Prognostic Implications of Codon-Specific <i>KRAS</i> Mutations in Localized and Advanced Stages of Pancreatic Cancer.

Abstract

Although <i>KRAS</i> mutations represent the primary oncogenic driver in pancreatic ductal adenocarcinoma (PDAC), the association between codon-specific alterations and patient outcomes remains poorly elucidated, largely because of a lack of data sets coupling genomic profiling with rich clinical annotations across disease stages. We used American Association for Cancer Research's GENIE Biopharma Consortium Pancreas v1.2 data set to test the association of codon-specific <i>KRAS</i> mutations with clinicogenomic features and patient outcomes in patients with PDAC diagnosed with localized (stages I to III) and advanced disease (stage IV). Overall survival (OS) was compared using Kaplan-Meier and multivariable Cox proportional hazards methods. Among 1,032 eligible patients, 949 (92%) exhibited mutant <i>KRAS</i>. These mutations were predominantly observed at G12D (n = 390, 41%), G12V (n = 305, 32%), and G12R (n = 149, 16%). In the group of patients who presented with localized disease, those with G12V mutation had notably longer survival compared with G12D mutation (<i>P</i> = .03). By contrast, patients with G12V mutation who presented with metastatic disease experienced shorter OS compared with those with G12R (<i>P</i> = .04) and G12D mutations (<i>P</i> = .04). Furthermore, no significant differences were observed in the frequencies of coaltered driver genes, including <i>TP53</i>, <i>CDKN2A</i>, and <i>SMAD4</i>, across the different <i>KRAS</i> mutations. These findings demonstrated that codon-specific <i>KRAS</i> mutations affect PDAC outcomes differently based on disease stage at diagnosis. As studies testing <i>KRAS</i> inhibitors continue to emerge and mature, the prognostic variability of individual <i>KRAS</i> mutations must be carefully considered to avoid confounding and ensure accurate evaluation of therapeutic efficacy in early-phase studies.