Clinical features of breast cancer in Ashkenazi Jewish carriers of the two founder BRCA1 pathogenic variants.

Abstract

e12557 Background: Germline pathogenic variants (PVs) in BRCA1 and BRCA2 are the most common cause of hereditary breast and ovarian cancer. Carriers have a significantly elevated risk of developing breast cancer (BC) and ovarian cancer (OC) compared to the general female population. Two prevalent PVs in Ashkenazi Jews (AJ) in the BRCA1 gene are 185delAG and 5382insC. This study aims to compare clinical features of disease between the PV carrier groups. Methods: Data was collected retrospectively on 282 BC patients who were carriers of 5382insC or 185delAG, treated in Hadassah and Shaare Zedek Medical Centers between the years 1978 and 2021. Data collected included features such as age at disease onset, staging at diagnosis, additional malignancies or recurrence of disease, pathological features such as hormone receptor status and HER2 status (tumor subtype), and treatments. Disease characteristics and outcomes were compared. Results: There were 207 carriers of the 185delAG PV, while 75 carried the 5382insC PV. Amongst carriers of 185delAG, vs. 5382InsC, 58.1% vs. 35.8% (p<0.01) had triple negative BC (TNBC), while 28.2% vs. 52.6% (p<0.01) had hormone positive BC, respectively (Table). There was no significant difference in disease-free or overall survival, even after adjusting for age, stage and other potential confounders. Although it appeared that 5382insC carriers suffered a higher rate of OC (14% vs. 9.6%), and that 185delAG had a higher rate of non-OC malignancies (8.2% vs. 4%), these differences did not reach statistical significance. Conclusions: Our study suggests that 5382insC and 185delAG differ in their patterns of disease. Despite the lower rates of TNBC, 5382insC carriers had similar survival to 185delAG carriers. This could suggest that the hormone receptor positive disease amongst 5382InsC carriers had a less favorable course of disease, with a similar outcome as in those with TNBC. Further studies are warranted to better understand this pattern of disease aggression. [Table: see text]