierry; Simon, Philippe; Schallier, Denis; Fontaine, Christel; Vaneycken, Ilse; Vanhove, Christian; De Greve, Jacques; Lamote, Jan; Caveliers, Vicky; Lahoutte, Tony

    2016-01-01

    Human epidermal growth factor receptor 2 (HER2) status is one of the major tumor characteristics in breast cancer to guide therapy. Anti-HER2 treatment has clear survival advantages in HER2-positive breast carcinoma patients. Heterogeneity in HER2 expression between primary tumor and metastasis has repeatedly been described, resulting in the need to reassess HER2 status during the disease course. To avoid repeated biopsy with potential bias due to tumor heterogeneity, Nanobodies directed against HER2 have been developed as probes for molecular imaging. Nanobodies, which are derived from unique heavy-chain-only antibodies, are the smallest antigen-binding antibody fragments and have ideal characteristics for PET imaging. The primary aims were assessment of safety, biodistribution, and dosimetry. The secondary aim was to investigate tumor-targeting potential. In total, 20 women with primary or metastatic breast carcinoma (score of 2+ or 3+ on HER2 immunohistochemical assessment) were included. Anti-HER2-Nanobody was labeled with (68)Ga via a NOTA derivative. Administered activities were 53-174 MBq (average, 107 MBq). PET/CT scans for dosimetry assessment were obtained at 10, 60, and 90 min after administration. Physical evaluation and blood analysis were performed for safety evaluation. Biodistribution was analyzed for 11 organs using MIM software; dosimetry was assessed using OLINDA/EXM. Tumor-targeting potential was assessed in primary and metastatic lesions. No adverse reactions occurred. A fast blood clearance was observed, with only 10% of injected activity remaining in the blood at 1 h after injection. Uptake was seen mainly in the kidneys, liver, and intestines. The effective dose was 0.043 mSv/MBq, resulting in an average of 4.6 mSv per patient. The critical organ was the urinary bladder wall, with a dose of 0.406 mGy/MBq. In patients with metastatic disease, tracer accumulation well above the background level was demonstrated in most identified sites of

  14. Cost-effectiveness and resource use of implementing MRI-guided NACT in ER-positive/HER2-negative breast cancers in The Netherlands

    International Nuclear Information System (INIS)

    Miquel-Cases, Anna; Steuten, Lotte M. G.; Rigter, Lisanne S.; Harten, Wim H. van

    2016-01-01

    Response-guided neoadjuvant chemotherapy (RG-NACT) with magnetic resonance imaging (MRI) is effective in treating oestrogen receptor positive/human epidermal growth factor receptor-2 negative (ER-positive/HER2-negative) breast cancer. We estimated the expected cost-effectiveness and resources required for its implementation compared to conventional-NACT. A Markov model compared costs, quality-adjusted-life-years (QALYs) and costs/QALY of RG-NACT vs. conventional-NACT, from a hospital perspective over a 5-year time horizon. Health services required for and health outcomes of implementation were estimated via resource modelling analysis, considering a current (4 %) and a full (100 %) implementation scenario. RG-NACT was expected to be more effective and less costly than conventional NACT in both implementation scenarios, with 94 % (current) and 95 % (full) certainty, at a willingness to pay threshold of €20.000/QALY. Fully implementing RG-NACT in the Dutch target population of 6306 patients requires additional 5335 MRI examinations and an (absolute) increase in the number of MRI technologists, by 3.6 fte (full-time equivalent), and of breast radiologists, by 0.4 fte. On the other hand, it prevents 9 additional relapses, 143 cancer deaths, 23 congestive heart failure events and 2 myelodysplastic syndrome/acute myeloid leukaemia events. Considering cost-effectiveness, RG-NACT is expected to dominate conventional-NACT. While personnel capacity is likely to be sufficient for a full implementation scenario, MRI utilization needs to be intensified

  15. Clinical outcomes in ER+ HER2 -node-positive breast cancer patients who were treated according to the Recurrence Score results: evidence from a large prospectively designed registry.

    Science.gov (United States)

    Stemmer, Salomon M; Steiner, Mariana; Rizel, Shulamith; Geffen, David B; Nisenbaum, Bella; Peretz, Tamar; Soussan-Gutman, Lior; Bareket-Samish, Avital; Isaacs, Kevin; Rosengarten, Ora; Fried, Georgeta; McCullough, Debbie; Svedman, Christer; Shak, Steven; Liebermann, Nicky; Ben-Baruch, Noa

    2017-01-01

    The Recurrence Score® is increasingly used in node-positive ER+ HER2-negative breast cancer. This retrospective analysis of a prospectively designed registry evaluated treatments/outcomes in node-positive breast cancer patients who were Recurrence Score-tested through Clalit Health Services from 1/2006 through 12/2011 ( N  = 709). Medical records were reviewed to verify treatments/recurrences/survival. Median follow-up, 5.9 years; median age, 62 years; 53.9% grade 2; 69.8% tumors ≤ 2 cm; 84.5% invasive ductal carcinoma; 42.0% N1mi, and 37.2%/15.5%/5.2% with 1/2/3 positive nodes; 53.4% Recurrence Score < 18, 36.4% Recurrence Score 18-30, and 10.2% Recurrence Score ≥ 31. Overall, 26.9% received adjuvant chemotherapy: 7.1%, 39.5%, and 86.1% in the Recurrence Score < 18, 18-30, and ≥ 31 group, respectively. The 5-year Kaplan-Meier estimates for distant recurrence were 3.2%, 6.3%, and 16.9% for these respective groups and the corresponding 5-year breast cancer death estimates were 0.5%, 3.4%, and 5.7%. In Recurrence Score < 18 patients, 5-year distant-recurrence rates for N1mi/1 positive node/2-3 positive nodes were 1.2%/4.4%/5.4%. As patients were not randomized to treatment and treatment decision is heavily influenced by Recurrence Score, analysis of 5-year distant recurrence by chemotherapy use was exploratory and should be interpreted cautiously: In Recurrence Score < 18, recurrence rate was 7.7% in chemotherapy-treated ( n  = 27) and 2.9% in chemotherapy-untreated patients ( n  = 352); P  = 0.245. In Recurrence Score 18-30, recurrence rate in chemotherapy-treated patients ( n  = 102) was significantly lower than in untreated patients ( n  = 156) (1.0% vs. 9.7% P  = 0.019); in Recurrence Score ≤ 25 (the RxPONDER study cutoff), recurrence rate was 2.3% in chemotherapy-treated ( n  = 89) and 4.4% in chemotherapy-untreated patients ( n  = 488); P  = 0.521. In conclusion, our findings

  16. Interação entre especialidades: miocardiopatia dilatada e neoplasia de mama HER2 positiva Interacción entre especialidades: miocardiopatía dilatada y neoplasia de mama HER2 positiva Interaction between specialties: dilated cardiomyopathy and HER2-positive breast Cancer

    Directory of Open Access Journals (Sweden)

    Solange Moraes Sanches

    2010-01-01

    Full Text Available O progresso no conhecimento dos mecanismos da doença e suas potenciais possibilidades de tratamento, têm com o incremento da pesquisa básica, trazido a algumas situações inusitadas. Como quando algo observado em uma situação específica, definida na prática clínica, pode ser transportado para o laboratório, instigando a investigação de uma provável terapêutica em uma doença não relacionada e fazendo o caminho inverso da "bench-to-bedside". Nos últimos anos, o uso de um anticorpo monoclonal, o trastuzumabe, mostrou-se imprescindível no tratamento das neoplasias de mama com amplificação/superexpressão de HER2, com ganho de sobrevida significativo nos contextos adjuvante e terapêutico. A observação da ocorrência de cardiotoxicidade induzida pelo trastuzumabe, assim como a identificação dos mecanismos relacionados a esse efeito colateral, possibilitaram a pesquisa desses mesmos fatores na miocardiopatia dilatada, de uma forma muito interessante.El progreso en el conocimiento de los mecanismos de la enfermedad y sus potenciales posibilidades de tratamiento ocurre mediante el incremento de la investigación básica que se añade a algunas situaciones inusitadas. Así como cuando algo observado en una situación específica, definida en la práctica clínica, se puede trasladar al laboratorio, fomentando la investigación de una probable terapéutica en una enfermedad no relacionada, y haciendo el camino inverso de la "bench-to-bedside". En los últimos años, el uso de un anticuerpo monoclonal, el trastuzumabe, se halló imprescindible en el tratamiento de las neoplasias de mama con amplificación/superexpresión de HER2, con ganancia de sobrevida significativa en los contextos adyuvante y terapéutico. La observación de la ocurrencia de cardiotoxicidad inducida por el trastuzumabe, así como la identificación de los mecanismos relacionados a este efecto colateral, posibilitaran la investigación de estos mismos factores

  17. CDC25A Protein Stability Represents a Previously Unrecognized Target of HER2 Signaling in Human Breast Cancer: Implication for a Potential Clinical Relevance in Trastuzumab Treatment

    Directory of Open Access Journals (Sweden)

    Emanuela Brunetto

    2013-06-01

    Full Text Available The CDC25A-CDK2 pathway has been proposed as critical for the oncogenic action of human epidermal growth factor receptor 2 (HER2 in mammary epithelial cells. In particular, transgenic expression of CDC25A cooperates with HER2 in promoting mammary tumors, whereas CDC25A hemizygous loss attenuates the HER2-induced tumorigenesis penetrance. On the basis of this evidence of a synergism between HER2 and the cell cycle regulator CDC25A in a mouse model of mammary tumorigenesis, we investigated the role of CDC25A in human HER2-positive breast cancer and its possible implications in therapeutic response. HER2 status and CDC25A expression were assessed in 313 breast cancer patients and we found statistically significant correlation between HER2 and CDC25A (P = .007. Moreover, an HER2-positive breast cancer subgroup with high levels of CDC25A and very aggressive phenotype was identified (P = .005. Importantly, our in vitro studies on breast cancer cell lines showed that the HER2 inhibitor efficacy on cell growth and viability relied also on CDC25A expression and that such inhibition induces CDC25A down-regulation through phosphatidylinositol 3-kinase/protein kinase B pathway and DNA damage response activation. In line with this observation, we found a statistical significant association between CDC25A overexpression and trastuzumab-combined therapy response rate in two different HER2-positive cohorts of trastuzumab-treated patients in either metastatic or neoadjuvant setting (P = .018 for the metastatic cohort and P = .021 for the neoadjuvant cohort. Our findings highlight a link between HER2 and CDC25A that positively modulates HER2- targeted therapy response, suggesting that, in HER2-positive breast cancer patients, CDC25A overexpression affects trastuzumab sensitivity.

  18. Efficacy of everolimus with exemestane versus exemestane alone in Asian patients with HER2-negative, hormone-receptor-positive breast cancer in BOLERO-2.

    Science.gov (United States)

    Noguchi, Shinzaburo; Masuda, Norikazu; Iwata, Hiroji; Mukai, Hirofumi; Horiguchi, Jun; Puttawibul, Puttisak; Srimuninnimit, Vichien; Tokuda, Yutaka; Kuroi, Katsumasa; Iwase, Hirotaka; Inaji, Hideo; Ohsumi, Shozo; Noh, Woo-Chul; Nakayama, Takahiro; Ohno, Shinji; Rai, Yoshiaki; Park, Byeong-Woo; Panneerselvam, Ashok; El-Hashimy, Mona; Taran, Tetiana; Sahmoud, Tarek; Ito, Yoshinori

    2014-11-01

    The addition of mTOR inhibitor everolimus (EVE) to exemestane (EXE) was evaluated in an international, phase 3 study (BOLERO-2) in patients with hormone-receptor-positive (HR(+)) breast cancer refractory to letrozole or anastrozole. The safety and efficacy of anticancer treatments may be influenced by ethnicity (Sekine et al. in Br J Cancer 99:1757-62, 2008). Safety and efficacy results from Asian versus non-Asian patients in BOLERO-2 are reported. Patients were randomized (2:1) to 10 mg/day EVE + EXE or placebo (PBO) + EXE. Primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival, response rate, clinical benefit rate, and safety. Of 143 Asian patients, 98 received EVE + EXE and 45 received PBO + EXE. Treatment with EVE + EXE significantly improved median PFS versus PBO + EXE among Asian patients by 38 % (HR = 0.62; 95 % CI, 0.41-0.94). Median PFS was also improved among non-Asian patients by 59 % (HR = 0.41; 95 % CI, 0.33-0.50). Median PFS duration among EVE-treated Asian patients was 8.48 versus 4.14 months for PBO + EXE, and 7.33 versus 2.83 months, respectively, in non-Asian patients. The most common grade 3/4 adverse events (stomatitis, anemia, elevated liver enzymes, hyperglycemia, and dyspnea) occurred at similar frequencies in Asian and non-Asian patients. Grade 1/2 interstitial lung disease occurred more frequently in Asian patients. Quality of life was similar between treatment arms in Asian patients. Adding EVE to EXE provided substantial clinical benefit in both Asian and non-Asian patients with similar safety profiles. This combination represents an improvement in the management of postmenopausal women with HR(+)/HER2(-) advanced breast cancer progressing on nonsteroidal aromatase inhibitors, regardless of ethnicity.

  19. Synthesis and stability test of radioimmunoconjugate 177Lu-DOTA-F(ab′2-trastuzumab for theranostic agent of HER2 positive breast cancer

    Directory of Open Access Journals (Sweden)

    Sandra Hermanto

    2016-10-01

    Full Text Available The use of trastuzumab as intact IgG labeling radionuclide for HER2 positive breast cancer theranostic agent is not ideal because it is slowly eliminated from the blood and normal tissues resulting in low tumor/blood (T/B and tumor/normal tissue (T/NT ratios. To overcome this limitation, we developed the trastuzumab F(ab′2 fragments and radiolabeling of the fragments by β and γ-particle of Lutetium-177. F(ab2 fragments were produced by digestion of trastuzumab IgG (Herceptin with pepsin for 18 h at 37 °C. The F(ab′2 fragment fractionated in PD-10 column, followed by the conjugation with 2-(4-isothiocyanatobenzyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (p-SCN-Bn-DOTA as a metal chelator and radiolabeling with 177LuCl3. Molecular weight of fragments was calculated by LCMS (Liquid Chromatography Mass Spectroscopy and the radiochemical purity was evaluated by ITLC-SG (Instan Thin Layer Chromatography. Our study showed that the purity of F(ab′2 fragment generated by PD-10 fractions was >98% and the molecular weight of F(ab′2 was 98.35 kDa. The average numbers of pSCN-Bn-DOTA chelates per antibody fragment were 5.03 ± 1.5 and the optimum conjugation reactions was performed at molar ratio 20:1 (chelator to antibody. The stability test of the radioimmunoconjugate in the human serum albumin (HSA at 37 °C showed the radiochemical purity was 91.96 ± 0.26% after 96 h storage. This indicated that the radioimmunoconjugate is relatively stable when applied to the human body's physiological condition.

  20. Podoplanin-positive Cancer-associated Stromal Fibroblasts in Primary Tumor and Synchronous Lymph Node Metastases of HER2-overexpressing Breast Carcinomas.

    Science.gov (United States)

    Niemiec, Joanna; Adamczyk, Agnieszka; Harazin-Lechowska, Agnieszka; Ambicka, Aleksandra; Grela-Wojewoda, Aleksandra; Majchrzyk, Kaja; Kruczak, Anna; Sas-Korczyńska, Beata; Ryś, Janusz

    2018-04-01

    We compared the status of stromal podoplanin-positive cancer-associated fibroblasts (ppCAFs) between primary tumors and paired synchronous lymph node metastases (LNMs) and analyzed the prognostic significance of tumoral ppCAFs in 203 patients with human epidermal growth factor receptor 2-positive breast carcinoma. ppCAFs were found in 167/203 and in 35/87 tumors and LNM, respectively. ppCAFs were most frequently found in tumors and corresponding LNM (n=52, 59.8%; p=0.001). However, for all LNMs (n=12) without ppCAFs, their paired tumors also lacked ppCAFs. In both tumors and LNMs, ppCAFs were α-smooth muscle actin-positive and cluster of differentiation 21 protein-negative, suggesting them not to be resident lymph node cells. Moreover, in our series, the presence of ppCAFs in tumors was borderline related to poor disease-free survival (p=0.058). These results speak in favor of a hypothesis suggesting ppCAFs accompany metastatic cancer cells migrating from tumor to LNMs. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  1. Current therapeutic strategies of anti-HER2 treatment in advanced breast cancer patients

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    Joanna Huszno

    2016-03-01

    Full Text Available The HER2/neu ( ERBB2 oncogene is amplified and/or overexpressed in approximately 20% of breast cancers, and is a strong prognostic factor for relapse and poor overall survival, particularly in node-positive patients. It is also an important predictor for response to trastuzumab, which has established efficacy against breast cancer with overexpression or amplification of the HER2 oncogene. Treatment with the anti-HER2 humanized monoclonal antibody – trastuzumab significantly improves progression-free and overall survival among patients with HER2-positive breast cancer. However, in most patients with HER2-positive metastatic breast cancer, the disease progresses occurred, what cause the need for new targeted therapies for advanced disease. In clinical trials, there are tested new drugs to improve the results of treatment for this group of patients. This paper presents new drugs introduced into clinical practice for treatment of advanced breast cancer, whose molecular target are receptors of the HER2 family. In addition, new therapeutic strategies and drugs that are currently in clinical researches are discussed.

  2. Developing Anti-HER2 Vaccines: Breast Cancer Experience.

    Science.gov (United States)

    Al-Awadhi, Aydah; Murray, James Lee; Ibrahim, Nuhad K

    2018-04-25

    Breast cancer accounts for more than one million new cases annually and is the leading cause of death in women globally. HER2 overexpression induces cellular and humoral immune responses against the HER2 protein and is associated with higher tumour proliferation rates. Trastuzumab-based therapies are effectively and widely used as standard of care in HER2-amplified/overexpressed breast cancer patients; one cited mechanism of action is the induction of passive immunity and antibody-dependent cellular cytotoxicity against malignant breast cancer cells. These findings drove the efforts to generate antigen-specific immunotherapy to trigger the patient's immune system to target HER2-overexpressing tumour cells, which led to the development of various vaccines against the HER2 antigen. This manuscript discusses the various anti-HER2 vaccine formulations and strategies and their potential role in the metastatic and adjuvant settings. This article is protected by copyright. All rights reserved. © 2018 UICC.

  3. Pertuzumab for the Neoadjuvant Treatment of Early-Stage HER2-Positive Breast Cancer: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

    Science.gov (United States)

    Squires, Hazel; Pandor, Abdullah; Thokala, Praveen; Stevens, John W; Kaltenthaler, Eva; Clowes, Mark; Coleman, Robert; Wyld, Lynda

    2018-01-01

    As part of its single technology appraisal process, the National Institute for Health and Care Excellence invited the manufacturer of pertuzumab (Perjeta ® ; Roche Products Limited) to submit evidence of its clinical and cost- effectiveness for the neoadjuvant treatment of women with high-risk, early-stage, HER2-positive breast cancer when used in combination with trastuzumab and chemotherapy. High-risk women included those with locally advanced (including inflammatory) breast cancer and women with high-risk early-stage breast cancer (classified as T2/3 or N1). The School of Health and Related Research Technology Appraisal Group at the University of Sheffield was commissioned to act as the independent Evidence Review Group. This article presents the critical review of the company's submission by the Evidence Review Group and the outcome of the National Institute for Health and Care Excellence guidance. The clinical data were mainly taken from a phase II, randomised, open-label, active controlled study (NeoSphere), which reported a significant advantage in terms of pathological complete response rates of pertuzumab in combination with trastuzumab and chemotherapy, compared with trastuzumab alone with chemotherapy (45.8 vs. 29.0%, p = 0.0141). The company did not make any indirect comparisons. A meta-analysis of 12 neoadjuvant studies investigating the relationship between pathological complete response and event-free survival was used to extrapolate the outcomes reported in the NeoSphere study. A cardiac safety study (TRYPHAENA) demonstrated the safety of pertuzumab. The company undertook a model-based economic evaluation of neoadjuvant pertuzumab plus trastuzumab and docetaxel compared with neoadjuvant trastuzumab and docetaxel over a lifetime horizon from the National Health Service and Personal Social Services perspective. The probabilistic incremental cost-effectiveness ratio was estimated to be £20,104 per quality-adjusted life-year gained for pertuzumab

  4. p95HER2 Methionine 611 Carboxy-Terminal Fragment Is Predictive of Trastuzumab Adjuvant Treatment Benefit in the FinHer Trial.

    Science.gov (United States)

    Sperinde, Jeff; Huang, Weidong; Vehtari, Aki; Chenna, Ahmed; Kellokumpu-Lehtinen, Pirkko-Liisa; Winslow, John; Bono, Petri; Lie, Yolanda S; Petropoulos, Christos J; Weidler, Jodi; Joensuu, Heikki

    2018-03-13

    Purpose: Expression of p95HER2 (p95), a truncated form of the HER2 receptor, which lacks the trastuzumab binding site but retains kinase activity, has been reported as a prognostic biomarker for poor outcomes in patients with trastuzumab-treated HER2-positive metastatic breast cancer. The impact of p95 expression on trastuzumab treatment efficacy in early HER2-positive breast cancer is less clear. In the current study, p95 was tested as a predictive marker of trastuzumab treatment benefit in the HER2-positive subset of the FinHer adjuvant phase III trial. Experimental Design: In the FinHer trial, 232 patients with HER2-positive early breast cancer were randomized to receive chemotherapy plus 9 weeks of trastuzumab or no trastuzumab treatment. Quantitative p95 protein expression was measured in formalin-fixed paraffin-embedded samples using the p95 VeraTag assay (Monogram Biosciences), specific for the M611 form of p95. Quantitative HER2 protein expression was measured using the HERmark assay (Monogram Biosciences). Distant disease-free survival (DDFS) was used as the primary outcome measure. Results: In the arm receiving chemotherapy only, increasing log 10 (p95) correlated with shorter DDFS (HR, 2.0; P = 0.02). In the arm receiving chemotherapy plus trastuzumab ( N = 95), increasing log 10 (p95) was not correlated with a shorter DDFS. In a combined analysis of both treatment arms, high breast tumor p95 content was significantly correlated with trastuzumab treatment benefit in multivariate models (interaction P = 0.01). Conclusions: A high p95HER2/HER2 ratio identified patients with metastatic breast cancer with poor outcomes on trastuzumab-based therapies. Further investigation of the p95HER2/HER2 ratio as a potential prognostic or predictive biomarker for HER2-targeted therapy is warranted. Clin Cancer Res; 1-7. ©2018 AACR. ©2018 American Association for Cancer Research.

  5. Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial.

    Science.gov (United States)

    Martin, Miguel; Holmes, Frankie A; Ejlertsen, Bent; Delaloge, Suzette; Moy, Beverly; Iwata, Hiroji; von Minckwitz, Gunter; Chia, Stephen K L; Mansi, Janine; Barrios, Carlos H; Gnant, Michael; Tomašević, Zorica; Denduluri, Neelima; Šeparović, Robert; Gokmen, Erhan; Bashford, Anna; Ruiz Borrego, Manuel; Kim, Sung-Bae; Jakobsen, Erik Hugger; Ciceniene, Audrone; Inoue, Kenichi; Overkamp, Friedrich; Heijns, Joan B; Armstrong, Anne C; Link, John S; Joy, Anil Abraham; Bryce, Richard; Wong, Alvin; Moran, Susan; Yao, Bin; Xu, Feng; Auerbach, Alan; Buyse, Marc; Chan, Arlene

    2017-12-01

    ExteNET showed that 1 year of neratinib, an irreversible pan-HER tyrosine kinase inhibitor, significantly improves 2-year invasive disease-free survival after trastuzumab-based adjuvant therapy in women with HER2-positive breast cancer. We report updated efficacy outcomes from a protocol-defined 5-year follow-up sensitivity analysis and long-term toxicity findings. In this ongoing randomised, double-blind, placebo-controlled, phase 3 trial, eligible women aged 18 years or older (≥20 years in Japan) with stage 1-3c (modified to stage 2-3c in February, 2010) operable breast cancer, who had completed neoadjuvant and adjuvant chemotherapy plus trastuzumab with no evidence of disease recurrence or metastatic disease at study entry. Patients who were eligible patients were randomly assigned (1:1) via permuted blocks stratified according to hormone receptor status (hormone receptor-positive vs hormone receptor-negative), nodal status (0 vs 1-3 vs or ≥4 positive nodes), and trastuzumab adjuvant regimen (given sequentially vs concurrently with chemotherapy), then implemented centrally via an interactive voice and web-response system, to receive 1 year of oral neratinib 240 mg/day or matching placebo. Treatment was given continuously for 1 year, unless disease recurrence or new breast cancer, intolerable adverse events, or consent withdrawal occurred. Patients, investigators, and trial funder were masked to treatment allocation. The predefined endpoint of the 5-year analysis was invasive disease-free survival, analysed by intention to treat. ExteNET is registered with ClinicalTrials.gov, number NCT00878709, and is closed to new participants. Between July 9, 2009, and Oct 24, 2011, 2840 eligible women with early HER2-positive breast cancer were recruited from community-based and academic institutions in 40 countries and randomly assigned to receive neratinib (n=1420) or placebo (n=1420). After a median follow-up of 5·2 years (IQR 2·1-5·3), patients in the neratinib

  6. For or against adjuvant trastuzumab for pT1a-bN0M0 breast cancer patients with HER2-positive tumors: a meta-analysis of published literatures.

    Directory of Open Access Journals (Sweden)

    Qiong Zhou

    Full Text Available BACKGROUND: Although the prognosis of patients with small (≤1cm tumors is generally favorable, emerging data suggests that biological behavior varies between intrinsic subtypes in such patients. Furthermore, it still remains unclear whether HER2-positive pT1a-bN0M0 patients could benefit from adjuvant trastuzumab. For further evaluation, we sought to conduct a meta-analysis so as to get a better understanding of the prognosis for HER2-positive pT1a-bN0M0 patients and their survival benefit from adjuvant trastuzumab, accordingly, offering the implications for current practice. METHODS: The PubMed database, the online proceedings of the American Society of Clinical Oncology (ASCO Annual Meetings, the online proceedings of the San Antonio Breast Cancer Symposium, and the CD proceedings of the International St. Gallen Breast Cancer Conference were searched for all relevant studies published before September 2012. Relative risks (RRs were used to compare the prognosis of different intrinsic subtypes for pT1a-bN0M0 breast cancer. Analyses were also performed to estimate the association between adjuvant trastuzumab and various survival outcomes. RESULTS: With eight eligible studies identified, this meta-analysis demonstrated a deleterious effect of HER2+ phenotype on disease-free survival (DFS; RR = 3.677, 95% CI 2.606-5.189, p <0.001 and distant disease-free survival (DDFS; RR = 3.824, 95% CI 2.249-6.501, p<0.001 as compared to HR+/HER2- subgroup. However, significant difference failed to be achieved in terms of any endpoint between HER2+ and triple negative breast cancer (TNBC. Besides, a marked improvement in DFS was observed with the addition of trastuzumab for HER2-positive pT1a-bN0M0 patients (RR = 0.323, 95% CI 0.191-0.547, p<0.001. CONCLUSION: This meta-analysis clarifies that intrinsic subtypes might be a reliable marker to predict the prognosis in pT1a-bN0M0 breast cancer. Besides, even for such early stage HER2-positive

  7. Functional imaging of human epidermal growth factor receptor 2-positive metastatic breast cancer using (64)Cu-DOTA-trastuzumab PET.

    Science.gov (United States)

    Mortimer, Joanne E; Bading, James R; Colcher, David M; Conti, Peter S; Frankel, Paul H; Carroll, Mary I; Tong, Shan; Poku, Erasmus; Miles, Joshua K; Shively, John E; Raubitschek, Andrew A

    2014-01-01

    Women with human epidermal growth factor receptor 2 (HER2)-positive breast cancer are candidates for treatment with the anti-HER2 antibody trastuzumab. Assessment of HER2 status in recurrent disease is usually made by core needle biopsy of a single lesion, which may not represent the larger tumor mass or other sites of disease. Our long-range goal is to develop PET of radiolabeled trastuzumab for systemically assessing tumor HER2 expression and identifying appropriate use of anti-HER2 therapies. The purpose of this study was to evaluate PET/CT of (64)Cu-DOTA-trastuzumab for detecting and measuring tumor uptake of trastuzumab in patients with HER2-positive metastatic breast cancer. Eight women with biopsy-confirmed HER2-positive metastatic breast cancer and no anti-HER2 therapy for 4 mo or longer underwent complete staging, including (18)F-FDG PET/CT. For 6 of the 8 patients, (64)Cu-DOTA-trastuzumab injection (364-512 MBq, 5 mg of trastuzumab) was preceded by trastuzumab infusion (45 mg). PET/CT (PET scan duration 1 h) was performed 21-25 (day 1) and 47-49 (day 2) h after (64)Cu-DOTA-trastuzumab injection. Scan fields of view were chosen on the basis of (18)F-FDG PET/CT. Tumor detection sensitivity and uptake analyses were limited to lesions identifiable on CT; lesions visualized relative to adjacent tissue on PET were considered PET-positive. Radiolabel uptake in prominent lesions was measured as maximum single-voxel standardized uptake value (SUVmax). Liver uptake of (64)Cu was reduced approximately 75% with the 45-mg trastuzumab predose, without significant effect on tumor uptake. The study included 89 CT-positive lesions. Detection sensitivity was 77%, 89%, and 93% for day 1, day 2, and (18)F-FDG, respectively. On average, tumor uptake was similar for (64)Cu-DOTA-trastuzumab and (18)F-FDG (SUVmax and range, 8.1 and 3.0-22.5 for day 1 [n = 48]; 8.9 and 0.9-28.9 for day 2 [n = 38]; 9.7 and 3.3-25.4 for (18)F-FDG [n = 56]), but same-lesion SUVmax was not correlated

  8. Can breast cancer patients with HER2 dual-equivocal tumours be managed as HER2-negative disease?

    Science.gov (United States)

    Tong, Yiwei; Chen, Xiaosong; Fei, Xiaochun; Lin, Lin; Wu, Jiayi; Huang, Ou; He, Jianrong; Zhu, Li; Chen, Weiguo; Li, Yafen; Shen, Kunwei

    2018-01-01

    Increasing human epidermal growth factor receptor 2 (HER2) immunohistochemistry (IHC)/fluorescence in situ hybridisation (FISH) dual-equivocal breast tumours are reported after the 2013 American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guideline update. The aim of this study is to investigate the clinico-pathologic characteristics, treatment patterns and disease outcome of these patients with HER2 dual-equivocal tumours. Patients with HER2 IHC 2+ and available FISH results were retrospectively analysed from the Comprehensive Breast Health Center, Shanghai Ruijin Hospital. The 2013 ASCO/CAP guideline was applied to define HER2-positive, dual-equivocal and -negative groups. Patient characteristics, systemic treatment patterns and survival were compared among these groups. Reverse transcriptase-polymerase chain reaction-based assays were applied to test HER2 mRNA expression level. Among 691 patients included, 133 (19.25%) were HER2 positive, 25 (3.62%) were HER2 dual-equivocal and 533 (77.13%) were HER2 negative. Univariate and multivariate analyses stated that HER2 dual-equivocal tumours shared more similarity with HER2-negative tumours, whereas HER2-positive tumours had rather different clinico-pathologic features. HER2 dual-equivocal tumours had similar HER2 mRNA levels compared with HER2-negative tumours (P = 0.26), which were much less compared with HER2-positive breast cancer. Besides, adjuvant systemic treatment patterns were comparable between HER2-negative and dual-equivocal tumours, and none of HER2 dual-equivocal patients received anti-HER2 treatment. There was no survival difference among these three groups (P = 0.43). HER2 dual-equivocal tumours share more similarity with HER2-negative disease in terms of clinico-pathologic features, HER2 mRNA levels, adjuvant systemic treatment patterns and disease outcome, which deserves further clinical evaluation. Copyright © 2017 Elsevier Ltd. All rights reserved.

  9. Neratinib Approved for HER2+ Breast Cancer.

    Science.gov (United States)

    2017-09-01

    The FDA approved the tyrosine kinase inhibitor neratinib for extended adjuvant treatment of early-stage HER2-positive breast cancer. The decision adds another treatment option to help prevent recurrence, but its relatively small potential benefit must be weighed against the risk of serious side effects. ©2017 American Association for Cancer Research.

  10. Predictive value and clinical utility of centrally assessed ER, PgR, and Ki-67 to select adjuvant endocrine therapy for premenopausal women with hormone receptor-positive, HER2-negative early breast cancer: TEXT and SOFT trials.

    Science.gov (United States)

    Regan, Meredith M; Pagani, Olivia; Francis, Prudence A; Fleming, Gini F; Walley, Barbara A; Kammler, Roswitha; Dell'Orto, Patrizia; Russo, Leila; Szőke, János; Doimi, Franco; Villani, Laura; Pizzolitto, Stefano; Öhlschlegel, Christian; Sessa, Fausto; Peg Cámara, Vicente; Rodríguez Peralto, José Luis; MacGrogan, Gaëtan; Colleoni, Marco; Goldhirsch, Aron; Price, Karen N; Coates, Alan S; Gelber, Richard D; Viale, Giuseppe

    2015-11-01

    The SOFT and TEXT randomized phase III trials investigated adjuvant endocrine therapies for premenopausal women with hormone receptor-positive (HR+) early breast cancer. We investigated the prognostic and predictive value of centrally assessed levels of estrogen receptor (ER), progesterone receptor (PgR), and Ki-67 expression in women with HER2-negative disease. Of 5707 women enrolled, 4115 with HER2-negative (HR+/HER2-) disease had ER, PgR, and Ki-67 centrally assessed by immunohistochemistry. Breast cancer-free interval (BCFI) was defined from randomization to first invasive local, regional, or distant recurrence or contralateral breast cancer. The prognostic and predictive values of ER, PgR and Ki-67 expression levels were assessed using Cox modeling and STEPP methodology. In this HR+/HER2- population, the median ER, PgR, and Ki-67 expressions were 95, 90, and 18 % immunostained cells. As most patients had strongly ER-positive tumors, the predictive value of ER levels could not be investigated. Lower PgR and higher Ki-67 expression were associated with reduced BCFI. There was no consistent evidence of heterogeneity of the relative treatment effects according to PgR or Ki-67 expression levels, though there was a greater 5-year absolute benefit of exemestane + ovarian function suppression (OFS) versus tamoxifen with or without OFS at lower levels of PgR and higher levels of Ki-67. Women with poor prognostic features of low PgR and/or high Ki-67 have greater absolute benefit from exemestane + OFS versus tamoxifen + OFS or tamoxifen alone, but individually PgR and Ki-67 are of limited predictive value for selecting adjuvant endocrine therapy for premenopausal women with HR+/HER2- early breast cancer.

  11. De-Escalation Strategies in Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Early Breast Cancer (BC): Final Analysis of the West German Study Group Adjuvant Dynamic Marker-Adjusted Personalized Therapy Trial Optimizing Risk Assessment and Therapy Response Prediction in Early BC HER2- and Hormone Receptor-Positive Phase II Randomized Trial-Efficacy, Safety, and Predictive Markers for 12 Weeks of Neoadjuvant Trastuzumab Emtansine With or Without Endocrine Therapy (ET) Versus Trastuzumab Plus ET.

    Science.gov (United States)

    Harbeck, Nadia; Gluz, Oleg; Christgen, Matthias; Kates, Ronald Ernest; Braun, Michael; Küemmel, Sherko; Schumacher, Claudia; Potenberg, Jochem; Kraemer, Stefan; Kleine-Tebbe, Anke; Augustin, Doris; Aktas, Bahriye; Forstbauer, Helmut; Tio, Joke; von Schumann, Raquel; Liedtke, Cornelia; Grischke, Eva-Maria; Schumacher, Johannes; Wuerstlein, Rachel; Kreipe, Hans Heinrich; Nitz, Ulrike Anneliese

    2017-09-10

    Purpose Human epidermal growth factor receptor 2 (HER2)-positive/hormone receptor (HR)-positive breast cancer is a distinct subgroup associated with lower chemotherapy sensitivity and slightly better outcome than HER2-positive/HR-negative disease. Little is known about the efficacy of the combination of endocrine therapy (ET) with trastuzumab or with the potent antibody-cytotoxic, anti-HER2 compound trastuzumab emtansine (T-DM1) with or without ET for this subgroup. The West German Study Group trial, ADAPT (Adjuvant Dynamic Marker-Adjusted Personalized Therapy Trial Optimizing Risk Assessment and Therapy Response Prediction in Early Breast Cancer) compares pathologic complete response (pCR) rates of T-DM1 versus trastuzumab with ET in early HER2-positive/HR-positive breast cancer. Patients and Methods In this prospective, neoadjuvant, phase II trial, 375 patients with early breast cancer with HER2-positive and HR-positive status (n = 463 screened) were randomly assigned to 12 weeks of T-DM1 with or without ET or to trastuzumab with ET. The primary end point was pCR (ypT0/is/ypN0). Early response was assessed in 3-week post-therapeutic core biopsies (proliferation decrease ≥ 30% Ki-67 or cellularity response). Secondary end points included safety and predictive impact of early response on pCR. Adjuvant therapy followed national standards. Results Baseline characteristics were well balanced among the arms. More than 90% of patients completed the therapy per protocol. pCR was observed in 41.0% of patients treated with T-DM1, 41.5% of patients treated with T-DM1 and ET, and 15.1% with trastuzumab and ET ( P < .001). Early responders (67% of patients with assessable response) achieved pCR in 35.7% compared with 19.8% in nonresponders (odds ratio, 2.2; 95% CI, 1.24 to 4.19). T-DM1 was associated with a significantly higher prevalence of grade 1 to 2 toxicities, especially thrombocytopenia, nausea, and elevation of liver enzymes. Overall toxicity was low; seventeen

  12. Analysis of PI3K/mTOR Pathway Biomarkers and Their Prognostic Value in Women with Hormone Receptor–Positive, HER2-Negative Early Breast Cancer

    Directory of Open Access Journals (Sweden)

    Hamdy A. Azim

    2016-04-01

    Full Text Available BACKGROUND: The PI3K/AKT/mTOR pathway alterations have been shown to play significant roles in the development, progression, and metastatic spread of breast cancer. Furthermore, they have been implicated in the process of drug resistance, especially endocrinal therapies. In this study, we aimed to define the correlation between the PI3K mutations and the expression of the phosphorylated forms of different downstream molecules in women with estrogen receptor (ER–positive, human epidermal growth factor receptor 2–negative (luminal early breast cancer treated at Cairo university hospitals. METHODS: Next-generation sequencing was used to detect mutations in the PIK3CA hotspots (in exons 9 and 20. Immunohistochemistry was performed on tissue microarray blocks prepared from samples of 35 Egyptian luminal breast cancer patients in the pathology department of Centre Léon Bérard (CLB. The intensity and the percentage of stained tumor cells were integrated to define high versus low biomarker expression. The cytoplasmic and nuclear stainings were graded separately. Patients were followed for a median of 4.7 years (2.1 to 6.9 years. Correlation was done between PI3K mutations and the immunohistochemistry expression of pAKT, LKB1, p4EBP1, and pS6 ribosomal protein (pS6RP with the clinicopathologic features and disease free survival (DFS of the patients. RESULTS: Median age at diagnosis was 51.3 years (range, 25 to 82 years. Tumors were larger than 20 mm in 79.2% of the cases, whereas 57.9% had axillary lymph node deposits. Only 12.3% of the patients had SBR grade I tumors, 50.8% had grade II, and 36.8% had grade III. ERs were negative in 6 patients (17% after pathology review. Thirty-two cases were assessable for LKB1 and pAKT, 33 for p4EBP1 and pS6RP, and 24 for PI3K mutations. Nuclear LKB1, cytoplasmic LKB1, nuclear pAKT, cytoplasmic pAKT, nuclear p4EBP1, and cytoplasmic pS6RP expression was high in 65.6%, 62.5%, 62.5%, 68.8%, 42.4%, and 57

  13. Serum HER-2 predicts response and resistance to trastuzumab treatment in breast cancer

    DEFF Research Database (Denmark)

    Petersen, Eva Rabing Brix; Sørensen, Patricia Diana; Jakobsen, Erik Hugger

    2013-01-01

    Serum HER2 (S-HER2) was approved in 2003 by the US Food and Drug Administration (FDA) for monitoring trastuzumab treatment in tissue HER2 positive breast cancer patients. Information of the value of S-HER2 is scarce. We hypothesised that S-HER2 would reflect the clinical effect of trastuzumab....

  14. Development of the designed ankyrin repeat protein (DARPin) G3 for HER2 molecular imaging

    Energy Technology Data Exchange (ETDEWEB)

    Goldstein, Robert; Livanos, Maria; Bhavsar, Gaurav; Rashid, Mohammed; Miranda, Enrique; Tolner, Berend; Meyer, Tim; Chester, Kerry [UCL Cancer Institute, London (United Kingdom); Sosabowski, Jane; Leyton, Julius; Mather, Stephen [Queen Mary University of London, Centre for Molecular Oncology, Barts Cancer Institute, London (United Kingdom); Vigor, Kim [Clare Hall Laboratories, Biotherapeutics Development Unit, Cancer Research UK, South Mimms (United Kingdom); Nagy-Davidescu, Gabriela; Plueckthun, Andreas [Universitaet Zuerich, Biochemisches Institut, Zuerich (Switzerland); Yeung, Jenny [UCL Cancer Institute, London (United Kingdom); UCL Institute of Child Health, London (United Kingdom)

    2014-11-13

    Human epidermal growth factor receptor-2 (HER2) overexpression is a predictor of response to anti-HER2 therapy in breast and gastric cancer. Currently, HER2 status is assessed by tumour biopsy, but this may not be representative of the larger tumour mass or other metastatic sites, risking misclassification and selection of suboptimal therapy. The designed ankyrin repeat protein (DARPin) G3 binds HER2 with high affinity at an epitope that does not overlap with trastuzumab and is biologically inert. We hypothesized that radiolabelled DARPin G3 would be capable of selectively imaging HER2-positive tumours, and aimed to identify a suitable format for clinical application. G3 DARPins tagged with hexahistidine (His{sub 6}) or with histidine glutamate (HE){sub 3} and untagged G3 DARPins were manufactured using a GMP-compatible Pichia pastoris protocol and radiolabelled with {sup 125}I, or with {sup 111}In via DOTA linked to a C-terminal cysteine. BALB/c mice were injected with radiolabelled G3 and tissue biodistribution was evaluated by gamma counting. The lead construct ((HE){sub 3}-G3) was assessed in mice bearing HER2-positive human breast tumour (BT474) xenografts. For both isotopes, (HE){sub 3}-G3 had significantly lower liver uptake than His{sub 6}-G3 and untagged G3 counterparts in non-tumour-bearing mice, and there was no significantly different liver uptake between His{sub 6}-G3 and untagged G3. (HE){sub 3}-G3 was taken forward for evaluation in mice bearing HER2-positive tumour xenografts. The results demonstrated that radioactivity from {sup 111}In-(HE){sub 3}-G3 was better maintained in tumours and cleared faster from serum than radioactivity from {sup 125}I-(HE){sub 3}-G3, achieving superior tumour-to-blood ratios (343.7 ± 161.3 vs. 22.0 ± 11.3 at 24 h, respectively). On microSPECT/CT, {sup 111}In-labelled and {sup 125}I-labelled (HE){sub 3}-G3 could image HER2-positive tumours at 4 h after administration, but there was less normal tissue uptake of

  15. Development of the designed ankyrin repeat protein (DARPin) G3 for HER2 molecular imaging

    International Nuclear Information System (INIS)

    Goldstein, Robert; Livanos, Maria; Bhavsar, Gaurav; Rashid, Mohammed; Miranda, Enrique; Tolner, Berend; Meyer, Tim; Chester, Kerry; Sosabowski, Jane; Leyton, Julius; Mather, Stephen; Vigor, Kim; Nagy-Davidescu, Gabriela; Plueckthun, Andreas; Yeung, Jenny

    2015-01-01

    Human epidermal growth factor receptor-2 (HER2) overexpression is a predictor of response to anti-HER2 therapy in breast and gastric cancer. Currently, HER2 status is assessed by tumour biopsy, but this may not be representative of the larger tumour mass or other metastatic sites, risking misclassification and selection of suboptimal therapy. The designed ankyrin repeat protein (DARPin) G3 binds HER2 with high affinity at an epitope that does not overlap with trastuzumab and is biologically inert. We hypothesized that radiolabelled DARPin G3 would be capable of selectively imaging HER2-positive tumours, and aimed to identify a suitable format for clinical application. G3 DARPins tagged with hexahistidine (His 6 ) or with histidine glutamate (HE) 3 and untagged G3 DARPins were manufactured using a GMP-compatible Pichia pastoris protocol and radiolabelled with 125 I, or with 111 In via DOTA linked to a C-terminal cysteine. BALB/c mice were injected with radiolabelled G3 and tissue biodistribution was evaluated by gamma counting. The lead construct ((HE) 3 -G3) was assessed in mice bearing HER2-positive human breast tumour (BT474) xenografts. For both isotopes, (HE) 3 -G3 had significantly lower liver uptake than His 6 -G3 and untagged G3 counterparts in non-tumour-bearing mice, and there was no significantly different liver uptake between His 6 -G3 and untagged G3. (HE) 3 -G3 was taken forward for evaluation in mice bearing HER2-positive tumour xenografts. The results demonstrated that radioactivity from 111 In-(HE) 3 -G3 was better maintained in tumours and cleared faster from serum than radioactivity from 125 I-(HE) 3 -G3, achieving superior tumour-to-blood ratios (343.7 ± 161.3 vs. 22.0 ± 11.3 at 24 h, respectively). On microSPECT/CT, 111 In-labelled and 125 I-labelled (HE) 3 -G3 could image HER2-positive tumours at 4 h after administration, but there was less normal tissue uptake of radioactivity with 111 In-(HE) 3 -G3. Preadministration of trastuzumab did not

  16. A comparison of 111In- or 64Cu-DOTA-trastuzumab Fab fragments for imaging subcutaneous HER2-positive tumor xenografts in athymic mice using microSPECT/CT or microPET/CT

    Science.gov (United States)

    2011-01-01

    radioactivity were observed for 64Cu-DOTA-trastuzumab Fab than 111In-DOTA-trastuzumab Fab. Conclusions We conclude that 111In-DOTA-trastuzumab Fab was more specific than 64Cu-DOTA-trastuzumab Fab for imaging HER2-positive tumors, especially those with low receptor density. This was due to higher levels of circulating radioactivity for 64Cu-DOTA-trastuzumab Fab which disrupted the relationship between HER2 density and T/B ratios. Use of alternative chelators that more stably bind 64Cu may improve the association between T/B ratios and HER2 density for 64Cu-labeled trastuzumab Fab. PMID:22214307

  17. Epirubicin With Cyclophosphamide Followed by Docetaxel With Trastuzumab and Bevacizumab as Neoadjuvant Therapy for HER2-Positive Locally Advanced Breast Cancer or as Adjuvant Therapy for HER2-Positive Pathologic Stage III Breast Cancer: A Phase II Trial of the NSABP Foundation Research Group, FB-5.

    Science.gov (United States)

    Smith, John W; Buyse, Marc E; Rastogi, Priya; Geyer, Charles E; Jacobs, Samuel A; Patocskai, Erica J; Robidoux, André; Conlin, Alison K; Ansari, Bilal; Keogh, George P; Stella, Philip J; Gross, Howard M; Lord, Raymond S; Polikoff, Jonathan A; Mauquoi, Celine; Mamounas, Eleftherios P; Swain, Sandra M; Wolmark, Norman

    2017-02-01

    The purpose of this study was to determine the cardiac safety and clinical activity of trastuzumab and bevacizumab with docetaxel after epirubicin with cyclophosphamide (EC) in patients with HER2-positive locally advanced breast cancer (LABC) or pathologic stage 3 breast cancer (PS3BC). Patients received every 3 week treatment with 4 cycles of EC (90/600 mg/m 2 ) followed by 4 cycles of docetaxel (100 mg/m 2 ). Targeted therapy with standard-dose trastuzumab with bevacizumab 15 mg/kg was given for a total of 1 year. Coprimary end points were (1) rate of cardiac events (CEs) in all patients defined as clinical congestive heart failure with a significant decrease in left ventricular ejection fraction or cardiac deaths; and (2) pathologic complete response (pCR) in breast and nodes in the neoadjuvant cohort. An independent cardiac review panel determined whether criteria for a CE were met. A total of 105 patients were accrued, 76 with LABC treated with neoadjuvant therapy and 29 with PS3BC treated with adjuvant therapy. Median follow-up was 59.2 months. Among 99 evaluable patients for cardiac safety, 4 (4%; 95% confidence interval [CI], 1.1%-10.0%) met CE criteria. The pCR percentage in LABC patients was 46% (95% CI, 34%-59%). Five-year recurrence-free survival (RFS) and overall survival (OS) for all patients was 79.9% and 90.8%, respectively. The regimen met predefined criteria for activity of interest with an acceptable rate of CEs. Although the pCR percentage was comparable with chemotherapy regimens with trastuzumab alone the high RFS and OS are of interest in these high-risk populations. Copyright © 2016 Elsevier Inc. All rights reserved.

  18. HER2 mutated breast cancer responds to treatment with single agent neratinib, a second generation HER2/EGFR tyrosine kinase inhibitor

    Science.gov (United States)

    Ben–Baruch, Noa Efrat; Bose, Ron; Kavuri, Shyam M.; Ma, Cynthia X.; Ellis, Matthew J.

    2015-01-01

    Activating mutations in the HER2 tyrosine kinase have been identified in human breast cancers that lack HER2 gene amplification. These patients are not candidates for HER2 targeted drugs under current standards of care, but preclinical data strongly suggest that these patients will benefit from anti-HER2 drugs. In this case report, we describe a young woman with metastatic breast cancer whose tumor was found to carry a HER2 L755S mutation, which is in the kinase domain of HER2. Treatment with the second generation HER2/EGFR tyrosine kinase inhibitor, neratinib, resulted in partial response and dramatic improvement in the patient’s function status. This partial response lasted 11 months and when the patient’s cancer progressed, she was treated with neratinib plus capecitabine and her cancer again responded. This second response parallels the benefit seen with continuing trastuzumab in HER2 amplified breast cancer after disease progression. This case is the first report, to our knowledge, of successful single agent treatment of HER2 mutated breast cancer. Two clinical trials of neratinib for HER2 mutated, metastatic breast cancer are currently enrolling patients. Further, data from The Cancer Genome Atlas project have identified HER2 mutations in a wide range of solid tumors, including bladder, colorectal, and non-small cell lung cancer, suggesting that clinical trials of neratinib or neratinib-based combinations for HER2 mutated solid tumors is warranted. PMID:26358790

  19. HER2-Mutated Breast Cancer Responds to Treatment With Single-Agent Neratinib, a Second-Generation HER2/EGFR Tyrosine Kinase Inhibitor.

    Science.gov (United States)

    Ben-Baruch, Noa Efrat; Bose, Ron; Kavuri, Shyam M; Ma, Cynthia X; Ellis, Matthew J

    2015-09-01

    Activating mutations in the HER2 tyrosine kinase have been identified in human breast cancers that lack HER2 gene amplification. These patients are not candidates for HER2-targeted drugs under current standards of care, but preclinical data strongly suggest that these patients will benefit from anti-HER2 drugs. This case report describes a young woman with metastatic breast cancer whose tumor was found to carry a HER2 L755S mutation, which is in the kinase domain of HER2. Treatment with the second-generation HER2/EGFR tyrosine kinase inhibitor neratinib resulted in partial response and dramatic improvement in the patient's functional status. This partial response lasted 11 months, and when the patient's cancer progressed, she was treated with neratinib plus capecitabine and her cancer again responded. This second response parallels the benefit seen with continuing trastuzumab in HER2-amplified breast cancer after disease progression. This case represents the first report, to our knowledge, of successful single-agent treatment of HER2-mutated breast cancer. Two clinical trials of neratinib for HER2-mutated metastatic breast cancer are currently enrolling patients. Further, data from The Cancer Genome Atlas project have identified HER2 mutations in a wide range of solid tumors, including bladder, colorectal, and non-small cell lung cancers, suggesting that clinical trials of neratinib or neratinib-based combinations for HER2-mutated solid tumors is warranted. Copyright © 2015 by the National Comprehensive Cancer Network.

  20. Clinicopathologic Characteristics of Oestrogen Receptor-Positive/Progesterone Receptor-Negative/Her2-Negative Breast Cancer According to a Novel Definition of Negative Progesterone Receptor Status: A Large Population-Based Study from China.

    Directory of Open Access Journals (Sweden)

    An-qi Li

    Full Text Available A lack of progesterone receptor (PgR expression in oestrogen receptor-positive (ER+ tumours is associated with worse survival. PgR status is usually defined as positive or negative using 1% positive nuclei as a cut-off point. In this study, we aimed to assess the clinicopathologic characteristics of ER+/PgR-/HER2- tumours by comparing them with ER+/PgR+/HER2- tumours using a PgR cut-off point of 20% as a divisive criterion.We analysed 1,522 patients with primary breast cancer who had undergone surgery at the Cancer Center of Fudan University between 2012 and 2014. Age, grade, tumour size, lymph node status and lymphovascular invasion were assessed. Multinomial logistic regression, linear regression and chi-square test models were applied to assess associations between ER, PR and clinical features.ER+/PgR-/HER2- tumours showed poorer clinicopathologic characteristics relative to ER+/PgR+/HER2- tumours using a PgR threshold of 20% instead of 1%. The clinicopathologic characteristics did not differ between tumours with purely negative PgR expression and tumours with a PgR percentage ranging from 1% to 19%. The prognostic significance of PR expression appeared more pronounced in patients under a high Ki-67 status than those under a low Ki-67 status.Based on these findings, we propose the use of a novel threshold of 20% to define PgR status. Nevertheless, the impact of this new criterion on patient management and clinical treatment requires additional study.

  1. Palbociclib as a first-line treatment in oestrogen receptor-positive, HER2-negative, advanced breast cancer not cost-effective with current pricing: a health economic analysis of the Swiss Group for Clinical Cancer Research (SAKK).

    Science.gov (United States)

    Matter-Walstra, K; Ruhstaller, T; Klingbiel, D; Schwenkglenks, M; Dedes, K J

    2016-07-01

    Endocrine therapy continues to be the optimal systemic treatment for metastatic ER(+)HER2(-) breast cancer. The CDK4/6 inhibitor palbociclib combined with letrozole has recently been shown to significantly improve progression-free survival. Here we examined the cost-effectiveness of this regimen for the Swiss healthcare system. A Markov cohort simulation based on the PALOMA-1 trial (Finn et al. in Lancet Oncol 16:25-35, 2015) was used as the clinical course. Input parameters were based on summary trial data. Costs were assessed from the Swiss healthcare system perspective. Adding palbociclib to letrozole (PALLET) compared to letrozole monotherapy was estimated to cost an additional CHF342,440 and gain 1.14 quality-adjusted life years, resulting in an incremental cost-effectiveness ratio (ICER) of CHF301,227/QALY gained. In univariate sensitivity analyses, no tested variation in key parameters resulted in an ICER below a willingness-to-pay threshold of CHF100,000/QALY. PALLET had a 0 % probability of being cost-effective in probabilistic sensitivity analyses. Lowering PALLET's price by 75 % resulted in an ICER of CHF73,995/QALY and a 73 % probability of being cost-effective. At current prices, PALLET would cost the Swiss healthcare system an additional CHF155 million/year. Palbociclib plus letrozole cannot be considered cost-effective for the first-line treatment of patients with metastatic breast cancer in the Swiss healthcare system.

  2. Dietary administration of δ- and γ-tocopherol inhibits tumorigenesis in the animal model of estrogen-receptor positive, but not HER-2 breast cancer

    Science.gov (United States)

    Smolarek, Amanda K.; So, Jae Young; Burgess, Brenda; Kong, Ah-Ng Tony; Reuhl, Kenneth; Lin, Yong; Shih, Weichung Joe; Li, Guangxun; Lee, Mao-Jung; Chen, Yu-Kuo; Yang, Chung S.; Suh, Nanjoo

    2012-01-01

    Tocopherol, a member of the vitamin E family, consists of four forms designated as α, β, γ, and δ. Several large cancer prevention studies with α-tocopherol have reported no beneficial results, but recent laboratory studies have suggested that δ- and γ-tocopherol may be more effective. In two different animal models of breast cancer, the chemopreventive activities of individual tocopherols were assessed using diets containing 0.3% of tocopherol (α-, δ- or γ-) or 0.3% of a γ-tocopherol rich mixture (γ-TmT). While administration of tocopherols did not prevent human epidermal growth factor receptor 2 (HER2/neu)-driven tumorigenesis, δ- and γ-tocopherols inhibited hormone-dependent mammary tumorigenesis in N-methyl-N-nitrosourea (NMU)-treated female Sprague Dawley rats. NMU-treated rats showed an average tumor burden of 10.6 ± 0.8 g in the control group at 11 weeks, whereas dietary administration of δ- and γ-tocopherols significantly decreased tumor burden to 7.2 ± 0.8 g (ptocopherol treatment groups by 42% (ptocopherol did not decrease tumor burden or multiplicity. In mammary tumors, the protein levels of pro-apoptotic markers (BAX, cleaved-caspase 9, cleaved-caspase 3, cleaved-PARP) were increased, while anti-apoptotic markers (Bcl2, XIAP) were inhibited by δ-tocopherol, γ-tocopherol and γ-TmT. Furthermore, markers of cell proliferation (PCNA, PKC α), survival (PPARγ, PTEN, phospho-Akt) and cell cycle (p53, p21) were affected by δ- and γ-tocopherols. Both δ- and γ-tocopherols, but not α-tocopherol, appear to be promising agents for the prevention of hormone-dependent breast cancer. PMID:22964476

  3. Dietary administration of δ- and γ-tocopherol inhibits tumorigenesis in the animal model of estrogen receptor-positive, but not HER-2 breast cancer.

    Science.gov (United States)

    Smolarek, Amanda K; So, Jae Young; Burgess, Brenda; Kong, Ah-Ng Tony; Reuhl, Kenneth; Lin, Yong; Shih, Weichung Joe; Li, Guangxun; Lee, Mao-Jung; Chen, Yu-Kuo; Yang, Chung S; Suh, Nanjoo

    2012-11-01

    Tocopherol, a member of the vitamin E family, consists of four forms designated as α, β, γ, and δ. Several large cancer prevention studies with α-tocopherol have reported no beneficial results, but recent laboratory studies have suggested that δ- and γ-tocopherol may be more effective. In two different animal models of breast cancer, the chemopreventive activities of individual tocopherols were assessed using diets containing 0.3% of tocopherol (α-, δ-, or γ-) or 0.3% of a γ-tocopherol rich mixture (γ-TmT). Although administration of tocopherols did not prevent human epidermal growth factor receptor 2 (HER2/neu)-driven tumorigenesis, δ- and γ-tocopherols inhibited hormone-dependent mammary tumorigenesis in N-methyl-N-nitrosourea (NMU)-treated female Sprague-Dawley rats. NMU-treated rats showed an average tumor burden of 10.6 ± 0.8 g in the control group at 11 weeks, whereas dietary administration of δ- and γ-tocopherols significantly decreased tumor burden to 7.2 ± 0.8 g (P tocopherol treatment groups by 42% (P tocopherol did not decrease tumor burden or multiplicity. In mammary tumors, the protein levels of proapoptotic markers (BAX, cleaved caspase-9, cleaved caspase-3, cleaved PARP) were increased, whereas antiapoptotic markers (Bcl-2, XIAP) were inhibited by δ-tocopherol, γ-tocopherol, and γ-TmT. Furthermore, markers of cell proliferation (PCNA, PKCα), survival (PPAR-γ, PTEN, phospho-Akt), and cell cycle (p53, p21) were affected by δ- and γ-tocopherols. Both δ- and γ-tocopherols, but not α-tocopherol, seem to be promising agents for the prevention of hormone-dependent breast cancer.

  4. BMP9 inhibits proliferation and metastasis of HER2-positive SK-BR-3 breast cancer cells through ERK1/2 and PI3K/AKT pathways.

    Science.gov (United States)

    Ren, Wei; Liu, Yuehong; Wan, Shaoheng; Fei, Chang; Wang, Wei; Chen, Yingying; Zhang, Zhihui; Wang, Ting; Wang, Jinshu; Zhou, Lan; Weng, Yaguang; He, Tongchuan; Zhang, Yan

    2014-01-01

    Bone morphogenetic protein 9 (BMP9), a member of TGF-β superfamily, is reported to inhibit the growth and migration of prostate cancer, osteosarcoma and triple-negative MDA-MB-231 breast cancer cells. However, little is known about the effect of on the biological behaviors of HER2-positive SK-BR-3 breast cancer cells and the underlying mechanisms. This study aimed to investigate the effects of BMP9 on the proliferation and metastasis of SK-BR-3 cells with BMP9 over-expression or BMP9 down-regulated expression. Results indicated that exogenously expressed BMP9 inhibited the proliferation and metastasis of SK-BR-3 cells while decreased endogenous BMP9 expression in SK-BR-3 cells promoted the proliferation and migration of breast cancer cells in vitro and in vivo. In SK-BR-3 cells with BMP9 over-expression, the phosphorylation of HER2, ERK1/2 and AKT was markedly suppressed and the HER2 expression decreased at both mRNA and protein levels, while opposite results were observed in SK-BR-3 cells with BMP9 knock down. When the phosphorylation of ERK1/2 and PI3K/AKT was inhibited by PD98059 and LY294002, respectively, the decreased proliferation and invasion induced by BMP9 knock down were eliminated. These findings suggest that BMP9 can inhibit the proliferation and metastasis of SK-BR-3 cells via inactivating ERK1/2 and PI3K/AKT signaling pathways. Thus, BMP9 may serve as a useful agent in the treatment of HER-2 positive breast cancer.

  5. A FISH-based method for assessment of HER-2 amplification status in breast cancer circulating tumor cells following CellSearch isolation

    Directory of Open Access Journals (Sweden)

    Frithiof H

    2016-11-01

    Full Text Available Henrik Frithiof,1 Kristina Aaltonen,1 Lisa Rydén2,3 1Division of Oncology and Pathology, 2Division of Surgery, Department of Clinical Sciences Lund, Lund University, Lund, 3Department of Surgery, Skåne University Hospital, Malmö, Sweden Introduction: Amplification of the HER-2/neu (HER-2 proto-oncogene occurs in 10%–15% of primary breast cancer, leading to an activated HER-2 receptor, augmenting growth of cancer cells. Tumor classification is determined in primary tumor tissue and metastatic biopsies. However, malignant cells tend to alter their phenotype during disease progression. Circulating tumor cell (CTC analysis may serve as an alternative to repeated biopsies. The Food and Drug Administration-approved CellSearch system allows determination of the HER-2 protein, but not of the HER-2 gene. The aim of this study was to optimize a fluorescence in situ hybridization (FISH-based method to quantitatively determine HER-2 amplification in breast cancer CTCs following CellSearch-based isolation and verify the method in patient samples. Methods: Using healthy donor blood spiked with human epidermal growth factor receptor 2 (HER-2-positive breast cancer cell lines, SKBr-3 and BT-474, and a corresponding negative control (the HER-2-negative MCF-7 cell line, an in vitro CTC model system was designed. Following isolation in the CellSearch system, CTC samples were further enriched and fixed on microscope slides. Immunocytochemical staining with cytokeratin and 4',6-diamidino-2'-phenylindole dihydrochloride identified CTCs under a fluorescence microscope. A FISH-based procedure was optimized by applying the HER2 IQFISH pharmDx assay for assessment of HER-2 amplification status in breast cancer CTCs. Results: A method for defining the presence of HER-2 amplification in single breast cancer CTCs after CellSearch isolation was established using cell lines as positive and negative controls. The method was validated in blood from breast cancer patients

  6. Droplet digital polymerase chain reaction detection of HER2 amplification in formalin fixed paraffin embedded breast and gastric carcinoma samples.

    Science.gov (United States)

    Zhu, Yazhen; Lu, Dan; Lira, Maruja E; Xu, Qing; Du, Yunzhi; Xiong, Jianghong; Mao, Mao; Chung, Hyun Cheol; Zheng, Guangjuan

    2016-04-01

    Human epidermal growth factor receptor 2 (HER2) is a key driver of tumorigenesis, and over-expression as a result of HER2 gene amplification has been observed in a number of solid tumors. Recently HER2 has become an important biomarker for the monoclonal antibody treatment of HER2-positive metastatic breast and advanced gastric cancer. The HER2 targeting antibody trastuzumab treatment requires accurate measurement of HER2 levels for proper diagnosis. Droplet digital PCR (ddPCR) with highly direct, precise and absolute nucleic acid quantification could be used to detect HER2 amplification levels. Our objective was to evaluate a robust, accurate and less subjective application of ddPCR for HER2 amplification levels and test the assay performance in clinical formalin-fixed paraffin-embedded (FFPE) breast and gastric carcinoma samples. Genomic DNA from HER2 amplified cell line SK-BR-3 was used to set up the ddPCR assays. The copy number of HER2 was compared to the chromosome 17 centromere reference gene (CEP17), expressed as HER2:CEP17 ratio. Genomic DNAs of FFPE specimens from 145 Asian patients with breast and gastric carcinomas were assayed using both standard methods, immunohistochemistry (IHC) and/or fluorescence in situ hybridization (FISH), and ddPCR. Based on 145 clinical breast and gastric carcinoma cases, our study demonstrated a high concordance of ddPCR results to FISH and IHC. In breast cancer specimens, the ddPCR results had high concordance with FISH and IHC defined HER2 status with a sensitivity of 90.9% (30/33) and a specificity of 100% (77/77). In gastric cancer specimens that were concordant in both FISH and IHC, our assay was 95.5% concordant with FISH and IHC (21/22). ddPCR has the advantage of automation and also allows levels of HER2 amplification to be easily evaluated in large numbers of samples, and presents a potential option to define HER2 status. Copyright © 2015 Elsevier Inc. All rights reserved.

  7. HER-2 amplification in tubular carcinoma of the breast.

    Science.gov (United States)

    Oakley, Gerard J; Tubbs, Raymond R; Crowe, Joseph; Sebek, Bruce; Budd, G Thomas; Patrick, Rebecca J; Procop, Gary W

    2006-07-01

    The prognostic and therapeutic implications of HER-2 gene amplification and estrogen and progesterone receptor status in breast cancer are well described. To address the relative paucity of information concerning HER-2 amplification for tubular carcinomas, we assessed the frequency of gene amplification in 55 tubular carcinomas of the breast from 54 patients, 5 of which had axillary node metastases. The HER-2 gene copy number was assessed by fluorescence in situ hybridization for the majority of tumors analyzed, whereas estrogen and progesterone receptor status was achieved by immunohistochemical analysis. HER-2 gene amplification was not observed in any of the tumors examined, and most were estrogen receptor-positive. This HER-2 gene amplification frequency was significantly lower than the frequency of gene amplification previously reported for all invasive ductal carcinoma of no special type (P < .01). HER-2 gene amplification likely occurs infrequently, or not at all, in tubular carcinomas of the breast, whereas most express estrogen receptors.

  8. Correlation between quantitative HER-2 protein expression and risk for brain metastases in HER-2+ advanced breast cancer patients receiving trastuzumab-containing therapy.

    Science.gov (United States)

    Duchnowska, Renata; Biernat, Wojciech; Szostakiewicz, Barbara; Sperinde, Jeff; Piette, Fanny; Haddad, Mojgan; Paquet, Agnes; Lie, Yolanda; Czartoryska-Arłukowicz, Bogumiła; Wysocki, Piotr; Jankowski, Tomasz; Radecka, Barbara; Foszczynska-Kłoda, Małgorzata; Litwiniuk, Maria; Debska, Sylwia; Weidler, Jodi; Huang, Weidong; Buyse, Marc; Bates, Michael; Jassem, Jacek

    2012-01-01

    Patients with human epidermal growth factor receptor (HER)-2+ breast cancer are at particularly high risk for brain metastases; however, the biological basis is not fully understood. Using a novel HER-2 assay, we investigated the correlation between quantitative HER-2 expression in primary breast cancers and the time to brain metastasis (TTBM) in HER-2+ advanced breast cancer patients treated with trastuzumab. The study group included 142 consecutive patients who were administered trastuzumab-based therapy for HER-2+ metastatic breast cancer. HER-2/neu gene copy number was quantified as the HER-2/centromeric probe for chromosome 17 (CEP17) ratio by central laboratory fluorescence in situ hybridization (FISH). HER-2 protein was quantified as total HER-2 protein expression (H2T) by the HERmark® assay (Monogram Biosciences, Inc., South San Francisco, CA) in formalin-fixed, paraffin-embedded tumor samples. HER-2 variables were correlated with clinical features and TTBM was measured from the initiation of trastuzumab-containing therapy. A higher H2T level (continuous variable) was correlated with shorter TTBM, whereas HER-2 amplification by FISH and a continuous HER-2/CEP17 ratio were not predictive (p = .013, .28, and .25, respectively). In the subset of patients that was centrally determined by FISH to be HER-2+, an above-the-median H2T level was significantly associated with a shorter TTBM (hazard ratio, [HR], 2.4; p = .005), whereas this was not true for the median HER-2/CEP17 ratio by FISH (p = .4). Correlation between a continuous H2T level and TTBM was confirmed on multivariate analysis (HR, 3.3; p = .024). These data reveal a strong relationship between the quantitative HER-2 protein expression level and the risk for brain relapse in HER-2+ advanced breast cancer patients. Consequently, quantitative assessment of HER-2 protein expression may inform and facilitate refinements in therapeutic treatment strategies for selected subpopulations of patients in this

  9. Neratinib overcomes trastuzumab resistance in HER2 amplified breast cancer.

    Science.gov (United States)

    Canonici, Alexandra; Gijsen, Merel; Mullooly, Maeve; Bennett, Ruth; Bouguern, Noujoude; Pedersen, Kasper; O'Brien, Neil A; Roxanis, Ioannis; Li, Ji-Liang; Bridge, Esther; Finn, Richard; Siamon, Dennis; McGowan, Patricia; Duffy, Michael J; O'Donovan, Norma; Crown, John; Kong, Anthony

    2013-10-01

    Trastuzumab has been shown to improve the survival outcomes of HER2 positive breast cancer patients. However, a significant proportion of HER2-positive patients are either inherently resistant or develop resistance to trastuzumab. We assessed the effects of neratinib, an irreversible panHER inhibitor, in a panel of 36 breast cancer cell lines. We further assessed its effects with or without trastuzumab in several sensitive and resistant breast cancer cells as well as a BT474 xenograft model. We confirmed that neratinib was significantly more active in HER2-amplified than HER2 non-amplified cell lines. Neratinib decreased the activation of the 4 HER receptors and inhibited downstream pathways. However, HER3 and Akt were reactivated at 24 hours, which was prevented by the combination of trastuzumab and neratinib. Neratinib also decreased pHER2 and pHER3 in acquired trastuzumab resistant cells. Neratinib in combination with trastuzumab had a greater growth inhibitory effect than either drug alone in 4 HER2 positive cell lines. Furthermore, trastuzumab in combination with neratinib was growth inhibitory in SKBR3 and BT474 cells which had acquired resistance to trastuzumab as well as in a BT474 xenograft model. Innately trastuzumab resistant cell lines showed sensitivity to neratinib, but the combination did not enhance response compared to neratinib alone. Levels of HER2 and phospho-HER2 showed a direct correlation with sensitivity to neratinib. Our data indicate that neratinib is an effective anti-HER2 therapy and counteracted both innate and acquired trastuzumab resistance in HER2 positive breast cancer. Our results suggest that combined treatment with trastuzumab and neratinib is likely to be more effective than either treatment alone for both trastuzumab-sensitive breast cancer as well as HER2-positive tumors with acquired resistance to trastuzumab.

  10. Is overexpression of HER-2 a predictor of prognosis in colorectal cancer?

    International Nuclear Information System (INIS)

    Kavanagh, Dara O; Chambers, Gillian; O' Grady, Liam; Barry, Kevin M; Waldron, Ronan P; Bennani, Fadel; Eustace, Paul W; Tobbia, Iqdam

    2009-01-01

    The development of novel chemotherapeutic agents in colorectal cancer has improved survival. Following initial response to chemotherapeutic strategies many patients develop refractory disease. This poses a significant challenge common to many cancer subtypes. Newer agents such as Bevacizumab have successfully targeted the tyrosine kinase receptor epidermal growth factor receptor in metastatic colorectal cancer. Human epidermal growth factor receptor-2 is another member of the tyrosine kinase receptor family which has been successfully targeted in breast cancer. This may play a role in colorectal cancer. We conducted a clinicopathological study to determine if overexpression of human epidermal growth factor receptor-2 is a predictor of outcome in a cohort of patients with colorectal cancer. Clinicopathological data and paraffin-embedded specimens were collected on 132 consecutive patients who underwent colorectal resections over a 24-month period at Mayo General Hospital. Twenty-six contained non-malignant disease. Her-2/neu protein overexpression was detected using immunohistochemistry (IHC). The HER-2 4B5 Ventana monoclonal antibody was used. Fluorescent insitu hybridisation (FISH) was performed using INFORM HER-2/Neu Plus. Results were correlated with established clinical and pathological predictors of outcome including TNM stage. Statistical analysis was performed using SPSS version 11.5. 114 were HER-2/Neu negative using IHC, 7 showed barely perceptible positivity (1+), 9 showed moderate staining (2+) and 2 were strongly positive (3+). There was no correlation with gender, age, grade, Dukes' stage, TNM stage, time to recurrence and 5-year survival (p > 0.05). FISH was applied to all 2+ and 3+ cases as well as some negative cases selected at random. Three were amplified (2 were 3+ and 1 was 2+). Similarly, HER-2 gene overexpression did not correlate with established prognostic indicators. HER-2 protein is over expressed in 11% of colorectal cancer patients

  11. Is overexpression of HER-2 a predictor of prognosis in colorectal cancer?

    LENUS (Irish Health Repository)

    Kavanagh, Dara O

    2012-01-31

    BACKGROUND: The development of novel chemotherapeutic agents in colorectal cancer has improved survival. Following initial response to chemotherapeutic strategies many patients develop refractory disease. This poses a significant challenge common to many cancer subtypes. Newer agents such as Bevacizumab have successfully targeted the tyrosine kinase receptor epidermal growth factor receptor in metastatic colorectal cancer. Human epidermal growth factor receptor-2 is another member of the tyrosine kinase receptor family which has been successfully targeted in breast cancer. This may play a role in colorectal cancer. We conducted a clinicopathological study to determine if overexpression of human epidermal growth factor receptor-2 is a predictor of outcome in a cohort of patients with colorectal cancer. METHODS: Clinicopathological data and paraffin-embedded specimens were collected on 132 consecutive patients who underwent colorectal resections over a 24-month period at Mayo General Hospital. Twenty-six contained non-malignant disease. Her-2\\/neu protein overexpression was detected using immunohistochemistry (IHC). The HER-2 4B5 Ventana monoclonal antibody was used. Fluorescent insitu hybridisation (FISH) was performed using INFORM HER-2\\/Neu Plus. Results were correlated with established clinical and pathological predictors of outcome including TNM stage. Statistical analysis was performed using SPSS version 11.5. RESULTS: 114 were HER-2\\/Neu negative using IHC, 7 showed barely perceptible positivity (1+), 9 showed moderate staining (2+) and 2 were strongly positive (3+). There was no correlation with gender, age, grade, Dukes\\' stage, TNM stage, time to recurrence and 5-year survival (p > 0.05). FISH was applied to all 2+ and 3+ cases as well as some negative cases selected at random. Three were amplified (2 were 3+ and 1 was 2+). Similarly, HER-2 gene overexpression did not correlate with established prognostic indicators. CONCLUSION: HER-2 protein is over

  12. Evaluation of human epidermal growth factor receptor 2 (HER2) single nucleotide polymorphisms (SNPs) in normal and breast tumor tissues and their link with breast cancer prognostic factors.

    Science.gov (United States)

    Furrer, Daniela; Lemieux, Julie; Côté, Marc-André; Provencher, Louise; Laflamme, Christian; Barabé, Frédéric; Jacob, Simon; Michaud, Annick; Diorio, Caroline

    2016-12-01

    Amplification of the human epidermal growth factor receptor 2 (HER2) gene is associated with worse prognosis and decreased overall survival in breast cancer patients. The HER2 gene contains several polymorphisms; two of the best-characterized HER2 polymorphisms are Ile655Val and Ala1170Pro. The aim of this study was to evaluate the association between these two HER2 polymorphisms in normal breast and breast cancer tissues and known breast cancer prognostic factors in a retrospective cohort study of 73 women with non-metastatic HER2-positive breast cancer. HER2 polymorphisms were assessed in breast cancer tissue and normal breast tissue using TaqMan assay. Ala1170Pro polymorphism in normal breast tissue was associated with age at diagnosis (p = 0.007), tumor size (p = 0.004) and lymphovascular invasion (p = 0.06). Similar significant associations in cancer tissues were observed. No association between the Ile655Val polymorphism and prognostic factors were observed. However, we found significant differences in the distribution of Ile655Val (p = 0.03) and Ala1170Pro (p = 0.01) genotypes between normal breast and breast tumor tissues. This study demonstrates that only the Ala1170Pro polymorphism is associated with prognostic factors in HER2-positive breast cancer patients. Moreover, our results suggest that both HER2 polymorphisms could play a significant role in carcinogenesis in non-metastatic HER2-positive breast cancer women. Copyright © 2016 Elsevier Ltd. All rights reserved.

  13. Expression of Her-2/neu in extrahepatic cholangiocarcinoma

    Directory of Open Access Journals (Sweden)

    Shamekh R

    2017-02-01

    Full Text Available Rania Shamekh,1,* Marilin Rosa,2,* Zena Sayegh,2 Masoumeh Ghayouri,2 Richard Kim,3 Mokenge P Malafa,3 Domenico Coppola2 1Department of Pathology, University of South Florida, 2Department of Anatomic Pathology, 3Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA *These authors contributed equally to this work Background: Receptor tyrosine-protein kinase erbB-2, which is also frequently called human epidermal growth factor receptor-2 (Her-2 or Her-2/neu, has been found to be overexpressed in various human cancers.Hypothesis: The aim of this pilot study was to explore the frequency of Her-2/neu gene amplification and protein expression in extrahepatic cholangiocarcinoma (EHBC. We used the World Health Organization classification criteria for EHBC.Materials and methods: This was a retrospective study using 88 tissue samples, including 45 samples from non-neoplastic biliary tissue (NNB and 43 samples of extrahepatic cholangiocarcinoma (EHBC. A tissue microarray including NNB and EHBC was constructed and analyzed by immunohistochemistry (IHC and dual in situ hybridization for Her-2/neu protein expression and amplification, respectively. The Her-2/neu expression was scored following the guidelines used for the ToGA study.Results: All NNB samples and all but one EHBC samples showed no expression of Her-2/neu by IHC. The one EHBC case immunohistochemically positive for Her-2/neu had an IHC score of 3+. Her-2/neu gene amplification was present in two EHBC samples only and included the case found to be positive by IHC.Conclusion: Our findings are similar to those reported in the literature. Although Her-2/neu overexpression has been documented in many types of cancer, Her-2/neu protein overexpression tends to have no role in the development and/or progression of EHBC. Keywords: extrahepatic, cholangiocarcinoma, Her-2/neu, ToGA, immunohistochemistry

  14. Trastuzumab and survival of patients with metastatic breast cancer.

    Science.gov (United States)

    Kast, Karin; Schoffer, Olaf; Link, Theresa; Forberger, Almuth; Petzold, Andrea; Niedostatek, Antje; Werner, Carmen; Klug, Stefanie J; Werner, Andreas; Gatzweiler, Axel; Richter, Barbara; Baretton, Gustavo; Wimberger, Pauline

    2017-08-01

    Prognosis of Her2-positive breast cancer has changed since the introduction of trastuzumab for treatment in metastatic and early breast cancer. It was described to be even better compared to prognosis of Her2-negative metastatic breast cancer. The purpose of this study was to evaluate the effect of trastuzumab in our cohort. Besides the effect of adjuvant pretreatment with trastuzumab on survival of patients with metastatic Her2-positive breast cancer was analyzed. All patients with primary breast cancer of the Regional Breast Cancer Center Dresden diagnosed during the years 2001-2013 were analyzed for treatment with or without trastuzumab in the adjuvant and in the metastatic treatment setting using Kaplan-Meier survival estimation and Cox regression. Age and tumor stage at time of first diagnosis of breast cancer as well as hormone receptor status, grading, time, and site of metastasis at first diagnosis of distant metastatic disease were analyzed. Of 4.481 female patients with primary breast cancer, 643 presented with metastatic disease. Her2-positive status was documented in 465 patients, including 116 patients with primary or secondary metastases. Median survival of patients with Her2-positive primary metastatic disease was 3.0 years (95% CI 2.3-4.0). After adjustment for other factors, survival was better in patients with Her2-positive breast cancer with trastuzumab therapy compared to Her2-negative metastatic disease (HR 2.10; 95% CI 1.58-2.79). Analysis of influence of adjuvant therapy with and without trastuzumab by Kaplan-Meier showed a trend for better survival in not pretreated patients. Median survival was highest in hormone receptor-positive Her2-positive (triple-positive) primary metastatic breast cancer patients with 3.3 years (95% CI 2.3-4.6). Prognosis of patients with Her2-positive metastatic breast cancer after trastuzumab treatment is more favorable than for Her2-negative breast cancer. The role of adjuvant chemotherapy with or without

  15. Safety and efficacy of everolimus with exemestane vs. exemestane alone in elderly patients with HER2-negative, hormone receptor-positive breast cancer in BOLERO-2.

    Science.gov (United States)

    Pritchard, Kathleen I; Burris, Howard A; Ito, Yoshinori; Rugo, Hope S; Dakhil, Shaker; Hortobagyi, Gabriel N; Campone, Mario; Csöszi, Tibor; Baselga, José; Puttawibul, Puttisak; Piccart, Martine; Heng, Daniel; Noguchi, Shinzaburo; Srimuninnimit, Vichien; Bourgeois, Hugues; Gonzalez Martin, Antonio; Osborne, Karen; Panneerselvam, Ashok; Taran, Tetiana; Sahmoud, Tarek; Gnant, Michael

    2013-12-01

    Postmenopausal women with hormone receptor-positive (HR(+)) breast cancer in whom disease progresses or there is recurrence while taking a nonsteroidal aromatase inhibitor (NSAI) are usually treated with exemestane (EXE), but no single standard of care exists in this setting. The BOLERO-2 trial demonstrated that adding everolimus (EVE) to EXE improved progression-free survival (PFS) while maintaining quality of life when compared with EXE alone. Because many women with HR(+) advanced breast cancer are elderly, the tolerability profile of EVE plus EXE in this population is of interest. BOLERO-2, a phase III randomized trial, compared EVE (10 mg/d) and placebo (PBO), both plus EXE (25 mg/d), in 724 postmenopausal women with HR(+) advanced breast cancer recurring/progressing after treatment with NSAIs. Safety and efficacy data in elderly patients are reported at 18-month median follow-up. Baseline disease characteristics and treatment histories among the elderly subsets (≥ 65 years, n = 275; ≥ 70 years, n = 164) were generally comparable with younger patients. The addition of EVE to EXE improved PFS regardless of age (hazard ratio, 0.59 [≥ 65 years] and 0.45 [≥ 70 years]). Adverse events (AEs) of special interest (all grades) that occurred more frequently with EVE than with PBO included stomatitis, infections, rash, pneumonitis, and hyperglycemia. Elderly EVE-treated patients had similar incidences of these AEs as did younger patients but had more on-treatment deaths. Adding EVE to EXE offers substantially improved PFS over EXE and was generally well tolerated in elderly patients with HR(+) advanced breast cancer. Careful monitoring and appropriate dose reductions or interruptions for AE management are recommended during treatment with EVE in this patient population. Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.

  16. Safety and efficacy of neratinib in combination with capecitabine in patients with metastatic human epidermal growth factor receptor 2-positive breast cancer.

    Science.gov (United States)

    Saura, Cristina; Garcia-Saenz, Jose A; Xu, Binghe; Harb, Wael; Moroose, Rebecca; Pluard, Timothy; Cortés, Javier; Kiger, Corinne; Germa, Caroline; Wang, Kongming; Martin, Miguel; Baselga, José; Kim, Sung-Bae

    2014-11-10

    Neratinib is a potent irreversible pan-tyrosine kinase inhibitor with antitumor activity and acceptable tolerability in patients with human epidermal growth factor receptor 2 (HER2) -positive breast cancer. A multinational, open-label, phase I/II trial was conducted to determine the maximum-tolerated dose (MTD) of neratinib plus capecitabine in patients with solid tumors (part one) and to evaluate the safety and efficacy of neratinib plus capecitabine in patients with HER2-positive metastatic breast cancer (part two). Part one was a 3 + 3 dose-escalation study in which patients with advanced solid tumors received oral neratinib once per day continuously plus capecitabine twice per day on days 1 to 14 of a 21-day cycle at predefined dose levels. In part two, patients with trastuzumab-pretreated HER2-positive metastatic breast cancer received neratinib plus capecitabine at the MTD. The primary end point in part two was objective response rate (ORR). In part one (n = 33), the combination of neratinib 240 mg per day plus capecitabine 1,500 mg/m(2) per day was defined as the MTD, which was further evaluated in part 2 (n = 72). The most common drug-related adverse events were diarrhea (88%) and palmar-plantar erythrodysesthesia syndrome (48%). In part two, the ORR was 64% (n = 39 of 61) in patients with no prior lapatinib exposure and 57% (n = 4 of 7) in patients previously treated with lapatinib. Median progression-free survival was 40.3 and 35.9 weeks, respectively. Neratinib in combination with capecitabine had a manageable toxicity profile and showed promising antitumor activity in patients with HER2-positive metastatic breast cancer pretreated with trastuzumab and lapatinib. © 2014 by American Society of Clinical Oncology.

  17. Durable Clinical Benefit of Pertuzumab in a Young Patient with BRCA2 Mutation and HER2-Overexpressing Breast Cancer Involving the Brain

    Directory of Open Access Journals (Sweden)

    Anna Koumarianou

    2016-01-01

    Full Text Available Patients with HER2-positive breast cancer and brain metastases have limited treatment options, and, as a result of their poor performance status and worse prognosis, they are underrepresented in clinical trials. Not surprisingly, these patients may not be fit enough to receive any active treatment and are offered supportive therapy. BRCA2 mutations are reported to be rarely associated with HER2-overexpressing advanced breast cancer and even more rarely with brain metastases at diagnosis. We report on a BRCA2-positive breast cancer patient with metastatic disease in multiple sites, including the brain, and poor performance status who exhibited an extraordinary clinical and imaging response to the novel anti-HER2 therapy pertuzumab after multiple lines of therapy including anti-HER2 targeting. To our knowledge, the clinicopathologic and therapeutic characteristics of this patient point to a unique case and an urgent need for further investigation of pertuzumab in patients with brain metastases.

  18. Emerging technologies for assessing HER2 amplification

    NARCIS (Netherlands)

    Penault-Llorca, Frédérique; Bilous, Michael; Dowsett, Mitch; Hanna, Wedad; Osamura, Robert Yoshiyuki; Rüschoff, Josef; van de Vijver, Marc

    2009-01-01

    Patients with human epidermal growth factor receptor-2 (HER2)+ breast cancer are eligible for trastuzumab treatment; therefore, accurate assessment of HER2 status is essential. Until recently, only 2 methods were validated for determining the HER2 status of breast tumors in the routine diagnostic

  19. 64Cu-DOTA-Trastuzumab PET Imaging in Women with HER2-Overexpressing Breast Cancer

    Science.gov (United States)

    2013-10-01

    and 1, 3, and 6 mo later, when possible, were eval- uated for immune responses using a size-exclusion high-performance liquid chromatography shift...3 4 HER2 IHC31 2 5 7 IHC21/FISH positive 1 1 Sites of metastatic disease Bone 2 4 6 Lymph nodes 2 5 7 Liver 2 2 4 Lung 1 1 2 Pleural effusion 1 1...jnm122630-pm n 10/28/13 complexes were observed in the high-performance liquid chroma- tography shift assays of 2 patients at baseline and 6 mo or

  20. HER 2/neu protein expression in colorectal cancer

    International Nuclear Information System (INIS)

    Schuell, B; Gruenberger, T; Scheithauer, W; Zielinski, Ch; Wrba, F

    2006-01-01

    Conflicting data exist about the prevalence of HER-2/neu overexpression in colorectal cancer ranging from 0 to 83 %. In our study we tried to clarify the extent of expression and its relationship to clinicopathological parameters. This study involved 77 specimens of malignant colorectal cancer lesions of surgically resected patients. HER-2/neu immunohistochemistry was performed using the Hercep-Test Kit. Out of 77 specimens, 56 were Her-2/neu negative (70%), 20 (26%) showed a barely immunostaining (1+), only 1 (1%) was moderately (2+) and 2 (3%) were strongly positive (3+). Her-2/neu staining (moderately and strongly positive) was only detected in primary tumours of patients with confirmed metastases. No relationship was found between membranous HER-2 expression and patients' gender or differentiation. The median survival time of patients with positive HER-2/neu immunostaining was 21 versus 39 months in patients without HER-2/neu expression (p = 0.088). The c-erbB protein expression was observed in colorectal cancer but rarely in the therapeutic range (2+ and 3+). There was no significant association with tumour grade, gender, localization of the primary tumour or survival. These data indicate that c-erbB-2 is unlikely to play a major role in the therapeutic management of colorectal cancer

  1. Neratinib overcomes trastuzumab resistance in HER2 amplified breast cancer.

    OpenAIRE

    Canonici, A; Gijsen, M; Mullooly, M; Bennett, R; Bouguern, N; Pedersen, K; O'Brien, NA; Roxanis, I; Li, J-L; Bridge, E; Finn, R; Siamon, D; McGowan, P; Duffy, MJ; O'Donovan, N

    2013-01-01

    Trastuzumab has been shown to improve the survival outcomes of HER2 positive breast cancer patients. However, a significant proportion of HER2-positive patients are either inherently resistant or develop resistance to trastuzumab. We assessed the effects of neratinib, an irreversible panHER inhibitor, in a panel of 36 breast cancer cell lines. We further assessed its effects with or without trastuzumab in several sensitive and resistant breast cancer cells as well as a BT474 xenograft model. ...

  2. Sensitivity of CA 15-3, CEA and serum HER2 in the early detection of recurrence of breast cancer

    DEFF Research Database (Denmark)

    Eriksen, Ann Christina; Sørensen, Patricia Diana; Jacobsen, Erik Hugger

    2013-01-01

    The aim of this project was to investigate the sensitivity of CA 15-3, CEA and HER2 in the early diagnosis of metastatic breast cancer.......The aim of this project was to investigate the sensitivity of CA 15-3, CEA and HER2 in the early diagnosis of metastatic breast cancer....

  3. The mannosylated extracellular domain of Her2/neu produced in P. pastoris induces protective antitumor immunity

    International Nuclear Information System (INIS)

    Dimitriadis, Alexios; Gontinou, Chrysanthi; Baxevanis, Constantin N; Mamalaki, Avgi

    2009-01-01

    Her2/neu is overexpressed in various human cancers of epithelial origin and is associated with increased metastatic potential and poor prognosis. Several attempts have been made using the extracellular domain of Her2/neu (ECD/Her2) as a prophylactic vaccine in mice with no success in tumor prevention. The extracellular domain of Her2/neu (ECD/Her2) was expressed in yeast P. pastoris, in a soluble highly mannosylated form. The immune response of the immunization with this recombinant ECD/Her2 was analyzed using immunoprecipitation and western blot analysis, proliferation and cytotoxicity assays as well as specific tumor growth assays. Mannosylated ECD/Her2 elicited a humoral response with HER2/neu specific antibodies in vaccinated mice, which were able to reduce the proliferation rate of cancer cells in vitro. Moreover, it elicited a cellular response with Her2/neu-specific CTL capable of lysing tumor cells, in vitro. When immunized Balb/c and HHD mice were challenged with Her2/neu-overexpressing cells, tumor growth was inhibited. Here we report on the efficacy of the extracellular domain of human Her2/neu produced in yeast P. pastoris, which confers mannosylation of the protein, to act as a potent anti-tumor vaccine against Her2/neu overexpressing tumors. Specific cellular and humoral responses were observed as well as efficacy

  4. A phase II study of weekly irinotecan in patients with locally advanced or metastatic HER2- negative breast cancer and increased copy numbers of the topoisomerase 1 (TOP1) gene

    DEFF Research Database (Denmark)

    Kümler, Iben; Balslev, Eva; Stenvang, Jan

    2015-01-01

    breast cancer and increased expression of the topoisomerase 1 gene have a high likelihood of obtaining a clinical benefit from treatment with irinotecan. Trial recruitment is two-staged as 19 patients are planned to participate in the first part. If less than 7 patients have clinical benefit the trial...... is a topoisomerase 1 inhibitor used for decades for the treatment of colorectal cancer. Four studies have investigated the efficacy of irinotecan monotherapy in breast cancer and all have included non-biomarker selected patients. In these studies response rates for irinotecan ranged from 5%-23% and are thus......BACKGROUND: About 20% of patients with primary breast cancer develop metastatic disease during the course of the disease. At this point the disease is considered incurable and thus treatment is aimed at palliation and life prolongation. As many patients will have received both an anthracycline...

  5. Safety and efficacy of vinorelbine in combination with pertuzumab and trastuzumab for first-line treatment of patients with HER2-positive locally advanced or metastatic breast cancer

    DEFF Research Database (Denmark)

    Perez, Edith A; López-Vega, José Manuel; Petit, Thierry

    2016-01-01

    .2% (95% CI 63.8-82.9) in intent-to-treat patients with measurable disease (89/106 [84.0%]). Median PFS was 14.3 months (95% CI 11.2-17.5) in the intent-to-treat population. Treatment was reasonably well tolerated, with no unexpected toxicities. Diarrhea (61/106 patients [57.5%]) and neutropenia (54....../106 [50.9%]) were the most common adverse events (AEs); neutropenia (33/106 [31.1%]) and leukopenia (14/106 [13.2%]) were the most common grade ≥3 AEs. Serious AEs were reported in 32/106 (30.2%) patients. AEs led to study drug discontinuation in 36/106 patients (34.0%). Eighteen of 106 patients (17...

  6. Safety results from a phase III study (TURANDOT trial by CECOG) of first-line bevacizumab in combination with capecitabine or paclitaxel for HER-2-negative locally recurrent or metastatic breast cancer.

    Science.gov (United States)

    Lang, I; Inbar, M J; Kahán, Z; Greil, R; Beslija, S; Stemmer, S M; Kaufman, B; Zvirbule, Z; Steger, G G; Messinger, D; Brodowicz, T; Zielinski, C

    2012-11-01

    We report safety data from a randomised, phase III study (CECOG/BC.1.3.005) evaluating first-line bevacizumab plus paclitaxel or capecitabine for locally recurrent or metastatic breast cancer. Patients aged ≥18 years with human epidermal growth factor receptor-2-negative breast adenocarcinoma were randomised to Arm A: bevacizumab 10 mg/kg days 1 and 15; paclitaxel 90 mg/m(2) days 1, 8, and 15, every 4 weeks; or Arm B: bevacizumab 15 mg/kg day 1; capecitabine 1000 mg/m(2) b.i.d., days 1-14, every 3 weeks, until disease progression, unacceptable toxicity or consent withdrawal. A post hoc interim safety analysis included 561 patients (Arm A: 284, Arm B: 277). The regimens demonstrated similar frequencies of all-grade and serious adverse events (SAEs), but different safety profiles. Treatment-related events occurred in 85.2% (Arm A) and 78.0% (Arm B) of patients. Fatigue was most common in Arm A (30.6% versus 23.5% Arm B), and hand-foot syndrome (HFS) most common in Arm B (49.5% versus 2.5% Arm A). Diarrhoea (Arm A: 0.4%, Arm B: 1.4%) and pulmonary embolism (Arm A: 0.7%, Arm B: 1.1%) were the most frequently reported SAEs. These findings are in-line with safety data for bevacizumab plus paclitaxel or capecitabine, reported in previous phase III trials. Copyright © 2012 Elsevier Ltd. All rights reserved.

  7. Comparison of central HER2 testing with quantitative total HER2 expression and HER2 homodimer measurements using a novel proximity-based assay.

    Science.gov (United States)

    Huang, Weidong; Reinholz, Monica; Weidler, Jodi; Yolanda, Lie; Paquet, Agnes; Whitcomb, Jeannette; Lingle, Wilma; Jenkins, Robert B; Chen, Beiyun; Larson, Jeffrey S; Tan, Yuping; Sherwood, Thomas; Bates, Michael; Perez, Edith A

    2010-08-01

    The accuracy and reliability of immunohistochemical analysis and in situ hybridization for the assessment of HER2 status remains a subject of debate. We developed a novel assay (HERmark Breast Cancer Assay, Monogram Biosciences, South San Francisco, CA) that provides precise quantification of total HER2 protein expression (H2T) and HER2 homodimers (H2D) in formalin-fixed, paraffin-embedded tissue specimens. H2T and H2D results of 237 breast cancers were compared with those of immunohistochemical studies and fluorescence in situ hybridization (FISH) centrally performed at the Mayo Clinic, Rochester, MN. H2T described a continuum across a wide dynamic range ( approximately 2.5 log). Excluding the equivocal cases, HERmark showed 98% concordance with immunohistochemical studies for positive and negative assay values. For the 94 immunohistochemically equivocal cases, 67% and 39% concordance values were observed between HERmark and FISH for positive and negative assay values, respectively. Polysomy 17 in the absence of HER2 gene amplification did not result in HER2 overexpression as evaluated quantitatively using the HERmark assay.

  8. HER2 in Breast Cancer Stemness: A Negative Feedback Loop towards Trastuzumab Resistance

    Directory of Open Access Journals (Sweden)

    Babak Nami

    2017-04-01

    Full Text Available HER2 receptor tyrosine kinase that is overexpressed in approximately 20% of all breast cancers (BCs is a poor prognosis factor and a precious target for BC therapy. Trastuzumab is approved by FDA to specifically target HER2 for treating HER2+ BC. However, about 60% of patients with HER2+ breast tumor develop de novo resistance to trastuzumab, partially due to the loss of expression of HER2 extracellular domain on their tumor cells. This is due to shedding/cleavage of HER2 by metalloproteinases (ADAMs and MMPs. HER2 shedding results in the accumulation of intracellular carboxyl-terminal HER2 (p95HER2, which is a common phenomenon in trastuzumab-resistant tumors and is suggested as a predictive marker for trastuzumab resistance. Up-regulation of the metalloproteinases is a poor prognosis factor and is commonly seen in mesenchymal-like cancer stem cells that are risen during epithelial to mesenchymal transition (EMT of tumor cells. HER2 cleavage during EMT can explain why secondary metastatic tumors with high percentage of mesenchymal-like cancer stem cells are mostly resistant to trastuzumab but still sensitive to lapatinib. Importantly, many studies report HER2 interaction with oncogenic/stemness signaling pathways including TGF-β/Smad, Wnt/β-catenin, Notch, JAK/STAT and Hedgehog. HER2 overexpression promotes EMT and the emergence of cancer stem cell properties in BC. Increased expression and activation of metalloproteinases during EMT leads to proteolytic cleavage and shedding of HER2 receptor, which downregulates HER2 extracellular domain and eventually increases trastuzumab resistance. Here, we review the hypothesis that a negative feedback loop between HER2 and stemness signaling drives resistance of BC to trastuzumab.

  9. Optimizing HER2 assessment in breast cancer

    DEFF Research Database (Denmark)

    Holten-Rossing, Henrik; Møller Talman, Maj-Lis; Kristensson, Martin

    2015-01-01

    In breast cancer, analysis of HER2 expression is pivotal for treatment decision. This study aimed at comparing digital, automated image analysis with manual reading using the HER2-CONNECT algorithm (Visiopharm) in order to minimize the number of equivocal 2+ scores and the need for reflex...

  10. Circulating HER2 DNA after trastuzumab treatment predicts survival and response in breast cancer

    DEFF Research Database (Denmark)

    Sorensen, Boe S; Mortensen, Lise S; Andersen, Jørn

    2010-01-01

    BACKGROUND: Only a subset of breast cancer patients responds to the HER2 inhibitor trastuzumab, and methods to identify responders are needed. PATIENTS AND METHODS: We studied 28 patients with metastatic breast cancer that had amplified human epidermal growth factor receptor 2 (HER2) genes...... in their primary tumour and were treated with a combination of trastuzumab and chemotherapy. Plasma was collected and amplification of the HER2 gene in circulating DNA and the amounts of the extracellular domain (ECD) of HER2 were measured just before first treatment (n=28) and just before second treatment three...... response (p=0.02), and overall survival (p=0.05). HER2 ECD kinetics did not correlate to clinical data. CONCLUSION: We suggest that a decrease in HER2 gene amplification in the plasma predicts a more favourable response to trastuzumab....

  11. Efficacy and safety of palbociclib in combination with letrozole as first-line treatment of ER-positive, HER2-negative, advanced breast cancer: expanded analyses of subgroups from the randomized pivotal trial PALOMA-1/TRIO-18.

    Science.gov (United States)

    Finn, Richard S; Crown, John P; Ettl, Johannes; Schmidt, Marcus; Bondarenko, Igor M; Lang, Istvan; Pinter, Tamas; Boer, Katalin; Patel, Ravindranath; Randolph, Sophia; Kim, Sindy T; Huang, Xin; Schnell, Patrick; Nadanaciva, Sashi; Bartlett, Cynthia Huang; Slamon, Dennis J

    2016-06-28

    Palbociclib is an oral small-molecule inhibitor of cyclin-dependent kinases 4 and 6. In the randomized, open-label, phase II PALOMA-1/TRIO-18 trial, palbociclib in combination with letrozole improved progression-free survival (PFS) compared with letrozole alone as first-line treatment of estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative, advanced breast cancer (20.2 months versus 10.2 months; hazard ratio (HR) = 0.488, 95 % confidence interval (CI) 0.319-0.748; one-sided p = 0.0004). Grade 3-4 neutropenia was the most common adverse event (AE) in the palbociclib + letrozole arm. We now present efficacy and safety analyses based on several specific patient and tumor characteristics, and present in detail the clinical patterns of neutropenia observed in the palbociclib + letrozole arm of the overall safety population. Postmenopausal women (n = 165) with ER+, HER2-negative, advanced breast cancer who had not received any systemic treatment for their advanced disease were randomized 1:1 to receive either palbociclib in combination with letrozole or letrozole alone. Treatment continued until disease progression, unacceptable toxicity, consent withdrawal, or death. The primary endpoint was PFS. We now analyze the difference in PFS for the treatment populations by subgroups, including age, histological type, history of prior neoadjuvant/adjuvant systemic treatment, and sites of distant metastasis, using the Kaplan-Meier method. HR and 95 % CI are derived from a Cox proportional hazards regression model. A clinically meaningful improvement in median PFS and clinical benefit response (CBR) rate was seen with palbociclib + letrozole in every subgroup evaluated. Grade 3-4 neutropenia was the most common AE with palbociclib + letrozole in all subgroups. Analysis of the frequency of neutropenia by grade during the first six cycles of treatment showed that there was a downward trend in Grade 3-4 neutropenia

  12. Synthesis and stability test of radiogadolinium(III-DOTA-PAMAM G3.0-trastuzumab as SPECT-MRI molecular imaging agent for diagnosis of HER-2 positive breast cancer

    Directory of Open Access Journals (Sweden)

    Hardiani Rahmania

    2015-01-01

    Full Text Available Nonivasive diagnosis of cancer can be provided by molecular imaging using hybrid modality to obtain better sensitivity, specificity and depiction localization of the disease. In this study, we developed a new molecular imaging agent, radiogadolinium(III-DOTA-PAMAM G3.0-trastuzumab in the form of 147Gd-DOTA-PAMAM G3.0-trastuzumab, that can be both target-specific radiopharmaceutical in SPECT as well as targeted contrast agent in MRI for the purpose of diagnosis of HER-2 positive breast cancer. 147Gd radionuclide emits γ-rays that can be used in SPECT modality, but because of technical constraint, 147Gd radionuclide was simulated by its radioisotope, 153Gd. Gd-DOTA complex has also been known as good MRI contrast agent. PAMAM G3.0 is useful to concentrate Gd-DOTA compelexes in large quantities, thus minimizing the number of trastuzumab molecules used. Trastuzumab is human monoclonal antibody that can spesifically interact with HER-2. Synthesis of radiogadolinium(III-DOTA-PAMAM G3.0-trastuzumab was initiated by conjugating DOTA NHS ester ligand with PAMAM G3.0 dendrimer. The DOTA-PAMAM G3.0 produced was conjugated to trastuzumab molecule and labeled with 153Gd. Characterization DOTA-PAMAM G3.0-trastuzumab immunoconjugate was performed using HPLC system equipped with SEC. The formation of immunoconjugate was indicated by the shorter retention time (6.82 min compared to that of trastuzumab (7.06 min. Radiochemical purity of radiogadolinium(III-DOTA-PAMAM G3.0-trastuzumab was >99% after purification process by PD-10 desalting column. Radiogadolinium(III-DOTA-PAMAM G3.0-trastuzumab compound was stable at room temperature and at 2–8 0C as indicated by its radiochemical purity 97.6 ± 0.5%–99.1 ± 0.5% after 144 h storage.

  13. IMMUNOHISTOCHEMICAL EXPRESSION OF HER2 IN ADENOCARCINOMA OF THE STOMACH

    Directory of Open Access Journals (Sweden)

    Diego Michelon DE CARLI

    2015-06-01

    Full Text Available Background Worldwide, gastric cancer is the fourth cancer in incidence and the second most common cause of cancer death. Gastric cancer is asymptomatic in the early stages and very often diagnosed at advanced stages, determining a dismal prognosis. Expression of the HER2 gene has been identified in about 20% of gastric cancer cases, and its hyper-expression is associated with poor prognosis. Objective To investigate HER2 immunohistochemical expression in gastric adenocarcinoma and its relationship to the histological type and anatomic location. Methods A cross-sectional retrospective study analyzed the immunohistochemical expression of HER2 in a sample of 48 specimens of gastric cancer. Immunohistochemical analysis were performed using avidin-biotin-peroxidase method with C-erb B2 (clone EP1045Y, as a primary antibody (Biocare Medical, USA. Standardized gastric adenocarcinoma‘s HER2 expression criteria has been used in the analysis of samples. Results There were seven cases with reactivity for HER2. Five were of intestinal-type while two cases were of mixed-type in which the expression occurred in the intestinal component. It was identified a significant association of HER2 expression in the intestinal subtype of gastric adenocarcinoma (P=0.003. Regarding the anatomical site, HER2 was positive in only one (16.6% of the six proximal cases and six (14.28% of the 42 distal cases (P=0.88. Conclusion HER2 immunoexpression was identified in 14.6% of the samples, and the expression was significantly associated to Lauren’s intestinal subtype.

  14. Trastuzumab has preferential activity against breast cancers driven by HER2 homodimers

    Science.gov (United States)

    Ghosh, Ritwik; Narasanna, Archana; Wang, Shizhen Emily; Liu, Shuying; Chakrabarty, Anindita; Balko, Justin M.; González-Angulo, Ana María; Mills, Gordon B.; Penuel, Elicia; Winslow, John; Sperinde, Jeff; Dua, Rajiv; Pidaparthi, Sailaja; Mukherjee, Ali; Leitzel, Kim; Kostler, Wolfgang J.; Lipton, Allan; Bates, Michael; Arteaga, Carlos L.

    2011-01-01

    In breast cancer cells with HER2 gene amplification, HER2 receptors exist on the cell surface as monomers, homodimers and heterodimers with EGFR/HER3. The therapeutic antibody trastuzumab, an approved therapy for HER2+ breast cancer, cannot block ligand-induced HER2 heterodimers, suggesting it cannot effectively inhibit HER2 signaling. Hence, HER2 oligomeric states may predict the odds of a clinical response to trastuzumab in HER2-driven tumors. To test this hypothesis, we generated non-transformed human MCF10A mammary epithelial cells stably expressing a chimeric HER2-FKBP molecule that could be conditionally induced to homodimerize by adding the FKBP ligand AP1510, or instead induced to heterodimerize with EGFR or HER3 by adding the heterodimer ligands EGF/TGFα or heregulin. AP1510, EGF, and heregulin each induced growth of MCF10A cells expressing HER2-FKBP. As expected, trastuzumab inhibited homodimer-mediated but not heterodimer-mediated cell growth. In contrast, the HER2 antibody pertuzumab, which blocks HER2 heterodimerization, inhibited growth induced by heregulin but not AP1510. Lastly, HER2/EGFR tyrosine kinase inhibitor lapatinib blocked both homodimer- and heterodimer-induced growth. AP1510 triggered phosphorylation of Erk1/2 but not AKT, whereas trastuzumab inhibited AP1510-induced Erk1/2 phosphorylation and Shc-HER2 homodimer binding, but not TGFα-induced AKT phosphorylation. Consistent with these observations, high levels of HER2 homodimers correlated with longer time to progression following trastuzumab therapy in a cohort of HER2-overexpressing patients. Together, our findings corroborate the hypothesis that HER2 oligomeric states regulate HER2 signaling, also arguing that trastuzumab sensitivity of homodimers reflects an inability to activate the PI3K/AKT pathway. One of the most important clinical implications of our results is that high levels of HER2 homodimers may predict a positive response to trastuzumab. PMID:21324925

  15. Immunotherapy with a HER2-Targeting Listeria Induces HER2-Specific Immunity and Demonstrates Potential Therapeutic Effects in a Phase I Trial in Canine Osteosarcoma.

    Science.gov (United States)

    Mason, Nicola J; Gnanandarajah, Josephine S; Engiles, Julie B; Gray, Falon; Laughlin, Danielle; Gaurnier-Hausser, Anita; Wallecha, Anu; Huebner, Margie; Paterson, Yvonne

    2016-09-01

    Recombinant Listeria vaccines induce tumor-specific T-cell responses that eliminate established tumors and prevent metastatic disease in murine cancer models. We used dogs with HER2/neu(+) appendicular osteosarcoma, a well-recognized spontaneous model for pediatric osteosarcoma, to determine whether a highly attenuated, recombinant Listeria monocytogenes expressing a chimeric human HER2/neu fusion protein (ADXS31-164) could safely induce HER2/neu-specific immunity and prevent metastatic disease. Eighteen dogs that underwent limb amputation or salvage surgery and adjuvant chemotherapy were enrolled in a phase I dose escalation clinical trial and received either 2 × 10(8), 5 × 10(8), 1 × 10(9), or 3.3 × 10(9) CFU of ADXS31-164 intravenously every 3 weeks for 3 administrations. Only low-grade, transient toxicities were observed. ADXS31-164 broke peripheral tolerance and induced antigen-specific IFNγ responses against the intracellular domain of HER2/neu in 15 of 18 dogs within 6 months of treatment. Furthermore, ADXS31-164 reduced the incidence of metastatic disease and significantly increased duration of survival time and 1-, 2-, and 3-year survival rates when compared with a historical control group with HER2/neu(+) appendicular osteosarcoma treated with amputation and chemotherapy alone. These findings demonstrate that ADXS31-164 administered in the setting of minimal residual disease can induce HER2/neu-specific immunity and may reduce the incidence of metastatic disease and prolong overall survival in a clinically relevant, spontaneous, large animal model of cancer. These findings, therefore, have important translational relevance for children with osteosarcoma and adults with other HER2/neu(+) cancers. Clin Cancer Res; 22(17); 4380-90. ©2016 AACR. ©2016 American Association for Cancer Research.

  16. Overcoming resistance and restoring sensitivity to HER2-targeted therapies in breast cancer.

    LENUS (Irish Health Repository)

    Mohd Sharial, M S N

    2012-12-01

    Approximately 15%-23% of breast cancers overexpress human epidermal growth factor receptor 2 (HER2), which leads to the activation of signaling pathways that stimulate cell proliferation and survival. HER2-targeted therapy has substantially improved outcomes in patients with HER2-positive breast cancer. However, both de novo and acquired resistance are observed.

  17. Real world cost of human epidermal receptor 2-positive metastatic breast cancer patients: a longitudinal incidence-based observational costing study in the Netherlands and Belgium.

    Science.gov (United States)

    Frederix, G W J; Severens, J L; Hövels, A M; van Hasselt, J G C; Hooiveld, M J J; Neven, P; Raaijmakers, J A M; Schellens, J H M

    2015-05-01

    Currently, no country-specific metastatic breast cancer (MBC) observational costing data are available for the Netherlands and Belgium. Our aim is to describe country-specific resource use and costs of human epidermal receptor 2 (HER-2)-positive MBC in the Netherlands and Belgium, making use of real-world data. The eligibility period for patient selection was from April 2004 to April 2010. Inclusion and retrospective data collection begins at the time of first diagnosis of HER-2-positive MBC during the eligibility period and ends 24 months post-index diagnosis of MBC or at patient death. We identified 88 eligible patients in the Netherlands and 44 patients in Belgium. The total costs of medical treatment and other resource use utilisation per patient was €48,301 in the Netherlands and €37,431 in Belgium. Majority of costs was related to the use of trastuzumab in both countries, which was 50% of the total costs in the Netherlands and 56% in Belgium respectively. Our study provides estimates of resource use and costs for HER-2-positive MBC in the Netherlands and Belgium. We noticed various differences in resource use patterns between both countries demonstrating caution is needed when transferring cost estimates between countries. © 2014 John Wiley & Sons Ltd.

  18. Determining sensitivity and specificity of HER2 testing in breast cancer using a tissue micro-array approach

    NARCIS (Netherlands)

    Dekker, Tim J. A.; Borg, Susan Ter; Hooijer, Gerrit K. J.; Meijer, Sybren L.; Wesseling, Jelle; Boers, James E.; Schuuring, Ed; Bart, Jos; van Gorp, Joost; Mesker, Wilma E.; Kroep, Judith R.; Smit, Vincent T. H. B. M.; van de Vijver, Marc J.

    2012-01-01

    Introduction: Overexpression of the human epidermal growth factor receptor 2 (HER2) as a result of HER2 gene amplification is associated with a relatively poor prognosis in breast cancer and is predictive of HER2-targeting therapy response. False-positive rates of up to 20% for HER2 testing have

  19. HER-2 Pulsed Dendritic Cell Vaccine Can Eliminate HER-2 Expression and Impact DCIS

    Science.gov (United States)

    Sharma, Anupama; Koldovsky, Ursula; Xu, Shuwen; Mick, Rosemarie; Roses, Robert; Fitzpatrick, Elizabeth; Weinstein, Susan; Nisenbaum, Harvey; Levine, Bruce L; Fox, Kevin; Zhang, Paul; Koski, Gary; Czerniecki, Brian J

    2011-01-01

    Background HER-2/neu over-expression plays a critical role in breast cancer development and its expression in ductal carcinoma in situ (DCIS) is associated with development of invasive breast cancer. A vaccine targeting HER-2/neu expression in DCIS may initiate immunity against invasive cancer. Methods A HER-2/neu dendritic cell (DC) vaccine was administered to 27 patients with HER-2/neu over-expressing DCIS. The HER-2/neu vaccine was administered prior to surgical resection and pre- and post-vaccination analysis was conducted to assess clinical results. Results At surgery, 5 of 27 (18.5%) vaccinated subjects had no evidence of remaining disease, while among 22 subjects with residual DCIS, HER-2/neu expression was eradicated in 11 (50%). When comparing ERneg with ERpos DCIS lesions, vaccination was more effective in hormone-independent DCIS. Following vaccination, no residual DCIS was found in 40% of ERneg subjects compared to 5.9% in ERpos subject. Sustained HER-2/neu expression was found in 10% of ERneg subjects compared to 47.1% in ERpos subjects (p=0.04). Post-vaccination phenotypes were significantly different between ERpos and ERneg subjects (p=0.01), with 7 of 16 (43.8%) initially presenting with ERpos HER-2/neupos Luminal B phenotype finishing with the ERpos HER-2/neuneg Luminal A phenotype, and 3 of 6 (50%) with the ERneg HER-2/neupos phenotype changing to the ERneg HER-2/neuneg phenotype. Conclusions Results suggest vaccination against HER-2/neu is safe, well-tolerated and induces decline and or eradication of HER-2/neu expression. These findings warrant further exploration of HER-2/neu vaccination in estrogen-independent breast cancer and highlight the need to target additional tumor associated antigens and pathways. PMID:22252842

  20. Label-free LC-MS analysis of HER2+ breast cancer cell line response to HER2 inhibitor treatment.

    Science.gov (United States)

    Di Luca, Alessio; Henry, Michael; Meleady, Paula; O'Connor, Robert

    2015-08-04

    Human epidermal growth-factor receptor (HER)-2 is overexpressed in 25 % of breast-cancers and is associated with an aggressive form of the disease with significantly shortened disease free and overall survival. In recent years, the use of HER2-targeted therapies, monoclonal-antibodies and small molecule tyrosine-kinase inhibitors has significantly improved the clinical outcome for HER2-positive breast-cancer patients. However, only a fraction of HER2-amplified patients will respond to therapy and the use of these treatments is often limited by tumour drug insensitivity or resistance and drug toxicities. Currently there is no way to identify likely responders or rational combinations with the potential to improve HER2-focussed treatment outcome. In order to further understand the molecular mechanisms of treatment-response with HER2-inhibitors, we used a highly-optimised and reproducible quantitative label-free LC-MS strategy to characterize the proteomes of HER2-overexpressing breast-cancer cell-lines (SKBR3, BT474 and HCC1954) in response to drug-treatment with HER2-inhibitors (lapatinib, neratinib or afatinib). Following 12 ours treatment with different HER2-inhibitors in the BT474 cell-line; compared to the untreated cells, 16 proteins changed significantly in abundance following lapatinib treatment (1 μM), 21 proteins changed significantly following neratinib treatment (150 nM) and 38 proteins changed significantly following afatinib treatment (150 nM). Whereas following 24 hours treatment with neratinib (200 nM) 46 proteins changed significantly in abundance in the HCC1954 cell-line and 23 proteins in the SKBR3 cell-line compared to the untreated cells. Analysing the data we found that, proteins like trifunctional-enzyme subunit-alpha, mitochondrial; heterogeneous nuclear ribonucleoprotein-R and lamina-associated polypeptide 2, isoform alpha were up-regulated whereas heat shock cognate 71 kDa protein was down-regulated in 3 or more comparisons. This proteomic

  1. Neratinib, A Novel HER2-Targeted Tyrosine Kinase Inhibitor.

    Science.gov (United States)

    Tiwari, Shruti Rakesh; Mishra, Prasun; Abraham, Jame

    2016-10-01

    HER2 gene amplification and receptor overexpression is identified in 20% to 25% of human breast cancers. Use of targeted therapy for HER2-amplified breast cancer has led to improvements in disease-free and overall survival in this subset of patients. Neratinib is an oral pan HER inhibitor, that irreversibly inhibits the tyrosine kinase activity of epidermal growth factor receptor (EGFR or HER1), HER2, and HER4, which leads to reduced phosphorylation and activation of downstream signaling pathways. Neratinib is currently being tested in a number of clinical trials for its safety and efficacy in lung cancer, and colorectal, bladder, and breast cancers. In this review we discuss the available phase I, II, and III data for use of neratinib in the metastatic, adjuvant, neoadjuvant, and extended adjuvant settings along with the ongoing clinical trials of neratinib in breast cancer. We also elaborate on the side effect profile of this relatively new drug and provide guidelines for its use in clinical practice. Copyright © 2016 Elsevier Inc. All rights reserved.

  2. A Single Domain–Based Anti-Her2 Antibody Has Potent Antitumor Activities

    Directory of Open Access Journals (Sweden)

    Xiaoqiong Wu

    2018-04-01

    Full Text Available Human epidermal growth factor receptor 2 (HER2 is overexpressed in approximately 20% to 30% of breast cancers and various other types of cancers, which plays a vital role in the cancer progression. Monoclonal antibodies targeting Her2 are now used in the clinic to treat Her2 overexpression cancer patients. However, relapse or resistance is frequent with the current therapies. To generate a new treatment avenue against Her2, we immunized and selected a specific anti-Her2 single domain antibody C3 for further studies. The C3-Fc antibody drove antibody-dependent cell-mediated cytotoxicity against Her2-positive tumor cells in vitro and resulted in potent antitumor growth in vivo. These data suggest that the C3-Fc antibody may provide an alternative avenue for Her2-positive cancer therapy.

  3. The SystHERs registry: an observational cohort study of treatment patterns and outcomes in patients with human epidermal growth factor receptor 2–positive metastatic breast cancer

    International Nuclear Information System (INIS)

    Tripathy, Debu; Lai, Catherine; Masaquel, Anthony; Hurvitz, Sara; Rugo, Hope S; Kaufman, Peter A; Swain, Sandra; O’Shaughnessy, Joyce; Jahanzeb, Mohammad; Mason, Ginny; Beattie, Mary; Yoo, Bongin

    2014-01-01

    Amplification of the human epidermal growth factor receptor 2 (HER2) gene occurs in approximately 20% of invasive breast cancer cases and is associated with a more aggressive disease course than HER2-negative breast cancer. HER2-targeted therapies have altered the natural history of HER2-positive breast cancer, a trend that will likely further improve with the recent approval of new agents. A prospective, observational cohort study was designed and initiated to provide real-world insights into current treatment patterns, long-term survival, and patients’ experiences with initial and subsequent treatments for HER2-positive metastatic breast cancer (MBC). The Systematic Therapies for HER2-positive Metastatic Breast Cancer Study (SystHERs) is a US-based prospective observational cohort study enrolling patients ≥18 years of age with recently diagnosed HER2-positive MBC not previously treated with systemic therapy in the metastatic setting. The primary objective of the study is to identify treatment patterns and clinical outcomes in recently diagnosed patients in a variety of practice settings. Secondary objectives include comparative efficacy, safety, and patient-reported outcomes (PROs). Healthcare resource utilization is an exploratory end point. Tumor tissue and blood sample collection is optional. The SystHERs registry will enroll approximately 1000 patients over a 3-year period, after which the study will continue for ≥5 years, allowing for a maximum follow-up of 8 years. The treating physician will determine all care and the frequency of visits. PRO measures will be completed at study enrollment and every 90 days. Clinical data will be abstracted quarterly from patient records. The first patient was enrolled in June 2012, and preliminary descriptive data based on 25% to 30% of the final study population are expected at the end of 2013, and as of April 25, 2014, 386 patients are enrolled. SystHERs is expected to provide in-depth data on demographic

  4. Long-term hazard of recurrence in HER2+ breast cancer patients untreated with anti-HER2 therapy

    DEFF Research Database (Denmark)

    Strasser-Weippl, Kathrin; Horick, Nora; Smith, Ian E

    2015-01-01

    INTRODUCTION: Worldwide, many patients with HER2+ (human epidermal growth factor receptor 2-positive) early breast cancer (BC) do not receive adjuvant trastuzumab. Hazards of recurrence of these patients with respect to hormone receptor status of the primary tumor have not been described. METHODS...

  5. Leptin/HER2 crosstalk in breast cancer: in vitro study and preliminary in vivo analysis

    International Nuclear Information System (INIS)

    Fiorio, Elena; Bonetti, Franco; Giordano, Antonio; Cetto, Gian Luigi; Surmacz, Eva; Mercanti, Anna; Terrasi, Marianna; Micciolo, Rocco; Remo, Andrea; Auriemma, Alessandra; Molino, Annamaria; Parolin, Veronica; Di Stefano, Bruno

    2008-01-01

    Obesity in postmenopausal women is associated with increased breast cancer risk, development of more aggressive tumors and resistance to certain anti-breast cancer treatments. Some of these effects might be mediated by obesity hormone leptin, acting independently or modulating other signaling pathways. Here we focused on the link between leptin and HER2. We tested if HER2 and the leptin receptor (ObR) can be coexpressed in breast cancer cell models, whether these two receptors can physically interact, and whether leptin can transactivate HER2. Next, we studied if leptin/ObR can coexist with HER2 in breast cancer tissues, and if presence of these two systems correlates with specific clinicopathological features. Expression of ObR, HER2, phospo-HER2 was assessed by immonoblotting. Physical interactions between ObR and HER2 were probed by immunoprecipitation and fluorescent immunostaining. Expression of leptin and ObR in breast cancer tissues was detected by immunohistochemistry (IHC). Associations among markers studied by IHC were evaluated using Fisher's exact test for count data. HER2 and ObR were coexpressed in all studied breast cancer cell lines. In MCF-7 cells, HER2 physically interacted with ObR and leptin treatment increased HER2 phosphorylation on Tyr 1248. In 59 breast cancers, the presence of leptin was correlated with ObR (the overall association was about 93%). This result was confirmed both in HER2-positive and in HER2-negative subgroups. The expression of leptin or ObR was numerically more frequent in larger (> 10 mm) tumors. Coexpression of HER2 and the leptin/ObR system might contribute to enhanced HER2 activity and reduced sensitivity to anti-HER2 treatments

  6. Efficacy and safety of ABP 980 compared with reference trastuzumab in women with HER2-positive early breast cancer (LILAC study): a randomised, double-blind, phase 3 trial.

    Science.gov (United States)

    von Minckwitz, Gunter; Colleoni, Marco; Kolberg, Hans-Christian; Morales, Serafin; Santi, Patricia; Tomasevic, Zorica; Zhang, Nan; Hanes, Vladimir

    2018-06-04

    ABP 980 (Amgen Inc, Thousand Oaks, CA, USA) is a biosimilar of trastuzumab, with analytical, functional, and pharmacokinetic similarities. We compared the clinical safety and efficacy of ABP 980 with that of trastuzumab in women with HER2-positive early breast cancer. We did a randomised, multicentre, double-blind, active-controlled equivalence trial at 97 study centres in 20 countries, mainly in Europe and South America. Eligible women were aged 18 years or older, had histologically confirmed HER2-positive invasive early breast cancer, an Eastern Cooperative Oncology Group performance status score of 0 or 1, and were planning to have surgical resection of the breast tumour with sentinel or axillary lymph node dissection and neoadjuvant chemotherapy. After four cycles of run-in anthracycline-based chemotherapy, patients were assigned 1:1 to receive ABP 980 or trastuzumab with a permuted block design (blocks of four) computer-generated randomisation schedule. Patients received neoadjuvant therapy with a loading dose (8 mg/kg) of ABP 980 or trastuzumab plus paclitaxel 175 mg/m 2 in a 90 min intravenous infusion, followed by three cycles of 6 mg/kg intravenous ABP 980 or trastuzumab plus paclitaxel 175 mg/m 2 every 3 weeks in 30 min intravenous infusions (or 80 mg/m 2 paclitaxel once per week for 12 cycles if that was the local standard of care). Randomisation was stratified by T stage, node status, hormone receptor status, planned paclitaxel dosing schedule, and geographical region. Surgery was completed 3-7 weeks after the last dose of neoadjuvant treatment, after which adjuvant treatment with ABP 980 or trastuzumab was given every 3 weeks for up to 1 year after the first dose in the study. Patients had been randomly assigned at baseline to continue APB 980, continue trastuzumab, or switch from trastuzumab to APB 980 as their adjuvant treatment. The co-primary efficacy endpoints were risk difference and risk ratio (RR) of pathological complete response in breast

  7. Clinical significance of Mena and Her-2 expression in breast cancer.

    Science.gov (United States)

    Du, J W; Xu, K Y; Fang, L Y; Qi, X L

    2012-01-01

    The aim of this study was to determine the expression patterns of Mena and Her-2 in breast cancer tissues and to explore their clinical significance and correlation with clinicopathological parameters. The expression of Mena and Her-2 was detected in 40 breast cancer tissues and 14 normal breast tissues by immunohistochemistry, and the relationship of Mena and Her-2 expression with clinicopathological parameters was analyzed. Both Mena (70%) and Her-2 (40%) were more commonly expressed in breast cancer than in normal breast tissue (7.1%, 0%, respectively; p Mena and Her-2 expression in breast cancer were positively correlated (r = 0.530, p Mena and Her-2 were both associated with axillary lymph node metastasis and TNM stage (p Mena and Her-2 are related to the malignancy degree and metastasis of breast cancer, and thus may play a coordinating role in the occurrence and progression of breast cancer.

  8. Serum HER-2 concentrations for monitoring women with breast cancer in a routine oncology setting

    DEFF Research Database (Denmark)

    Sørensen, Patricia Diana; Jakobsen, Erik Hugger; Langkjer, Sven Tyge

    2009-01-01

    BACKGROUND: The purpose of this study was to determine the positive predictive value (PPV) of positive serum human epidermal growth factor receptor-2 (HER-2) for monitoring women with breast cancer following diagnosis and treatment in a routine clinical setting. METHODS: Serum HER-2 was measured...... could be determined in ten tissue-positive patients was 3-24 months (mean 11.3 months), when compared to standard clinical imaging methods. CONCLUSIONS: Serum HER-2 is a useful marker for the detection of recurrence of breast cancer and for monitoring the effect of treatment, especially in tissue HER-2...... in 1348 patients with breast cancer: 837 during routine oncology clinic visits and 511 following new diagnosis. All patients with positive serum HER-2, 1/5 of negative patients from the oncology clinic, and all the newly diagnosed were followed; a total of 862 patients. Serum HER-2 was measured using...

  9. Discordance Rate of HER2 Status in Primary Gastric Carcinomas and Synchronous Lymph Node Metastases: A Multicenter Retrospective Analysis

    Directory of Open Access Journals (Sweden)

    Antonio Ieni

    2014-12-01

    Full Text Available Background: The assessment of human epidermal growth factor receptor 2 (HER2 gene amplification is essential in order to identify those patients affected by advanced gastric cancer who may benefit from Trastuzumab targeted therapy. Materials and Methods: With the aim to investigate the concordance rate in HER2 status between primary gastric carcinoma (GC and synchronous lymphnode metastases, we investigated HER2 status in a cohort of 108 surgical formalin-fixed paraffin-embedded specimens of GC and matched synchronous metastatic lymph nodes collected from three different units of Anatomic Pathology in southern of Italy. Fleiss-Cohen weighted k statistics were used to assess the concordance rate of HER2 status. Results: HER2 amplification was observed in 17% of primary GCs and the overall concordance rate with corresponding nodal metastases was 90.74%. Changes in HER2 status between primary GC and matched synchronous metastases were evidenced in 10 (9.26% cases. Of these, 6 cases were HER2 amplified in the primary GC and not amplified in the metastases, while 4 were HER2 not amplified in the primary tumour and amplified in the lymph node metastases. Conclusions: Although at present the simultaneous determination of HER2 in advanced gastric cancer and corresponding metastatic lymph nodes is not mandatory, the possibility that the synchronous metastases of GC have a different HER2 status from that of the primary tumour is of remarkable significance; Indeed this may have influence on the therapeutic management and prognosis of the patients.

  10. Tumor Uptake of 64Cu-DOTA-Trastuzumab in Patients with Metastatic Breast Cancer.

    Science.gov (United States)

    Mortimer, Joanne E; Bading, James R; Park, Jinha M; Frankel, Paul H; Carroll, Mary I; Tran, Tri T; Poku, Erasmus K; Rockne, Russell C; Raubitschek, Andrew A; Shively, John E; Colcher, David M

    2018-01-01

    The goal of this study was to characterize the relationship between tumor uptake of 64 Cu-DOTA-trastuzumab as measured by PET/CT and standard, immunohistochemistry (IHC)-based, histopathologic classification of human epidermal growth factor receptor 2 (HER2) status in women with metastatic breast cancer (MBC). Methods: Women with biopsy-confirmed MBC and not given trastuzumab for 2 mo or more underwent complete staging, including 18 F-FDG PET/CT. Patients were classified as HER2-positive (HER2+) or -negative (HER2-) based on fluorescence in situ hybridization (FISH)-supplemented immunohistochemistry of biopsied tumor tissue. Eighteen patients underwent 64 Cu-DOTA-trastuzumab injection, preceded in 16 cases by trastuzumab infusion (45 mg). PET/CT was performed 21-25 (day 1) and 47-49 (day 2) h after 64 Cu-DOTA-trastuzumab injection. Radiolabel uptake in prominent lesions was measured as SUV max Average intrapatient SUV max ( pt ) was compared between HER2+ and HER2- patients. Results: Eleven women were HER2+ (8 immunohistochemistry 3+; 3 immunohistochemistry 2+/FISH amplified), whereas 7 were HER2- (3 immunohistochemistry 2+/FISH nonamplified; 4 immunohistochemistry 1+). Median pt for day 1 and day 2 was 6.6 and 6.8 g/mL for HER 2+ and 3.7 and 4.3 g/mL for HER2- patients ( P pt overlapped between the 2 groups, and interpatient variability was greater for HER2+ than HER2- disease ( P DOTA-trastuzumab in MBC is strongly associated with patient HER2 status and is indicative of binding to HER2. The variability within and among HER2+ patients, as well as the overlap between the HER2+ and HER2- groups, suggests a role for 64 Cu-DOTA-trastuzumab PET/CT in optimizing treatments that include trastuzumab. © 2018 by the Society of Nuclear Medicine and Molecular Imaging.

  11. Inhibitor of Apoptosis (IAP) survivin is indispensable for survival of HER2 gene-amplified breast cancer cells with primary resistance to HER1/2-targeted therapies

    International Nuclear Information System (INIS)

    Oliveras-Ferraros, Cristina; Vazquez-Martin, Alejandro; Cufi, Silvia; Torres-Garcia, Violeta Zenobia; Sauri-Nadal, Tamara; Barco, Sonia Del; Lopez-Bonet, Eugeni; Brunet, Joan; Martin-Castillo, Begona; Menendez, Javier A.

    2011-01-01

    Highlights: → Intrinsic trastuzumab resistance occurs in ∼70% of metastatic HER2 + breast carcinomas (BC). → Approximately 15% of early HER2 + BC relapse in spite of treatment with trastuzumab-based therapies. → HER2-independent downstream pro-survival pathways might underlie trastuzumab refractoriness. → Survivin is indispensable for proliferation and survival of HER2 + BC unresponsive to HER2-targeted therapies ab initio. → Survivin antagonists may clinically circumvent the occurrence of de novo resistance to HER2-directed drugs. -- Abstract: Primary resistance of HER2 gene-amplified breast carcinomas (BC) to HER-targeted therapies can be explained in terms of overactive HER2-independent downstream pro-survival pathways. We here confirm that constitutive overexpression of Inhibitor of Apoptosis (IAP) survivin is indispensable for survival of HER2-positive BC cells with intrinsic cross-resistance to multiple HER1/2 inhibitors. The IC 50 values for the HER1/2 Tyrosine Kinase Inhibitors (TKIs) gefitinib, erlotinib and lapatinib were up to 40-fold higher in trastuzumab-unresponsive JIMT-1 cells than in trastuzumab-naive SKBR3 cells. ELISA-based and immunoblotting assays demonstrated that trastuzumab-refractory JIMT-1 cells constitutively expressed ∼4 times more survivin protein than trastuzumab-responsive SKBR3 cells. In response to trastuzumab, JIMT-1 cells accumulated ∼10 times more survivin than SKBR3 cells. HER1/2 TKIs failed to down-regulate survivin expression in JIMT-1 cells whereas equimolar doses of HER1/HER2 TKIs drastically depleted survivin protein in SKBR3 cells. ELISA-based detection of histone-associated DNA fragments confirmed that trastuzumab-refractory JIMT-1 cells were intrinsically protected against the apoptotic effects of HER1/2 TKIs. Of note, when we knocked-down survivin expression using siRNA and then added trastuzumab, cell proliferation and colony formation were completely suppressed in JIMT-1 cells. Our current findings may

  12. Inhibitor of Apoptosis (IAP) survivin is indispensable for survival of HER2 gene-amplified breast cancer cells with primary resistance to HER1/2-targeted therapies

    Energy Technology Data Exchange (ETDEWEB)

    Oliveras-Ferraros, Cristina; Vazquez-Martin, Alejandro; Cufi, Silvia; Torres-Garcia, Violeta Zenobia [Unit of Translational Research, Catalan Institute of Oncology-Girona, Avenida de Francia S/N, E-17007 Girona, Catalonia (Spain); Girona Biomedical Research Institute, Avenida de Francia S/N, E-17007 Girona, Catalonia (Spain); Sauri-Nadal, Tamara; Barco, Sonia Del [Girona Biomedical Research Institute, Avenida de Francia S/N, E-17007 Girona, Catalonia (Spain); Medical Oncology, Catalan Institute of Oncology-Girona, Avenida de Francia S/N, E-17007 Girona, Catalonia (Spain); Lopez-Bonet, Eugeni [Girona Biomedical Research Institute, Avenida de Francia S/N, E-17007 Girona, Catalonia (Spain); Department of Anatomical Pathology, Dr. Josep Trueta University Hospital, Avenida de Francia S/N, E-17007 Girona, Catalonia (Spain); Brunet, Joan [Girona Biomedical Research Institute, Avenida de Francia S/N, E-17007 Girona, Catalonia (Spain); Medical Oncology, Catalan Institute of Oncology-Girona, Avenida de Francia S/N, E-17007 Girona, Catalonia (Spain); Martin-Castillo, Begona [Girona Biomedical Research Institute, Avenida de Francia S/N, E-17007 Girona, Catalonia (Spain); Unit of Clinical Research, Catalan Institute of Oncology-Girona, Avenida de Francia S/N, E-17007 Girona, Catalonia (Spain); Menendez, Javier A., E-mail: jmenendez@idibgi.org [Unit of Translational Research, Catalan Institute of Oncology-Girona, Avenida de Francia S/N, E-17007 Girona, Catalonia (Spain); Girona Biomedical Research Institute, Avenida de Francia S/N, E-17007 Girona, Catalonia (Spain)

    2011-04-08

    Highlights: {yields} Intrinsic trastuzumab resistance occurs in {approx}70% of metastatic HER2 + breast carcinomas (BC). {yields} Approximately 15% of early HER2 + BC relapse in spite of treatment with trastuzumab-based therapies. {yields} HER2-independent downstream pro-survival pathways might underlie trastuzumab refractoriness. {yields} Survivin is indispensable for proliferation and survival of HER2 + BC unresponsive to HER2-targeted therapies ab initio. {yields} Survivin antagonists may clinically circumvent the occurrence of de novo resistance to HER2-directed drugs. -- Abstract: Primary resistance of HER2 gene-amplified breast carcinomas (BC) to HER-targeted therapies can be explained in terms of overactive HER2-independent downstream pro-survival pathways. We here confirm that constitutive overexpression of Inhibitor of Apoptosis (IAP) survivin is indispensable for survival of HER2-positive BC cells with intrinsic cross-resistance to multiple HER1/2 inhibitors. The IC{sub 50} values for the HER1/2 Tyrosine Kinase Inhibitors (TKIs) gefitinib, erlotinib and lapatinib were up to 40-fold higher in trastuzumab-unresponsive JIMT-1 cells than in trastuzumab-naive SKBR3 cells. ELISA-based and immunoblotting assays demonstrated that trastuzumab-refractory JIMT-1 cells constitutively expressed {approx}4 times more survivin protein than trastuzumab-responsive SKBR3 cells. In response to trastuzumab, JIMT-1 cells accumulated {approx}10 times more survivin than SKBR3 cells. HER1/2 TKIs failed to down-regulate survivin expression in JIMT-1 cells whereas equimolar doses of HER1/HER2 TKIs drastically depleted survivin protein in SKBR3 cells. ELISA-based detection of histone-associated DNA fragments confirmed that trastuzumab-refractory JIMT-1 cells were intrinsically protected against the apoptotic effects of HER1/2 TKIs. Of note, when we knocked-down survivin expression using siRNA and then added trastuzumab, cell proliferation and colony formation were completely

  13. Standardization of HER2 testing: results of an international proficiency-testing ring study

    NARCIS (Netherlands)

    Dowsett, Mitch; Hanna, Wedad M.; Kockx, Mark; Penault-Llorca, Frederique; Rüschoff, Josef; Gutjahr, Thorsten; Habben, Kai; van de Vijver, Marc J.

    2007-01-01

    Human epidermal growth factor receptor 2 (HER2) positivity in breast cancer is a prognostic factor regarding tumor aggressiveness and a predictive factor for response to trastuzumab (Herceptin). Early and accurate HER2 testing of all breast cancer patients at primary diagnosis is essential for

  14. Relationship Between HER2 Status and Prognosis in Women With Brain Metastases From Breast Cancer

    International Nuclear Information System (INIS)

    Xu Zhiyuan; Marko, Nicholas F.; Chao, Sam T.; Angelov, Lilyana; Vogelbaum, Michael A.; Suh, John H.; Barnett, Gene H.; Weil, Robert J.

    2012-01-01

    Purpose: To analyze factors affecting outcomes in breast cancer patients with brain metastases (BM) and characterize the role of HER2 status. Methods and Materials: We identified 264 breast cancer patients treated between 1999 and 2008 for BM. HER2 status was known definitively for 172 patients and was used to define cohorts in which survival and risk factors were analyzed. Results: Kaplan-Meier survival analysis demonstrated improved mean overall survival (105.7 vs. 74.3 months, p < 0.02), survival after diagnosis of BM (neurologic survival, NS) (32.2 vs. 18.9 months, p < 0.01), and survival after treatment with stereotactic radiosurgery (RS) (31.3 vs. 14.1, p < 0.01) in HER2+ patients relative to those with HER2− breast cancer. HER2+ status was an independent, positive prognostic factor for survival on univariate and multivariate hazard analysis (hazard ratio: overall survival = 0.66, 0.18; NS = 0.50, 0.34). Additionally, subgroup analysis suggests that stereotactic radiosurgery may be of particular benefit in patients with HER2+ tumors. Conclusions: Overall survival, NS, and RS are improved in patients with HER2+ tumors, relative to those with HER2− lesions, and HER2 amplification is independently associated with increased survival in patients with BM from breast cancer. Our findings suggest that the prognosis of HER2+ patients may be better than that of otherwise similar patients who are HER2− and that stereotactic radiosurgery may be beneficial for some patients with HER2+ lesions.

  15. Clinicopathological and prognostic significance of HER-2/neu and VEGF expression in colon carcinomas

    Directory of Open Access Journals (Sweden)

    Li Jing

    2011-06-01

    Full Text Available Abstract Background HER-2/neu and VEGF expression is correlated with disease behaviors in various cancers. However, evidence for their expression in colon cancer is rather contradictory both for the protein expression status and prognostic value. HER-2/neu is found to participate in VEGF regulation, and has known correlation with VEGF expression in some tumors. In this study, we investigated HER-2/neu and VEGF expression in Chinese colon patients and explored whether there was any correlation between their expression patterns. Methods HER-2/neu and VEGF were investigated immunohistochemically using tumor samples obtained from 317 colon cancer patients with all tumor stages. Correlation of the degree of staining with clinicopathological parameters and survival was investigated. Results Positive expression rates of HER-2/neu and VEGF in colon cancer were 15.5% and 55.5% respectively. HER-2/neu expression was significantly correlated with tumor size and distant metastases (P (P > 0.05. Expression of VEGF was significantly correlated with tumor size, tumor stage, lymph node metastases, and distant metastases (P (P = 0.146. No correlation between HER-2/neu and VEGF expression was detected (P = 0.151. Conclusions HER-2/neu and VEGF are not important prognostic markers of colon cancer. The present results do not support any association between HER2/neu and VEGF expression in this setting.

  16. Correlation between apparent diffusion coefficients and HER2 status in gastric cancers: pilot study

    International Nuclear Information System (INIS)

    He, Jian; Shi, Hua; Zhou, Zhuping; Chen, Jun; Guan, Wenxian; Wang, Hao; Yu, Haiping; Liu, Song; Zhou, Zhengyang; Yang, Xiaofeng; Liu, Tian

    2015-01-01

    To evaluate whether apparent diffusion coefficient (ADC) value of gastric cancer obtained from diffusion weighted imaging (DWI) correlates with the HER2 status. Forty-five patients, who had been diagnosed with gastric cancer through biopsy, were enrolled in this IRB-approved study. Each patient underwent a DWI (b values: 0 and 1,000 sec/mm 2 ) prior to surgery (curative gastrectomy or palliative resection). Postoperative microscopic findings, HER2 status by immunohistochemical analysis and fluorescence in situ hybridization (FISH) were obtained. HER2 status was compared among gastric cancers with various histopathological features using the chi square test. The ADC values of gastric cancers with positive and negative HER2 were compared using the student t test. A weak yet significant correlation was observed between the mean ADC values and HER2 status (r = 0.312, P = 0.037) and scores (r = 0.419, P = 0.004). The mean ADC value of HER2-positive gastric cancers was significantly higher than those of HER2-negative tumors (1.211 vs. 0.984 mm 2 /s, P = 0.020). The minimal ADC value of HER2-positive gastric cancers was significantly higher than those of HER2-negative tumors (1.105 vs. 0.905 × 10 −3 mm 2 /s, P = 0.036). In this pilot study, we have demonstrated that the ADC values of gastric cancer correlate with the HER2 status. Future research is warranted to see if DWI can predict HER2 status and help in tailoring therapy for gastric cancer

  17. Metastatic hepatocellular carcinoma to the skin staining positive with HMB-45.

    Science.gov (United States)

    Gross, Joshua A; Perniciaro, Charles; Gross, David J; Barksdale, Sarah K

    2012-02-01

    Hepatocellular carcinoma (HCC) is uncommonly observed as a cutaneous metastasis. We report a 76-year-old man with metastatic HCC to the skin of the nasal ala, diagnosed antecedent to the primary tumor. HCC was confirmed by positive immunostaining with Hep Par 1 in tissue from the metastasis and from a needle biopsy of the primary lesion. In addition, tumor cells from both the metastasis and liver stained positive with HMB-45. To our knowledge, HMB-45 positive staining has not been reported in either primary or metastatic HCC.

  18. Quantification of HER2 autoantibodies in the amplification phenomenon of HER2 in breast cancer

    DEFF Research Database (Denmark)

    Lauterlein, Jens-Jacob L; Petersen, Eva R B; Olsen, Dorte Aa

    2011-01-01

    Gene amplification of HER2 (human epidermal growth factor receptor 2) is a well-known phenomenon in various cancers. However, little is known about the mechanism of the gene amplification phenomenon itself. Autoantibodies to cellular receptors have been described in several cancer types. We hypot...

  19. Study of HER2/neu status in Qatari women with breast carcinoma

    International Nuclear Information System (INIS)

    Rasul, Kaki I.; Abdalla, Awidi S.; Mohammed, Kelta; Ahmad, Mubarak A.; Al-Homsi, Mohammed U.; Al-Hassan, Asma M.; Al-Alosi, Ahmad S.; Bener, A.

    2003-01-01

    The study is aimed at determining the prevalence of HER2/neu overexpression in Qatari women with breast cancer and to acess the survival in patients with HER2/neu positive tumors. This is a retropspective study of clinical data of 70 Qatari female patients diagonosed with breast cancer during the priod 1991through to 2001,at Hamad Medical Corporation, Doha, Qatar. We also performed a retrospective review of breast tissue for those patients using paraffin sections and applying immunohistochemistry staining -[Hercep test (DAKO Inc)] to determine the HER/neu status. Out of all the eighteen patients (26%) were HER2/neu positive(2+ and 3+) wih a mean age at diagonosis of 49.3 years, and 52 (74%) were negative (0and 1+)with mean age at diagonosis of 46.6 years.Of patients with positive HER2/neu, 5(28%) had a relapse of disease and 4 (22%) died of disease during followup. Of the patients with HER2/neu, negative test 9(17%) had a relapse of disease and10(19%) died of the disease . The median survival function at mean of covaritesfor HER2/neu positve patients was 26 months, and for HER2/neu negative patients was 28 months. The prevalence of HER2/neu and overexpression in Qatari female with breast cancer in study is 26%, but due to small sample size it may not reflect really the prevalence. Patients with HER/neu positive were older at diagonosis than ptients with HER2/neu negative also they had higher relapse rate and mortality. Median survival function was better for HER2/neu negative patients. (author)

  20. Quantification and imaging of HER2 protein using nanocrystals conjugated with single-domain antibodies

    International Nuclear Information System (INIS)

    Glukhov, S; Berestovoy, M; Nabiev, I; Sukhanova, A; Chames, P; Baty, D

    2017-01-01

    This study dealt with quantification and imaging of human epidermal growth factor receptor 2 (HER2), an important prognostic marker for cancer diagnosis and treatment, using specific quantum-dot-based conjugates. Fluorescent inorganic nanocrystals or quantum dots (QDs) are extremely highly resistant to photobleaching and have a high emission quantum yield and a continuous range of emission spectra, from the ultraviolet to the infrared regions. Ultrasmall nanoprobes consisting of highly affine anti-HER2 single-domain antibodies (sdAbs or 'nanobodies') conjugated with QDs in a strictly oriented manner have been designed. QDs with a fluorescence peak maxima at wavelengths of 562 nm, 569 nm, 570 nm or in the near-infrared region were used. Here, we present our results of ISA quantification of HER2 protein, in situ imaging of HER2 protein on the surface of HER2-positive SK-BR-3 cells in immunohistochemical experiments, and counting of stained with anti-HER2 conjugates HER2-positive SK-BR-3 cells in their mixture with unstained cells of the same culture in flow cytometry experiments. The data demonstrate that the anti-HER2 QD–sdAb conjugates obtained are highly specific and sensitive and could be used in numerous applications for advanced integrated diagnosis. (paper)

  1. Quantification and imaging of HER2 protein using nanocrystals conjugated with single-domain antibodies

    Science.gov (United States)

    Glukhov, S.; Berestovoy, M.; Chames, P.; Baty, D.; Nabiev, I.; Sukhanova, A.

    2017-01-01

    This study dealt with quantification and imaging of human epidermal growth factor receptor 2 (HER2), an important prognostic marker for cancer diagnosis and treatment, using specific quantum-dot-based conjugates. Fluorescent inorganic nanocrystals or quantum dots (QDs) are extremely highly resistant to photobleaching and have a high emission quantum yield and a continuous range of emission spectra, from the ultraviolet to the infrared regions. Ultrasmall nanoprobes consisting of highly affine anti-HER2 single-domain antibodies (sdAbs or "nanobodies") conjugated with QDs in a strictly oriented manner have been designed. QDs with a fluorescence peak maxima at wavelengths of 562 nm, 569 nm, 570 nm or in the near-infrared region were used. Here, we present our results of ISA quantification of HER2 protein, in situ imaging of HER2 protein on the surface of HER2-positive SK-BR-3 cells in immunohistochemical experiments, and counting of stained with anti-HER2 conjugates HER2-positive SK-BR-3 cells in their mixture with unstained cells of the same culture in flow cytometry experiments. The data demonstrate that the anti-HER2 QD-sdAb conjugates obtained are highly specific and sensitive and could be used in numerous applications for advanced integrated diagnosis.

  2. The clinical significance of HER-2 and NF-KB expression in gastric cancer.

    Science.gov (United States)

    Li, Xiaogai; Tu, Jiancheng; Zhang, Di; Xu, Zhigao; Yang, Guifang; Gong, Lingling; Yu, Mingxia

    2013-09-01

    To investigate the expression of human epidermal growth factor 2 (HER-2) and Nuclear factor-Kb (NF-KB) in gastric cancer, and the relation of these two parameters with stage, grade and metastasis of gastric cancer. The serum level of HER-2 in 75 gastric cancer patients and control participants were determined by enzyme-linked immunosorbent assay (ELISA) kits. Expression of HER-2 and NF-KB protein were detected by immunohistochemical staining (SP method) of paraffin-embedded tissues in 75 tumors (observed group) and 22 normal gastric specimens. The clinical pathological data was statistically analyzed. Serum HER-2 level were significantly increased in study group compared with those in the control group (pKB in the observed group was 24.00% (18/75) and 62.67% (47/75) respectively. The expression of HER-2 and NF-KB were not correlated with age and gender, but with stage, grade and metastasis (pKB was correlated with tumor size (pKB had a positive rate of 94.44% (17/18), but a positive rate of 52.63% (30/57) when HER-2 was negative. Expression of NF-KB in gastric cancer tissue was correlated with HER-2 expression (X2 = 8.514, pKB in gastric cancer tissue is correlated with HER-2 expression, and they may play a very important role in the progress of gastric cancer.

  3. A gene-protein assay for human epidermal growth factor receptor 2 (HER2: brightfield tricolor visualization of HER2 protein, the HER2 gene, and chromosome 17 centromere (CEN17 in formalin-fixed, paraffin-embedded breast cancer tissue sections

    Directory of Open Access Journals (Sweden)

    Nitta Hiroaki

    2012-05-01

    Full Text Available Abstract Background The eligibility of breast cancer patients for human epidermal growth factor receptor 2 (HER2-directed therapies is determined by the HER2 gene amplification and/or HER2 protein overexpression status of the breast tumor as determined by in situ hybridization (ISH or immunohistochemistry (IHC, respectively. Our objective was to combine the US Food and Drug Administration (FDA-approved HER2 & chromosome 17 centromere (CEN17 brightfield ISH (BISH and HER2 IHC assays into a single automated HER2 gene-protein assay allowing simultaneous detection of all three targets in a single tissue section. Methods The HER2 gene-protein assay was optimized using formalin-fixed, paraffin-embedded (FFPE samples of the xenograft tumors MCF7 [HER2 negative (non-amplified gene, protein negative] and Calu-3 [HER2 positive (amplified gene, protein positive]. HER2 IHC was performed using a rabbit monoclonal anti-HER2 antibody (clone 4B5 and a conventional 3,3'-diaminobenzidine IHC detection. The HER2 & CEN17 BISH signals were visualized using horseradish peroxidase-based silver and alkaline phosphatase-based red detection systems, respectively with a cocktail of 2,4-dinitrophenyl-labeled HER2 and digoxigenin-labeled CEN17 probes. The performance of the gene-protein assay on tissue microarray slides containing 189 randomly selected FFPE clinical breast cancer tissue cores was compared to that of the separate HER2 IHC and HER2 & CEN17 BISH assays. Results HER2 protein detection was optimal when the HER2 IHC protocol was used before (rather than after the BISH protocol. The sequential use of HER2 IHC and HER2 & CEN17 BISH detection steps on FFPE xenograft tumor sections appropriately co-localized the HER2 protein, HER2 gene, and CEN17 signals after mitigating the silver background staining by using a naphthol phosphate-containing hybridization buffer for the hybridization step. The HER2 protein and HER2 gene status obtained using the multiplex HER2 gene

  4. First line chemotherapy plus trastuzumab in metastatic breast cancer ...

    African Journals Online (AJOL)

    First line chemotherapy plus trastuzumab in metastatic breast cancer HER2 positive - Observational institutional study. ... The progression free survival was estimated by the Kaplan-Meier method, from the date of first cycle to the date of progression or at the last consultation, and the median was 12.8 months. Trastuzumab ...

  5. Immunohistochemical expression of HER-2/neu in patients with lung carcinoma and its prognostic significance

    International Nuclear Information System (INIS)

    Petrusevska, G.; Banev, S.; Ilievska-Poposka, B.; Smickova, S.; Spirovski, Z.

    2004-01-01

    Background. The HER-2 protein or p185her2 is a membrane receptor with tyrosine kinase activity encoded by HER-2/neu gene. Overexpression of HER-2/neu has been observed in many human cancers, including lung cancer. In the study, the expression of HER-2 protein is determined in the spectrum of lung cancer (adenocarcinoma, squamous cell carcinoma and small cell carcinoma). Patients and methods. The study population consisted of two groups: 19 patients that had undergone surgical treatment and 10 patients that had undergone fiber-optic bronchoscopy and biopsy for primary diagnosis only. Tissue specimens were neutral formaldehyde-fixed and paraffin-embedded. Standard histochemical and immunohistochemical staining were used for diagnosis. Expression of HER-2/neu protein was determined by immunohistochemical staining with Hercep Test (DAKO). The results were graded 0-1 as negative and 2-3 as positive. Results. Overall incidence of HER-2/neu overexpression was 34.4% (10 of 29). Higher incidence was found in the patients with adenocarcinoma 45.4% (5 of 11). In squamous cell carcinoma and small cell carcinoma, the overexpression incidence was 30.7% (4 of 13) and 20% (1 of 5), respectively. No statistically significant difference was seen given the age and gender. HER-2/neu overexpression was more pronounced in the patients with advanced tumour: all patients with squamous cell carcinoma and HER-2/neu overexpression had stage IIIB and stage IV disease, while 80 % of adenocarcinoma patients with HER-2/neu overexpression had stage IIIA and IIIB disease. Conclusions. These results are satisfactory and encourage us to continue this work in the follow-up study to evaluate HER-2/neu role as predictive and prognostic factor for the patients with lung cancer. (author)

  6. HER2-Targeted Polyinosine/Polycytosine Therapy Inhibits Tumor Growth and Modulates the Tumor Immune Microenvironment.

    Science.gov (United States)

    Zigler, Maya; Shir, Alexei; Joubran, Salim; Sagalov, Anna; Klein, Shoshana; Edinger, Nufar; Lau, Jeffrey; Yu, Shang-Fan; Mizraji, Gabriel; Globerson Levin, Anat; Sliwkowski, Mark X; Levitzki, Alexander

    2016-08-01

    The development of targeted therapies that affect multiple signaling pathways and stimulate antitumor immunity is greatly needed. About 20% of patients with breast cancer overexpress HER2. Small molecules and antibodies targeting HER2 convey some survival benefits; however, patients with advanced disease succumb to the disease under these treatment regimens, possibly because HER2 is not completely necessary for the survival of the targeted cancer cells. In the present study, we show that a polyinosine/polycytosine (pIC) HER2-homing chemical vector induced the demise of HER2-overexpressing breast cancer cells, including trastuzumab-resistant cells. Targeting pIC to the tumor evoked a number of cell-killing mechanisms, as well as strong bystander effects. These bystander mechanisms included type I IFN induction, immune cell recruitment, and activation. The HER2-targeted pIC strongly inhibited the growth of HER2-overexpressing tumors in immunocompetent mice. The data presented here could open additional avenues in the treatment of HER2-positive breast cancer. Cancer Immunol Res; 4(8); 688-97. ©2016 AACR. ©2016 American Association for Cancer Research.

  7. Imaging HER2 in response to T-DM1 therapy in breast cancer xenografts

    Energy Technology Data Exchange (ETDEWEB)

    Massicano, Adriana Vidal; Aweda, Tolulope; Marqueznostra, Bernadette; El Sayed, Reeta; Beacham, Rebecca; Lapi, Suzanne [University Of Alabama, Birmingham, AL (United States)

    2017-07-01

    Full text: Introduction: Monoclonal antibodies (mAbs) have become broadly used for the treatment of cancer because they can be engineered to bind specifically to the target and therefore typically have less toxicity compared to broad spectrum chemotherapies (Jauw YWS, Menke-van der Houven van Oordt CW, Hoekstra OS, et al. Front Pharmacol 2016, 7:1-15). Ado-trastuzumab emtansine (TDM1) is a newly approved HER2 targeted therapy which consists of a cytotoxic agent (DM1) linked to trastuzumab and has shown promising results in patients with HER2 positive metastatic breast cancer (Barok MT, Köninki M, Isola K et al. Breast Cancer Res 2011, 13:1465-5411). Although {sup 18}F-FDG is considered the gold standard in the diagnosis and staging of various types of cancer, it is a relatively non-specific marker (Janjigian YY, Viola-Villegas N, Holland JP, Divilov V, Carlin SD et al. J Nucl Med 2013;54:936-43). Alternatively, {sup 89}Zr-Pertuzumab which binds to a different epitope than trastuzumab on the HER2 receptor has shown high selectively in imaging variations in HER2 expression in breast cancer xenograft models (Marquez BV, Ikotun OF, Zheleznyak A, Wright B et al. Mol Pharm 2014;11:3988-95). Therefore, in this work, we investigated the specificity of {sup 89}Zr-Pertuzumab compared to {sup 18}F-FDG to identify early response to ado-trastuzumab emtansine (T-DM1) in a breast cancer xenograft model. Methods: Pertuzumab was conjugated top-NCS-Bz-DFO at varying molar ratios and labeled with {sup 89}Zr in different conditions. The optimal conditions were used in further in vitro and in vivo studies. In vivo PET imaging was conducted in nude female mice implanted with 17β-estradiol pellets and inoculated with 1 x 107 BT-474 HER2 positive breast cancer cells. In order to acquire baseline images, mice were injected via tail-vein with 200 μCi of 18F-FDG and imaged after 1 hour. The following day, they were injected with 100 μCi of {sup 89}Zr-Pertuzumab (20 μCi/μg) imaged 5

  8. Divisional role of quantitative HER2 testing in breast cancer.

    Science.gov (United States)

    Yamamoto-Ibusuki, Mutsuko; Yamamoto, Yutaka; Fu, Peifen; Yamamoto, Satoko; Fujiwara, Saori; Honda, Yumi; Iyama, Ken-ichi; Iwase, Hirotaka

    2015-03-01

    Human epidermal growth factor receptor 2 (HER2) is amplified in human breast cancers in which therapy targeted to HER2 significantly improves patient outcome. We re-visited the use of real-time quantitative polymerase chain reaction (qPCR)-based assays using formalin-fixed paraffin-embedded (FFPE) tissues as alternative methods and investigated their particular clinical relevance. DNA and RNA were isolated from FFPE specimens and HER2 status was assessed by qPCR in 249 consecutive patients with primary breast cancer. Concordance with results forg immunohistochemistry (IHC) and in situ hybridization (ISH), clinical characteristics and survival was assessed. HER2 gene copy number had a stronger correlation with clinicopathological characteristics and excellent concordance with IHC/ISH results (Sensitivity: 96.7 %; concordance: 99.2 %). HER2 gene expression showed inadequate sensitivity, rendering it unsuitable to determine HER2 status (Sensitivity: 46.7 %; concordance: 92.1 %), but lower HER2 gene expression, leading to the classification of many cases as "false negative", contributed to a prediction of better prognosis within the HER2-amplified subpopulation. Quantitative HER2 assessments are suggested to have evolved their accuracy in this decade, which can be a potential alternative for HER2 diagnosis in line with the in situ method, while HER2 gene expression levels could provide additional information regarding prognosis or therapeutic strategy within a HER2-amplified subpopulation.

  9. HER2 specific delivery of methotrexate by dendrimer conjugated anti-HER2 mAb

    International Nuclear Information System (INIS)

    Shukla, Rameshwer; Thomas, Thommey P; Desai, Ankur M; Kotlyar, Alina; Park, Steve J; Baker, James R Jr

    2008-01-01

    Herceptin, a humanized monoclonal antibody that binds to human growth factor receptor-2 (HER2), was covalently attached to a fifth-generation (G5) polyamidoamine dendrimer containing the cytotoxic drug methotrexate. The specific binding and internalization of this conjugate labeled with FITC was clearly demonstrated in cell lines overexpressing HER2 by flow cytometry as well as confocal microscopic analysis. In addition, binding and uptake of antibody conjugated dendrimers was completely blocked by excess non-conjugated herceptin. The dendrimer conjugate was also shown to inhibit the dihydrofolate reductase with similar activity to methotrexate. Co-localization experiments with lysotracker red indicate that antibody conjugate, although internalized efficiently into cells, has an unusually long residence time in the lysosome. Somewhat lower cytotoxicity of the conjugate in comparison to free methotrexate was attributed to the slow release of methotrexate from the conjugate and its long retention in the lysosomal pocket

  10. Targeted treatment of advanced and metastatic breast cancer with lapatinib

    Directory of Open Access Journals (Sweden)

    Brendan Corkery

    2008-09-01

    Full Text Available Brendan Corkery1,2, Norma O’Donovan2, John Crown1,21St. Vincent’s University Hospital, Dublin, Ireland; 2National Institute for Cellular Biotechnology, Dublin City University, Dublin, IrelandAbstract: Improved molecular understanding of breast cancer in recent years has led to the discovery of important drug targets such as HER-2 and EGFR. Lapatinib is a potent dual inhibitor of HER-2 and EGFR. Preclinical and phase I studies have shown activity with lapatinib in a number of cancers, including breast cancer, and the drug is well tolerated. The main known drug interactions are with paclitaxel and irinotecan. The most significant side-effects of lapatinib are diarrhea and adverse skin events. Rates of cardiotoxicity compare favorably with trastuzumab, a monoclonal antibody against HER-2. This paper focuses on lapatinib in advanced and metastatic breast cancer, which remains an important therapeutic challenge. Phase II and III studies show activity as monotherapy, and in combination with chemotherapy or hormonal agents. Results from these studies suggest that the main benefit from lapatinib is in the HER-2 positive breast cancer population. Combinations of lapatinib and trastuzumab are also being studied and show encouraging results, particularly in trastuzumab-refractory metastatic breast cancer. Lapatinib may have a specific role in treating HER-2 positive CNS metastases. The role of lapatinib as neoadjuvant therapy and in early breast cancer is also being evaluated.Keywords: HER-2, EGFR, erbB, lapatinib, Tykerb®, tyrosine kinase

  11. A Splice Variant of HER2 Corresponding to Herstatin Is Expressed in the Noncancerous Breast and in Breast Carcinomas

    Directory of Open Access Journals (Sweden)

    Triantafyllia Koletsa

    2008-07-01

    Full Text Available Herstatin (HST is an alternatively spliced HER2 product with growth-inhibitory properties in experimental cancer systems. The role of HST in adult human tissues and disease remains unexplored. Here, we investigated HST expression at the mRNA and protein (immunohistochemistry [IHC] level in parallel with parameters reflecting HER activation in 187 breast carcinomas and matched noncancerous breast tissues (NCBT. Noncancerous breast tissues demonstrated the highest HST/HER2 transcript ratios corresponding to a few positive epithelial and stromal cells by IHC. Although HST/HER2 transcript ratios in tumors were inversely associated with HER2 IHC grading (P = .0048 for HER2 IHC-1+ and P = .0006 for HER2 IHC-2+ vs HER2-negative tumors, relative HST expression within the same tumor/NCBT system remained constant. HST/HER2 ratios did not predict the presence of HST protein, which was found in 46 (25% of 187 tumors. A subgroup of HER2 IHC-3+ tumors exhibited high HST/HER2 transcript ratios, strong HST protein positivity, and cytoplasmic phospho-Akt/PKB and p21CIP1/WAF1 localization. In conclusion, HST may act as a paracrine factor in the adult breast. Because HST is described as an endogenous pan-HER inhibitor, the presence of this protein in breast carcinomas may portent the inefficiency of exogenous efforts to block HER2 dimerization, whereas its absence may justify such interventions.

  12. C-Cbl reverses HER2-mediated tamoxifen resistance in human breast cancer cells.

    Science.gov (United States)

    Li, Wei; Xu, Ling; Che, Xiaofang; Li, Haizhou; Zhang, Ye; Song, Na; Wen, Ti; Hou, Kezuo; Yang, Yi; Zhou, Lu; Xin, Xing; Xu, Lu; Zeng, Xue; Shi, Sha; Liu, Yunpeng; Qu, Xiujuan; Teng, Yuee

    2018-05-02

    Tamoxifen is a frontline therapy for estrogen receptor (ER)-positive breast cancer in premenopausal women. However, many patients develop resistance to tamoxifen, and the mechanism underlying tamoxifen resistance is not well understood. Here we examined whether ER-c-Src-HER2 complex formation is involved in tamoxifen resistance. MTT and colony formation assays were used to measure cell viability and proliferation. Western blot was used to detect protein expression and protein complex formations were detected by immunoprecipitation and immunofluorescence. SiRNA was used to examine the function of HER2 in of BT474 cells. An in vivo xenograft animal model was established to examine the role of c-Cbl in tumor growth. MTT and colony formation assay showed that BT474 cells are resistant to tamoxifen and T47D cells are sensitive to tamoxifen. Immunoprecipitation experiments revealed ER-c-Src-HER2 complex formation in BT474 cells but not in T47D cells. However, ER-c-Src-HER2 complex formation was detected after overexpressing HER2 in T47D cells and these cells were more resistant to tamoxifen. HER2 knockdown by siRNA in BT474 cells reduced ER-c-Src-HER2 complex formation and reversed tamoxifen resistance. ER-c-Src-HER2 complex formation was also disrupted and tamoxifen resistance was reversed in BT474 cells by the c-Src inhibitor PP2 and HER2 antibody trastuzumab. Nystatin, a lipid raft inhibitor, reduced ER-c-Src-HER2 complex formation and partially reversed tamoxifen resistance. ER-c-Src-HER2 complex formation was disrupted by overexpression of c-Cbl but not by the c-Cbl ubiquitin ligase mutant. In addition, c-Cbl could reverse tamoxifen resistance in BT474 cells, but the ubiquitin ligase mutant had no effect. The effect of c-Cbl was validated in BT474 tumor-bearing nude mice in vivo. Immunofluorescence also revealed ER-c-Src-HER2 complex formation was reduced in tumor tissues of nude mice with c-Cbl overexpression. Our results suggested that c-Cbl can reverse tamoxifen

  13. Human epidermal growth factor receptor 2 (HER2) immunoreactivity

    DEFF Research Database (Denmark)

    Rasmussen, Anne-Sofie Schrohl; Pedersen, Hans Christian; Jensen, Sussie Steen

    2011-01-01

    The availability of specific antibody-based test systems is essential to testing of HER2 protein expression. Here, we mapped epitopes recognized by three pharmacodiagnostic HER2 antibodies and investigated their specificity towards peptides and fusion proteins homologous to the intracellular doma...... domains of HER1, HER2, HER3 and HER4. The investigated antibodies were PATHWAY(®) HER2 (clone 4B5; Ventana Medical Systems Inc., Tucson, AZ, USA), HercepTest™ (Dako Denmark A/S, Glostrup, Denmark), and Oracle(®) HER2 (clone CB11; Leica Microsystems GmbH, Wetzlar, Germany)....

  14. Microenvironment-Mediated Mechanisms of Resistance to HER2 Inhibitors Differ between HER2+ Breast Cancer Subtypes.

    Science.gov (United States)

    Watson, Spencer S; Dane, Mark; Chin, Koei; Tatarova, Zuzana; Liu, Moqing; Liby, Tiera; Thompson, Wallace; Smith, Rebecca; Nederlof, Michel; Bucher, Elmar; Kilburn, David; Whitman, Matthew; Sudar, Damir; Mills, Gordon B; Heiser, Laura M; Jonas, Oliver; Gray, Joe W; Korkola, James E

    2018-03-28

    Extrinsic signals are implicated in breast cancer resistance to HER2-targeted tyrosine kinase inhibitors (TKIs). To examine how microenvironmental signals influence resistance, we monitored TKI-treated breast cancer cell lines grown on microenvironment microarrays composed of printed extracellular matrix proteins supplemented with soluble proteins. We tested ∼2,500 combinations of 56 soluble and 46 matrix microenvironmental proteins on basal-like HER2+ (HER2E) or luminal-like HER2+ (L-HER2+) cells treated with the TKIs lapatinib or neratinib. In HER2E cells, hepatocyte growth factor, a ligand for MET, induced resistance that could be reversed with crizotinib, an inhibitor of MET. In L-HER2+ cells, neuregulin1-β1 (NRG1β), a ligand for HER3, induced resistance that could be reversed with pertuzumab, an inhibitor of HER2-HER3 heterodimerization. The subtype-specific responses were also observed in 3D cultures and murine xenografts. These results, along with bioinformatic pathway analysis and siRNA knockdown experiments, suggest different mechanisms of resistance specific to each HER2+ subtype: MET signaling for HER2E and HER2-HER3 heterodimerization for L-HER2+ cells. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

  15. (18)F-nanobody for PET imaging of HER2 overexpressing tumors.

    Science.gov (United States)

    Xavier, Catarina; Blykers, Anneleen; Vaneycken, Ilse; D'Huyvetter, Matthias; Heemskerk, Jan; Lahoutte, Tony; Devoogdt, Nick; Caveliers, Vicky

    2016-04-01

    Radiolabeled nanobodies are exciting new probes for molecular imaging due to high affinity, high specificity and fast washout from the blood. Here we present the labeling of an anti-HER2 nanobody with (18)F and its validation for in vivo assessment of HER2 overexpression. The GMP grade anti-HER2 nanobody was labeled with the prosthetic group, N-succinimidyl-4-[(18)F]fluorobenzoate ([(18)F]-SFB), and its biodistribution, tumor targeting and specificity were evaluated in mouse and rat tumor models. [(18)F]FB-anti-HER2 nanobody was prepared with a 5-15% global yield (decay corrected) and a specific activity of 24.7 ± 8.2 MBq/nmol. In vivo studies demonstrated a high specific uptake for HER2 positive xenografts (5.94 ± 1.17 and 3.74 ± 0.52%IA/g, 1 and 3h p.i.) with high tumor-to-blood and tumor-to-muscle ratios generating high contrast PET imaging. The probe presented fast clearance through the kidneys (4%IA/g at 3h p.i.). [(18)F]FB-anti-HER2 nanobody is able to image HER2 expressing tumors when co-administered with the anti-HER2 therapeutic antibody trastuzumab (Herceptin), indicating the possibility of using the tracer in patients undergoing Herceptin therapy. The GMP grade anti-HER2 nanobody was labeled with (18)F. This new PET probe for imaging HER2 overexpression in tumors has ample potential for clinical translation. Copyright © 2016 Elsevier Inc. All rights reserved.

  16. 18F-nanobody for PET imaging of HER2 overexpressing tumors

    International Nuclear Information System (INIS)

    Xavier, Catarina; Blykers, Anneleen; Vaneycken, Ilse; D'Huyvetter, Matthias; Heemskerk, Jan; Lahoutte, Tony; Devoogdt, Nick; Caveliers, Vicky

    2016-01-01

    Introduction: Radiolabeled nanobodies are exciting new probes for molecular imaging due to high affinity, high specificity and fast washout from the blood. Here we present the labeling of an anti-HER2 nanobody with 18 F and its validation for in vivo assessment of HER2 overexpression. Methods: The GMP grade anti-HER2 nanobody was labeled with the prosthetic group, N-succinimidyl-4-[ 18 F]fluorobenzoate ([ 18 F]-SFB), and its biodistribution, tumor targeting and specificity were evaluated in mouse and rat tumor models. Results: [ 18 F]FB-anti-HER2 nanobody was prepared with a 5–15% global yield (decay corrected) and a specific activity of 24.7 ± 8.2 MBq/nmol. In vivo studies demonstrated a high specific uptake for HER2 positive xenografts (5.94 ± 1.17 and 3.74 ± 0.52%IA/g, 1 and 3 h p.i.) with high tumor-to-blood and tumor-to-muscle ratios generating high contrast PET imaging. The probe presented fast clearance through the kidneys (4%IA/g at 3 h p.i.). [ 18 F]FB-anti-HER2 nanobody is able to image HER2 expressing tumors when co-administered with the anti-HER2 therapeutic antibody trastuzumab (Herceptin), indicating the possibility of using the tracer in patients undergoing Herceptin therapy. Conclusions: The GMP grade anti-HER2 nanobody was labeled with 18 F. This new PET probe for imaging HER2 overexpression in tumors has ample potential for clinical translation.

  17. Heat Shock Protein 90 (HSP90 and Her2 in Adenocarcinomas of the Esophagus

    Directory of Open Access Journals (Sweden)

    Julia Slotta-Huspenina

    2014-06-01

    Full Text Available Her2 overexpression and amplification can be found in a significant subset of esophageal adenocarcinomas. The activity of Her2 has been shown to be modulated by molecular chaperones such as HSP90. We analyzed expression/amplification data for HSP90 and Her2 on 127 primary resected esophageal adenocarcinomas in order to evaluate a possible relationship between these two molecules. HSP90 expression determined by immunohistochemistry was observed in various levels. Thirty nine (39 tumors (30.7% were classified as Her2-positive according to their immunoreactivity and amplification status. There was a significant correlation between HSP90 expression and Her2-status (p = 0.008. This could also be demonstrated by quantitative protein expression analysis with reverse phase protein arrays (r = 0.9; p < 0.001. Her2-status was associated withpT-category (p = 0.041, lymph node metastases (p = 0.049 and tumor differentiation (p = 0.036 with a higher percentage of cases with negative Her2 status in lower tumor stagesA negative Her2-status was also associated with better survival in univariate and multivariate analysis (p = 0.001 and p = 0.014. For HSP90, no associations between clinical and pathological parameters were found. The observed association between HSP90 expression and Her2 suggests a co-regulation of these molecules in at least a subset of esophageal adenocarcinomas. Anti-HSP90 drugs, which recently have been introduced in cancer treatment, may also be an option for these tumors by targeting HSP90 alone or in combination with Her2.

  18. Heat Shock Protein 90 (HSP90) and Her2 in Adenocarcinomas of the Esophagus

    Energy Technology Data Exchange (ETDEWEB)

    Slotta-Huspenina, Julia; Becker, Karl-Friedrich [Institute of Pathology, Technische Universität München, München 81765 (Germany); Feith, Marcus [Department of Surgery, Klinikum Rechts der Isar der Technischen Universität München, München 81622 (Germany); Walch, Axel [Institute of Pathology, Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), Neuherberg 85764 (Germany); Langer, Rupert, E-mail: rupert.langer@pathology.unibe.ch [Institute of Pathology, University of Bern, Bern 3010 (Switzerland)

    2014-06-27

    Her2 overexpression and amplification can be found in a significant subset of esophageal adenocarcinomas. The activity of Her2 has been shown to be modulated by molecular chaperones such as HSP90. We analyzed expression/amplification data for HSP90 and Her2 on 127 primary resected esophageal adenocarcinomas in order to evaluate a possible relationship between these two molecules. HSP90 expression determined by immunohistochemistry was observed in various levels. Thirty nine (39) tumors (30.7%) were classified as Her2-positive according to their immunoreactivity and amplification status. There was a significant correlation between HSP90 expression and Her2-status (p = 0.008). This could also be demonstrated by quantitative protein expression analysis with reverse phase protein arrays (r = 0.9; p < 0.001). Her2-status was associated withpT-category (p = 0.041), lymph node metastases (p = 0.049) and tumor differentiation (p = 0.036) with a higher percentage of cases with negative Her2 status in lower tumor stagesA negative Her2-status was also associated with better survival in univariate and multivariate analysis (p = 0.001 and p = 0.014). For HSP90, no associations between clinical and pathological parameters were found. The observed association between HSP90 expression and Her2 suggests a co-regulation of these molecules in at least a subset of esophageal adenocarcinomas. Anti-HSP90 drugs, which recently have been introduced in cancer treatment, may also be an option for these tumors by targeting HSP90 alone or in combination with Her2.

  19. Analysis of molecular subtypes for the increased HER2 equivocal cases caused by application of the updated 2013 ASCO/CAP HER2 testing guidelines in breast cancer.

    Science.gov (United States)

    Guo, Lei; Yuan, Pei; Zhang, Jing; Ling, Yun; Li, Wenbin; Zhao, Bohui; Ying, Jianming; Xuan, Lixue

    2017-11-01

    Accurate testing of the status of human epidermal growth factor receptor type 2 (HER2) is a prerequisite for HER2-directed therapy. The American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) published joint guideline recommendations for HER2 testing in breast cancer in 2007 and it was updated in 2013. We compared the HER2 gene amplification status based on these two guidelines and analyzed the molecular characteristics of the equivocal cases. A total of 1894 patient samples were analyzed for both immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). HER2 FISH amplification was examined and re-assessed using 2013 guidelines. According to the 2013 ASCO/CAP recommendations, 763 (40.3%) cases were classified as HER2 positive compared with 729 (38.5%) cases defined by 2007 guidelines. There was a significant increase of 6.1% in the proportion of HER2 FISH equivocal cases that were interpreted using ASCO/CAP 2013 (7.3%) compared with 2007 (1.2%) guidelines (P guidelines, 125 cases were IHC2+ and 13 cases were IHC1+. These 125 cases included 4 double equivocal cases which were defined as equivocal by both 2007 and 2013 guidelines and 121 cases whose status was changed from negative defined by 2007 guidelines to equivocal defined by 2013 guidelines. Compared with luminal A type and luminal B type respectively, these 121 equivocal cases demonstrated no significant difference with luminal B type in T stage and N stage (P = 0.192, P = 0.421). When we divided the luminal B type into two parts that included HER2 negative cases and HER2 positive cases, the equivocal cases also showed no significant difference with these two subtypes in T stage and N stage. Our study suggested that implementation of the revised ASCO/CAP 2013 guidelines resulted in an increase of 1.7% in overall HER2 positivity rate and of 6.1% in equivocal cases. Pathological analysis revealed that these equivocal cases exhibit similar biological

  20. [{sup 18}F]FBEM-Z{sub HER2:342}-Affibody molecule - a new molecular tracer for in vivo monitoring of HER2 expression by positron emission tomography

    Energy Technology Data Exchange (ETDEWEB)

    Kramer-Marek, Gabriela; Lee, Sang Bong; Capala, Jacek [National Institutes of Health, National Cancer Institute, Bethesda, MD (United States); Kiesewetter, Dale O.; Jagoda, Elaine [National Institutes of Health, National Institute of Biomedical Imaging and Bioengineering, Bethesda, MD (United States); Martiniova, Lucia [National Institutes of Health, National Institute of Child Health and Human Development, Bethesda, MD (United States)

    2008-05-15

    The expression of human epidermal growth factor receptor-2 (HER2) receptors in cancers is correlated with a poor prognosis. If assessed in vivo, it could be used for selection of appropriate therapy for individual patients and for monitoring of the tumor response to targeted therapies. We have radiolabeled a HER2-binding Affibody molecule with fluorine-18 for in vivo monitoring of the HER2 expression by positron emission tomography (PET). The HER2-binding Z{sub HER2:342}-Cys Affibody molecule was conjugated with N-2-(4-[{sup 18}F]fluorobenzamido)ethylmaleimide ([{sup 18}F]FBEM). The in vitro binding of the resulting radioconjugate was characterized by receptor saturation and competition assays. For in vivo studies, the radioconjugate was injected into the tail vein of mice bearing subcutaneous HER2-positive or HER2-negative tumors. Some of the mice were pre-treated with non-labeled Z{sub HER2:342}-Cys. The animals were sacrificed at different times post-injection, and the radioactivity in selected tissues was measured. PET images were obtained using an animal PET scanner. In vitro experiments indicated specific, high-affinity binding to HER2. PET imaging revealed a high accumulation of the radioactivity in the tumor as early as 20 min after injection, with a plateau being reached after 60 min. These results were confirmed by biodistribution studies demonstrating that, as early as 1 h post-injection, the tumor to blood concentration ratio was 7.5 and increased to 27 at 4 h. Pre-saturation of the receptors with unlabeled Z{sub HER2:342}-Cys lowered the accumulation of radioactivity in HER2-positive tumors to the levels observed in HER2-negative ones. Our results suggest that the [{sup 18}F]FBEM-Z{sub HER2:342} radioconjugate can be used to assess HER2 expression in vivo. (orig.)

  1. HER2 amplification, overexpression and score criteria in esophageal adenocarcinoma

    Science.gov (United States)

    Hu, Yingchuan; Bandla, Santhoshi; Godfrey, Tony E.; Tan, Dongfeng; Luketich, James D.; Pennathur, Arjun; Qiu, Xing; Hicks, David G.; Peters, Jeffrey; Zhou, Zhongren

    2011-01-01

    The HER2 oncogene was recently reported to be amplified and overexpressed in esophageal adenocarcinoma. However, the relationship of HER2 amplification in esophageal adenocarcinoma with prognosis has not been well defined. The scoring systems for clinically evaluating HER2 in esophageal adenocarcinoma are not established. The aims of the study were to establish a HER2 scoring system and comprehensively investigate HER2 amplification and overexpression in esophageal adenocarcinoma and its precursor lesion. Using a tissue microarray, containing 116 cases of esophageal adenocarcinoma, 34 cases of BE, 18 cases of low grade dysplasia and 15 cases of high grade dysplasia, HER2 amplification and overexpression were analyzed by HercepTest and CISH methods. The amplification frequency in an independent series of 116 esophageal adenocarcinoma samples was also analyzed using Affymetrix SNP 6.0 microarrays. In our studies, we have found that HER2 amplification does not associate with poor prognosis in total 232 esophageal adenocarcinoma patients by CISH and high density microarrays. We further confirm the similar frequency of HER2 amplification by CISH (18.10%; 21/116) and SNP 6.0 microarrays (16.4%, 19/116) in esophageal adenocarcinoma. HER2 protein overexpression was observed in 12.1 % (14/116) of esophageal adenocarcinoma and 6.67% (1/15) of HGD. No HER2 amplification or overexpression was identified in BE or LGD. All HER2 protein overexpression cases showed HER2 gene amplification. Gene amplification was found to be more frequent by CISH than protein overexpression in esophageal adenocarcinoma (18.10% vs 12.9%). A modified two-step model for esophageal adenocarcinoma HER-2 testing is recommend for clinical esophageal adenocarcinoma HER-2 trial. PMID:21460800

  2. High Ki-67 score is indicative of a greater benefit from adjuvant chemotherapy when added to endocrine therapy in luminal B HER2 negative and node-positive breast cancer.

    Science.gov (United States)

    Criscitiello, Carmen; Disalvatore, Davide; De Laurentiis, Michele; Gelao, Lucia; Fumagalli, Luca; Locatelli, Marzia; Bagnardi, Vincenzo; Rotmensz, Nicole; Esposito, Angela; Minchella, Ida; De Placido, Sabino; Santangelo, Michele; Viale, Giuseppe; Goldhirsch, Aron; Curigliano, Giuseppe

    2014-02-01

    The indication of adjuvant chemotherapy for patients with highly proliferative estrogen receptor-positive breast cancer is controversial. We analyzed the predictive value of Ki67 for the efficacy of adjuvant chemotherapy in patients with estrogen receptor-positive, node-positive breast cancer. We identified 1241 patients with Luminal B early stage breast cancer with 1-3 axillary positive nodes who underwent surgery between 1995 and 2005 at the European Institute of Oncology and received adjuvant hormonotherapy and/or chemotherapy. Differences in the distribution of characteristics according to treatment were evaluated by the Chi-square test. To evaluate the effect of adding chemotherapy to hormonotherapy, the propensity score method was used to match patients' characteristics minimizing bias related to the non-random assignment of treatment. The probability of receiving chemotherapy was significantly associated with age, tumor grade, degree of hormone responsiveness, tumor size and peripheral vascular invasion. The propensity score distribution was statistically different between the two treatment groups (p chemotherapy group (log-rank test p-value 0.663). The 5-year DFS percentages were 84.6% (95% CI, 81.0-87.6%) in the hormonotherapy group and 84.2% (95% CI, 81.3-86.7%) in the hormonotherapy/chemotherapy group (log-rank test p-value 0.388). However, when analyzing the 5-year DFS by Ki-67 distribution, Subpopulation Treatment Effect Pattern Plot (STEPP) analysis showed a beneficial effect of chemotherapy in patients with highly proliferative tumor (Ki-67 ≥ 32%). The interaction between Ki-67 and treatment was statistically significant (p = 0.027). Ki67 expression identifies a subset of patients with Luminal B and node-positive breast cancer who could benefit from addition of adjuvant chemotherapy to hormonotherapy. Dichotomy was observed for Ki67 at 32% level. Copyright © 2013 Elsevier Ltd. All rights reserved.

  3. Clinicopathologic factors associated with de novo metastatic breast cancer.

    Science.gov (United States)

    Shen, Tiansheng; Siegal, Gene P; Wei, Shi

    2016-12-01

    While breast cancers with distant metastasis at presentation (de novo metastasis) harbor significantly inferior clinical outcomes, there have been limited studies analyzing the clinicopathologic characteristics in this subset of patients. In this study, we analyzed 6126 breast cancers diagnosed between 1998 and 2013 to identify factors associated with de novo metastatic breast cancer. When compared to patients without metastasis at presentation, race, histologic grade, estrogen/progesterone receptor (ER/PR) and HER2 statuses were significantly associated with de novo metastasis in the entire cohort, whereas age, histologic grade, PR and HER2 status were the significant parameters in the subset of patients with locally advanced breast cancer (Stage IIB/III). The patients with de novo metastatic breast cancer had a significant older mean age and a lower proportion of HER2-positive tumors when compared to those with metastatic recurrence. Further, the HER2-rich subtype demonstrated a drastically higher incidence of de novo metastasis when compared to the luminal and triple-negative breast cancers in the entire cohort [odds ratio (OR)=5.68 and 2.27, respectively] and in the patients with locally advanced disease (OR=4.02 and 2.12, respectively), whereas no significant difference was seen between de novo metastatic cancers and those with metastatic recurrence. Moreover, the luminal and HER2-rich subtypes showed bone-seeking (OR=1.92) and liver-homing (OR=2.99) characteristics, respectively, for the sites of de novo metastasis, while the latter was not observed in those with metastatic recurrence. Our data suggest that an algorithm incorporating clinicopathologic factors, especially histologic grade and receptor profile, remains of significant benefit during decision making in newly diagnosed breast cancer in the pursuit of precision medicine. Copyright © 2016 Elsevier GmbH. All rights reserved.

  4. Efficacy of chemotherapy after hormone therapy for hormone receptor-positive metastatic breast cancer.

    Science.gov (United States)

    Mori, Ryutaro; Nagao, Yasuko

    2014-01-01

    According to the guidelines for metastatic breast cancer, hormone therapy for hormone receptor-positive metastatic breast cancer without life-threatening metastasis should be received prior to chemotherapy. Previous trials have investigated the sensitivity of chemotherapy for preoperative breast cancer based on the efficacy of neoadjuvant hormone therapy. In this retrospective study, we investigated the efficacy of chemotherapy for metastatic breast cancer in hormone therapy-effective and hormone therapy-ineffective cases. Patients who received chemotherapy after hormone therapy for metastatic breast cancer between 2006 and 2013 at our institution were investigated. A total of 32 patients received chemotherapy after hormone therapy for metastatic breast cancer. The median patient age was 59 years, and most of the primary tumors exhibited a T2 status. A total of 26 patients had an N(+) status, while 7 patients had human epidermal growth factor receptor 2-positive tumors. A total of 13 patients received clinical benefits from hormone therapy, with a rate of clinical benefit of subsequent chemotherapy of 30.8%, which was not significantly different from that observed in the hormone therapy-ineffective patients (52.6%). A total of 13 patients were able to continue the hormone therapy for more than 1 year, with a rate of clinical benefit of chemotherapy of 38.5%, which was not significantly different from that observed in the short-term hormone therapy patients (47.4%). The luminal A patients were able to continue hormone therapy for a significantly longer period than the non-luminal A patients (median survival time: 17.8 months vs 6.35 months, p = 0.0085). However, there were no significant differences in the response to or duration of chemotherapy. The efficacy of chemotherapy for metastatic breast cancer cannot be predicted based on the efficacy of prior hormone therapy or tumor subtype, and clinicians should administer chemotherapy in all cases of

  5. Advantages and disadvantages of technologies for HER2 testing in breast cancer specimens.

    Science.gov (United States)

    Furrer, Daniela; Sanschagrin, François; Jacob, Simon; Diorio, Caroline

    2015-11-01

    Human epidermal growth factor receptor 2 (HER2) plays a central role as a prognostic and predictive marker in breast cancer specimens. Reliable HER2 evaluation is central to determine the eligibility of patients with breast cancer to targeted anti-HER2 therapies such as trastuzumab and lapatinib. Presently, several methods exist for the determination of HER2 status at different levels (protein, RNA, and DNA level). In this review, we discuss the main advantages and disadvantages of the techniques developed so far for the evaluation of HER2 status in breast cancer specimens. Each technique has its own advantages and disadvantages. It is therefore not surprising that no consensus has been reached so far on which technique is the best for the determination of HER2 status. Currently, emphasis must be put on standardization of procedures, internal and external quality control assessment, and competency evaluation of already existing methods to ensure accurate, reliable, and clinically meaningful test results. Development of new robust and accurate diagnostic assays should also be encouraged. In addition, large clinical trials are warranted to identify the technique that most reliably predicts a positive response to anti-HER2 drugs. Copyright© by the American Society for Clinical Pathology.

  6. Neratinib: Inching up on the cure rate of HER2+ breast cancer?

    Science.gov (United States)

    Unni, Nisha; Sudhan, Dhivya R; Arteaga, Carlos L

    2018-05-25

    Neratinib was recently approved by FDA for extended adjuvant treatment of HER-2 positive breast cancer. ExteNET trial showed improvement in invasive disease-free survival (iDFS) in the neratinib arm compared to placebo. The benefit was more pronounced in patients with ER+/HER2+ tumors, suggesting bidirectional crosstalk between the two pathways. Copyright ©2018, American Association for Cancer Research.

  7. Ekspresi HER2/neu(c-ErbB2 pada Kanker Kolorektal

    Directory of Open Access Journals (Sweden)

    Nita Afriani

    2014-12-01

    Full Text Available Kanker kolorektal merupakan keganasan pada kolon dan rektum, penyebab morbiditas danmortalitas ketiga terbanyak diantara keganasan lainnya. Penelitian ekspresi HER2 pada kankerkolorektal memiliki rentang yang cukup jauh yaitu 0-83% dan belum pernah dipublikasi dilndonesia. Penelitian ini bertujuan untuk menilai ekspresi HER2 pada kanker kolorektal. Studicross-secfiona/ dilakukan terhadap 51 sediaan blok parafin kanker kolorektal rentang tahunJanuari 2011-Desember 2012 di Departemen Patologi Anatorni RS Cipto MangunkusumoJakarta. Penilaian karakteristik sampel diambil dari rekam medis dan penilaian histopatologidari sediaan HE pasien kanker kolorektal. Pulasan imunohistokimia HER2 menggunakanantibodipoliklonalantiHER2(DAKO. Rata-rata usia penderita adalah 57.8t13.54tahun,58.8%penderita adalah laki-laki dan 41.2o/o perempuan. Semua sediaan adalah adenokarsinomakolorektal. Ekspresi HER2 positif ditemukan sebanyak 5(9.8% kasus.AbstractColorectal cancer is a neoplasia of colon and rectum ,and also the 3rd leading cause ofmorbidity and mortality among men and women in the world. HER2 expression has controversialresults ranging from 0-83% and never been pubiished in lndonesia. This research aims tostudy HER2 expression in colorectal cancer. Cross-sectional study was conducted in 51 casesof colorectal cancer from January 2011 until December 2012 in Pathology Department ofCipto Mangunkusumo Hospital. Patient characteristic was reviewed from medical record andhistopathologic was evaluated from HE slides. lmunohistochemistry staining used anti HER2polyclonal antibody frorn DAKO. Mean age was 57.8113.54 years, 58.8% were males and41.2o4 were females. Positive HER2 was 5 cases (9.8%.

  8. Reciprocal regulation of annexin A2 and EGFR with Her-2 in Her-2 negative and herceptin-resistant breast cancer.

    Directory of Open Access Journals (Sweden)

    Praveenkumar K Shetty

    Full Text Available Alternative survival pathways are commonly seen to be upregulated upon inhibition of receptor tyrosine kinases (RTK, including Her-2. It is established that treatment with Herceptin leads to selective overexpression and activation of epidermal growth factor receptor (EGFR and Src which further contributes to oncogenesis in Herceptin resistant and triple negative breast cancer (TNBC patients. Here, we show a co-regulated upregulation in the expression of Annexin A2 (AnxA2, a known substrate of Src and one of the regulators of EGFR receptor endocytosis, in Herceptin resistant and Her-2 negative breast cancer. Immunohistochemical expression analysis revealed a reciprocal regulation between Her-2 and AnxA2 in breast cancer clinical samples as well as in cell lines as confirmed by protein and RNA analysis. The siRNA and Herceptin mediated downregulation/inhibition of Her-2 in Her-2 amplified cells induced AnxA2 expression and membrane translocation. In this study we report a possible involvement of AnxA2 in maintaining constitutively activated EGFR downstream signaling intermediates and hence in cell proliferation, migration and viability. This effect was consistent in Herceptin resistant JIMT-1 cells as well as in Her-2 negative breast cancer. The siRNA mediated AnxA2 downregulation leads to increased apoptosis, decreased cell viability and migration. Our studies further indicate the role of AnxA2 in EGFR-Src membrane bound signaling complex and ligand induced activation of downstream signaling pathways. Targeting this AnxA2 dependent positive regulation of EGFR signaling cascade may be of therapeutic value in Her-2 negative breast cancer.

  9. The HER2-binding affibody molecule (Z(HER2∶342₂ increases radiosensitivity in SKBR-3 cells.

    Directory of Open Access Journals (Sweden)

    Lina Ekerljung

    Full Text Available We have previously shown that the HER2-specific affibody molecule (Z(HER2∶342₂ inhibits proliferation of SKBR-3 cells. Here, we continue to investigate its biological effects in vitro by studying receptor dimerization and clonogenic survival following irradiation. We found that (Z(HER2∶342₂ sensitizes the HER2-overexpressing cell line SKBR-3 to ionizing radiation. The survival after exposure to (Z(HER2∶342₂ and 8 Gy (S(8Gy 0.006 was decreased by a factor four compared to the untreated (S(8Gy 0.023. The low HER2-expressing cell line MCF-7 was more radiosensitive than SKBR-3 but did not respond to (Z(HER2∶342₂. Treatment by (Z(HER2∶342₂ strongly increased the levels of dimerized and phosphorylated HER2 even after 5 minutes of stimulation. The monomeric Z(HER2∶342 does not seem to be able to induce receptor phosphorylation and dimerization or sensitize cells to irradiation.

  10. Dual blockade of HER2 in HER2-overexpressing tumor cells does not completely eliminate HER3 function.

    Science.gov (United States)

    Garrett, Joan T; Sutton, Cammie R; Kuba, María Gabriela; Cook, Rebecca S; Arteaga, Carlos L

    2013-02-01

    Dual blockade of HER2 with trastuzumab and lapatinib or with pertuzumab is a superior treatment approach compared with single-agent HER2 inhibitors. However, many HER2-overexpressing breast cancers still escape from this combinatorial approach. Inhibition of HER2 and downstream phosphoinositide 3-kinase (PI3K)/AKT causes a transcriptional and posttranslational upregulation of HER3 which, in turn, counteracts the antitumor action of the HER2-directed therapies. We hypothesized that suppression of HER3 would synergize with dual blockade of HER2 in breast cancer cells sensitive and refractory to HER2 antagonists. Inhibition of HER2/HER3 in HER2(+) breast cancer cell lines was evaluated by Western blotting. We analyzed drug-induced apoptosis and two- and three-dimensional growth in vitro. Growth inhibition of PI3K was examined in vivo in xenografts treated with combinations of trastuzumab, lapatinib, and the HER3-neutralizing monoclonal antibody U3-1287. Treatment with U3-1287 blocked the upregulation of total and phosphorylated HER3 that followed treatment with lapatinib and trastuzumab and, in turn, enhanced the antitumor action of the combination against trastuzumab-sensitive and -resistant cells. Mice bearing HER2(+) xenografts treated with lapatinib, trastuzumab, and U3-1287 exhibited fewer recurrences and better survival than mice treated with lapatinib and trastuzumab. Dual blockade of HER2 with trastuzumab and lapatinib does not eliminate the compensatory upregulation of HER3. Therapeutic inhibitors of HER3 should be considered as part of multidrug combinations aimed at completely and rapidly disabling the HER2 network in HER2-overexpressing breast cancers.

  11. Expression of HER2/Neu in B-Cell Acute Lymphoblastic Leukemia.

    Science.gov (United States)

    Rodriguez-Rodriguez, Sergio; Pomerantz, Alan; Demichelis-Gomez, Roberta; Barrera-Lumbreras, Georgina; Barrales-Benitez, Olga; Aguayo-Gonzalez, Alvaro

    2016-01-01

    The expression of HER2/neu in B-cell acute lymphoblastic leukemia has been reported in previous studies. The objective of this research was to study the expression of HER2/neu on the blasts of patients with acute leukemia from the Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran. From June 2015 to February 2016, a HER2/neu monoclonal antibody was added to the panel of antibodies that we routinely use in patients with acute leukemia. An expression of ≥ 30% was considered positive. We studied 33 patients: 19 had de novo leukemia (57.6%), three (9.1%) were in relapse, and in 11 (33.3%) their status could not be specified. Seventeen patients (51.5%) were classified as B-cell acute lymphoblastic leukemia with a median expression of HER2/neu of 0.3% (range 0-90.2). Three patients with B-cell acute lymphoblastic leukemia were positive for HER2/neu: 89.4%, 90.9%, and 62.4%. The first and third patient had de novo B-cell acute lymphoblastic leukemia. The second patient was in second relapse after allogeneic stem cell transplant. All three patients were categorized as high-risk at the time of diagnosis. In the studied Mexican population, we found a positive expression of HER2/neu in 17% of the B-cell acute lymphoblastic leukemia patients, similar to previous studies in which the expression was found in 15-50%.

  12. Immunohistochemistry and alternative FISH testing in breast cancer with HER2 equivocal amplification.

    Science.gov (United States)

    Agersborg, Sally; Mixon, Christopher; Nguyen, Thanh; Aithal, Sramila; Sudarsanam, Sucha; Blocker, Forrest; Weiss, Lawrence; Gasparini, Robert; Jiang, Shiping; Chen, Wayne; Hess, Gregory; Albitar, Maher

    2018-03-22

    While HER2 testing is well established in directing appropriate treatment for breast cancer, a small percentage of cases show equivocal results by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). Alternative probes may be used in equivocal cases. We present a single community-based institution's experience in further evaluating these cases. Between 2014 and 2016, 4255 samples were submitted for HER2 amplification testing by alternative probes, TP53, RAI1, and RARA. Of the patients tested by FISH, 505/3908 (12.9%) also had IHC data. Most (73.9%) FISH equivocal cases remained equivocal after IHC testing. However, 50.5% of equivocal cases were classified as HER2 amplified by alternative probes. Most cases were positive by more than one probe: 78% of positive cases by RAI1 and 73.9% by TP53. There was a significant difference between IHC and FISH alternative testing (p alternative FISH testing. Available data showed that 41% of patients were treated with palbociclib and were positive by alternative FISH. The prevalence of double HER2 equivocal cases and the discrepancy between IHC and alternative FISH testing suggest that FISH alternative testing using both RAI1 and TP53 probes is necessary for conclusive classification. Because almost half of FISH equivocal cases converted to HER2 amplified upon alternative testing, clinical studies to determine the benefit of anti-HER2 therapy in these patients are urgently needed.

  13. Refinement of immunohistologic parameters for Her2/neu scoring validation by FISH and CISH.

    Science.gov (United States)

    Leong, Anthony S-Y; Formby, Mark; Haffajee, Zenobia; Clarke, Megan; Morey, Adrienne

    2006-12-01

    The conventional method of scoring Her2/neu immunostaining is recognized to result in a high false-positive rate among 2+ cases when compared with results obtained with fluorescence in situ hybridization (FISH); however, costs and convenience dictates that immunohistochemistry remains the screening test for Her2/neu status in patients with breast cancer. We describe refined criteria for scoring of Her2/neu on the basis of anatomic localization rather than the subjective assessment of intensity. The presence of a circumferential tram track pattern that results from the staining of apposing cell membranes in >25% of the tumor cells was necessary for a 3+ score (Her2/neu overexpressed) and the presence of the tram track pattern in CISH testing in selected cases from the other categories validated the revised scoring method. These criteria reduced the numbers of equivocal staining cases that required FISH testing.

  14. Color feature extraction of HER2 Score 2+ overexpression on breast cancer using Image Processing

    Directory of Open Access Journals (Sweden)

    Muhimmah Izzati

    2018-01-01

    Full Text Available One of the major challenges in the development of early diagnosis to assess HER2 status is recognized in the form of Gold Standard. The accuracy, validity and refraction of the Gold Standard HER2 methods are widely used in laboratory (Perez, et al., 2014. Method determining the status of HER2 (human epidermal growth factor receptor 2 is affected by reproductive problems and not reliable in predicting the benefit from anti-HER2 therapy (Nuciforo, et al., 2016. We extracted color features by methods adopting Statistics-based segmentation using a continuous-scale naïve Bayes approach. In this study, there were three parts of the main groups, namely image acquisition, image segmentation, and image testing. The stages of image acquisition consisted of image data collection and color deconvolution. The stages of image segmentation consisted of color features, classifier training, classifier prediction, and skeletonization. The stages of image testing were image testing, expert validation, and expert validation results. Area segmentation of the membrane is false positive and false negative. False positive and false negative from area are called the area of system failure. The failure of the system can be validated by experts that the results of segmentation region is not membrane HER2 (noise and the segmentation of the cytoplasm region. The average from 40 data of HER2 score 2+ membrane images show that 75.13% of the area is successfully recognized by the system.

  15. Complete response in HER2+ leptomeningeal carcinomatosis from breast cancer with intrathecal trastuzumab.

    Science.gov (United States)

    Oliveira, Mafalda; Braga, Sofia; Passos-Coelho, José Luís; Fonseca, Ricardo; Oliveira, João

    2011-06-01

    Trastuzumab, a monoclonal antibody against the HER2 receptor, is a major breakthrough in the treatment of HER2+ breast cancer. However, its high molecular weight precludes it from crossing the intact blood-brain barrier, making the central nervous system a sanctuary to HER2+ breast cancer metastases. We prospectively assessed functional outcome and toxicity of administering trastuzumab directly into the cerebrospinal fluid of a patient with leptomeningeal carcinomatosis (LC) and brain metastases from HER2+ breast cancer that had already been treated with other intrathecal chemotherapy, with no benefit. Upon signed informed consent, weekly lumbar puncture with administration of trastuzumab 25 mg was begun to a 44 year-old women with metastatic breast cancer (lymph node, bone, lung, and liver involvement) previously treated with tamoxifen, letrozole, anthracyclines, taxanes, capecitabine, intravenous trastuzumab, and lapatinib. She received 67 weekly administrations of intrathecal trastuzumab with marked clinical improvement and no adverse events. She survived 27 months after LC diagnosis. A complete leptomeningeal response, with no evidence of leptomeningeal metastasis at necropsy, was achieved. We believe that intrathecal trastuzumab administration should be prospectively evaluated to confirm clinical activity and optimize dose, schedule, and duration of treatment.

  16. Alphavirus replicon particles containing the gene for HER2/neu inhibit breast cancer growth and tumorigenesis

    International Nuclear Information System (INIS)

    Wang, Xiaoyan; Wang, Jian-Ping; Maughan, Maureen F; Lachman, Lawrence B

    2005-01-01

    Overexpression of the HER2/neu gene in breast cancer is associated with an increased incidence of metastatic disease and with a poor prognosis. Although passive immunotherapy with the humanized monoclonal antibody trastuzumab (Herceptin) has shown some effect, a vaccine capable of inducing T-cell and humoral immunity could be more effective. Virus-like replicon particles (VRP) of Venezuelan equine encephalitis virus containing the gene for HER2/neu (VRP-neu) were tested by an active immunotherapeutic approach in tumor prevention models and in a metastasis prevention model. VRP-neu prevented or significantly inhibited the growth of HER2/neu-expressing murine breast cancer cells injected either into mammary tissue or intravenously. Vaccination with VRP-neu completely prevented tumor formation in and death of MMTV-c-neu transgenic mice, and resulted in high levels of neu-specific CD8 + T lymphocytes and serum IgG. On the basis of these findings, clinical testing of this vaccine in patients with HER2/neu + breast cancer is warranted

  17. Immunohistochemical detection of Her-2/neu overexpression in ...

    African Journals Online (AJOL)

    Materials and Methods: Immunohistochemical staining for Her-2/neu was performed on 10% formalin-fixed, paraffinembedded primary carcinoma of the breast from 83 patients, between 2003 and 2007 using anti-Her-2/neu rabbit polyclonal antibody (DakoCytomation, CA, USA) and reactivity detected by an avidin-biotin ...

  18. Analysis of EGFR, HER2, and TOP2A gene status and chromosomal polysomy in gastric adenocarcinoma from Chinese patients

    International Nuclear Information System (INIS)

    Liang, Zhiyong; Zeng, Xuan; Gao, Jie; Wu, Shafei; Wang, Peng; Shi, Xiaohua; Zhang, Jing; Liu, Tonghua

    2008-01-01

    The EGFR and HER2 genes are located on chromosomes 7 and 17, respectively. They are therapeutic targets in some tumors. The TOP2A gene, which is located near HER2 on chromosome 17, is the target of many chemotherapeutic agents, and co-amplification of HER2 and TOP2A has been described in several tumor types. Herein, we investigated the gene status of EGFR, HER2, and TOP2A in Chinese gastric carcinoma patients. We determined the rate of polysomy for chromosomes 7 and 17, and we attempted to clarify the relationship between EGFR, HER2, and TOP2A gene copy number and increased expression of their encoded proteins. Furthermore, we tried to address the relationship between alterations in EGFR, HER2, and TOP2A and chromosome polysomy. One hundred cases of formalin fixed and paraffin embedded tumor tissues from Chinese gastric carcinoma patients were investigated by immunohistochemistry and fluorescence in situ hybridization (FISH) methods. Forty-two percent of the cases showed EGFR overexpression; 16% showed EGFR FISH positive; 6% showed HER2 overexpression; and 11% showed HER2 gene amplification, including all six HER2 overexpression cases. TOP2A nuclear staining (nuclear index, NI) was determined in all 100 tumors: NI values ranged from 0.5 – 90%. Three percent of the tumors showed TOP2A gene amplification, which were all accompanied by HER2 gene amplification. Nineteen percent of the tumors showed chromosome 7 polysomy, and 16% showed chromosome 17 polysomy. Chromosome 7 polysomy correlated significantly with EGFR FISH-positivity, but was not associated with EGFR overexpression. HER2 overexpression associated significantly with HER2 gene amplification. TOP2A gene amplification was significantly associated with HER2 gene amplification. No relationship was found between alterations in the EGFR, HER2, and TOP2A genes and clinicopathologic variables of gastric carcinoma. The data from our study suggest that chromosome 7 polysomy may be responsible for increased EGFR

  19. Reduced risk of breast cancer associated with recreational physical activity varies by HER2 status

    International Nuclear Information System (INIS)

    Ma, Huiyan; Xu, Xinxin; Ursin, Giske; Simon, Michael S; Marchbanks, Polly A; Malone, Kathleen E; Lu, Yani; McDonald, Jill A; Folger, Suzanne G; Weiss, Linda K; Sullivan-Halley, Jane; Deapen, Dennis M; Press, Michael F; Bernstein, Leslie

    2015-01-01

    Convincing epidemiologic evidence indicates that physical activity is inversely associated with breast cancer risk. Whether this association varies by the tumor protein expression status of the estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), or p53 is unclear. We evaluated the effects of recreational physical activity on risk of invasive breast cancer classified by the four biomarkers, fitting multivariable unconditional logistic regression models to data from 1195 case and 2012 control participants in the population-based Women’s Contraceptive and Reproductive Experiences Study. Self-reported recreational physical activity at different life periods was measured as average annual metabolic equivalents of energy expenditure [MET]-hours per week. Our biomarker-specific analyses showed that lifetime recreational physical activity was negatively associated with the risks of ER-positive (ER+) and of HER2-negative (HER2−) subtypes (both P trend ≤ 0.04), but not with other subtypes (all P trend > 0.10). Analyses using combinations of biomarkers indicated that risk of invasive breast cancer varied only by HER2 status. Risk of HER2–breast cancer decreased with increasing number of MET-hours of recreational physical activity in each specific life period examined, although some trend tests were only marginally statistically significant (all P trend ≤ 0.06). The test for homogeneity of trends (HER2– vs. HER2+) reached statistical significance only when evaluating physical activity during the first 10 years after menarche (P homogeneity = 0.03). Our data suggest that physical activity reduces risk of invasive breast cancers that lack HER2 overexpression, increasing our understanding of the biological mechanisms by which physical activity acts

  20. Targeted biomarker profiling of matched primary and metastatic estrogen receptor positive breast cancers.

    Directory of Open Access Journals (Sweden)

    Erica B Schleifman

    Full Text Available Patients with newly diagnosed, early stage estrogen receptor positive (ER+ breast cancer often show disease free survival in excess of five years following surgery and systemic adjuvant therapy. An important question is whether diagnostic tumor tissue from the primary lesion offers an accurate molecular portrait of the cancer post recurrence and thus may be used for predictive diagnostic purposes for patients with relapsed, metastatic disease. As the class I phosphatidylinositol 3' kinase (PI3K pathway is frequently activated in ER+ breast cancer and has been linked to acquired resistance to hormonal therapy, we hypothesized pathway status could evolve over time and treatment. Biomarker analyses were conducted on matched, asynchronous primary and metastatic tumors from 77 patients with ER+ breast cancer. We examined whether PIK3CA and AKT1 alterations or PTEN and Ki67 levels showed differences between primary and metastatic samples. We also sought to look more broadly at gene expression markers reflective of proliferation, molecular subtype, and key receptors and signaling pathways using an mRNA analysis platform developed on the Fluidigm BioMark™ microfluidics system to measure the relative expression of 90 breast cancer related genes in formalin-fixed paraffin-embedded (FFPE tissue. Application of this panel of biomarker assays to matched tumor pairs showed a high concordance between primary and metastatic tissue, with generally few changes in mutation status, proliferative markers, or gene expression between matched samples. The collection of assays described here has been optimized for FFPE tissue and may have utility in exploratory analyses to identify patient subsets responsive to targeted therapies.

  1. Systematic Review of the Side Effects Associated With Anti-HER2-Targeted Therapies Used in the Treatment of Breast Cancer, on Behalf of the EORTC Quality of Life Group.

    Science.gov (United States)

    Sodergren, Samantha C; Copson, Ellen; White, Alice; Efficace, Fabio; Sprangers, Mirjam; Fitzsimmons, Deborah; Bottomley, Andrew; Johnson, Colin D

    2016-06-01

    Targeted therapies (TTs), notably trastuzumab, have improved outcomes for breast cancer characterised by overexpression of human epidermal growth factor receptors including HER2. Compared with chemotherapy treatments, TTs are more specific in their targets and are delivered over longer periods of time, thus presenting different side-effect profiles. The objective of this paper is to systematically review and describe the side effects associated with TTs used in the adjuvant and metastatic settings for HER2+ breast cancer. The MEDLINE, EMBASE, CINAHL, Web of Science and Cochrane Library databases were searched from January 2007 to March 2015 to identify clinical trials and prospective studies reporting toxicities associated with TTs (mainly trastuzumab and lapatinib) used without other therapies in the treatment of HER2-positive breast cancer. Two independent reviewers selected papers based on their titles and abstracts. All papers selected by either reviewer were included. A third reviewer extracted and tabulated the relevant data using a data extraction form. We identified 5478 papers, of which 299 were reviewed and 18 trials identified involving 6980 patients. A total of 66 side effects were identified, including 46 "patient-based" symptoms and 20 "medically defined" outcomes. Side effects were more common for patients treated with therapies other than trastuzumab or with dual-HER2 regimens and for patients with metastatic disease. Diarrhoea and skin rash were the most prevalent symptoms, experienced by 29 % and 22 % of patients overall, respectively. There were 119 (2 %) cardiac events reported, and these were not exclusive to trastuzumab-treated patients. The majority of side effects (n = 52) were experienced by 1 % or less of patients and were predominantly of grade 1/2 toxicity. This systematic review provides a detailed analysis of side effects of HER2+ therapies in a large number of patients included in trials, enabling an accurate estimate of

  2. HER2 expression in cervical cancer as a potential therapeutic target

    International Nuclear Information System (INIS)

    Chavez-Blanco, Alma; Perez-Sanchez, Victor; Gonzalez-Fierro, Aurora; Vela-Chavez, Teresa; Candelaria, Myrna; Cetina, Lucely; Vidal, Silvia; Dueñas-Gonzalez, Alfonso

    2004-01-01

    Trastuzumab, a humanized monoclonal antibody against the HER2 receptor is currently being used in breast and other tumor types. Early studies have shown that a variable proportion of cervical carcinoma tumors overexpress the HER2 receptor as evaluated by diverse techniques and antibodies. Currently it is known that a tumor response to trastuzumab strongly correlates with the level of HER2 expression evaluated by the Hercep Test, thus, it seems desirable to evaluate the status of expression of this receptor using the FDA-approved Hercep Test and grading system to gain insight in the feasibility of using trastuzumab in cervical cancer patients. We analyzed a series of cervical cancer cell lines, the primary tumors of 35 cases of cervical cancer patients and four recurrent cases, with the Hercep Test in order to establish whether this tumor type overexpress HER2 at level of 2+/3+ as trastuzumab is currently approved for breast cancer having such level of expression. The results indicate that only 1 out of 35 primary tumors cases overexpress the receptor at this level, however, two out of four recurrent tumors that tested negative at diagnosis shifted to Hercep Test 2+ and 3+ respectively. The low frequency of expression in primary cases suggests that trastuzumab could have a limited value for the primary management of cervical cancer patients, however, the finding of 'conversion' to Hercep Test 2+ and 3+ of recurrent tumors indicates the need to further evaluate the expression of HER2 in the metastatic and recurrent cases

  3. Forward genetic screens identify a role for the mitochondrial HER2 in E-2-hexenal responsiveness.

    Science.gov (United States)

    Scala, Alessandra; Mirabella, Rossana; Goedhart, Joachim; de Vries, Michel; Haring, Michel A; Schuurink, Robert C

    2017-11-01

    This work adds a new player, HER2, downstream of the perception of E-2-hexenal, a green leaf volatile, and shows that E-2-hexenal specifically changes the redox status of the mitochondria. It is widely accepted that plants produce and respond to green leaf volatiles (GLVs), but the molecular components involved in transducing their perception are largely unknown. The GLV E-2-hexenal inhibits root elongation in seedlings and, using this phenotype, we isolated E-2-hexenal response (her) Arabidopsis thaliana mutants. Using map-based cloning we positioned the her2 mutation to the At5g63620 locus, resulting in a phenylalanine instead of serine on position 223. Knockdown and overexpression lines of HER2 confirmed the role of HER2, which encodes an oxidoreductase, in the responsiveness to E-2-hexenal. Since E-2-hexenal is a reactive electrophile species, which are known to influence the redox status of cells, we utilized redox sensitive GFP2 (roGFP2) to determine the redox status of E-2-hexenal-treated root cells. Since the signal peptide of HER2 directed mCherry to the mitochondria, we targeted the expression of roGFP2 to this organelle besides the cytosol. E-2-hexenal specifically induced a change in the redox status in the mitochondria. We did not see a difference in the redox status in her2 compared to wild-type Arabidopsis. Still, the mitochondrial redox status did not change with Z-3-hexenol, another abundant GLV. These results indicate that HER2 is involved in transducing the perception of E-2-hexenal, which changes the redox status of the mitochondria.

  4. [Internal quality control on HER2 status determination in breast cancers: Experience of a cancer center].

    Science.gov (United States)

    Ngo, Carine; Laé, Marick; Ratour, Julia; Hamel, Frédérique; Taris, Corinne; Caly, Martial; Le Cunff, Annie; Reyal, Fabien; Kirova, Youlia; Pierga, Jean-Yves; Vincent-Salomon, Anne

    The implementation of an internal quality control is mandatory to guarantee the accuracy of HER2 status in invasive breast cancers. To evaluate the impact of our quality control assurance on HER2 status results in invasive breast carcinomas from 2008 to 2014. HER2 status was determined by immunohistochemistry as the first-line indication, completed by fluorescence in situ hybridization (FISH) for scores 2+ by immunohistochemistry. Internal quality control of HER2 status relied on the standardization of pre-analytical phases, the use of external controls with a known number of HER2 gene copies determined by FISH and continued monitoring of concordance between immunohistochemistry and FISH. The proportion of HER2-positive cases corresponding to scores 3+ by immunohistochemistry and 2+ amplified by FISH varied from 10.6% to 13.8% (median of 11.3%). The proportion of scores 2+ amplified by FISH varied from 13.3% to 32.7% during period of study. The rate of concordance between FISH and immunohistochemistry for score 0/1+ and 3+ cases were≥97%. Eight among 12 discordant cases were false positive resulting from errors in interpretation of immunohistochemistry (score 2+ instead of 3+). Calibration of immunohistochemistry on FISH for HER2 status contributes to limit variability of immunohistochemistry results due to technical issues or interpretation. The implementation of an external control of score 3+ on each slide enables accurate interpretation of score 2+ and 3+ by immunohistochemistry. Copyright © 2017 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

  5. Concordance Between FISH Analysis of Her-2/Neu Gene in Breast Duct Carcinoma and Corresponding Axillary Nodal Metastases: Egyptian National Cancer Institute Experience.

    Science.gov (United States)

    Badawy, Omnia M; Hassan, Hannan; ELBakey, Heba A; Mosaad, Maha

    2018-05-10

    Breast cancer is a major health problem in Egypt. Her-2/Neu gene is routinely assessed for all breast cancer patients primarily by immunohistochemistry. At National Cancer Institute (NCI), Cairo University, Flourescence In Situ hybridization (FISH) analysis of Her-2/Neu gene is carried out for Her-2/Neu score 2 and for some cases of score 3 (particularly those assessed outside NCI). The test is performed essentially on the primary tumor. However, some situations require testing on corresponding lymph node metastases. There is a debate about the concordance between Her-2/Neu status in the primary tumor and synchronous lymph node metastases in various studies. The aim of this study was to test for the concordance between Her-2/Neu status in the primary breast tumor and corresponding axillary nodal metastases. This is a retrospective study in which FISH analysis of Her-2/Neu was carried out simultaneously on archived material of 50 cases previously diagnosed as invasive duct carcinoma and the corresponding nodal metastases from the Pathology Department, NCI. There was complete concordance between Her-2 status in the primary tumor and the corresponding axillary lymph node metastatic deposits in which Her-2 was amplified in 44% of the studied cohort of Egyptian patients. Her-2/Neu gene assessed by FISH analysis on synchronous lymph node metastases is strongly correlated with the primary tumor. Hence, it is justified to carry out the Her-2/Neu test on synchronous lymph nodes to decide on whether to carry out anti-Her-2/Neu target therapy. Further studies on other metastatic sites is recommended.

  6. Estrogen receptor, progesterone receptor, HER-2, and response to postmastectomy radiotherapy in high-risk breast cancer: The Danish Breast Cancer Cooperative Group

    DEFF Research Database (Denmark)

    Kyndi, M.; Sorensen, F.B.; Overgaard, M.

    2008-01-01

    . End points were locoregional recurrence as isolated first event, distant metastases, and overall survival. For statistical analyses four subgroups were constructed from hormonal receptors (Rec). Rec+ was defined as ER+ and/or PgR+. Rec- as both ER- and PgR-. The four subgroups were Rec+/HER-2-, Rec......+/HER-2+, Rec-/HER-2- (triple negative), and Rec-/HER-2+. Results A significantly improved overall survival after PMRT was seen only among patients characterized by good prognostic markers such as hormonal receptor-positive and HER-2- patients (including the two Rec+ subtypes). No significant overall...... after PMRT were found for ER- and PgR- tumors compared with the ER+ and PgR+ tumors (P = .003 and 04, respectively), and for the triple-negative (P = .02), and the Rec-/HER-2+ subtypes (P = .003) compared with the Rec-/HER-2- subtype. Conclusion Hormonal receptor status, HER-2, and the constructed...

  7. Differences in radiosensitivity between three HER2 overexpressing cell lines

    International Nuclear Information System (INIS)

    Steffen, Ann-Charlott; Tolmachev, Vladimir; Stenerloew, Bo; Goestring, Lovisa; Palm, Stig; Carlsson, Joergen

    2008-01-01

    HER2 is a potential target for radionuclide therapy, especially when HER2 overexpressing breast cancer cells are resistant to Herceptin registered treatment. Therefore, it is of interest to analyse whether HER2 overexpressing tumour cells have different inherent radiosensitivity. The radiosensitivity of three often used HER2 overexpressing cell lines, SKOV-3, SKBR-3 and BT-474, was analysed. The cells were exposed to conventional photon irradiation, low linear energy transfer (LET), to characterise their inherent radiosensitivity. The analysis was made with clonogenic survival and growth extrapolation assays. The cells were also exposed to alpha particles, high LET, from 211 At decays using the HER2-binding affibody molecule 211 At-(Z HER2:4 ) 2 as targeting agent. Assays for studies of internalisation of the affibody molecule were applied. SKOV-3 cells were most radioresistant, SKBR-3 cells were intermediate and BT-474 cells were most sensitive as measured with the clonogenic and growth extrapolation assays after photon irradiation. The HER2 dependent cellular uptake of 211 At was qualitatively similar for all three cell lines. However, the sensitivity to the alpha particles from 211 At differed; SKOV-3 was most resistant, SKBR-3 intermediate and BT-474 most sensitive. These differences were unexpected because it is assumed that all types of cells should have similar sensitivity to high-LET radiation. The sensitivity to alpha particle exposure correlated with internalisation of the affibody molecule and with size of the cell nucleus. There can be differences in radiosensitivity, which, if they also exist between patient breast cancer cells, are important to consider for both conventional radiotherapy and for HER2-targeted radionuclide therapy. (orig.)

  8. ER, PgR, Ki67, p27Kip1, and histological grade as predictors of pathological complete response in patients with HER2-positive breast cancer receiving neoadjuvant chemotherapy using taxanes followed by fluorouracil, epirubicin, and cyclophosphamide concomitant with trastuzumab

    International Nuclear Information System (INIS)

    Kurozumi, Sasagu; Inoue, Kenichi; Takei, Hiroyuki; Matsumoto, Hiroshi; Kurosumi, Masafumi; Horiguchi, Jun; Takeyoshi, Izumi; Oyama, Tetsunari

    2015-01-01

    Neoadjuvant chemotherapy (NAC) with taxanes followed by fluorouracil, epirubicin, and cyclophosphamide (FEC), and concurrent trastuzumab is a potent regimen for HER2 over-expressing breast cancer. A high pathological complete response (pCR) rate has been achieved using this regimen; however, the predictive factors and prognostic effects of pCR currently remain unclear. In the present study, we determined whether pCR was related to histological grade (HG) and several biological factors including p27 Kip1 . We also assessed the prognosis of the pCR and non-pCR groups, and expected differences between those positive and negative for lymph node metastasis after chemotherapy. A total of 129 Japanese women with HER2-positive invasive breast cancer received either paclitaxel or docetaxel followed by FEC, with the concomitant administration of trastuzumab. The statuses of HG, ER, PgR, Ki67, and p27 Kip1 were evaluated to determine their relationship with pCR. Relapse-free survival (RFS) and overall survival (OS) were also analyzed for their relationship with pCR and pathological nodal involvement. pCR was obtained in 84 out of 129 patients and the pCR rate was 65.1 %. The pCR rates related to 5 factors were as follows: HG (grade 3, 70.0 % vs. grades 1–2, 36.8 %), ER (negative, 78.6 % vs. positive, 40.0 %), PgR (negative, 75.3 % vs. positive, 38.9 %), Ki67 (high, 72.0 % vs. low, 47.2 %), and p27 Kip1 (low, 71.0 % vs. high, 50.0 %). RFS was significantly better in the pCR group than in the non-pCR group (p = 0.018). Patients with remaining nodal disease in the pCR group had worse OS (p = 0.0002). High-HG, low-ER, low-PgR, high-Ki67, and low-p27 Kip1 were identified as predictive factors of pCR in NAC with trastuzumab, while pCR and negative nodes were predictive of better survivals. The online version of this article (doi:10.1186/s12885-015-1641-y) contains supplementary material, which is available to authorized users

  9. Feasibility Study of EndoTAG-1, a Tumor Endothelial Targeting Agent, in Combination with Paclitaxel followed by FEC as Induction Therapy in HER2-Negative Breast Cancer.

    Directory of Open Access Journals (Sweden)

    Michail Ignatiadis

    Full Text Available EndoTAG-1, a tumor endothelial targeting agent has shown activity in metastatic triple-negative breast cancer (BC in combination with paclitaxel.HER2-negative BC patients candidates for neoadjuvant chemotherapy were scheduled to receive 12 cycles of weekly EndoTAG-1 22mg/m2 plus paclitaxel 70mg/m2 followed by 3 cycles of FEC (Fluorouracil 500mg/m2, Epirubicin 100mg/m2, Cyclophosphamide 500mg/m2 every 3 weeks followed by surgery. Primary endpoint was percent (% reduction in Magnetic Resonance Imaging (MRI estimated Gadolinium (Gd enhancing tumor volume at the end of EndoTAG-1 plus paclitaxel administration as compared to baseline. Safety, pathological complete response (pCR defined as no residual tumor in breast and axillary nodes at surgery and correlation between % reduction in MRI estimated tumor volume and pCR were also evaluated.Fifteen out of 20 scheduled patients were included: Six patients with estrogen receptor (ER-negative/HER2-negative and 9 with ER-positive/HER2-negative BC. Nine patients completed treatment as per protocol. Despite premedication and slow infusion rates, grade 3 hypersensitivity reactions to EndoTAG-1 were observed during the 1st, 2nd, 3rd and 6th weekly infusion in 4 patients, respectively, and required permanent discontinuation of the EndoTAG-1. Moreover, two additional patients stopped EndoTAG-1 plus paclitaxel after 8 and 9 weeks due to clinical disease progression. Two patients had grade 3 increases in transaminases and 1 patient grade 4 neutropenia. pCR was achieved in 5 of the 6 ER-/HER2- and in none of the 9 ER+/HER2- BC patients. The mean % reduction in MRI estimated tumor volume at the end of EndoTAG-1 plus paclitaxel treatment was 81% (95% CI, 66% to 96%, p<0.001 for the 15 patients that underwent surgery; 96% for patients with pCR and 73% for patients with no pCR (p = 0.04.The EndoTAG-1 and paclitaxel combination showed promising preliminary activity as preoperative treatment, especially in ER-/HER2

  10. Regional Delivery of Chimeric Antigen Receptor-Engineered T Cells Effectively Targets HER2+ Breast Cancer Metastasis to the Brain.

    Science.gov (United States)

    Priceman, Saul J; Tilakawardane, Dileshni; Jeang, Brook; Aguilar, Brenda; Murad, John P; Park, Anthony K; Chang, Wen-Chung; Ostberg, Julie R; Neman, Josh; Jandial, Rahul; Portnow, Jana; Forman, Stephen J; Brown, Christine E

    2018-01-01

    Purpose: Metastasis to the brain from breast cancer remains a significant clinical challenge, and may be targeted with CAR-based immunotherapy. CAR design optimization for solid tumors is crucial due to the absence of truly restricted antigen expression and potential safety concerns with "on-target off-tumor" activity. Here, we have optimized HER2-CAR T cells for the treatment of breast to brain metastases, and determined optimal second-generation CAR design and route of administration for xenograft mouse models of breast metastatic brain tumors, including multifocal and leptomeningeal disease. Experimental Design: HER2-CAR constructs containing either CD28 or 4-1BB intracellular costimulatory signaling domains were compared for functional activity in vitro by measuring cytokine production, T-cell proliferation, and tumor killing capacity. We also evaluated HER2-CAR T cells delivered by intravenous, local intratumoral, or regional intraventricular routes of administration using in vivo human xenograft models of breast cancer that have metastasized to the brain. Results: Here, we have shown that HER2-CARs containing the 4-1BB costimulatory domain confer improved tumor targeting with reduced T-cell exhaustion phenotype and enhanced proliferative capacity compared with HER2-CARs containing the CD28 costimulatory domain. Local intracranial delivery of HER2-CARs showed potent in vivo antitumor activity in orthotopic xenograft models. Importantly, we demonstrated robust antitumor efficacy following regional intraventricular delivery of HER2-CAR T cells for the treatment of multifocal brain metastases and leptomeningeal disease. Conclusions: Our study shows the importance of CAR design in defining an optimized CAR T cell, and highlights intraventricular delivery of HER2-CAR T cells for treating multifocal brain metastases. Clin Cancer Res; 24(1); 95-105. ©2017 AACR . ©2017 American Association for Cancer Research.

  11. Dual gain of HER2 and EGFR gene copy numbers impacts the prognosis of carcinoma ex pleomorphic adenoma.

    Science.gov (United States)

    Nishijima, Toshimitsu; Yamamoto, Hidetaka; Nakano, Takafumi; Nakashima, Torahiko; Taguchi, Ken-ichi; Masuda, Muneyuki; Motoshita, Jun-ichi; Komune, Shizuo; Oda, Yoshinao

    2015-11-01

    We investigated the potential roles of HER2 and EGFR and evaluated their prognostic significance in carcinoma ex pleomorphic adenoma (CXPA). We analyzed HER2 and EGFR overexpression status using immunohistochemistry (IHC) and gene copy number gain by chromogenic in situ hybridization (CISH) in 50 cases of CXPA (40 ductal-type and 10 myoepithelial-type CXPAs). Salivary duct carcinoma was the most common histologic subtype of malignant component (n = 21). Immunohistochemistry positivity and chromogenic in situ hybridization positivity were closely correlated in both HER2 and EGFR. HER2 CISH positivity (mostly gene amplification) and EGFR CISH positivity (mostly gene high polysomy) were present in 19 (40%) and 21 (44%) cases, respectively, and were each significantly correlated with poor outcome (P = .0009 and P = .0032, respectively). Dual gain of HER2 and EGFR gene copy numbers was present in 11 cases (23%) and was the most aggressive genotype. HER2 CISH positivity was more frequently present in ductal-type CXPAs (47%) than in myoepithelial-type CXPAs (10%), whereas the prevalence of EGFR CISH positivity was similar in both histologic subtypes (42% and 50%, respectively). Our results suggest that HER2 and EGFR gene copy number gains may play an important role in the progression of CXPA, in particular ductal-type CXPAs. HER2 CISH-positive/EGFR CISH-positive tumors may be the most aggressive subgroup in CXPA. The molecular subclassification of CXPA based on the HER2 and EGFR status may be helpful for prognostic prediction and decisions regarding the choice of therapeutic strategy. Copyright © 2015 Elsevier Inc. All rights reserved.

  12. Neratinib Plus Paclitaxel vs Trastuzumab Plus Paclitaxel in Previously Untreated Metastatic ERBB2-Positive Breast Cancer: The NEfERT-T Randomized Clinical Trial.

    Science.gov (United States)

    Awada, Ahmad; Colomer, Ramon; Inoue, Kenichi; Bondarenko, Igor; Badwe, Rajendra A; Demetriou, Georgia; Lee, Soo-Chin; Mehta, Ajay O; Kim, Sung-Bae; Bachelot, Thomas; Goswami, Chanchal; Deo, Suryanarayan; Bose, Ron; Wong, Alvin; Xu, Feng; Yao, Bin; Bryce, Richard; Carey, Lisa A

    2016-12-01

    Efficacious ERBB2 (formerly HER2 or HER2/neu)-directed treatments, in addition to trastuzumab and lapatinib, are needed. To determine whether neratinib, an irreversible pan-ERBB tyrosine kinase inhibitor, plus paclitaxel improves progression-free survival compared with trastuzumab plus paclitaxel in the first-line treatment of recurrent and/or metastatic ERBB2-positive breast cancer. In the randomized, controlled, open-label NEfERT-T trial conducted from August 2009 to December 2014 at 188 centers in 34 countries in Europe, Asia, Africa, and North America, 479 women with previously untreated recurrent and/or metastatic ERBB2-positive breast cancer were randomized to 1 of 2 treatment arms (neratinib-paclitaxel [n = 242] or trastuzumab-paclitaxel [n = 237]). Women with asymptomatic central nervous system metastases were eligible, and randomization was stratified by prior trastuzumab and lapatinib exposure, hormone-receptor status, and region. Women received neratinib (240 mg/d orally) or trastuzumab (4 mg/kg then 2 mg/kg weekly), each combined with paclitaxel (80 mg/m2 on days 1, 8, and 15 every 28 days). Primary prophylaxis for diarrhea was not mandatory. The primary outcome was progression-free survival. Secondary end points were response rate, clinical benefit rate, duration of response, frequency, and time to symptomatic and/or progressive central nervous system lesions, and safety. The intent-to-treat population comprised 479 women 18 years or older (neratinib-paclitaxel, n = 242; trastuzumab-paclitaxel, n = 237) randomized and stratified in their respective treatment arms by prior trastuzumab and lapatinib exposure, hormone-receptor status, and region. Median progression-free survival was 12.9 months (95% CI, 11.1-14.9) with neratinib-paclitaxel and 12.9 months (95% CI, 11.1-14.8) with trastuzumab-paclitaxel (hazard ratio [HR], 1.02; 95% CI, 0.81-1.27; P =.89). With neratinib-paclitaxel, the incidence of central nervous system recurrences was

  13. The pioneer factor PBX1 is a novel driver of metastatic progression in ERα-positive breast cancer

    Science.gov (United States)

    Magnani, Luca; Patten, Darren K.; Nguyen, Van T.M.; Hong, Sung-Pil; Steel, Jennifer H.; Patel, Naina; Lombardo, Ylenia; Faronato, Monica; Gomes, Ana R.; Woodley, Laura; Page, Karen; Guttery, David; Primrose, Lindsay; Garcia, Daniel Fernandez; Shaw, Jacqui; Viola, Patrizia; Green, Andrew; Nolan, Christopher; Ellis, Ian O.; Rakha, Emad A.; Shousha, Sami; Lam, Eric W.-F.; Győrffy, Balázs; Lupien, Mathieu; Coombes, R. Charles

    2015-01-01

    Over 30% of ERα breast cancer patients develop relapses and progress to metastatic disease despite treatment with endocrine therapies. The pioneer factor PBX1 translates epigenetic cues and mediates estrogen induced ERα binding. Here we demonstrate that PBX1 plays a central role in regulating the ERα transcriptional response to epidermal growth factor (EGF) signaling. PBX1 regulates a subset of EGF-ERα genes highly expressed in aggressive breast tumours. Retrospective stratification of luminal patients using PBX1 protein levels in primary cancer further demonstrates that elevated PBX1 protein levels correlate with earlier metastatic progression. In agreement, PBX1 protein levels are significantly upregulated during metastatic progression in ERα-positive breast cancer patients. Finally we reveal that PBX1 upregulation in aggressive tumours is partly mediated by genomic amplification of the PBX1 locus. Correspondingly, ERα-positive breast cancer patients carrying PBX1 amplification are characterized by poor survival. Notably, we demonstrate that PBX1 amplification can be identified in tumor derived-circulating free DNA of ERα-positive metastatic patients. Metastatic patients with PBX1 amplification are also characterized by shorter relapse-free survival. Our data identifies PBX1 amplification as a functional hallmark of aggressive ERα-positive breast cancers. Mechanistically, PBX1 amplification impinges on several critical pathways associated with aggressive ERα-positive breast cancer. PMID:26215677

  14. Preclinical Evaluation of 18F-Labeled Anti-HER2 Nanobody Conjugates for Imaging HER2 Receptor Expression by Immuno-PET.

    Science.gov (United States)

    Vaidyanathan, Ganesan; McDougald, Darryl; Choi, Jaeyeon; Koumarianou, Eftychia; Weitzel, Douglas; Osada, Takuya; Lyerly, H Kim; Zalutsky, Michael R

    2016-06-01

    The human growth factor receptor type 2 (HER2) is overexpressed in breast as well as other types of cancer. Immuno-PET, a noninvasive imaging procedure that could assess HER2 status in both primary and metastatic lesions simultaneously, could be a valuable tool for optimizing application of HER2-targeted therapies in individual patients. Herein, we have evaluated the tumor-targeting potential of the 5F7 anti-HER2 Nanobody (single-domain antibody fragment; ∼13 kDa) after (18)F labeling by 2 methods. The 5F7 Nanobody was labeled with (18)F using the novel residualizing label N-succinimidyl 3-((4-(4-(18)F-fluorobutyl)-1H-1,2,3-triazol-1-yl)methyl)-5-(guanidinomethyl)benzoate ((18)F-SFBTMGMB; (18)F-RL-I) and also via the most commonly used (18)F protein-labeling prosthetic agent N-succinimidyl 3-(18)F-fluorobenzoate ((18)F-SFB). For comparison, 5F7 Nanobody was also labeled using the residualizing radioiodination agent N-succinimidyl 4-guanidinomethyl-3-(125)I-iodobenzoate ((125)I-SGMIB). Paired-label ((18)F/(125)I) internalization assays and biodistribution studies were performed on HER2-expressing BT474M1 breast carcinoma cells and in mice with BT474M1 subcutaneous xenografts, respectively. Small-animal PET/CT imaging of 5F7 Nanobody labeled using (18)F-RL-I also was performed. Internalization assays indicated that intracellularly retained radioactivity for (18)F-RL-I-5F7 was similar to that for coincubated (125)I-SGMIB-5F7, whereas that for (18)F-SFB-5F7 was lower than coincubated (125)I-SGMIB-5F7 and decreased with time. BT474M1 tumor uptake of (18)F-RL-I-5F7 was 28.97 ± 3.88 percentage injected dose per gram of tissue (%ID/g) at 1 h and 36.28 ± 14.10 %ID/g at 2 h, reduced by more than 90% on blocking with trastuzumab, indicating HER2 specificity of uptake, and was also 26%-28% higher (P < 0.05) than that of (18)F-SFB-5F7. At 2 h, the tumor-to-blood ratio for (18)F-RL-I-5F7 (47.4 ± 13.1) was significantly higher (P < 0.05) than for (18)F-SFB-5F7 (25.4 ± 10

  15. NSCLC and HER2: between lights and shadows.

    Science.gov (United States)

    Ricciardi, Giuseppina Rosaria Rita; Russo, Alessandro; Franchina, Tindara; Ferraro, Giuseppa; Zanghì, Mariangela; Picone, Antonio; Scimone, Antonino; Adamo, Vincenzo

    2014-12-01

    The therapeutic landscape of non-small-cell lung cancer (NSCLC) has dramatically changed in the last few years with the introduction of molecularly targeted agents, leading to unprecedented results in lung tumors with a paradigmatic shift from a "one size fits all" approach to an histologic and molecular-based approach. The discovery of epidermal growth factor receptor (EGFR) mutations in NSCLC in 2004 and the marked response to the EGFR tyrosine kinase inhibitor gefitinib, in a small subset of patients harboring these genetic abnormalities, stimulated the study of other kinase mutants involvement in NSCLC. The incredible story of ALK rearranged tumors, with the rapid Food and Drug Administration approval of Crizotinib after only 4 years from the discovery of EML4-ALK translocation in NSCLC, has profoundly influenced the concept of drug development in NSCLC, paving the way to a novel series of molecularly selected studies with specific inhibitors. The identification of these oncogenic drivers has dramatically changed the genetic landscape of NSCLC moving away from the old concept of a large indistinct histological entity to a combination of rare clinically relevant molecular subsets. Recently, a renewed interest has been emerging on the human epidermal growth factor-2 (HER2) pathway. Genetic aberrations of this signaling pathway have been reported over time to be associated in NSCLC with different sensitivity to the EGFR tyrosine kinase inhibitors, to have a possible prognostic role and more recently HER2 amplification has been emerged as a possible mechanism in EGFR-mutated tumors of acquired resistance to the EGFR tyrosine kinase inhibitors. In addition, dysregulation of the HER2 pathway, in particular HER2 mutations (mostly, in-frame exon 20 insertions), may represent a possible novel therapeutic target in NSCLC, paving the way for a new generation of targeted agents in NSCLC. Since anecdotal case reports of clinical activity of anti-HER2 agents in NSCLC

  16. Metastatic breast cancer to the liver with hepatoid features and Hep Par 1 antibody positive mimicking hepatocellular carcinoma.

    Science.gov (United States)

    Affleck, Authur; Lyman, William B; Jacobs, W Carl; Livasy, Chad A; Martinie, John B; Iannitti, David A; Vrochides, Dionisios

    2018-05-09

    The hepatocyte paraffin 1 antibody (Hep Par 1) has a high positive predictive value for differentiating hepatocellular carcinoma from cholangiocarcinoma and metastatic carcinoma. 1 We report a case of metastatic breast cancer to the liver with hepatoid histology and strong positive staining for Hep Par 1 mimicking hepatocellular carcinoma. To our knowledge, primary breast carcinoma staining Hep Par 1 positive has not been reported in the setting of hepatic metastasis. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  17. Evaluation of HER2 and p53 expression in predicting response to docetaxel-based first-line chemotherapy in advanced breast cancer

    Directory of Open Access Journals (Sweden)

    Martini Leonardo

    2011-04-01

    Full Text Available Abstract Background The human epidermal growth factor receptor 2 (HER2 and p53 pathways may be involved in chemotherapy sensitivity and/or resistance. We explore the value of HER2 and p53 status to foretell docetaxel sensitivity in advanced breast cancer. Methods HER2 and p53 expression was analysed in 36 (median age 55 yrs; range 37-87 metastatic breast cancer patients receiving docetaxel-based first-line chemotherapy. HER2 was determined by immunohistochemistry (IHC and fluorescence in situ hybridization (FISH, p53 was tested by IHC. We correlate the expression of study parameters with pathologic parameters, RECIST response and survival. The standard cut-off value of 2 was used to determine HER2 overexpression while p53 mean expression level was used to divide low/high expressors tumors. Results Median time to progression and overall survival were 9 (range 2 - 54 and 20 (range 3 - 101 months. Overall response rate was 41.6%. Nine cases showed HER2 overexpression. HER2 was more frequently overexpressed in less differentiated (p = 0.05 and higher stage (p = 0.003 disease. Mean FISH-HER2 values were significantly higher in responder than in non-responder pts (8.53 ± 10.21 vs 2.50 ± 4.12, p = 0.027. Moreover, HER2 overexpression correlates with treatment response at cross-tabulation analysis (p = 0.046. p53 expression was only associated with higher stage disease (p = 0.02 but lack of any significant association with HER status or docetaxel response. No significant relation with survival was observed for any parameter. Conclusion Our data seem to indicate that FISH-determined HER2 status but not p53 is associated with docetaxel sensitivity in metastatic breast cancer.

  18. HER2 gene amplification in patients with breast cancer with equivocal IHC results

    NARCIS (Netherlands)

    S. Meijer (Sybren); J. Wesseling (Jelle); V.T.H.B.M. Smit (Vincent); P.M. Nederlof (Petra); J. Hooijer; H. Ruijter (Henrique); J.W. Arends (Jan Willem); M. Kliffen (Mike); J. van Gorp (Joost); L. Sterk (Lotus); M.J. Vijver (Marc )

    2011-01-01

    textabstractAims: Equivocal human epidermal growth factor receptor 2 protein (HER2) (2+) immunohistochemistry (IHC) is subject to significant interobserver variation and poses a challenge in obtaining a definitive positive or negative test result. This equivocal test result group accounts for

  19. HER2 gene amplification in patients with breast cancer with equivocal IHC results

    NARCIS (Netherlands)

    Meijer, Sybren L.; Wesseling, Jelle; Smit, Vincent T.; Nederlof, Petra M.; Hooijer, Gerrit K. J.; Ruijter, Henrique; Arends, Jan Willem; Kliffen, Mike; van Gorp, Joost M.; Sterk, Lotus; van de Vijver, Marc J.

    2011-01-01

    Equivocal human epidermal growth factor receptor 2 protein (HER2) (2+) immunohistochemistry (IHC) is subject to significant interobserver variation and poses a challenge in obtaining a definitive positive or negative test result. This equivocal test result group accounts for approximately 15% of all

  20. HER2 gene amplification in patients with breast cancer with equivocal IHC results

    NARCIS (Netherlands)

    Meijer, Sybren L.; Wesseling, Jelle; Smit, Vincent T.; Nederlof, Petra M.; Hooijer, Gerrit K. J.; Ruijter, Henrique; Arends, Jan Willem; Kliffen, Mike; van Gorp, Joost M.; Sterk, Lotus; van de Vijver, Marc J.

    2011-01-01

    Aims Equivocal human epidermal growth factor receptor 2 protein (HER2) (2+) immunohistochemistry (IHC) is subject to significant interobserver variation and poses a challenge in obtaining a definitive positive or negative test result. This equivocal test result group accounts for approximately 15%

  1. SU-E-I-81: Targeting of HER2-Expressing Tumors with Dual PET-MR Imaging Probes

    Energy Technology Data Exchange (ETDEWEB)

    Xu, P; Peng, Y; Sun, M; Yang, X [Suzhou Institute of Biomedical Engineering and Technology Chinese Academy o, Suzhou, Jiangsu (China)

    2015-06-15

    Purpose: The detection of human epidermal growth factor receptor type 2 (HER2) expression in malignant tumors provides important information influencing patient management. Radionuclide in vivo imaging of HER2 may permit the detection of HER2 in both primary tumors and metastases by a single noninvasive procedure. Trastuzumab, effective in about 15 % of women with breast cancer, downregulates signalling through the Akt/PI3K and MAPK pathways.These pathways modulate metabolism which can be monitored by positron emission tomography (PET) and magnetic resonance imaging (MRI). Methods: The relationship between response of HER2 overexpressing tumours and changes in imaging PET or SPECT and MRI will be examined by a integrated bimodal imaging probe.Small (7 kDa) high-affinity anti-HER2 Affibody molecules and KCCYSL targeting peptide may be suitable tracers for visualization of HER2-expressing tumors. Peptide-conjugated iron oxide nanoparticles (Fe3O4 NPs) as MRI imaging and CB-TE2A as PET imaging are integrated into a single synthetic molecule in the HER2 positive cancer. Results: One of targeted contrast bimodal imaging probe agents was synthesized and evaluated to target HER2-expressing tumors in a HER2 positive rat model. We will report the newest results regarding the development of bimodal imaging probes. Conclusion: The preliminary results of the bimodal imaging probe presents high correlation of MRI signal and PET imaging intensity in vivo. This unique feature can hardly be obtained by single model contrast agents. It is envisioned that this bimodal agents can hold great potential for accurate detection of HER2-expressing tumors which are critical for clinical management of the disease.

  2. Clinical significance of assessing Her2/neu expression in gastric cancer with dual tumor tissue paraffin blocks.

    Science.gov (United States)

    Ge, Xiaowen; Wang, Haixing; Zeng, Haiying; Jin, Xuejuan; Sujie, Akesu; Xu, Chen; Liu, Yalan; Huang, Jie; Ji, Yuan; Tan, Yunshan; Liu, Tianshu; Hou, Yingyong; Qin, Jing; Sun, Yihong; Qin, Xinyu

    2015-06-01

    One paraffin block is routinely used for human epidermal growth factor receptor 2 (Her