Impact of <i>BRCA</i> 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.

Abstract

The prognostic significance of <i>BRCA1/2</i> mutation and <i>RB1</i> 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. 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 <i>BRCA1/2</i> mutation or <i>RB1 Alt</i> status. A separate analysis of individual-patient data for metastatic HR+/HER2- BC extracted from MSK-MET project was performed. 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), <i>BRCA1/2 mutant type</i> (<i>MT</i>) was associated with a marginally significant worse DFS (hazard ratio, 1.64 [95% CI, 1 to 2.69]; <i>P</i> = .05) and a significantly worse OS (hazard ratio, 1.52 [95% CI, 1.20 to 1.92]; <i>P</i> = .0006) versus <i>BRCA</i> wild-type (<i>WT</i>). In the metastatic setting, in 11 studies (n = 12,670 patients received ET+ CDK4/6i), <i>BRCA1/2</i> mutation was associated with a significantly worse PFS (hazard ratio, 1.87 [95% CI, 1.45 to 2.41]; <i>P</i> < .00001) and OS (hazard ratio, 1.38 [95% CI, 1.15 to 1.65]; <i>P</i> = .0005) versus <i>BRCA WT</i>. The individual-patient data confirmed the poorer prognosis of <i>BRCA2 MT</i> and <i>RB1 Alt</i>, but not <i>BRCA1 MT</i>, and a significant co-occurrence of <i>RB1</i> loss of heterozygosity (<i>LOH</i>) among <i>BRCA2 MT</i> carriers. The current analysis adds to the body of evidence supporting the inferior outcomes of ET± CDK4/6i in <i>BRCA MT</i> compared with <i>BRCA WT</i>. Given its significant coexistence with <i>RB1</i> LOH, <i>BRCA2 MT</i> BC seems uniquely resistant to ET± CDK4/6i, a point that is profoundly different from sporadic or even <i>BRCA1 MT</i> HR+/HER2- BC.