Distinct molecular and clinical features of specific variants of KRAS codon 12 in pancreatic adenocarcinoma

Abstract PURPOSE Oncogenic mutations in KRAS have been identified in > 85% of pancreatic ductal adenocarcinoma (PDAC) cases. G12D, G12V, and G12R are the most frequent variants. Using large clinical and genomic databases, this study characterizes prognostic and molecular differences between KRAS variants, focusing on KRAS G12D and G12R. METHODS PDAC samples were tested using DNA and RNA sequencing. MAPK activation score and tumor microenvironment were analyzed from RNA expression data. Real-world overall survival (OS) obtained from insurance claims data was calculated from tissue collection to last contact. Significance was determined by X2 and Fisher-Exact tests. RESULTS 3,755 PDAC patients harboring KRAS G12D (n = 1,766), G12V (n = 1,294) G12R (n = 621) or G12C (n = 74) variants were identified. Patients with G12R mutations had longer OS compared to G12D overall (12.7 vs 10.1 months, p-value=0.0001), with similar trends in patients treated with gemcitabine/nab-paclitaxel (13.5 vs 10.4 months, p-value=0.0002) or FOLFIRINOX (18.3 vs 14.0 months, p-value<0.001). ARID1A and KMT2D mutations were more frequent in the G12D subgroup. Several glucose and glutamine metabolism genes were less expressed in G12R vs G12D. PD-L1 expression was lower in G12R vs G12D (13% vs 19%). CONCLUSION KRAS G12D tumors exhibited a distinct molecular profile compared to G12R tumors, including genes involved in the MAPK pathway, immune activation, and glucose and glutamine metabolism. Patients with G12D mutations had lower OS compared to G12R. Based on this data, future studies should address the KRAS mutation status and explore distinct therapeutic vulnerabilities.