Matteo Lambertini, MD, PhD

Patients with germline BRCA gene mutations and a history of early-onset breast cancer who underwent a bilateral risk-reducing mastectomy and/or a risk-reducing salpingo-oophorectomy had lower rates of recurrence, secondary breast and/or ovarian malignancies, and death than those who did not undergo these surgeries, according to the results of a study presented by Matteo Lambertini, MD, PhD, of the University of Genova–IRCCS Ospedale Policlinico San Martino, at the 2024 San Antonio Breast Cancer Symposium (Abstract GS1-08).

The international retrospective cohort study found that patients with these characteristics who had a risk-reducing mastectomy had a 35% lower risk of death and a 42% lower risk of breast cancer recurrence or a second primary malignancy. Patients who underwent a risk-reducing salpingo-oophorectomy had a 42% lower risk of death and a 32% lower risk of breast cancer recurrence or second primary malignancy.

Study Methodology

The researchers analyzed data from the BRCA BCY Collaboration study (ClinicalTrials.gov identifier NCT03673306), an international, multicenter, hospital-based, retrospective cohort study. The current study included 5,292 patients with germline pathogenic or likely pathogenic variants of BRCA who were diagnosed between January 2000 and December 2020 with stage I to III breast cancer at age 40 or younger.

The primary endpoint of the study was overall survival. Disease-free survival and breast cancer–free interval were secondary endpoints. Survival endpoints were computed from breast cancer diagnosis. To account for potential lead-time bias, in the primary analysis, Cox models were used to explore the association between risk-reducing mastectomy and risk-reducing salpingo-oophorectomy included as time-dependent covariates and survival outcomes.

Stratification factors included year at breast cancer diagnosis, region or country, and nodal status. Overall survival models were also adjusted for the development of distant recurrences or second primary malignancies as time-dependent covariates. In addition, sensitivity analyses—a 3-year landmark analysis and a subgroup analysis—included only patients tested for BRCA mutations before or within 6 months after their breast cancer diagnosis.

Key Results

A total of 3,364 patients (63.6%) were BRCA1 mutation carriers, 2,723 (51.5%) had node-negative disease, and 2,422 (45.8%) had hormone receptor–positive breast cancer. Among these patients, 2,911 (55.0%) underwent risk-reducing mastectomy, and 2,782 (52.6%) underwent risk-reducing salpingo-oophorectomy.

The median time from a breast cancer diagnosis to risk-reducing mastectomy was 0.8 years (interquartile range [IQR] = 0.5–2.7 years) and to risk-reducing salpingo-oophorectomy was 3.0 years (IQR = 1.3– 6.8 years); median follow-up was 5.1 years (IQR = 2.7–8.3 years) after risk-reducing mastectomy and 4.9 years (IQR = 2.3–8.1 years) after risk-reducing salpingo-oophorectomy. At a median follow-up of 8.2 years (IQR = 4.7–12.8 years), 691 (13.0%) overall survival events, 1,928 (36.3%) disease-free survival events, and 1,753 (33.0%) breast cancer–free interval events were observed.

The researchers found that risk-reducing mastectomy was associated with a significantly reduced risk of overall survival events (adjusted hazard ratio [aHR] = 0.64, 95% confidence interval [CI] = 0.53–0.78). This association was observed regardless of specific BRCA gene mutation, age at breast cancer diagnosis, tumor subtype, tumor size, and nodal status. Risk-reducing mastectomy was also associated with a significantly reduced risk of disease-free survival events (aHR = 0.58, 95% CI = 0.52–0.65) and breast cancer–free interval events (aHR = 0.55, 95% CI = 0.48–0.62).

Risk-reducing salpingo-oophorectomy was associated with a significantly reduced risk of overall survival events (aHR = 0.58, 95% CI = 0.47–0.70). This association was observed regardless of age at breast cancer diagnosis, tumor size, and nodal status.

A significant interaction was observed according to specific BRCA gene (BRCA1 mutation carriers: aHR = 0.44, 95% CI = 0.34–0.57; BRCA2 carriers: aHR = 0.85, 95% CI = 0.63–1.14) and tumor subtype (triple-negative breast cancer: aHR = 0.43, 95% CI = 0.32–0.58; hormone receptor–positive breast cancer: aHR = 0.80, 95% CI = 0.61–1.06). Risk-reducing salpingo-oophorectomy was also associated with a significantly reduced risk of disease-free survival events (aHR = 0.68, 95% CI = 0.61–0.77) and breast cancer–free interval events (aHR = 0.65, 95% CI = 0.57–0.74). Sensitivity analyses provided consistent results.

Clinical Significance

“In this unique international cohort of BRCA [mutation] carriers with a prior breast cancer diagnosis at a young age, risk-reducing mastectomy and risk-reducing salpingo-oophorectomy were both associated with a significant improvement in overall survival, disease-free survival, and breast cancer–free interval. These findings are critical for improving the counseling of young BRCA [mutation] carriers with breast cancer on cancer risk-management strategies,” concluded the study authors.

Disclosure: Funding for this study was provided by the Italian Association for Cancer Research and the European Society for Medical Oncology. For full disclosures of the study authors, visit sabcs.org.