Risk-Reducing Mastectomy in BRCA1/2 and Other High-Risk Gene Carriers: Current Evidence and Practical Guidance.

Women carrying pathogenic/likely pathogenic variants of high- or moderate-penetrance genes, such as BRCA1/2, TP53, PTEN, PALB2, CDH1, STK11, CHEK2, and ATM, face markedly elevated lifetime risks of breast cancer. Risk-reducing mastectomy (RRM) reduces incidence by approximately 90% as shown in large observational cohort studies and meta-analyses. However, the survival advantage of RRM remains uncertain given the observational design, heterogeneous population, and the lack of randomized controlled trials. For moderate-penetrance genes, guidance relies more on absolute risk modeling and expert consensus than on direct outcome data. Hence, RRM is recognized as an option for women at high-risk, while emphasizing individualized, multidisciplinary decision-making that incorporates oncological, genetic, reconstructive, and psychosocial perspectives. In addition, choices are shaped by many factors, such as age, family plans, culture, and healthcare systems in real practice. This review integrates the current evidence and evolving guidelines to clarify the benefits, limitations, and controversies surrounding RRM. By addressing existing knowledge gaps and decision-making challenges, it aims to facilitate informed patient-centered counseling for the management of hereditary breast cancer.