1221P The functional domain of BRCA1/2 pathogenic variants (PVs) as potential biomarkers of second tumor and domain-related sensitivity to PARP-inhibitors

Women carrying BRCA1/2 germline pathogenic/likely pathogenic variants (gPVs) have elevated lifetime risk of developing both breast cancer and high grade serous ovarian/tubal or peritoneal cancer (EOC), but also pancreatic and endometrial cancer. The purpose of this study was to identify the BRCA1/2 functional domains (FDs) associated to develop of multiple primary tumors, and the potential effect of BRCA PVs within the FDs on PARP-inhibitors response in EOC patients. In this real-world, hospital-based, study we collected genetic and clinical data on EOC patients subjected to somatic and germline BRCA1/2 genetic testing, and evaluated the presence of personal second tumor history according to mutated gene (BRCA1 or BRCA2), PV type, and PV location. The BRCA1 FDs were RING, DNA-binding domain (DBD), BRCA1 C terminus (BRCT), or other locations, and the BRCA2 FDs were RAD51-BD, DBD, or other locations. The treatment efficacy by PV type and FD was evaluated. From May 2015 to March 2023, data from 907 patients were collected. Overall, 325 were carriers of gPVs in BRCA1/2 genes: 228 in BRCA1 (70.2%) and 97 in BRCA2 gene (29.8%). In the population of BRCA-mutated patients, at the median age of 57 years (range 23-78), 67 showed personal second tumor history (20.6%), including 49 carriers of gBRCA1 PVs (73.1%), and 18 of gBRCA2 PVs (26.9%). In the group of 582 patients with genetic testing not informative, only 46 patients showed second tumor history (7.9%). The most frequent second tumors was breast cancer at the median age of 48.5 years, but also endometrial and renal carcinoma, melanoma and cholangiocarcinoma. When DFs of mutated gene were compared, the distribution was different between EOC patients with and without second tumor history. Notably, BRCA-mutated patients with second tumors showed an higher involvement of BRCT of BRCA1 (24.5%) and DBD of BRCA2 (17.8%), than BRCA carriers without second tumor history (27.8% and 6.3%, respectively)(p=0.02). In the EOC BRCA-mutated patients, BRCA1/2 PVs located in specific functional domains (FDs) might be associated to higher probability to develop multiple primary cancers, with potential effect on PARP-inhibitors benefit.