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Original Investigation
July 13, 2017

Germline Mutation Status, Pathological Complete Response, and Disease-Free Survival in Triple-Negative Breast CancerSecondary Analysis of the GeparSixto Randomized Clinical Trial

Author Affiliations
  • 1Center for Hereditary Breast and Ovarian Cancer, Medical Faculty, University Hospital Cologne, Cologne, Germany
  • 2Center for Integrated Oncology, Medical Faculty, University Hospital Cologne, Cologne, Germany
  • 3German Breast Group, Neu-Isenburg, Germany
  • 4Brustzentrum, Sana Kliniken Offenbach, Offenbach, Germany
  • 5Nationales Centrum für Tumorerkrankungen, Universität Heidelberg, Heidelberg, Germany
  • 6Institute of Pathology, and German Cancer Consortium (Deutsches Konsortium für Translationale Krebsforschung), Charité Berlin, Berlin, Germany
  • 7Department of Gynecology and Obstetrics, University Hospital Erlangen, Erlangen, Germany
  • 8Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
  • 9Klinik für Gynäkologie mit Brustzentrum der Charité, Charité-Universitätsmedizin Berlin, Berlin, Germany
  • 10Klinikum rechts der Isar der Technischen Universität München, Frauenklinik, München, Germany
  • 11Frauenklinik, Universität Rostock, Rostock, Germany
  • 12Frauenklinik, Kliniken Essen-Mitte, Essen, Germany
  • 13Frauenklinik, Universität Kiel, Kiel, Germany
  • 14Frauenklinik, Universität Ulm, Ulm, Germany
  • 15Frauenklinik, Universität Magdeburg, Magdeburg, Germany
  • 16Cologne Center for Genomics, University of Cologne, Cologne, Germany
  • 17Institute for Human Genetics, University of Cologne, Cologne, Germany
  • 18Frauenklinik, Klinikum zum Roten Kreuz, München, Germany
  • 19Department of Gynecology, University Hospital Hamburg-Eppendorf, Hamburg, Germany
  • 20Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany
  • 21Frauenklinik, Universität Frankfurt, Frankfurt, Germany
  • 22Helios-Klinikum, Berlin-Buch, Berlin, Germany
JAMA Oncol. Published online July 13, 2017. doi:10.1001/jamaoncol.2017.1007
Key Points

Question  Does BRCA1 and BRCA2 germline mutation status predict therapy response in patients with triple-negative breast cancer enrolled in the GeparSixto trial?

Findings  In this secondary analysis of a randomized clinical trial of 291 patients with triple-negative breast cancer, patients with BRCA1 and BRCA2 mutations showed superior response rates, without additive effects observed for carboplatin. Patients without BRCA1 and BRCA2 germline mutations benefited from the addition of carboplatin to a regimen of paclitaxel, low-dose doxorubicin, and bevacizumab.

Meaning  A less-intense treatment regimen might be considered for BRCA1 and BRCA2 mutation carriers, but further prospective studies are needed to identify the optimal regimen.

Abstract

Importance  The GeparSixto trial provided evidence that the addition of neoadjuvant carboplatin to a regimen consisting of anthracycline, taxane, and bevacizumab increases pathological complete response (pCR) rates in patients with triple-negative breast cancer (TNBC). Whether BRCA1 and BRCA2 germline mutation status affects treatment outcome remains elusive.

Objective  To determine whether BRCA1 and BRCA2 germline mutation status affects therapy response in patients with TNBC.

Design, Setting, and Participants  This secondary analysis of a randomized clinical trial used archived DNA samples and cancer family history of 315 patients with TNBC enrolled between August 1, 2011, and December 31, 2012, in the GeparSixto trial. In all, 291 participants (92.4%) were included in this multicenter prospective investigation. DNA samples were analyzed for germline mutations in BRCA1, BRCA2, and 16 other cancer predisposition genes. The pCR rates between the carboplatin and noncarboplatin arms were compared. Genetic analyses were performed at the Center for Familial Breast and Ovarian Cancer in Cologne, Germany; data analysis, November 1 through December 31, 2015.

Main Outcomes and Measures  Proportion of patients who achieved pCR and disease-free survival after neoadjuvant treatment according to BRCA1 and BRCA2 germline mutation status. For pCR rates, the ypT0/is ypN0 definition was used as a primary end point.

Results  Of the 291 patients with TNBC, all were women; the mean (SD) age was 48 (11) years. The pCR rate in the carboplatin group was 56.8% (83 of 146) and 41.4% (60 of 145) in the noncarboplatin group (odds ratio [OR], 1.87; 95% CI, 1.17-2.97; P = .009). Pathogenic BRCA1 and BRCA2 germline mutations were present in 50 of the 291 patients (17.2%). In the noncarboplatin arm, the pCR rate was 66.7% (16 of 24) for patients with BRCA1 and BRCA2 mutations and 36.4% (44 of 121) for patients without (OR, 3.50; 95% CI, 1.39-8.84; P = .008). The high pCR rate observed in BRCA1 and BRCA2 mutation carriers (16 of 24 [66.7%]) was not increased further by adding carboplatin (17 of 26 [65.4%]). In contrast, carboplatin increased response rates in patients without BRCA1 and BRCA2 mutations: 66 of the 120 patients (55%) without BRCA1 and BRCA2 mutations achieved pCR in the carboplatin arm vs 44 of the 121 patients (36.4%) in the noncarboplatin arm (OR, 2.14; 95% CI, 1.28-3.58; P = .004). Patients without pathogenic BRCA1 and BRCA2 alterations showed elevated disease-free survival rates when carboplatin was added (without carboplatin, 73.5%; 95% CI, 64.1%-80.8% vs with carboplatin, 85.3%; 95% CI, 77.0%-90.8%; hazard ratio, 0.53; 95% CI, 0.29-0.96; P = .04).

Conclusions and Relevance  Under the nonstandard GeparSixto polychemotherapy regimen, patients without BRCA1 and BRCA2 germline mutations benefited from the addition of carboplatin and those with BRCA1 and BRCA2 mutations showed superior response rates without additive effects observed for carboplatin.

Trial Registration  clinicaltrials.gov Identifier: NCT01426880

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