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
[Skip to Navigation]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address Please contact the publisher to request reinstatement.
Schneeweiss  A, Möbus  V, Tesch  H,  et al.  Intense dose-dense epirubicin, paclitaxel, cyclophosphamide versus weekly paclitaxel, liposomal doxorubicin (plus carboplatin in triple-negative breast cancer) for neoadjuvant treatment of high-risk early breast cancer (GeparOcto-GBG 84): a randomised phase III trial.   Eur J Cancer. 2019;106:181-192. doi:10.1016/j.ejca.2018.10.015PubMedGoogle ScholarCrossref
Hahnen  E, Lederer  B, Hauke  J,  et al.  Germline mutation status, pathological complete response, and disease-free survival in triple-negative breast cancer: secondary analysis of the GeparSixto randomized clinical trial.   JAMA Oncol. 2017;3(10):1378-1385. doi:10.1001/jamaoncol.2017.1007PubMedGoogle ScholarCrossref
Hahnen  E, Hauke  J, Engel  C, Neidhardt  G, Rhiem  K, Schmutzler  RK.  Germline mutations in triple-negative breast cancer.   Breast Care (Basel). 2017;12(1):15-19. doi:10.1159/000455999PubMedGoogle ScholarCrossref
Severson  TM, Peeters  J, Majewski  I,  et al.  BRCA1-like signature in triple negative breast cancer: molecular and clinical characterization reveals subgroups with therapeutic potential.   Mol Oncol. 2015;9(8):1528-1538. doi:10.1016/j.molonc.2015.04.011PubMedGoogle ScholarCrossref
Evans  DG, Lalloo  F, Howell  S, Verhoef  S, Woodward  ER, Howell  A.  Low prevalence of HER2 positivity amongst BRCA1 and BRCA2 mutation carriers and in primary BRCA screens.   Breast Cancer Res Treat. 2016;155(3):597-601. doi:10.1007/s10549-016-3697-zPubMedGoogle ScholarCrossref
Easton  DF, Pharoah  PD, Antoniou  AC,  et al.  Gene-panel sequencing and the prediction of breast-cancer risk.   N Engl J Med. 2015;372(23):2243-2257. doi:10.1056/NEJMsr1501341PubMedGoogle ScholarCrossref
Neidhardt  G, Hauke  J, Ramser  J,  et al.  Association between loss-of-function mutations within the FANCM gene and early-onset familial breast cancer.   JAMA Oncol. 2017;3(9):1245-1248. doi:10.1001/jamaoncol.2016.5592PubMedGoogle ScholarCrossref
Hauke  J, Horvath  J, Groß  E,  et al.  Gene panel testing of 5589 BRCA1/2-negative index patients with breast cancer in a routine diagnostic setting: results of the German Consortium for Hereditary Breast and Ovarian Cancer.   Cancer Med. 2018;7(4):1349-1358. doi:10.1002/cam4.1376PubMedGoogle ScholarCrossref
Byrski  T, Huzarski  T, Dent  R,  et al.  Pathologic complete response to neoadjuvant cisplatin in BRCA1-positive breast cancer patients.   Breast Cancer Res Treat. 2014;147(2):401-405. doi:10.1007/s10549-014-3100-xPubMedGoogle ScholarCrossref
Tutt  A, Tovey  H, Cheang  MCU,  et al.  Carboplatin in BRCA1/2-mutated and triple-negative breast cancer BRCAness subgroups: the TNT trial.   Nat Med. 2018;24(5):628-637. doi:10.1038/s41591-018-0009-7PubMedGoogle ScholarCrossref
Limit 200 characters
Limit 25 characters
Conflicts of Interest Disclosure

Identify all potential conflicts of interest that might be relevant to your comment.

Conflicts of interest comprise financial interests, activities, and relationships within the past 3 years including but not limited to employment, affiliation, grants or funding, consultancies, honoraria or payment, speaker's bureaus, stock ownership or options, expert testimony, royalties, donation of medical equipment, or patents planned, pending, or issued.

Err on the side of full disclosure.

If you have no conflicts of interest, check "No potential conflicts of interest" in the box below. The information will be posted with your response.

Not all submitted comments are published. Please see our commenting policy for details.

Limit 140 characters
Limit 3600 characters or approximately 600 words
    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.


    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 Identifier: NCT02125344