Conclusions:

KRAS WT PC is significantly more enriched with targetable alterations (e.g., BRAF, ALK, ROS1, NRG1, MSI-H) as compared to KRAS MT tumors, suggesting potential benefit of using targeted therapies. – The use of WTS in combination with NGS identifies activated molecular pathways in the majority of KRAS WT tumors. – Based on our findings, comprehensive profiling of PC at the DNA and RNA level is recommended to provide patients with therapeutic opportunities beyond standard treatments. – TMB and MSI tend to be higher in KRAS WT tumors; microenvironment inferred from WTS using MCP counter suggest more activated innate immunity with a lower fibroblast abundance, suggesting unique immune treatment strategy design.