Abstract 4980: Genomic and clinical characteristics of advanced pancreatobiliary cancer, stratified by KRAS mutation status
Authors: Miyashita Hirotaka , Shah Parth S. , Brooks Gabriel A. 
Published: March 2024

Abstract
Mutations in KRAS are common in pancreatobiliary cancer, occurring in 90% of advanced pancreatic ductal adenocarcinomas (PDAC) and 20% of advanced cholangiocarcinomas (CCA). We analyzed clinico-genomic databases to evaluate the hypothesis that KRAS mutation status defines subsets of PDAC and CCA with similar genomic characteristics and clinical behavior. Using the genomic data of PDAC and CCA from AACR Project GENIE Cohort version 14.0-public, we analyzed the genomic landscape of four cohorts of pancreatobiliary cancer: KRAS mutated PDAC, KRAS wild-type PDAC, KRAS mutated CCA, and KRAS wild-type CCA. Excluding KRAS mutations, there were 53 gene alterations observed in &gt;2.5% of cases in at least one of the four cohorts. The three most common gene alterations in each cohort were; TP53, SMAD4, and CDKN2A mutations (KRAS mutated PDAC), TP53, ARID1A, and SMAD4 mutations (KRAS wild-type PDAC), TP53 mutation, CDKN2A deletion and SMAD4 mutation (KRAS mutated CCA), and TP53, ARID1D and IDH1 mutations. (KRAS wild-type CCA) The similarity of gene alteration patterns was evaluated by principal component analysis (PCA) 3D plot and calculation of average Euclidean distance. The PCA plot suggested heterogeneous genomic profiles in KRAS wild-type CCA in contrast to relatively monotonous profiles in KRAS mutated PDAC. The average Euclidean distance between KRAS mutated CCA and KRAS wild-type CCA was significantly longer than that between KRAS mutated CCA and KRAS mutated PDAC (2.00 vs. 1.89, p &lt; 0.001), suggesting that KRAS mutated CCA is more genomically related to KRAS mutated PDAC than KRAS wild-type CCA. The average Euclidean distance between KRAS mutated PDAC and KRAS wild-type PDAC was significantly shorter than that between KRAS wild-type CCA and KRAS wild-type PDAC. To compare the clinical characteristics of the four cohorts, we evaluated the data of patients with stage IV pancreatobiliary cancer, using cBioPortal. The number of cases in each cohort was 1544 (KRAS mutated PDAC), 121 (KRAS wild-type PDAC), 91 (KRAS mutated CCA), and 459 (KRAS wild-type CCA). Median overall survival (OS) was 14.7, 21.5, 10.7, and 15.4 months, respectively. Compared to KRAS wild-type CCA, KRAS mutated CCA had a significantly shorter OS (hazard ratio [HR] = 1.45, 95% confidence interval [CI] = 1.12 - 1.89). The OS of KRAS mutated CCA was shorter than KRAS mutated PDAC (HR 1.32, 95% CI 1.03 - 1.68). KRAS wild-type PDAC had a significantly longer OS compared to KRAS mutated PDAC. (HR 0.72, 95% CI 0.57 - 0.92) In conclusion, KRAS mutated CCA has a poor OS and a genomic landscape distinct from KRAS wild-type CCA; it is genomically more similar to KRAS mutated PDAC. KRAS wild-type PDAC has a better OS than KRAS mutated PDAC, though it was not genomically similar to KRAS wild-type CCA. Therapeutic approaches stratified by KRAS mutation status should be considered for pancreaticobiliary cancers.
Citation Format: Hirotaka Miyashita, Parth S. Shah, Gabriel A. Brooks. Genomic and clinical characteristics of advanced pancreatobiliary cancer, stratified by KRAS mutation status [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4980.