MLH1 promoter hypermethylation and associations with survival outcomes: A real-world endometrial cancer molecularly targeted therapy consortium cohort study.

OBJECTIVE: We assessed the underlying etiology of MMR deficiency (dMMR), genetic (germline/somatic) versus epigenetic hMLH1, and associations between response rate, and survival outcomes in patients with advanced and recurrent dMMR endometrial adenocarcinoma treated with immune checkpoint inhibitors. METHODS: The Endometrial Cancer Molecularly Targeted Therapy Consortium (ECMT2) database was used to identify patients with mismatch repair deficient (dMMR) tumors treated with pembrolizumab or dostarlimab from 2016 to 2023. Cases were categorized into two groups- germline Lynch Syndrome mutation (gLS) and somatic Lynch Syndrome mutation (sLS), or MLH1 promoter hypermethylation (hMLH1). Clinical and pathologic data included patient demographics, tumor characteristics, recurrence date, survival, and treatment. RESULTS: A total of 133 patients were included: gLS/sLS (n = 34, 25.6%) or hMLH1 (n = 99, 74.4%). Demographic and tumor characteristics, including stage at diagnosis and histology were similar between groups. The response rate was 57.1% for the entire cohort [55.9% gLS/sLS, 57.6% hMLH1; (p = 0.90)]. The survival outcomes were not significantly different in the gLS/sLS and hMLH1 groups [2-year progression-free survival: 68.0% and 59.0% (p = 0.77); 2-year overall survival: 70.9% and 62.2% (p = 0.55)], respectively. CONCLUSION: Our findings suggest that response to immune checkpoint inhibitors and survival outcomes are not associated with different mechanisms of dMMR.

Duke Scholars

Author Angeles Alvarez Secord Obstetrics and Gynecology, Gynecologic Oncology