Impact of BRCA Mutation on Treatment Outcomes of Endocrine Therapy ± CDK4/6 Inhibitors in Hormone Receptor–Positive/Human Epidermal Growth Factor Receptor-2–Negative Breast Cancer: A Systematic Review and Meta-Analysis

PURPOSE The prognostic significance of BRCA1/2 mutation and RB1 alteration (Alt) in patients with hormone receptor–positive (HR+)/human epidermal growth factor receptor-2–negative (HER2–) breast cancer (BC) treated with endocrine therapy (ET) ± cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) remains unresolved. This meta-analysis aimed to define their influence on therapy outcomes in the early and metastatic stages. MATERIALS AND METHODS We systematically searched PubMed, Cochrane, and Google Scholar databases. Primary end points included disease-free (or progression-free) survival (DFS/PFS) and overall survival (OS) according to BRCA1/2 mutation or RB1 Alt status. A separate analysis of individual-patient data for metastatic HR+/HER2– BC extracted from MSK-MET project was performed. RESULTS Twenty-two studies comprising 34,960 patients were eligible for meta-analysis. In the early setting, in eight studies (n = 7,857 patients with HR+ BC received ET), BRCA1/2 mutant type ( MT ) was associated with a marginally significant worse DFS (hazard ratio, 1.64 [95% CI, 1 to 2.69]; P = .05) and a significantly worse OS (hazard ratio, 1.52 [95% CI, 1.20 to 1.92]; P = .0006) versus BRCA wild-type ( WT ). In the metastatic setting, in 11 studies (n = 12,670 patients received ET+ CDK4/6i), BRCA1/2 mutation was associated with a significantly worse PFS (hazard ratio, 1.87 [95% CI, 1.45 to 2.41]; P < .00001) and OS (hazard ratio, 1.38 [95% CI, 1.15 to 1.65]; P = .0005) versus BRCA WT . The individual-patient data confirmed the poorer prognosis of BRCA2 MT and RB1 Alt , but not BRCA1 MT , and a significant co-occurrence of RB1 loss of heterozygosity ( LOH ) among BRCA2 MT carriers. CONCLUSION The current analysis adds to the body of evidence supporting the inferior outcomes of ET± CDK4/6i in BRCA MT compared with BRCA WT . Given its significant coexistence with RB1 LOH, BRCA2 MT BC seems uniquely resistant to ET± CDK4/6i, a point that is profoundly different from sporadic or even BRCA1 MT HR+/HER2– BC.