Abstract
INTRODUCTION: While KRAS mutations represent the primary oncogenic driver in pancreatic ductal adenocarcinoma (PDAC), the association between codon-specific alterations and patient outcomes remains poorly elucidated, largely due to a lack of datasets coupling genomic profiling with rich clinical annotations across disease stages. PATIENTS AND METHODS: We utilized AACR's GENIE Biopharma Consortium Pancreas v1.2 dataset to test the associating of codon-specific KRAS mutations with clinicogenomic features and patient outcomes in PDAC patients diagnosed with localized (stages I-III) and advanced disease (stage IV). Overall survival was compared using Kaplan-Meier and multivariable Cox proportional hazards methods. RESULTS: Among 1,032 eligible patients, 949 (92%) exhibited mutant KRAS . 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 to G12D mutation ( P = 0.002). In contrast, patients with G12V mutation who presented with metastatic disease experienced shorter overall survival compared to those with G12R ( P = 0.005), and G12D mutations ( P = 0.009). Furthermore, no significant differences were observed in the frequencies of co-altered driver genes, including TP53 , CDKN2A , and SMAD4 , across the different KRAS mutations. CONCLUSIONS: These findings demonstrated that codon-specific KRAS mutations impact PDAC outcomes differently based on disease stage at diagnosis. As studies testing KRAS inhibitors continue to emerge and mature, these data offer important contextual insights regarding survival outcomes associated with codon-specific KRAS mutations based on existing therapeutic approaches.