Contralateral breast cancer risk in irradiated breast cancer patients with a germline-BRCA1/2 pathogenic variant

BACKGROUND: Radiation-induced secondary breast cancer may be a concern after radiotherapy for primary breast cancer (PBC), especially in young germline (g)BRCA-associated breast cancer patients with already high contralateral breast cancer (CBC) risk and potentially increased genetic susceptibility to radiation. AIM: To investigate whether adjuvant radiotherapy for PBC increases the risk of CBC in gBRCA1/2-associated BC patients. METHODS: gBRCA1/2 pathogenic variant carriers diagnosed with PBC were selected from the prospective International BRCA1/2 Carrier Cohort Study. We used multivariable Cox proportional hazards models to investigate the association between radiotherapy (yes versus no) and CBC risk. We further stratified for BRCA status and PBC age (<40 and >40?years). Statistical significance tests were two-sided. RESULTS: Of 3,602 eligible patients, 2,297 (64%) received adjuvant radiotherapy. Median follow-up was 9.6?years. The radiotherapy group had more stage III PBC patients compared to the non-radiotherapy group (15% versus 3%, p?<?0.001), received more often chemotherapy (81% vs. 70%, p?<?0.001) and endocrine therapy (50% vs. 35%, p?<?0.001). The radiotherapy group had an increased CBC risk compared to the non-radiotherapy group (adjusted HR: 1.44, 95% CI: 1.12-1.86). Statistical significance was observed in gBRCA2 (HR: 1.77, 95% CI: 1.13-2.77), but not in gBRCA1 pathogenic variant carriers (HR: 1.29, 95% CI: 0.93-1.77; p-value for interaction, 0.39). In the combined gBRCA1/2 group, patients irradiated below and above age 40 at PBC diagnosis showed similar risks (HR: 1.38, 95% CI: 0.93-2.04 and HR: 1.56, 95% CI: 1.11-2.19, respectively). DISCUSSION/CONCLUSION: Radiotherapy regimens minimizing contralateral breast dose should be considered in gBRCA1/2 pathogenic variant carriers