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

Abstract

Background: 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. Method(s): 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. Result(s): 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). Conclusion(s): 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.