Survival After Risk-Reducing Mastectomy in Patients With Pathogenic Variants in BRCA1 and BRCA2

Importance: The independent survival benefit of risk-reducing mastectomy (RRM), separate from risk-reducing salpingo-oophorectomy (RRSO), remains uncertain among patients with pathogenic variants (PVs) in BRCA1 and BRCA2 genes. Objective: To evaluate the association of RRM, magnetic resonance imaging (MRI)-based screening, and mammography alone with all-cause and breast cancer-specific mortality using RRSO-adjusted estimates. Data Sources: MEDLINE, Embase, and Web of Science were searched from January 1, 1990, to May 28, 2026. Search structures, subject headings, and keywords were tailored to each database. Study Selection: Inclusion criteria were English-language prospective and retrospective observational studies of adult female patients with PV or likely PV in BRCA1 and BRCA2 who underwent RRM or breast cancer screening (MRI-based with or without mammography, or mammography alone), with RRSO excluded by design or adjusted for in multivariable analysis. Studies including females with prior breast or ovarian cancer were excluded. Data Extraction and Synthesis: Study reporting followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 network meta-analysis extension. Two authors independently performed study selection, data extraction, and bias assessment using a risk-of-bias assessment tool (ROBINS-I V2) and a grading approach (Grading of Recommendations Assessment, Development, and Evaluation [GRADE]). Frequentist random-effects network meta-analysis was performed with surface under the cumulative ranking curve (SUCRA) estimation. Sensitivity analysis was conducted for the BRCA1 cohort. Main Outcomes and Measures: Primary outcome was all-cause mortality. Secondary outcome was breast cancer-specific mortality. All outcomes were analyzed and reported as hazard ratios (HRs) with corresponding 95% CIs. Results: Five observational studies with 7937 female patients (median [range] age, 35.9 [unreported] years to 43.4 [32.0-55.7] years) met the inclusion criteria. RRM was associated with lower all-cause mortality compared with MRI-based screening (HR, 0.37; 95% CI, 0.22-0.63) and mammography alone (HR, 0.16; 95% CI, 0.08-0.32). RRM was also associated with lower breast cancer-specific mortality compared with mammography alone (HR, 0.07; 95% CI, 0.01-0.44) but did not have significantly lower mortality than MRI-based screening (HR, 0.26; 95% CI, 0.05-1.35). In BRCA1-only analyses, RRM was associated with lower breast cancer-specific mortality compared with MRI-based screening (HR, 0.13; 95% CI, 0.03-0.66) and mammography alone (HR, 0.03; 95% CI, 0.00-0.15). SUCRA rankings indicated RRM had the highest likelihood of association with the lowest all-cause mortality (SUCRA value, 99.9%). Risk of bias was critical for 4 studies, and certainty of evidence was rated as very low for all 5 studies. Conclusions and Relevance: In this systematic review and network meta-analysis of RRSO-adjusted analyses, RRM was associated with lower all-cause mortality compared with breast cancer screening among females with PVs in BRCA1 and BRCA2, with the greatest magnitude of association for breast cancer-specific mortality observed in BRCA1 PV carriers. These findings provide less confounded survival estimates to support individualized shared decision-making for RRM.