Retrospective study of survival outcomes in patients with hereditary pathogenic and variants of unknown significance mutations in pancreatic adenocarcinoma

616 Background: Since 2019, all patients with pancreatic adenocarcinoma (PDAC) are recommended to undergo germline testing per the National Comprehensive Cancer Network guidelines. Outside of PARP inhibitors in germline BRCA mutated PDAC, the predictive and prognostic implications of these genetic alterations are unclear. Many hereditable mutations are continually discovered, but the majority are considered Variants of Unknown Significance (VUS). The purpose of this retrospective study is to characterize the clinical characteristics of multiple pathogenic and VUS germline mutations in PDAC. Methods: An IRB approved institutional database of PDAC patients (n=442) was queried for patients diagnosed between 2007 and 2021. Only patients who tested positive for hereditary mutations (n=35) or VUS (n=41) were included. Patients with both pathogenic mutation and VUS were considered in the pathogenic mutation group. Results: 76 patients (35 pathogenic, 41 VUS) were included in the analysis. Pathogenic mutations were divided into subcategories including DNA repair (n=21), polyposis (n=2), pancreatitis-associated (n=11), and other (n=2). With a mean follow-up period of 636 days, the overall survival (OS) for pathogenic mutations at 90 days, 180 days, 1 year, and 2 years was 100%, 97.1%, 88.6%, and 74.3% respectively. The cumulative recurrence was 2.9%, 11.4%, 22.9%, and 37.1%. For VUS, the OS was 97.6%, 95.1%, 75.6%, and 56.1% and cumulative recurrence was 0%, 14.6%, 31.7%, and 43.9% in the same time intervals. Conclusions: This data suggests that patients with germline mutations may have favorable outcomes when compared to the general population. Overall germline alterations in our intuitional cohort had a 2-year survival of nearly 75%. Notably, pancreatitis-associated hereditable mutations consisted a sizeable portion of our overall cohort. Although current therapy is most focused on DNA repair mechanisms, these results show that other novel germline genetic alterations may be prognostic and warrant further investigation.[Table: see text]