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- (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 to wild-type (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 two (HR 1.71) or three-plus (HR 1.63) driver mutation genes was associated with shorter mOS compared to 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 two or more driver gene mutations was associated with worse mOS.