Differential outcomes and immune checkpoint inhibitor response among endometrial cancer patients with MLH1 hypermethylation versus MLH1 "Lynch-like" mismatch repair gene mutation

Michael D Toboni; Sharon Wu; Alex Farrell; Joanne Xiu; Jennifer R Ribeiro; Matthew J Oberley; Rebecca Arend; Britt K Erickson; Thomas J Herzog; Premal H Thaker; Matthew A Powell

doi:10.1016/j.ygyno.2023.08.015

Differential outcomes and immune checkpoint inhibitor response among endometrial cancer patients with MLH1 hypermethylation versus MLH1 "Lynch-like" mismatch repair gene mutation

Gynecol Oncol. 2023 Oct:177:132-141. doi: 10.1016/j.ygyno.2023.08.015. Epub 2023 Sep 8.

Authors

Affiliations

¹ University of Alabama at Birmingham, Division of Gynecologic Oncology, Birmingham, AL, USA. Electronic address: MDToboni@uabmc.edu.
² Caris Life Sciences, Phoenix, AZ, USA.
³ UAB Comprehensive Cancer Center Experimental Therapeutics Program, Birmingham, AL, USA.
⁴ University of Minnesota, Division of Gynecologic Oncology, Minneapolis, MN, USA.
⁵ University of Cincinnati Cancer Center, Cincinnati, OH, USA.
⁶ Washington University School of Medicine, Division of Gynecologic Oncology, St. Louis, MO, USA.

PMID: 37683549
DOI: 10.1016/j.ygyno.2023.08.015

Abstract

Objectives: To identify differential survival outcomes and immune checkpoint inhibitor (ICI) response in MLH1 hypermethylated versus MLH1 mutated ("Lynch-like") endometrial tumors and determine whether their molecular profiles can elucidate the differential outcomes.

Methods: 1673 mismatch repair deficient endometrial tumors were analyzed by next-generation sequencing and whole transcriptome sequencing (Caris Life Sciences, Phoenix, AZ). PD-L1, ER, and PR were tested by immunohistochemistry and immune cell infiltrates were calculated using MCP-counter. Significance was determined using Chi-square and Mann-Whitney U tests and adjusted for multiple comparisons. Overall survival (OS) was depicted using Kaplan-Meier survival curves.

Results: The endometrial cancer cohort comprised 89.2% patients with MLH1 hypermethylated tumors and 10.8% with MLH1 mutated tumors, with median ages of 67 and 60 years, respectively (p < 0.01). Patients with MLH1 hypermethylated tumors had significantly worse OS and trended toward worse OS following ICI treatment than patients with MLH1 mutated tumors. The immune microenvironment of MLH1 hypermethylated relative to MLH1 mutated was characterized by decreased PD-L1 positivity, immune checkpoint gene expression, immune cell infiltration, T cell inflamed scores, and interferon gamma (IFNγ) scores. MLH1 hypermethylation was also associated with decreased mutation rates in TP53 and DNA damage repair genes, but increased rates of JAK1, FGFR2, CCND1, and PTEN mutations, as well as increased ER and PR positivity.

Conclusions: Endometrial cancer patients with MLH1 hypermethylation display significantly decreased survival and discrepant immunotherapy responses compared to patients with MLH1 mutated tumors, which was associated with differential mutational profiles, a more immune cold phenotype, and increased ER/PR expression in MLH1 hypermethylated tumors. Providers may consider early transition from single agent ICI to a multi-agent regimen or hormonal therapy for patients with MLH1 hypermethylated tumors.

Keywords: Endometrial cancer; Hormonal therapy; Immune microenvironment; Immunotherapy; MLH1 hypermethylation; MLH1 mutation; Mismatch repair deficiency; Molecular profiling; Precision oncology.