Prognostic significance of germline BRCA mutations in patients with HER2-positive breast cancer. Epidemiological analysis in primary BRCA screens

Background: HER2-amplified breast cancers are rare amongst BRCA mutation carriers. No data exist regarding clinico-histological characteristics and prognosis of this subgroup of patients. Materials and Methods: Using a retrospective matched cohort design, we collected data from 728 women who were diagnosed with breast cancer from January 2006 to December 2016 and were screened for germline BRCA mutations. Clinical and histological characteristics of the primary tumor, time to relapse, and survival were analyzed by BRCA and HER2 status. Results: One hundred and twenty HER2-positive, BRCA mutated cases were evaluated with respect to three control groups: HER2-positive, BRCA wild-type (n=136); HER2-negative, BRCA-mutated (n=226); HER2-negative, BRCA wild-type (n=246). Breast cancers with hormone receptor-negative status or high histologic grade (odds ratio=1.7; 95% confidence interval [CI]: 1.0-2.9) were more likely HER2-positive, with no restriction by BRCA mutation status. Disease-free and overall survival for HER2-positive, BRCA mutated cases were lower than those for the other subgroups. An interaction between BRCA mutations and HER2-positive status was found for poorer overall survival after adjusting for prognostic variables (HR = 3.4; 95% CI: 1.3-16.7). Conclusions: Germline BRCA mutations confer worse prognosis in patients with HER2-positive breast cancer. Ongoing trials testing novel therapeutic approaches (e.g. anti-HER2 therapies combined with PARP inhibitors) are warranted