Association of Germline Variant Status With Therapy Response in High-risk Early-Stage Breast Cancer: A Secondary Analysis of the GeparOcto Randomized Clinical Trial | Breast Cancer | JAMA Oncology | JAMA Network
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    Brief Report
    March 12, 2020

    Association of Germline Variant Status With Therapy Response in High-risk Early-Stage Breast Cancer: A Secondary Analysis of the GeparOcto Randomized Clinical Trial

    Author Affiliations
    • 1Center for Familial Breast and Ovarian Cancer, Center for Integrated Oncology, Cologne, Faculty of Medicine, University Hospital Cologne, Cologne, Germany
    • 2German Breast Group, Neu-Isenburg, Germany
    • 3Department of Medicine II, Hematology and Oncology, University of Frankfurt, Frankfurt, Germany
    • 4Institut für Pathologie, Philipps-Universität Marburg und Universitätsklinikum Marburg, Marburg, Germany
    • 5Department of Gynecology and Obstetrics, University Hospital Erlangen, Erlangen, Germany
    • 6Rotkreuzklinikum München, Frauenklinik, Munich, Germany
    • 7Hämatologisch-Onkologische Gemeinschaftspraxis, Frankfurt, Germany
    • 8Department of Gynecology, Hamburg-Eppendorf University Medical Center, Hamburg, Germany
    • 9Cologne Center for Genomics, University of Cologne, Cologne, Germany
    • 10Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
    • 11Department of Gynecology and Obstetrics, Helios Klinikum Berlin-Buch, Berlin, Germany
    • 12Breast Center, Diakovere Henriettenstift, Hannover, Germany
    • 13Cologne Excellence Cluster on Cellular Stress Responses in Aging-associated Diseases, University of Cologne, Cologne, Germany
    • 14Sana Klinikum Offenbach GmbH, Offenbach, Germany
    • 15National Center for Tumor Diseases, Heidelberg University Hospital and German Cancer Research Center, Heidelberg, Germany
    JAMA Oncol. 2020;6(5):744-748. doi:10.1001/jamaoncol.2020.0007
    Key Points

    Question  Is germline variant status of BRCA1/2 and non-BRCA1/2 breast cancer predisposition genes associated with higher response rates in patients enrolled in the GeparOcto trial?

    Findings  In this secondary analysis of 914 patients included in a randomized clinical trial, women with triple-negative breast cancer with BRCA1/2 variants benefited most from both treatment regimens (paclitaxel and nonpegylated liposomal doxorubicin plus carboplatin, 74.3%; epirubicin, paclitaxel, and cyclophosphamide, 64.7%). A positive BRCA1/2 variant status also was associated with higher response rates in ERBB2-negative, hormone receptor–positive breast cancer.

    Meaning  Effective chemotherapy for BRCA1/2-mutated triple-negative breast cancer is commonly suggested to be platinum based; sequential intense dose-dense epirubicin, paclitaxel, and cyclophosphamide appears to also be effective in these patients, though with a lower point estimate. Patients with ERBB2-negative, hormone receptor–positive breast cancer may benefit from BRCA1/2 testing prior to treatment.

    Abstract

    Importance  The GeparOcto randomized clinical trial compared the efficacy of 2 neoadjuvant breast cancer (BC) treatment regimens: sequential intense dose-dense epirubicin, paclitaxel, and cyclophosphamide (iddEPC) vs weekly paclitaxel and nonpegylated liposomal doxorubicin (PM) in patients with different biological BC subtypes. Patients with triple-negative BC (TNBC) randomized to the PM arm received additional carboplatin (PMCb). Overall, no difference in pathologic complete response (pCR) rates was observed between study arms. It remained elusive whether the germline variant status of BRCA1/2 and further BC predisposition genes are associated with treatment outcome.

    Objective  To determine treatment outcome for BC according to germline variant status.

    Design, Setting, and Participants  This retrospective biomarker study is a secondary analysis of the GeparOcto multicenter prospective randomized clinical trial conducted between December 2014 and June 2016. Genetic analyses assessing for variants in BRCA1/2 and 16 other BC predisposition genes in 914 of 945 women were performed at the Center for Familial Breast and Ovarian Cancer, Cologne, Germany, from August 2017 through December 2018.

    Main Outcomes and Measures  Proportion of patients who achieved pCR (ypT0/is ypN0 definition) after neoadjuvant treatment according to germline variant status.

    Results  In the study sample of 914 women with different BC subtypes with a mean (range) age at BC diagnosis of 48 (21-76) years, overall higher pCR rates were observed in patients with BRCA1/2 variants than in patients without (60.4% vs 46.7%; odds ratio [OR], 1.74; 95% CI, 1.13-2.68; P = .01); variants in non-BRCA1/2 BC predisposition genes were not associated with therapy response. Patients with TNBC with BRCA1/2 variants achieved highest pCR rates. In the TNBC subgroup, a positive BRCA1/2 variant status was associated with therapy response in both the PMCb arm (74.3% vs 47.0% without BRCA1/2 variant; OR, 3.26; 95% CI, 1.44-7.39; P = .005) and the iddEPC arm (64.7% vs 45.0%; OR, 2.24; 95% CI, 1.04-4.84; P = .04). A positive BRCA1/2 variant status was also associated with elevated pCR rates in patients with ERBB2-negative, hormone receptor–positive BC (31.8% vs 11.9%; OR, 3.44; 95% CI, 1.22-9.72; P = .02).

    Conclusions and Relevance  Effective chemotherapy for BRCA1/2-mutated TNBC is commonly suggested to be platinum based. With a pCR rate of 64.7%, iddEPC may also be effective in these patients, though further prospective studies are needed. The elevated pCR rate in BRCA1/2-mutated ERBB2-negative, hormone receptor–positive BC suggests that germline BRCA1/2 testing should be considered prior to treatment start.

    Trial Registration  ClinicalTrials.gov Identifier: NCT02125344

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