Risk-reducing bilateral mastectomy (RRBM) is associated with lower overall- and breast cancer-specific mortality among women carrying BRCA1 or BRCA2 pathogenic variants, according to a large systematic review and meta-analysis.

Although RRBM is already known to reduce the incidence of breast cancer, evidence of a survival benefit has remained uncertain. To clarify its impact, researchers at St Vincent’s University Hospital in Dublin, Ireland, reviewed the evidence base to assess whether it translates into improved overall- and breast cancer-specific mortality – information central to shared decision-making.

The team reviewed five major databases and identified six observational studies comprising 6,135 female BRCA1/2 carriers with no previous breast cancer. Ages ranged from 15.3 to 85.3 years, with a weighted median of 38 years at entry and a median follow-up of 75.6 months.

Of the six observational studies, four were retrospective cohorts, one was a prospective cohort, and one was a prospective pseudo-randomised matched design. Occult breast cancers detected after RRBM were reported in four studies and incorporated differently in the analyses.

Of the women identified, 2,558 underwent RRBM, while 3,577 opted for surveillance. More BRCA1 carriers (n=3,442) than BRCA2 carriers (n=2,236) were included. Surveillance approaches varied, although two studies reported comprehensive screening regimens.

Significantly reduced overall mortality with RRBM

RRBM was associated with significantly reduced overall mortality (62–63%). Unadjusted pooled data yielded an odds ratio (OR) of 0.38 (95% CI 0.27–0.55), and adjusted hazard ratios (HRs) showed a similar effect (HR 0.37; 95% CI 0.23–0.60).

Breast cancer-specific mortality also fell markedly (81–86%) among women undergoing RRBM (OR 0.19; 95% CI 0.08–0.47 and HR 0.14; 95% CI 0.04–0.49).

Subgroup analyses were more limited. For BRCA1 carriers, two studies reported an 85% reduction in breast cancer-specific mortality, but equivalent data for BRCA2 carriers were unavailable.

Attempts to assess the isolated effect of RRBM, independent of risk-reducing bilateral oophorectomy, proved inconclusive, likely owing to heterogeneity and small sample sizes.

As all six studies included were observational, the overall certainty of the evidence was rated low under the Grading of Recommendations Assessment, Development, and Evaluation criteria. Most were also judged to have a serious risk of bias in the ROBINS-I V2 assessment, largely due to immortal time bias and inconsistent adjustment for key confounders, including age and oophorectomy.

Reporting of oophorectomy, use of endocrine therapy and the intensity of surveillance varied widely, and several analyses were based on very few mortality events, particularly in the smaller cohorts, and all acknowledged as key limitations by the authors.

Trial sequential analysis added a further note of caution. Although the combined sample size exceeded the required information threshold, the results should still be considered exploratory.

Implications and future directions

The review offers a comprehensive synthesis to support RRBM as a potentially life-extending option within personalised risk-reduction strategies. However, important questions remain regarding optimal timing, comparisons with contemporary intensive screening and the relative contributions of RRBM and risk-reducing oophorectomy to survival gains.

Future research that more robustly accounts for age, adheres to current screening recommendations in comparator groups and employs methods to reduce bias is required. But the researchers concluded that the current findings support RRBM as a potentially life-extending intervention that should be considered in shared decision-making discussions for women with BRCA1 or BRCA2.

Reference
O’Reilly C et al. Risk-Reducing Bilateral Mastectomy and Mortality in Carriers of BRCA1 and BRCA2 Variants. A Systematic Review and Meta-Analysis. JAMA Surg 2026;Jan 7:doi:10.1001/jamasurg.2025.5929.