Prognostic impact of common pathologic alterations in pancreatic ductal adenocarcinoma from the veterans health administration.

Abstract

603 Background: The Veteran Health Administration’s (VHA) National Precision Oncology Program was established to provide comprehensive molecular profiling for US military veterans with advanced cancers. There is an urgent need for precision strategies in pancreatic ductal adenocarcinoma (PDAC), as it is a leading cause of cancer-related mortality. We hypothesized that contributions of molecular alterations in PDAC would fail to stratify overall survival (OS), as current strategies are largely dependent on the activity of cytotoxic chemotherapy. Methods: A retrospective, multicenter cohort of 342 veterans with PDAC were identified from January 2016 to March 2021 who underwent comprehensive next-generation sequencing of tumor using FoundationOne CDx (UW IRB#2020-0696). Subjects were stratified by localized (L) or metastatic (M) disease at the time of diagnosis. Molecular alterations were compared by disease presentation using chi-squared analysis, and the clinical outcomes of overall survival (OS) were evaluated using Student’s t-test. Results: Baseline characteristics were representative of the VA population across 80 independent sites. The cohort was male-dominant (97%) with a median age of 69 years at diagnosis. Of this sample, 55% had M disease (n=189) compared to 45% with L disease (n=153). Median OS for M PDAC was 8.9±10.2 months (mo) v. L PDAC with median OS 22.5±18.0 mo (p<0.00005). Primary driver alterations were representative of PDAC and comparable between L and M on presentation, respectively; these included KRAS (92% v. 91%), TP53 (73% v. 80%), CDKN2A (29% v. 32%), SMAD4 (18% v. 23%), ARID1A (15% v. 16%) and BRCA2 (9% v. 12%). Primary driver alterations did not confer differences in OS across the population when comparing mutant (mt) to wildtype (wt) for KRAS (10.7 v. 11.8 mo, n=312), TP53 (10.3 v. 11.8 mo, n=263), CDKN2A (10.2 v. 10.9 mo, n=105), ARID1A (10.8 v. 10.9 mo, n=53), SMAD4 (11.3 vs 10.7 mo, n=72), and BRCA2 (13.8 v. 10.7 mo, n=37). Conclusions: Using the largest report of molecular profiles in veterans with PDAC to date, current therapeutic strategies fail to differentiate clinical outcomes by common molecular alterations with cytotoxic chemotherapy. The molecular profiles of veterans are representative of PDAC and do not vary significantly between localized and metastatic disease. There remains a persistent unmet need for therapeutic strategies including ongoing investigations of novel metabolic and immune-based therapies.