Landscape and clinical significance of germline pathogenic variants (PV) in pancreatic cancer (PC)-predisposing genes in PC patients

International guidelines recommend multigene germline (MGP) testing for PC pts, although no surveillance program for high-risk individuals has been validated. The implementation of this recommendation is limited by the uncertainty around its clinical utility. Preliminary data from Italian PC pts showed a high prevalence of CDKN2A PV, regardless of familial status, and BRCA1/2 PVs only in pts<74 yo. Here, we provide a comprehensive analysis by MGP in unselected Italian PC pts. We evaluated the prevalence and impact on outcomes of PVs in 51 PC susceptibility genes in a real-life retrospective and prospective series of 422 Italian PC pts. Characteristics of pts with PV were compared to WT pts using Student’s t-test or chi square test. Cox proportional hazard regression models were performed to estimate hazard ratios (HR) and 95% confidential interval (CI). We found PVs in 70/422 pts (17%). The most frequently altered genes were BRCA1-2 (4.5%, all<70yo), CDKN2A (4.5%), ATM (2.1%), CHEK2 (1,7%) and COL7A1 (1,2%). Overall, mean age was 67yo, 22% were resectable PC at diagnosis, and median follow-up was 9.8 months (0.02–156). When compared with WT (N=352), PVs carriers were associated with younger age at diagnosis (67 vs 64; P=0.02), positive family history (FH) for PC (10 vs 26%; P