August 1, 2025

Evaluating the Effect of KRAS Variants on Survival Outcomes and Therapy Response in Pancreatic Cancer

Key Points

KRAS variants significantly impact overall survival and therapy response in pancreatic cancer, suggesting a personalized approach.
Median overall survival for KRAS wild type was 2.1 years compared to 1.4 years for G12D/V, with a hazard ratio of 0.61.
Retrospective analysis based on real-world data included 1359 patients with early-stage and metastatic pancreatic cancer.
A variance in KRAS type significantly influences prognosis and therapeutic response, indicating tailored therapy may improve outcomes.

Abstract

PURPOSE Tumor molecular profiling is recommended in pancreatic ductal adenocarcinoma (PDAC). However, the predictive and prognostic value of KRAS variants on clinical outcomes including response to standard therapies remains unknown. METHODS In this retrospective analysis using real-world data from patients with early-stage (I to III) and metastatic PDAC who underwent molecular profiling via referrals to Perthera or the PanCAN Know Your Tumor program, patients included were 18 years and older, received standard chemotherapy in the first- and second-line setting, and had complete records. Main outcomes were overall survival (OS) and progression-free survival (PFS) measured from the date of diagnosis of metastatic/recurrent metastatic disease stratified by the KRAS variants and chemotherapy regimen. OS and PFS on first- or second-line therapies were analyzed using Cox regression. Outcomes from each subgroup were compared with reference cohort G12D/V using a Bonferroni-adjusted significance threshold of α = .00714 (0.05/7). RESULTS A total of 1359 patients (median range age, 64 28-94 years; 689 50.7% male; 707 52.0% White) were included. KRAS wild type had significantly longer OS compared with G12D/V (2.1 v 1.4 years; hazard ratio HR, 0.61 95% CI, 0.48 to 0.77; P < .0001). Q61 had shorter OS (1.1 v 1.5 years; HR, 2.28 95% CI, 1.33 to 3.92; P = .0027) and PFS (3.13 v 9.03 months; HR, 2.54 95% CI, 1.43 to 4.52; P = .0015) on first-line fluorouracil-based therapy compared with G12D/V. G12R had numerically longer OS (1.8 v 1.5 years; HR, 0.69 95% CI, 0.48 to 0.98; P = .0366) and PFS (12.17 v 9.03 months; HR, 0.6 95% CI, 0.41 to 0.88; P = .0091) on first-line fluorouracil-based therapy compared with G12D/V. CONCLUSION KRAS variants are associated with survival and may be predictive of response to standard therapies. A molecularly driven, variant-specific approach is recommended to guide PDAC treatment and better inform prognosis.

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