Expression of Oncodrivers HER-3 and C-MET during Breast Tumorigenesis in BRCA Mutation Carriers

BRCA1 and BRCA2 germ line mutations confer a substantial risk of breast cancer, with studies reporting an average cumulative risk of breast cancer by age 70 years as 57-65% in BRCA1-mutation carriers 45-47% in BRCA2-mutation carriers . Today, the prevention of breast cancer among mutation carriers has focused on surgical options such as risk-reducing bilateral mastectomy and bilateral salpingooophorectomy  which have significant associated morbidity. In the general population chemoprevention strategies have been developed to target the known phenotypes of spontaneous DCIS in order to prevent the development of invasive breast cancer. As such, evaluation of the pre-invasive progression pathways of BRCA-associated tumors is critical in the effort to develop directed prevention therapies for this vulnerable population.

Prior studies have demonstrated the morphological and immunohistochemical differences between BRCA-associated and sporadic invasive breast cancers, specifically with regards to the low expression of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor in BRCA1-associated breast cancers . While much is known about the phenotypic differences between BRCA-associated and sporadic breast invasive cancers, there is a paucity of data about the differences in their pre-invasive progression pathways. Furthermore, because more BRCA-related breast cancers are discovered between screening mammograms and with no prior pathologic findings it has previously been thought that the DCIS-associated premalignant pathway that exists in sporadic breast cancers is not present within the BRCA-associated disease spectrum.

 In our recent original article “DCIS in BRCA1 and BRCA2 Mutation Carriers: Prevalence, Phenotype, and Expression of Oncodrivers C-MET and HER3”, we examined 114 tumor specimens from BRCA mutation carriers who underwent breast surgery at a single academic institution over a 20-year time period. We found that 80.2% of all BRCA-associated invasive breast cancer (IBC) specimens had ductal carcinoma in situ (DCIS) present, and this did not differ by mutation status (p=0.95). We found that the majority of BRCA-associated DCIS was high grade (BRCA1: 68.9%, BRCA2: 53.6%) and the DCIS was either intermixed with the IBC (BRCA1: 42.9%, BRCA2: 56.0%) or just on the periphery of the IBC (BRCA1: 50.0%, BRCA2: 44.0%). In BRCA1 mutation carriers with IBC and concurrent DCIS, the correlation between the DCIS and IBC was highly significant for ER, PR, HER1, HER3, and C-MET (p<0.01). In BRCA2 mutation carriers with IBC and concurrent DCIS, the correlation between the DCIS and IBC was highly significant for ER, PR, HER2, and HER3 (p<0.01). Most BRCA1-associated DCIS and IBC had 0/3 staining intensity for ER, PR and HER2, while most BRCA2-associated DCIS and IBC had 3/3 staining intensity for ER and PR. BRCA1-associated DCIS had higher expression of HER3 and CMET (H-Score 99.5 and 101.9, respectively) and lower expression of HER1 (H-Score 6.5). BRCA-2 associated DCIS similarly had higher expression of HER3 and C-MET (H-Score 84.3 and 124.8, respectively) and lower expression of HER1 (H-Score 16.5).