20 Beyond KRAS G12D Mutation: The Prognostic Significance of The KRAS Mutation Variants on Progression-Free Survival in Pancreatic Ductal Adenocarcinoma

Pancreatic ductal adenocarcinomas (PDACs) are aggressive neoplasms with poor outcomes. The prognostic significance of major driver gene mutation, beyond KRAS G12D, is yet to be explored. A 10-year retrospective comprehensive study of the prognostic significance of major driver genes in PDACs was conducted. Next-generation sequencing was performed on 131 PDACs. The highest mutation rates observed were in KRAS (n = 121; 92.4%), followed by TP53 (n = 92; 70.2%), SMAD4 (n = 38; 29%), and CDKN2A (n = 30; 22.9%). Among KRAS-mutated PDACs that underwent neoadjuvant chemotherapy (n = 96; 73.3%), the presence of SMAD4 and/or TP53 mutations was associated with worse progression-free survival (PFS). Patients with KRAS G12V mutations exhibited a trend where those with SMAD4/TP53 wild-type had better PFS compared to those with the mutated SMAD4/TP53, particularly during the early months of follow-up. KRAS G12R mutations showed the most distinct separation pattern in PFS, with SMAD4/TP53 wild-type PDACs showing relatively better PFS. In contrast, KRAS G12D had a more uniform effect on disease progression, regardless of SMAD4 and TP53 mutation status. Our study shows that the prognostic impact of SMAD4 and TP53 mutations in PDACs may vary depending on the specific KRAS variants. The presence of SMAD4/TP53 mutations was generally associated with poorer survival outcomes in KRAS-mutated cases receiving neoadjuvant chemotherapy, especially among those with the KRAS G12R mutation. Patients with KRAS G12V and G12R mutations had better PFS when SMAD4/TP53 were wild-type, while the impact of KRAS G12D mutations on PFS remained consistent regardless of SMAD4/TP53 mutation status.