The Mutational Status of Driver Genes in Patients With Resected Pancreatic Ductal Adenocarcinoma Is Associated With Pathological Characteristics and Overall Survival

Objective: To evaluate whether mutations in pancreatic ductal adenocarcinoma (PDAC) driver genes ( KRAS , TP53 , SMAD4 , and CDKN2A ) are associated with pathological characteristics and prognosis. Background: The prognostic significance of specific mutations in PDAC driver genes is incompletely understood. Methods: We analyzed patients who underwent pancreatectomy between 2018 and 2022 for localized PDAC and whose cancer was profiled using targeted next-generation DNA sequencing. We investigated associations between mutational status, clinical-pathological characteristics, and overall survival (OS). Results: Analysis of 508 patients defined KRAS mutations as the most common genetic mutation (456, 89.8%), followed by TP53 (292, 57.5%), SMAD4 (104, 20.3%), and CDKN2A (88, 17.3%). The presence of wild-type KRAS ( KRAS -wt) was associated with lower T-stage ( P <0.001) and N-stage ( P =0.04) and lower rates of perineural invasion ( P =0.03), when adjusting for receipt of neoadjuvant therapy. TP53 mutations compared with TP53 -wt were associated with higher T-stage ( P =0.02), perineural invasion ( P =0.01), and advanced tumor grade ( P =0.03). Mutations in KRAS and TP53 were associated with shorter mOS compared with wild-type [hazard ratio (HR): 2.29, P =0.002 and HR: 1.62, P <0.001, respectively]. On multivariable analysis, N0 stage, anatomically resectable cancer, and absent lympho-vascular invasion were associated with improved mOS (all P <0.02). The presence of 2 (HR: 1.71) or 3-plus (HR: 1.63) driver mutation genes was associated with shorter mOS compared with one mutation ( P <0.01). Conclusions: In patients with resected PDAC, KRAS -wt, and TP53 -wt were associated with improved pathological characteristics and mOS, regardless of neoadjuvant therapy. The co-occurrence of 2 or more driver gene mutations was associated with worse mOS.