Abstract B049: Molecular Characteristics of <i>KRAS</i> Q61 Mutated Gastrointestinal Malignancies and Clinical Outcomes

Abstract Background and Aims: KRAS Q61 is rare and not well characterized in cancer patients. Here we investigate the clinical and molecular features of KRAS Q61 mutated gastrointestinal (GI) malignancies. Methods: We used the Foundry system to query electronic health records of patients diagnosed with colorectal (CRC), pancreatic (PDAC), appendiceal (AA), cholangiocarcinoma (CC) and gastroesophageal carcinoma and tested for KRASmutations in our institution between 2002-2025. Clinical, molecular, and overall survival (OS) data were analyzed with subsets of PDCA and CRC patients who had bulk RNA sequencing and tumor microenvironment (TME) characterized. Results: KRAS mutation was tested in 13,535 patients with CRC, PDAC, CC, AA, and gastroesophageal carcinoma. KRAS was mutated in 46.4% (n= 4,516) of CRC, 87.1% of PDAC (n=1,357), 18.4% of CC (n=100), 50.3% of AA (n=393), 7.3% of gastroesophageal carcinoma (n=51) and 7.4% of HCC (n=16). KRAS Q61 consisted of 5.3% (n=340) of KRAS mutation (n= 6,433). Frequencies of KRAS Q61 was 2.2% (n=210) for CRC, 6.2% (n=97) for PDAC, 2.4% (n= 13) for CC, 2% (n= 16) for AA and 0.6% (n= 4) for gastroesophageal carcinoma. KRAS Q61H was the most common KRAS Q61 allele. Compared to KRAS wildtype, patients with KRAS mutations had worse OS in PDAC (median OS 19.9 vs 38.7 months, HR=2.2, 95% CI=1.6-3, p&amp;lt;0.001) and CRC (50.8 vs 63.7 months, HR=1.3, 95% CI=1.1-1.5, p=0.01), while KRAS mutated AA had longer OS in AA. Compared to other KRAS mutations, KRAS Q61 had worse OS in PDAC (19.9 vs 24.6 months, HR=1.3, 95%CI=1-1.7, p=0.049). Top genes with KRAS were TP53 (71%) and APC (63%) for CRC, TP53 (76%) and CDKN2A (28%) for PDAC, GNAS (34%) and TP53 (34%) for AA, and TP53 (30%) and ARID1A (19%) for CC. Co-mutated genes showed cancer specificites, such as APC in CRC, CDKN2A and SMAD4 in PDAC, GNAS in AA and BAP1 and IHD1 in CC. KRAS mutated tumors especially KRAS Q61 mutated tumors, had more immunosuppressive, fibrotic TME and enrichment of hypoxia and TGF-β pathway gene expression in PDAC. Conclusion: KRAS Q61 mutations frequency varied from 1% to 5% across different GI malignancies, with highest frequency in PDAC and CC. KRAS Q61 mutations had worse OS in patients with PDAC and more immune suppressive and fibrotic TME. Citation Format: Dan Zhao, Mahmoud Yousef, Sali Albarouki, Ahemed Elhariri, Abdelrahman Yousef, Saikat Chowdhury, Mark Knafl, Paul Roy, Brandon Smaglo, Robert A. Wolff, Shubham Pant, Jason Willis, Ryan Huey, Michael J. Overman, Camila L. Lopez, Anthony B. Chen, Eugene Koay, Ethan B. Ludmir, Mark Hurd, Yang Chen, Haoqiang Ying, Rebecca A. Snyder, Matthew H.G. Katz, Anirban Maitra, John Paul. Shen. Molecular Characteristics of KRAS Q61 Mutated Gastrointestinal Malignancies and Clinical Outcomes [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr B049.