Alterations in driver genes are predictive of survival in patients with resected pancreatic ductal adenocarcinoma

Background KRAS, TP53, CDKN2A, and SMAD4 are established driver genes in pancreatic ductal adenocarcinoma (PDAC). This study was aimed at determining whether the mutational status of driver genes and those involved in DNA repair pathways are associated with clinical outcomes for individuals who undergo resection. Methods Eligible individuals were those who underwent resection of PDAC and consented to targeted sequencing of their primary tumor via Memorial Sloan Kettering–Integrated Mutation Profiling of Actionable Cancer Targets (MSK‐IMPACT). Genomic alterations were determined on the basis of MSK‐IMPACT results from formalin‐fixed, paraffin‐embedded samples. Associations between genomic alterations and clinical outcomes were assessed. Results Targeted sequencing was performed on 283 primary tumors resected between 2004 and 2017. The median follow‐up was 23 months among survivors. Alterations in KRAS and TP53 were associated with worse overall survival (OS) in comparison to wild type (median for KRAS, 38.8 months [95% CI, 33.0‐45.5 months] vs 91.0 months [95% CI, 34.8 months to not available (NA)]; P = .043; median for TP53, 37.4 months [95% CI, 32.1‐42.8 months] vs 65.0 months [95% CI, 33.0 months to NA]; P = .035). KRAS G12D mutations were associated with worse OS (median, 31.6 months [95% CI, 25.3‐45.5 months] vs 39.2 months [95% CI, 37.4‐75.2 months]; P = .012). TP53 truncating mutations (median, 39.6 months [95% CI, 32.4‐75.2 months] vs 33.9 months [95% CI, 24.0‐39.0 months]; P = .020) and those associated with loss of heterozygosity (median, 26.6 months [95% CI, 21.6‐44.2 months] vs 39.2 months [95% CI, 34.5‐49.1 months]; P = .048) had decreased OS. TP53 alterations were independently associated with OS in a multivariate analysis (hazard ratio, 1.54; 95% CI, 1.01‐2.33; P = .042). Individuals with germline alterations in homologous recombination deficiency (HRD) genes had improved OS in comparison with those without them (median, not reached vs 37.0 months; 95% CI, 33.0‐49.8 months; P = .035). Conclusions In patients with resected PDAC, genomic alterations in KRAS and TP53 are associated with worse outcomes, whereas alterations in HRD genes are associated with a favorable prognosis. Further studies are needed to better define these alterations as biomarkers in resected PDAC. Results from a routinely used, clinically actionable targeted sequencing panel demonstrate that alterations in KRAS and TP53 are associated with worse outcomes in patients undergo