Comprehensive analysis of KRAS variants in patients (pts) with pancreatic cancer (PDAC): Clinical/molecular correlations and real-world outcomes across standard therapies.

Abstract

4641 Background: Approximately 90% of PDAC tumors are driven by activating KRAS mutations. The biological and clinical impact of common KRAS variants (e.g. G12D, G12V, G12R) and less common variants (e.g. G12C, Q61H, Q61R) remains largely unknown despite the emergence of variant-specific treatment strategies. Methods: We retrospectively analyzed real-world outcomes from 1475 PDAC pts who underwent molecular profiling via the Know Your Tumor program. Overall survival (OS) and progression-free survival (PFS) were analyzed by choice of 1st line standard therapies. Outcomes in pts with specific KRAS mutations were compared against the KRAS G12D cohort using Cox regression. Based on our prior data, tumor profiles with actionable molecular findings (DDR mutations or other drivers) were evaluated separately. Results: The prognostic/predictive value of specific KRAS variants revealed differences in real-world outcomes (Table). OS was greater in pts with KRAS G12V and G12R variants, as was PFS on 5FU-Based Therapy (e.g. FOLFIRINOX) but not for Gemcitabine/nab-Paclitaxel. Opposing trends were noted for KRAS Q61. Pts with KRAS wild type tumors as well as both actionable subgroups also had an improved OS. Conclusions: In this large national dataset, we demonstrate that KRAS mutation status and specific variants appear to be prognostic as well as predictive in pancreatic cancer. [Table: see text]