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.
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.
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
clinicaltrials.gov Identifier: NCT01426880.
Hahnen E, Lederer B, Hauke J, Loibl S, Kröber S, Schneeweiss A,
Denkert C, Fasching P A, Blohmer J U, Jackisch C, Paepke S, Gerber
B, Kümmel S, Schem C, Neidhardt G, Huober J, Rhiem K, Costa S,
Altmüller J, Hanusch C, Thiele H, Müller V, Nürnberg P, Karn T,
Nekljudova V, Untch M, von Minckwitz G, Schmutzler R K. 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; 3:1378-1385.