Background: PC is a lethal disease with limited treatment options. We utilized Comprehensive Genomic Profiling (CGP) to identify putative prognostic and/or predictive biomarkers. Methods: We retrospectively reviewed PC patients (pts) at our institution who underwent CGP utilizing the Foundation One assay. CGP was performed on hybrid-capture, adaptor ligation-based libraries for up to 315 genes plus 47 introns from 19 genes frequently rearranged in cancer. PC pts were categorized by clinical stage – localized (resectable and borderline resectable PC; LPC), locally advanced (LAPC) and metastatic (mPC). Effect of gene alterations (GAs) with at least 10% prevalence were analyzed. The marginal effect of each gene on radiographic response and survival outcomes was estimated using proportional odds and multivariate Cox regression analysis, respectively, adjusting for stage. Results: Ninety-three pts were identified - median age was 63, 55% were male, and 50% were smokers. Clinical stage at diagnosis was LPC, LAPC and mPC in 42 (45%), 23 (25%) and 28 (30%) pts, respectively. The most commonly altered genes were KRAS (94%), TP53 (75%), CDKN2A (41.2%) and SMAD4 (32.9%). All patients were microsatellite stable and the median tumor mutational burden was 1.7. 5-FU (52%) or Gemcitabine (46%) based chemotherapy combinations were utilized as the first systemic therapy. Median overall survival for patients with LPC, LAPC and mPC were 30.7, 28.8 and 9.6 months respectively. Thirty-eight (91%) pts with LPC underwent curative intent surgery compared to 15 (65%) pts with LAPC (p = 0.019). Thirty-five (95%) pts with wild type (WT) CDKN2A and 47 (94%) pts with WT CDKN2B underwent curative intent surgery compared to 13 (65%) and 1(14%) pt(s) with GAs in CDKN2A and CDKN2B respectively (p = 0.003 and p < 0.0001 respectively). The response to chemotherapy was statistically significantly higher in pts with WT CDKN2A (53%) and CDKN2B (48%) compared to pts with GAs in CDKN2A (19%) and CDKN2B (12%) (p = 0.03 and p = 0.05, respectively). Conclusions: GAs in CDKN2A/B may have a predictive and possibly a prognostic impact. The clinical validity and biological relevance of these findings need to be further explored in larger studies.