Distinct Molecular and Clinical Features of Specific Variants of KRAS Codon 12 in Pancreatic Adenocarcinoma

Purpose: Oncogenic mutations in KRAS have been identified in >85% of pancreatic ductal adenocarcinoma (PDAC) cases, with G12D, G12V, and G12R being 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 KRAS^G12R. Experimental Design: PDAC samples were tested using DNA and RNA sequencing. The 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 χ² and Fisher exact tests. Results: A total of 3,755 patients with PDAC harboring KRAS^G12D (n ¼ 1,766), KRAS^G12V (n ¼ 1,294), KRAS^G12R (n ¼ 621), or KRAS^G12C (n ¼ 74) variants were identified. Patients with G12R mutations had longer OS compared with those with G12D overall (12.7 vs. 10.1 months; P value ¼ 0.0001), with similar trends in patients treated with gemcitabine/nab-paclitaxel (13.5 vs. 10.4 months; P value ¼ 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 genes involved in glucose and glutamine metabolism were less expressed in G12R compared with G12D. PD-L1 expression was lower in G12R compared with G12D (13% vs. 19%). Conclusions: KRAS^G12D tumors exhibited a distinct molecular profile compared with G12R tumors, including genes involved in the MAPK pathway, immune activation, and glucose and glutamine metabolism. Patients with G12D mutations had lower OS compared with those with G12R. Based on these data, future studies should address the KRAS mutation status and explore distinct therapeutic vulnerabilities.