Interaction between Hormonal Receptor Status, Age and Survival in Patients with BRCA1/2 Germline Mutations: A Systematic Review and Meta-Regression

BACKGROUND Germline mutations in the BRCA1 and BRCA2 genes are the most frequent known hereditary causes of familial breast cancer. Little is known about the interaction of age at diagnosis, estrogen receptor (ER) and progesterone receptor (PgR) expression and outcomes in patients with BRCA1 or BRCA2 mutations. METHODS A PubMed search identified publications exploring the association between BRCA mutations and clinical outcome. Hazard ratios (HR) for overall survival were extracted from multivariable analyses. Hazard ratios were weighted and pooled using generic inverse-variance and random-effect modeling. Meta-regression weighted by total study sample size was conducted to explore the influence of age, ER and PgR expression on the association between BRCA mutations and overall survival. RESULTS A total of 16 studies comprising 10,180 patients were included in the analyses. BRCA mutations were not associated with worse overall survival (HR 1.06, 95% CI 0.84-1.34, p = 0.61). A similar finding was observed when evaluating the influence of BRCA1 and BRCA2 mutations on overall survival independently (BRCA1: HR 1.20, 95% CI 0.89-1.61, p = 0.24; BRCA2: HR 1.01, 95% CI 0.80-1.27, p = 0.95). Meta-regression identified an inverse association between ER expression and overall survival (β = -0.75, p = 0.02) in BRCA1 mutation carriers but no association with age or PgR expression (β = -0.45, p = 0.23 and β = 0.02, p = 0.97, respectively). No association was found for BRCA2 mutation status and age, ER, or PgR expression. CONCLUSION ER-expression appears to be an effect modifier in patients with BRCA1 mutations, but not among those with BRCA2 mutations.