Prognostic Properties of KRAS Gene Mutation Subtypes in Resected Pancreatic Ductal Adenocarcinoma.

Background: Pancreatic ductal adenocarcinoma (PDAC) has a distinct genomic profile, with somatic KRAS mutations occurring in 85%-95% of all PDAC cases. This study aimed to measure the prognostic impact of specific KRAS mutations in resected PDAC patients from a large, high-volume center.

Methods: This retrospective study included a cohort of PDAC patients who underwent curative-intent pancreatic resection at our institution between 2016 and 2021. Demographic, histologic, and oncologic outcome data were recorded. KRAS status was assessed via next-generation sequencing. Thirty-six (12.8%) wtKRAS, 109 (38.8%) G12D, 76 (27.0%) G12V, 36 (12.8%) G12R, 11 (3.9%) Q61H.

Results: A total of 281 patients were included with wtKRAS (12.8%), G12D (38.8%), G12V (27.0%), G12R (12.8%), accounting for over 90% of the KRAS genotypes. Kaplan-Meier analysis revealed wild-type KRAS to be associated with improved overall survival (68.5±0 vs. 32.1±2.3 mo, P=0.005), and disease-free survival (35.4±0 vs. 20.3±3.9 mo, P=0.043). Cox regression analysis demonstrated worse overall survival with increased age (HR=1.04/y, P<0.01), neoadjuvant chemotherapy (HR=2.01, P<0.01), the presence of lymphovascular invasion (HR=2.47, P<0.01), G12D or G12V KRAS subtypes (P≤0.05), and lack of adjuvant chemotherapy (HR=0.6, P=0.02).

Conclusions: Next-generation sequencing of the KRAS subtype in resectable PDAC tumors shows that the KRAS G12D/G12V subtypes confer a worse prognosis compared with wild-type KRAS tumors.