Association of Germline Variant Status With Therapy Response in High-risk Early-Stage Breast Cancer

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 ofBRCA1/2and 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 inBRCA1/2and 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 withBRCA1/2variants 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-BRCA1/2BC predisposition genes were not associated with therapy response. Patients with TNBC withBRCA1/2variants achieved highest pCR rates. In the TNBC subgroup, a positiveBRCA1/2variant status was associated with therapy response in both the PMCb arm (74.3% vs 47.0% withoutBRCA1/2variant; 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 positiveBRCA1/2variant status was also associated with elevated pCR rates in patients withERBB2-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 forBRCA1/2-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 inBRCA1/2-mutatedERBB2-negative, hormone receptor–positive BC suggests that germlineBRCA1/2testing should be considered prior to treatment start.

Trial Registration

ClinicalTrials.gov Identifier:NCT02125344