Abstract C098: Impact of KRAS mutations and co-mutations on clinical outcomes in pancreatic ductal adenocarcinoma
Authors: Yousef Abdelrahman , Yousef Mahmoud , Chowdhury Saikat , Abdilleh Kawther , Knafl Mark , Edelkamp Paul , Alfaro-Munoz Kristin , Chacko Ray , Peterson Jennifer , Smaglo Brandon , Wolff Robert , Pant Shubham , Lee Michael , Willis Jason , Overman Michael , Doss Sudheer , Matrisian Lynn , Hurd Mark , Snyder Rebecca , Katz Matthew , Wang Huamin , Maitra Anirban , Shen John Paul , Zhao Dan 
Published: January 2024

Abstract
Background KRAS is the most frequently mutated gene in pancreatic ductal adenocarcinoma (PDAC). Over the past decade, targeting KRAS has emerged as a promising approach for PDAC treatment. However, the associations between KRAS mutations status and comutation landscape with clinical outcomes remain understudied. We investigated the impact of KRAS mutant allelic status and genomic co-mutations with clinical outcomes. Methods 803 patients with PDAC who underwent CLIA somatic tumor mutation testing at MD Anderson Cancer Center (MDACC) from 1997 to 2023 were identified after an IRB approval. Tumor genomic alterations, demographics, clinical, molecular, and pathological data were extracted from electronic medical records and tumor registry through the Palantir Foundry platform. An external cohort from PanCAN’s Know Your Tumor® dataset with 408 patients served as the validation cohort. Overall Survival (OS) was calculated from the date of initial diagnosis to death or last follow-up. Pearson’s chi-squared tests (or Fisher’s exact tests) were used to determine the association between groups. The Kaplan-Meier method was used to estimate the median OS. Results 703 patients had KRAS gene included in the mutation testing at MDACC from 1997 to 2023. KRAS was the top mutated gene (82%), followed by TP53 (69%), then CDKN2A (20%). In KRAS mutant patients, G12D was the most common variant (39%), followed by G12V (31%), then G12R (14%), and Q61 (6%). In patients tested with multi-gene panels, a co-mutation analysis revealed that the most common co-occurring mutations with KRAS mutation was TP53 (75%), followed by CDKN2A (22%), SMAD4 (14%) and ARID1A (10%). The median follow-up was 41 months and median OS was 19 months in the overall population. KRAS mutation status and subtypes was prognostic of OS (p&lt;0.001). Patients with KRAS wildtype had median OS of 38 months and KRASG12R had median OS of 34 months (HR:1.0, 95% CI 0.71-1.5, p=0.88), while patients with KRASQ61 had worst median OS of 20 months (HR: 1.9, 95% CI 1.2-3.0, p=0.006) and KRASG12D had median OS of 22 months (HR: 1.7, 95% CI 1.3-2.3, p&lt;0.001). Similar findings were observed in patients with stage IV disease (n=302), KRASG12D remained associated with significantly worse OS (HR= 1.7, 95% CI 1.1-2.6, p=0.009). There was a significant enrichment of KRASG12D mutation in metastatic disease compared to localized disease (stage I-III) (OR: 1.7, 95% CI 1.2-2.4, p=0.001) and enrichment of KRASG12R mutation in well and moderately differentiated tumors versus poorly differentiated tumors (OR: 1.7, 95% CI 1.05-2.99, p=0.04). In the external cohort (PanCAN’s Know Your Tumor® dataset), similar findings were observed. KRASG12R was associated with longer median OS (32 months), while KRASQ61 (16 months, HR: 2.6, 95% CI 0.88-7.8, p=0.02) and KRASG12D (23 months, HR: 1.68, 95% CI 1.06-2.65, p=0.04) were associated with significantly worse median OS. Conclusion Allele specific associations of KRAS mutation with clinical outcomes were identified in PDAC. We found better OS with G12R and worse OS with G12D and Q61.
Citation Format: Abdelrahman Yousef, Mahmoud Yousef, Saikat Chowdhury, Kawther Abdilleh, Mark Knafl, Paul Edelkamp, Kristin Alfaro-Munoz, Ray Chacko, Jennifer Peterson, Brandon Smaglo, Robert Wolff, Shubham Pant, Michael Lee, Jason Willis, Michael Overman, Sudheer Doss, Lynn Matrisian, Mark Hurd, Rebecca Snyder, Matthew Katz, Huamin Wang, Anirban Maitra, John Paul Shen, Dan Zhao. Impact of KRAS mutations and co-mutations on clinical outcomes in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C098.