PMID- 27100299 OWN - NLM STAT- MEDLINE DCOM- 20170130 LR - 20220318 IS - 2374-2445 (Electronic) IS - 2374-2437 (Linking) VI - 2 IP - 8 DP - 2016 Aug 1 TI - Effects of Estrogen Receptor and Human Epidermal Growth Factor Receptor-2 Levels on the Efficacy of Trastuzumab: A Secondary Analysis of the HERA Trial. PG - 1040-7 LID - 10.1001/jamaoncol.2016.0339 [doi] AB - IMPORTANCE: A number of studies suggest that response to antihuman epidermal growth factor receptor-2 (currently known as ERBB2, butreferred to asHER2 in this study) agents differs by estrogen receptor (ER) level status. The clinical relevance of this is unknown. OBJECTIVE: To determine the magnitude of trastuzumab benefit according to quantitative levels of ER and HER2 in the HERceptin Adjuvant (HERA) trial. DESIGN, SETTING, AND PARTICIPANTS: The HERA trial was an international, multicenter, randomized trial that included 5099 patients with early-stage HER2-positive breast cancer, randomized between 2001 and 2005 to receive either no trastuzumab or trastuzumab, after adjuvant chemotherapy. This is a secondary analysis of the HERA study. Local ER immunohistochemical (IHC) analyses, HER2 fluorescence in situ hybridization (FISH) ratio, and copy number results were available for 3037 patients (59.6%) randomized to observation and trastuzumab (1 or 2 years) (cohort 1). Transcript levels of ESR1 and HER2 genes were available for 615 patients (12.1%) (cohort 2). INTERVENTIONS: Patients were randomized to receive either no trastuzumab or 1 year vs 2 years of trastuzumab. Endocrine therapy was given to patients with hormone receptor-positive disease as per local guidelines. MAIN OUTCOMES AND MEASURES: Disease-free survival (DFS) and overall survival (OS) were the primary and secondary end points in the intent-to-treat population (ITT). Analyses adjusting for crossover (censored and inverse probability weighted [IPW]) were also performed. Interactions among treatment, ER status, and HER2 amplification using predefined cutoffs were assessed in Cox proportional hazards regression models. RESULTS: Median follow-up time was 8 years. Levels of FISH and HER2 copy numbers were significantly higher in ER-negative patients (P < .001). In cohort 1, for DFS and OS, a significant treatment effect was found for all ER, IHC, and FISH levels, except for the ER-positive/HER2 low FISH ratio (>/=2 to <5) group (DFS: 3-way ITT Pvalue for interaction = .07; censored = .02; IPW = .03; OS ITT Pvalue for interaction = .007; censored = .04; IPW = .03). In cohort 2, consistent with cohort 1, a significant predictive effect of the ESR1 gene for both end points was also observed (DFS Pvalue for interaction = .06; OS = .02), indicating that breast cancers with higher ESR1 levels also derive less benefit from trastuzumab. CONCLUSIONS AND RELEVANCE: Patients with HER2-positive breast cancers that are ER-positive by IHC analyses with low FISH ratio (>/=2 to <5), or with higher ESR1 levels derive significantly less benefit from adjuvant trastuzumab after chemotherapy. These data may explain heterogeneity in response to anti-HER2 agents in HER2-positive, ER-positive breast cancers as some may be more luminal-like than HER2 driven. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00045032. FAU - Loi, Sherene AU - Loi S AD - Division of Research and Clinical Medicine, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. FAU - Dafni, Urania AU - Dafni U AD - Frontier Science Foundation- Hellas, Athens, Greece3University of Athens, Athens, Greece. FAU - Karlis, Dimitris AU - Karlis D AD - Frontier Science Foundation- Hellas, Athens, Greece4Athens University of Economics and Business, Athens, Greece. FAU - Polydoropoulou, Varvara AU - Polydoropoulou V AD - Frontier Science Foundation- Hellas, Athens, Greece. FAU - Young, Brandon M AU - Young BM AD - Avera Cancer Institute, Department of Molecular and Experimental Medicine, Sioux Falls, South Dakota. FAU - Willis, Scooter AU - Willis S AD - Avera Cancer Institute, Department of Molecular and Experimental Medicine, Sioux Falls, South Dakota. FAU - Long, Bradley AU - Long B AD - Department of Pathology, University of Chicago, Chicago, Illinois. FAU - de Azambuja, Evandro AU - de Azambuja E AD - BREAST Datacentre, Institute Jules Bordet, Universite Libre de Bruxelles, Brussels, Belgium. FAU - Sotiriou, Christos AU - Sotiriou C AD - Breast Cancer Translational Research Laboratory, Institute Jules Bordet, Universite Libre de Bruxelles, Brussels, Belgium. FAU - Viale, Giuseppe AU - Viale G AD - University of Milan, European Institute of Oncology, Milan, Italy. FAU - Ruschoff, Josef AU - Ruschoff J AD - Targos Molecular Pathology GmbH, Kassel, Germany. FAU - Piccart, Martine J AU - Piccart MJ AD - Department of Medicine, Institute Jules Bordet, Universite Libre de Bruxelles and Breast International Group (BIG), Brussels, Belgium12Breast International Group (BIG), Brussels, Belgium. FAU - Dowsett, Mitch AU - Dowsett M AD - Royal Marsden Hospital, London, England. FAU - Michiels, Stefan AU - Michiels S AD - INSERM U1018 CESP, Service de Biostatistique et d'Epidemiologie, Villejuif, France. FAU - Leyland-Jones, Brian AU - Leyland-Jones B AD - Avera Cancer Institute, Department of Molecular and Experimental Medicine, Sioux Falls, South Dakota. LA - eng SI - ClinicalTrials.gov/NCT00045032 PT - Journal Article PL - United States TA - JAMA Oncol JT - JAMA oncology JID - 101652861 RN - 0 (Antineoplastic Agents) RN - 0 (ESR1 protein, human) RN - 0 (Estrogen Receptor alpha) RN - 0 (RNA, Messenger) RN - EC 2.7.10.1 (ERBB2 protein, human) RN - EC 2.7.10.1 (Receptor, ErbB-2) RN - P188ANX8CK (Trastuzumab) SB - IM CIN - JAMA Oncol. 2016 Aug 1;2(8):1047-8. PMID: 27099974 MH - Adult MH - Antineoplastic Agents/*therapeutic use MH - Breast Neoplasms/drug therapy/*metabolism MH - Carcinoma/drug therapy/*metabolism MH - Chemotherapy, Adjuvant MH - Disease-Free Survival MH - Estrogen Receptor alpha/genetics/*metabolism MH - Female MH - Humans MH - Immunohistochemistry MH - In Situ Hybridization, Fluorescence MH - Middle Aged MH - Multivariate Analysis MH - Prognosis MH - Proportional Hazards Models MH - RNA, Messenger/*metabolism MH - Randomized Controlled Trials as Topic MH - Receptor, ErbB-2/genetics/*metabolism MH - Trastuzumab/*therapeutic use EDAT- 2016/04/22 06:00 MHDA- 2017/01/31 06:00 CRDT- 2016/04/22 06:00 PHST- 2016/04/22 06:00 [entrez] PHST- 2016/04/22 06:00 [pubmed] PHST- 2017/01/31 06:00 [medline] AID - 2513897 [pii] AID - 10.1001/jamaoncol.2016.0339 [doi] PST - ppublish SO - JAMA Oncol. 2016 Aug 1;2(8):1040-7. doi: 10.1001/jamaoncol.2016.0339.