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

PURPOSETumor 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.METHODSIn 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).RESULTSA 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.CONCLUSIONKRAS 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.