1305P 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<.001), breast and ovarian cancer (13 vs 29%, P=.001), and melanoma (4% vs 10%; P=.034) and with personal history of other tumors (13% vs 32%, P<.001). Of note, 46% of pts carrying PVs in CDKN2A, BRCA2 and ATM had no FH. Overall, median OS was 11.5 months (10.3-13.3). Pts carrying any PVs showed a trend for better OS (HR 0.78; 0.59-1.04; P=0.090), compared to WT. This trend may be led by the group with ATM PVs (N=9) that showed a better prognosis (HR 0.33; 0.10-1.02; P=0.054); while no significant differences were observed between pts with PVs in other genes and WT pts. A High PV overall frequency was found in our cohort (17%), with a 4.5% rate for CDKN2A and for BRCA. ATM PVs were associated with better prognosis. Around 50% of pts would have been missed by traditional referral, since they had no FH. These findings may have a great impact on PC pts management and on high-risk family member genetic counselling and follow-up.