Driver mutation profiling by next-generation sequencing predicts survival and recurrence after curative-intent resection for pancreatic ductal adenocarcinoma: a genomic cohort study

BACKGROUND: Next-generation sequencing (NGS) is standard practice in metastatic pancreatic ductal adenocarcinoma (PDAC), yet its prognostic utility in patients undergoing curative-intent resection remains poorly defined. Characterizing whether driver mutations independently influence post-surgical outcomes [overall survival (OS), time-to-recurrence (TTR), and pathological response (PR)] may inform perioperative risk stratification and patient selection for emerging targeted therapies. METHODS: We conducted a retrospective cohort study of adults undergoing pancreatectomy for PDAC at a single high-volume academic center (2016-2025), with concurrent NGS profiling. Clinicopathologic and genomic data (KRAS, TP53, CDKN2A, SMAD4, and BRCA2 mutations) were obtained from an integrated institutional data commons. OS and TTR were evaluated using Kaplan-Meier analysis and multivariable Cox proportional hazards regression. PR (College of American Pathologists grade 0-1) was assessed using logistic regression. RESULTS: Of 188 eligible patients (median age: 66; 42.5% female), 83.5% received neoadjuvant chemotherapy and 12.8% achieved major pathological response. KRAS was the most prevalent mutation (84.6%), followed by TP53 (61.7%), CDKN2A (33.0%), SMAD4 (18.1%), and BRCA2 (3.2%). Median TTR and OS were 10.8 and 27.1 months, respectively. In multivariable analysis, TP53 mutation was associated with shorter OS (HR, 1.65 95% CI 1.02-2.66), and CDKN2A mutation with shorter TTR (HR 1.69, 95% CI 1.19-2.39). KRAS was associated with poorer PR compared to wild type (OR 4.45, 95% CI 1.26-15.65). CONCLUSION: In this exploratory analysis, TP53 and CDKN2A mutations were independently associated with poorer outcomes post-PDAC resection, supporting the potential of upfront NGS for perioperative risk stratification. Prospective, multicenter validation is needed to establish clinical utility.