Distinct Tumor Subtypes and Contralateral Breast Cancer Risk in BRCA1 and BRCA2 Carriers

Background: The high risk of contralateral breast cancer (CBC) in carriers of germline BRCA1/2 pathogenic variants (PVs) is well established, whereas differences in tumor subtype and risk of CBC between BRCA1 and BRCA2 carriers remain largely unknown. Methods: This cohort study included 738 unselected Chinese patients with breast cancer who carried BRCA1/2 PVs (289 BRCA1 and 449 BRCA2 carriers) and were treated at Peking University Cancer Hospital between October 2003 and August 2021. Tumor subtypes and the cumulative incidence of CBC were analyzed in both BRCA1 and BRCA2 carriers. Results: After a median follow-up of 9.0 years, 52 (18.0%) of 289 BRCA1 carriers and 49 (10.9%) of 449 BRCA2 carriers had developed CBC. The 10-year cumulative incidence of CBC was significantly higher in BRCA1 than in BRCA2 carriers (18.9% vs. 11.7%; p = 0.01). Among patients aged 40 years or younger, the 10-year cumulative incidence of CBC was higher in BRCA1 carriers than in BRCA2 carriers (27.5% vs. 12.5%; p = 0.007; adjusted hazard ratio, 2.58 [95% CI, 1.06–6.29]; p = 0.04). In addition, among BRCA1 carriers who developed CBC, the majority of primary tumors (62.7%) were triple-negative breast cancers (TNBCs). Among these patients with primary TNBC, approximately 77.4% of contralateral breast tumors were also TNBC. In contrast, primary and contralateral tumors in BRCA2 carriers were predominantly hormone receptor-positive (72.9% and 66.7%, respectively). Conclusions:BRCA1 carriers have a higher CBC risk than BRCA2 carriers. TNBC is the predominant phenotype of both primary and subsequent contralateral tumors in BRCA1 carriers. These findings provide useful data to inform the optimal management of CBC risk in BRCA1/2 carriers.