Abstract 2547: KRAS Q61 mutations in patients with gastrointestinal malignancies and association with real-world clinical outcomes
Authors: Yousef Mahmoud , Yousef Abdelrahman , Chowdhury Saikat , Fanaeian Mohammad Mahdi , Knafl Mark , Roy Paul M. , Pillai Ashwathy , Zeineddine Mohammad , Zeineddine Fadl , Peterson Jennifer , Smaglo Brandon G. , Wolff Robert A. , Pant Shubham , Lee Michael Sangmin , Willis Jason A. , Overman Michael James , Ludmir Ethan Bernard , Hurd Mark W. , Shen John Paul , Zhao Dan 
Published: March 2024

Abstract
Introduction: Gene-wide KRAS mutation has been associated with worse outcomes in multiple malignancies with newer data suggesting differential impact based on specific allele. Mutation at codon Q61 is relatively infrequent with clinical significance not well understood. Here we aim to investigate the clinical significance of KRASQ61 mutation in gastrointestinal (GI) malignancies.
Methods: The Foundry software platform was used to retrospectively query electronic health records to identify patients diagnosed with colorectal (CRC), pancreatic (PDAC), appendiceal (AA), cholangiocarcinoma (CC) and gastroesophageal carcinoma who underwent clinical testing for KRAS mutations in our institution between 2002-2023; clinical, molecular, and overall survival (OS) data were collected.
Results: KRAS mutation was tested in 9,088 patients with CRC, PDAC, CC, AA, and gastroesophageal carcinoma. Incidence of KRAS mutation was 47% (n= 3,181) for patient with CRC, 82% for PDAC (n= 579), 16% for CC (n= 76), 51% for AA (n= 236), and 7% for gastroesophageal carcinoma (n= 43). KRASQ61 mutation was in 5% (n=218) of patients with KRAS mutation (n= 4,115). Overall frequency of KRASQ61 was 2% (n= 156) for CRC, 5% (n= 36) for PDAC, 3% (n= 12) for CC, 2% (n= 10) for AA and 1% (n= 4) for gastroesophageal carcinoma. KRASQ61 fraction of KRAS mutations was 5% for CRC, 6% for PDAC, 16% for CC, 4% for AA, 9% for gastroesophageal carcinoma. KRASQ61H was the most frequent KRASQ61 mutation among all tumor types, 57%, 61%, 60%, 50% out of KRASQ61 for CRC, PDAC, AA, and gastroesophageal carcinoma respectively; followed by KRASQ61L (20%) for CRC, but KRASQ61R for PDAC (25%), AA (20%), and gastroesophageal (25%); Patients with CC showed exclusively KRASQ61H mutations. Compared to patients with KRAS wildtype, patients with KRASQ61 mutations had worse OS in PDAC (median OS=20 vs 37 months, HR=1.9, 95%CI=1.2-3, p=0.006), while (55 vs 63 months, HR=1.2, 95%CI=0.98-1.5, p=0.076) for CRC, (29 vs 25 months, HR=1.3, 95%CI=0.64-2.6, p=0.47) for CC, and (33 vs 52 months, HR=1.1, 95%CI=0.5-2.6, p=0.75) for AA. Compared to other KRAS mutations, KRASQ61 median OS was (55 vs 53 months, HR=1, 95%CI=0.81-1.3, p=0.96) for patients with CRC, (20 vs 26 months, HR=1.4, 95%CI=0.91-2.1, p=0.1) for PDAC, (25 vs 28 months, HR=1.1, 95%CI=0.54-2.5, p=0.72) for CC, (33 vs 78 months, HR=1.6, 95%CI=0.72-3.7, p=0.24) for AA.
Conclusion: KRASQ61 mutations frequency varied from 1% to 5% across different GI malignancies, with highest frequency in PDAC and CC. KRASQ61 mutations had worse OS in patients with PDAC which may suggest different co-mutations rather than specific KRASQ61 activity difference. Further allele specific analysis of KRASQ61 and co-mutations landscape is underway.
Citation Format: Mahmoud Yousef, Abdelrahman Yousef, Saikat Chowdhury, Mohammad Mahdi Fanaeian, Mark Knafl, Paul M. Roy, Ashwathy Pillai, Mohammad Zeineddine, Fadl Zeineddine, Jennifer Peterson, Brandon G. Smaglo, Robert A. Wolff, Shubham Pant, Michael Sangmin Lee, Jason A. Willis, Michael James Overman, Ethan Bernard Ludmir, Mark W. Hurd, John Paul Shen, Dan Zhao. KRAS Q61 mutations in patients with gastrointestinal malignancies and association with real-world clinical outcomes [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 2547.