Background: Prognosis in pancreatic ductal adenocarcinoma (PDAC) remains poor despite improved systemic therapies and surgical techniques. The identification of biomarkers to advance insight in tumor biology and achieve better individualized prognostication could help improve outcomes. Our aim was to elucidate the prognostic role of the four main driver mutations (KRAS, TP53, SMAD4, CDKN2A) and their combinations in resected PDAC. Patients and Methods: A retrospective analysis was conducted utilizing the cBioPortal database and National Cancer Institute’s Cancer Genomic Atlas (TCGA) on patients in whom next-generation sequencing was performed on upfront resected PDAC from 2012 to 2020. Multivariable Cox regression was implemented to elucidate risk-adjusted predictors of overall (OS) and recurrence-free survival (RFS). Results were validated employing a Johns Hopkins Hospital (JHH) cohort.’ Results: In the discovery cohort (n = 587), increased number of mutated driver genes was associated with worse OS (p = 0.047). Specifically, patients with mutations in ≥ 2 driver genes had worse OS than ≤ 1 mutated gene (18.2 versus 32.3 months, p = 0.033). Co-occurrence of mutant (mt)KRAS p.G12D with mtTP53 (median OS, 25.9 months) conferred better prognosis than co-occurrence of other mtKRAS variants (p.G12V/R/other) with mtTP53 (median OS, 16.9 months, p = 0.038). The findings were validated using a JHH cohort. Multivariable risk-adjustment found co-occurrence of mtKRAS p.G12D with mtTP53 to be an independent predictor of beneficial OS and RFS [HR (95% CI): 0.18 (0.03–0.81) and 0.31 (0.11–0.89) respectively]. Conclusion: In chemo-naïve resected PDAC, combinations of mutations in the four driver genes are associated with prognosis. In patients with combined mtKRAS and mtTP53, KRAS p.G12D variant confers a better OS and RFS.
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