Risk-reducing surgeries, including bilateral mastectomy and salpingo-oophorectomy, significantly improve survival in BRCA carriers with a prior history of breast cancer at a young age (≤40 years).
Cancer risk management including bilateral risk-reducing mastectomy (RRM) and risk-reducing salpingo-oophorectomy (RRSO) are widely recommended in healthy carriers of germline BRCA1 and/or BRCA2 pathogenic or likely pathogenic variants.1 While RRSO has shown to improve overall survival (OS), bilateral RRM reduces the risk of developing breast cancer but its impact on OS remains controversial.2-5 No prior studies focused specifically on the role of RRM and/or RRSO among BRCA carriers with a prior history of breast cancer at a young age (≤40 years). At SABCS 2024, the results of a large retrospective cohort study that evaluated the association between risk-reducing surgeries and survival among young BRCA carriers with a history of breast cancer were presented.6
Study design
The BRCA BCY Collaboration is an international, multi-centre, hospital-based, retrospective cohort study in young women (≤40 years) harbouring germline BRCA1/2 pathogenic or likely pathogenic variants and diagnosed with stage I-III invasive breast cancer (January 2000 – December 2000). The primary endpoint was OS. Secondary endpoints included disease-free survival (DFS) and breast cancer-free interval (BCFI). Survival endpoints were computed from breast cancer diagnosis. Cox models were used to explore the association between risk-reducing surgeries and survival outcomes with RRM and RRSO as time-dependent covariates. Stratification factors were year at breast cancer diagnosis, region and nodal status. OS models were also adjusted for development of distant recurrences and secondary primary malignancies as time-dependent covariates. In addition, sensitivity analyses were performed including a 3-year landmark analysis and a subgroup analysis including only patients tested for BRCA before or within 6 months from breast cancer diagnosis.
Results
A total of 5,290 patients from 109 centres in 33 countries were included. Median follow-up in the overall cohort was 8.2 years. Median age at breast cancer diagnosis was 35.0 years and 48.8% underwent BRCA testing before or within 6 months from breast cancer diagnosis. A total of 63.5% of patients were BRCA1 carriers, 51.2% had node-negative disease, 35.9% had luminal-like disease, 49.1% had triple-negative disease (TNBC), and 91.8% received chemotherapy in the (neo)adjuvant setting.
A total of 2,910 patients underwent RRM at a median age of 36.6 years. Median time from diagnosis to RRM was 0.8 years, and median follow-up after RRM was 5.1 years. RRM was associated with a significant improvement in OS (aHR[95% CI]: 0.65[0.53-0.78]), irrespective of specific BRCA gene, age at breast cancer diagnosis, tumour subtype, tumour size or nodal status. RRM was also associated with a significant improvement in DFS (aHR[95% CI]: 0.58[0.52-0.65]) and BCFI (aHR[95% CI]: 0.55[0.48-0.62]).
A total of 2,782 patients underwent RRSO at a median age of 39.7 years. Median time from diagnosis to RRSO was 3.0 years, and median follow-up after RRSO was 4.9 years. RRSO was associated with a significant improvement in OS (HR[95% CI]: 0.58 [0.48-0.71]). A significant interaction was observed according to specific BRCA gene (greater benefit in BRCA1 vs BRCA2 carrier) and tumour subtype (greater benefit in patients with TNBC vs HR+ HER2- disease). RRSO was also associated with a significant improvement in DFS (aHR[95% CI]: 0.68[0.61-0.77] and BCFI (aHR[95% CI]: 0.65[0.57-0.74]).
In patients who underwent both RRM and RRSO (N= 1,804), the effect of RRM and RRSO on OS was independent. However, the effect of RRSO on DFS and BCFI was more pronounced in patients who also underwent RRM.
Conclusion
This worldwide retrospective study showed that RRM and/or RRSO was associated with improved OS, DFS and BCFI in young BRCA carriers with a prior history of breast cancer. The favourable impact of RRM on OS was seen irrespective of the specific BRCA gene, while the beneficial effect of RRSO was more pronounced among BRCA1 carriers.
References
1. Sessa C, et al. Risk reduction and screening of cancer in hereditary breast-ovarian cancer syndromes: ESMO clinical practice guideline. Ann Oncol 2023;34:33-47.
2. Metcalfe K, et al. Effect of oophorectomy on survival after breast cancer in BRCA1 and BRCA2 mutation carriers. JAMA Oncol 2015;1:306-13.
3. Domcheck SM, et al. Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality. JAMA 2010;304:967-75.
4. Cortesi L, et al. Can contralateral prophylactic mastectomy and oophorectomy increase survival in BRCA-related breast cancer? Results from the Italian MUTina study. Eur J Surg Oncol 2024;50:108603.
5. Heemskerk-Gerritsen BAM, et al. Improved overall survival after contralateral risk-reducing mastectomy in BRCA1/2 carriers with a history of unilateral breast cancer: a prospective analysis. Int J Cancer 2015;136:668-77.
6. Lambertini M, et al. Association between risk-reducing surgeries and survival in young BRCA carriers with breast cancer: results from an international cohort study. Presented at SABCS 2024; Abstract GS1-08.
Top
