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.