Distribution of driver and allele-specific KRAS mutations across racial and ethnic groups in pancreatic adenocarcinoma.

773 Background: Pancreatic ductal adenocarcinoma (PDAC) arises from recurrent alterations in core driver genes, yet the incidence of these mutations in patients according to self-identified race and ethnicity remains poorly characterized. Methods: We identified patients with PDAC diagnosed from 2016-2024 who underwent targeted molecular testing at a single, high-volume institution. Clinical and genomic data were extracted from the institutional cancer registry and electronic health record and harmonized using Palantir Foundry. Sequencing was performed by institutional panels (MDA MAPP, STGA-DNA) and commercial assays (FoundationOne, Guardant360, BostonGene, etc). Mutation and allele frequencies were compared according to self-reported race and ethnicity using chi-squared or Fisher’s tests. False discovery rate (FDR) correction was performed independently for gene-level and allele-level analyses using the Benjamini-Hochberg method. Results: Among 1610 patients identified, 73.7% of patients self-identified as non-Hispanic White (NHW), 10.6% Hispanic, 7.6% Asian, and 8.1% Black. Mutations in KRAS were detected in 87.9% of patients (88.2% NHW, 85.6% Hispanic, 83.2% Asian, 92.7% Black; FDR=0.103). Among the 1369 patients with KRAS -mutant tumors, the most common allele subtypes were KRAS G12D (39.5%) and KRAS G12V (32.2%), followed by KRAS G12R (15.9%), and KRAS Q61 (7.2%). Mutation allele subtype distributions differed by self-reported race and ethnicity (FDR=0.021). NHW and Hispanic patients most often had tumors with KRAS G12D mutations (40.5% and 36.5%, respectively). Asian patients showed a relative increase compared to other groups in tumors with KRAS G12R mutations (20.2%) and rarely had KRAS Q61 mutated tumors (2.0%). Black patients predominantly had mutations in KRAS G12V (37.7%) with a relative increase in KRAS Q61 subtypes (11.4%) compared to others. CDKN2A was the only other gene demonstrating differences between groups (14.7% Hispanic, range 21.1%–23.4% non-Hispanic; FDR = 0.033). Alterations in TP53 (74.6%), SMAD4 (18.7%), ARID1A (9.2%), ATM (6.9%), RNF43 (6.6%), BRCA2 (4.6%), and PIK3CA (4.6%) did not show a significant variation by self-reported race and ethnicity (FDR>0.05 for all). Conclusions: Apart from CDKN2A , overall frequencies of driver mutations were similar across self-reported racial and ethnic groups in patients with PDAC, but allele-specific differences in KRAS mutations highlight potentially meaningful biologic heterogeneity. Because allele-specific subtypes may be associated with therapeutic sensitivity, prognosis, and eligibility for emerging targeted therapies, recognizing these distinctions is essential to ensure equitable advances in precision oncology.