Pathology of BRCA1- and BRCA2-associated breast cancers: known and less known connections

BRCA1 and BRCA2 mutation carriers face an elevated lifetime risk for breast and ovarian cancer diagnosis. BRCA-related tumors display characteristic pathological features, with the BRCA1-associated being predominantly triple-negative. On the contrary, BRCA2-associated tumors are more commonly found to be estrogen/progesterone receptor (ER/PgR)-positive. The incidence of BRCA1 and BRCA2 deleterious mutations in HER2-positive breast cancers, as well as the incidence of BRCA2 deleterious mutations in triple-negative breast cancer cases has not been investigated in depth. Our aim was to explore the clinicopathological characteristics of breast cancers in BRCA mutation carriers in a Greek population. Patients diagnosed with breast cancer between 1999 and 2016 were tested for BRCA1 and BRCA2 mutations, either by Sanger sequencing or by next generation sequencing using the Trusight Cancer 94-gene panel. A retrospective review of the medical records was conducted to retrieve patient demographics and tumor histopathological characteristics. Out of 2096 high-risk breast cancer families tested, we identified 303 BRCA1 and 88 BRCA2 carriers (18.7%). Mean age of breast cancer diagnosis for BRCA1 and BRCA2 carriers was 40.0 years (range 19-74) and 42.8 years (range 25-71), respectively. Information on clinicopathological characteristics (including ER/PgR and HER2 status) was available for 282 (72%) of the 391 mutation carrier patients. Tumor histological subtypes in BRCA1 carriers were predominantly ductal (79%) and medullary (10%), while in BRCA2 carriers these were more frequently ductal (74%) and lobular (15%). Interestingly, 20% of the BRCA2 tumors were triple-negative, in contrast to the expected, significantly higher proportion (75%) observed in BRCA1 carriers (chi-square, p < 0.001). Moreover, a significantly higher percentage of BRCA2 tumors were HER2-positive compared to BRCA1 tumors (24% vs 4.7%, p < 0.001). These data confirm established observations in the pathology of BRCA-related tumors, but provide further insight on the association of rare histological and immunohistochemical entities with loss-of-function mutations in these genes, which can be clinically important.