Abstract 2128: Genomic alterations in DNA mismatch repair (dMMR)

Abstract Background PD-1 inhibitors have been shown to be effective in advanced cancer patients with mismatch repair deficient tumors (dMMR) in a tumor agnostic fashion. dMMR testing by immunohistochemistry (IHC) is infrequently performed outside of colorectal and endometrial cancer. In contrast, comprehensive genomic sequencing (CGS) for somatic genomic alterations, is frequently perfomed across tumor types. We hypothesized that CGS may identify alterations in dMMR genes (MLH1, MSH2, MSH6, PMS2), and that patients with genomic MMR alterations will have higher rates of dMMR loss by IHC. Methods From Jan 2016 to Dec 2021, 15,701 patients were identified as receiving CGS. Sequencing results were analyzed for mutations in dMMR genes, tumor type distribution and concordance with IHC results. Results 627 (4%) of 15,701 patients had mutations in one of the dMMR genes; mutations were found across tumor types. Majority of patients with mutations in MMR genes had single nucleotide variants (SNV, 430, 68.6%) followed by frameshift/truncating (155, 24.7%), splice site (31, 4.9%) and in frame deletions/indel (11, 1.6%) mutations. A subset of the MMR gene mutant patients (n=279) had IHC testing for dMMR proteins: 99 (35.5%) demonstrated dMMR loss, including 55 (53.4%) of 103 patients with colorectal cancer, 3 (25%) of 12 patients with endometrial cancer and 41 (25%) of 164 with other tumor types. dMMR loss on IHC was found in 70 (71%) of 99 patients with frameshift/truncation/splice site/indel mutations compared with 29 (29%) of patients with SNVs (x2=8.49; p=0.00038). Conclusion Mutations in MMR genes are found in multiple tumor types. Reflex IHC testing of patients carrying dMMR mutations inferred to be inactivating may identify patients with dMMR, expanding the pool of patients eligible for immunotherapy. Citation Format: Vijaykumar Holla, Arash Ronaghy, Richard K. Yang, Keyur P. Patel, Mark J. Routbort, Michael J. Overman, Ecaterina E. Dumbrava, Kenna R. Shaw, Daniel D. Karp, Funda Meric-Bernstam. Genomic alterations in DNA mismatch repair (dMMR) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2128.