Risk-Reducing Bilateral Mastectomy and Mortality in Carriers of <i>BRCA1</i> and <i>BRCA2</i> Variants

Importance: Risk-reducing bilateral mastectomy reduces the incidence of breast cancer in female carriers of the BRCA pathogenic variants, but its association with mortality remains uncertain. Objective: To evaluate the association between risk-reducing bilateral mastectomy and overall and breast cancer-specific mortality in female carriers of BRCA pathogenic variants. Data Sources: PubMed, Scopus, CINAHL, Embase, and CENTRAL were searched in May 2025, with English-language restriction and no date limit. Reference lists of included studies and relevant reviews were also examined. Study Selection: Eligible studies compared female carriers of BRCA1 and BRCA2 pathogenic variants who underwent risk-reducing bilateral mastectomy with those who did not and reported overall mortality or breast cancer-specific mortality. Studies including patients with a history of breast cancer were excluded. Data Extraction and Synthesis: This meta-analysis followed the Meta-Analysis of Observational Studies in Epidemiology (MOOSE) guidelines. Two authors independently performed study selection, data extraction, and risk of bias assessment (using Risk of Bias in Nonrandomized Studies-of Interventions, version 2). Odds ratios (ORs) and hazard ratios (HRs) were pooled using fixed- and random-effects models according to methodological assessment. Main Outcomes and Measures: Overall and breast cancer-specific mortality. Results: Six observational studies met the inclusion criteria, comprising 6135 carriers of the BRCA1 or BRCA2 variant. Weighted median age at inclusion was 38.0 years, with reported age ranges spanning 15.3 to 85.3 years. Risk-reducing bilateral mastectomy was associated with lower overall mortality in both unadjusted (OR, 0.38; 95% CI, 0.27-0.55; P < .001) and adjusted (HR, 0.37; 95% CI, 0.23-0.60; P < .001) analyses. Breast cancer-specific mortality was also reduced (OR, 0.19; 95% CI, 0.08-0.47; P < .001; HR, 0.14; 95% CI, 0.04-0.49; P = .002). Conclusions and Relevance: Risk-reducing bilateral mastectomy was associated with lower overall and breast cancer-specific mortality in carriers of the BRCA variants. These findings support the role of risk-reducing bilateral mastectomy as a potentially life-extending intervention and may inform the shared decision-making discussions in these women.