Objective To compare the clinicopathological characteristics between primary and contralateral cancers in patients with metachronous bilateral breast cancer (MBBC) who carried a BRCA1/2 germline pathogenic variant. Methods A total of 496 BRCA1/2 carriers with primary unilateral breast cancer were included (196 with BRCA1 and 300 with BRCA2). Clinicopathological information of patients was collected, and the median follow-up for the entire cohort was 10.4 years (0.4-20.8 years). Results Among all patients, 31 (15.8%) of the 196 BRCA1 carriers and 49 (16.3%) of the 300 BRCA2 carriers had MBBC, respectively. Among the 31 BRCA1 carriers who developed MBBC, the proportion of triple-negative breast cancer (TNBC) in primary cancer and contralateral cancer was 61.3% and 67.7%, respectively. If the primary cancer of BRCA1-mutated MBBC was TNBC, the probability of the contralateral breast cancer with TNBC was 89.5% (17/19), which was significantly higher than that if the primary cancer was non-TNBC (33.3%, 4/12) (P=0.004). Among the 49 BRCA2 carriers who developed MBBC, the predominant molecular phenotype of the primary and contralateral cancers was HR+ & HER2- (77.6% and 67.3%, respectively; P=0.53). Conclusion Approximately 60% of BRCA1 carriers exhibit TNBC. If a BRCA1 carrier with a TNBC primary breast cancer had an MBBC, the probability of the contralateral breast cancer being TNBC phenotype is almost 89.5%.

Objective To investigate the potential significance of FOXP3 expression in BRCA1/2-mutant breast cancer. Methods A total of 48 BRCA mutation carriers (16 with BRCA1 and 32 with BRCA2) and 78 age-matched non-carriers were included in this study. Immunohistochemistry was used to detect the expression of FOXP3 in breast cancer tissues. The FOXP3 RNA expression in 39 BRCA1, 36 BRCA2, and 948 non-carrier breast cancer patients from TCGA-BRCA and the correlation with homologous recombination deficiency scores were evaluated to validate the immunohistochemistry results. Results The FOXP3 positive rate was 43.8% (7/16) in BRCA1 mutation carriers, 59.4% (19/32) in BRCA2 mutation carriers, and 9.0% (7/78) in non-carriers. The FOXP3 positive rates in patients with BRCA1/2 mutant breast cancer were significantly higher than those in non-carriers (P=0.002; P<0.001). TCGA-BRCA results showed that the FOXP3 RNA level in BRCA1/2 mutant breast cancer was significantly higher than that in non-carriers (P=0.02, P=0.004). The FOXP3 RNA level was positively correlated with the homologous recombination deficiency score (Spearman R=0.30, P<2.2e-16). Conclusion Patients with BRCA1/2 mutant breast cancers have higher FOXP3 expression than non-carriers, and may be more sensitive to immunotherapy.