Identifying Novel Genetic Alterations For Risk Stratification And Prognostication In Pancreatic Cancer.

e15754 Background: Despite advances in systemic therapy, pancreatic adenocarcinoma (PDA) is associated with poor outcomes. Identifying novel prognostic genetic alterations will improve risk stratification and treatment selection and response. Methods: DNA was extracted from biopsies of 63 consecutive patients with PDA at Cedars-Sinai Medical Center. DNA sequencing was performed for 3,769 exons of 236 cancer-related genes plus 47 introns from 19 genes to an average depth of 1000X using the Illumina HiSeq 2000 platform (Foundation Medicine, Cambridge, MA). We report all genetic alterations including those classified as variants of unknown significance. Results: Of 63 patients (average age 66, 38% male), 30 were stage 1 or 2 patients and 33 were stage 3 or 4 patients. For the entire cohort, median overall survival (mOS) and progression free survival (mPFS) were 25.5 months and 12 months. Patients with initial CA-19-9 greater than 900 had a significantly worse median OS 9.4 months p = 0.031 regardless of stage. Major genetic alterations identified in our cohort included KRAS(94%), P53(69%)%, CDK2NA(48%), and SMAD4(39% ). Patients with all 4 of these mutations had statistically significant decrease in mOS (13.3 months); p = 0.01 and a trend toward decrease in mPFS (11.0 months); p = .02. Additional alterations identified included a number of chromatin remodeling genes: ARID1A (17%), ARID1b(17%), MLL(8%), MLL2(22%), MLL3(15%). Alteration in ARID1A, resulted in a significant decrease in mOS (14.5 mo) P = 0.03 and PFS p = 0.02 (8 months) regardless of the clinical stage. Alterations of genes involved in DNA repair were also frequent in our cohort. These include ATM (19%), ATR (11%),BRCA1 (12.5%), BRCA2 (14%) PMS2 (9%). Conclusions: In a cohort of PDA patients we identified novel gene alterations associated with chromatin modeling and DNA repair, which may aid in risk stratification, selection of novel therapies and predict response to such agents. Alterations in ARID1a were found to be a significant prognosticator of decreased OS and PFS and warrants further investigation.