Abstract Background: KRAS inhibitors showed promising results in clinical trials. Understanding KRAS mutations and immune regulation is critical for more effective and durable KRAS targeted therapy. KRAS Q61 is rare and less studied in cancer patients. Here we investigate the clinical, molecular, tumor microenvironment (TME) features of KRAS Q61 mutated gastrointestinal (GI) malignancies. Methods: We used the Palantir Foundry system to query electronic health records of patients diagnosed with colorectal (CRC), pancreatic (PDAC), appendiceal (AA), cholangiocarcinoma (CC), hepatocellular carcinoma (HCC) and gastroesophageal carcer who were tested for KRAS mutations in our institution between 2002-2025. Clinical, molecular, and overall survival (OS) data were collected and studied. Subsets of PDCA and CRC patients who had tumoral bulk RNA sequencing and their TME characteristics were also analyzed. Results: KRAS mutation was tested in 13, 535 patients with CRC, PDAC, CC, AA, and gastroesophageal cancer. 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 all KRAS mutations (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. The other top mutated genes 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. Compared to KRAS wildtype, patients with KRAS mutations had worse OS in CRC (p0. 05) and longer OS in AA patients (p0. 05). Compared to other KRAS mutations, KRAS Q61 had worse OS in PDAC than other KRAS mutated PDAC and wildtype patients (19. 9 months for KRAS Q61, 24. 6 months for other KRAS mutations and 38. 7 months for wildtype, p0. 05). KRAS mutated tumors, especially KRAS Q61 mutated tumors, had more immunosuppressive, fibrotic TME than KRAS wildtype tumors and showed enrichment of hypoxia and TGF-β pathway gene expression in PDAC. Conclusions: KRAS Q61 mutations frequencies varied across different GI malignancies, with the highest frequency in PDAC (6. 2%). KRAS co-mutation landscape showed cancer specificities such as APC mutation in CRC, CDKN2A in PDAC, ARID1A for CC and GNAS mutations in AA. KRAS Q61 mutations had worse OS in patients with PDAC and more immune suppressive and fibrotic TME and enrichment of hypoxia and TGF-β pathway gene expression. Citation Format: Dan Zhao, Sali Albarouki, Ahemd 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, Ethan B. Ludmir, Mark Hurd, Yang Chen, Haoqiang Ying, Rebecca A Snyder, Matthew H. G. Katz, Anirban Maitra, John Paul. Shen. Clinical and Molecular Characteristics of KRAS Q61 Mutated Pancreatic Cancer and Other Gastrointestinal Malignancies abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85 (18Suppl₃): Abstract nr B076.
Zhao et al. (Sun,) studied this question.