MLH1 hypermethylation predicts poor outcomes with pembrolizumab in recurrent endometrial cancer

Objectives: To determine response rate, recurrence-free survival, and overall survival to pembrolizumab in recurrent endometrial adenocarcinomas based upon the classification of mismatch repair (MMR) deficiency. Methods: A retrospective study was conducted among all women with recurrent endometrial adenocarcinomas treated with single-agent pembrolizumab at our institution from 2017 to 2021. Cases were included if complete mismatch repair data were available and were categorized based upon MMR status – germline Lynch Syndrome mutation (gLS), somatic Lynch Syndrome mutation (sLS), or MLH1 promoter hypermethylation (hMLH1). Clinical and pathologic data were abstracted by chart review and included patient demographics, tumor characteristics, recurrence date, and treatment. Continuous predictors were compared between groups using two-sample t-tests. Ordinal predictors such as stage and grade were compared using Wilcoxon rank-sum tests. Categorical predictors were compared using Fisher’s exact tests due to small counts. Unadjusted differences in survival were compared with log-rank tests and visualized with Kaplan-Meier curves. Cox proportional hazards models were used to compare differences in survival between groups after adjusting for BMI. All statistical tests were conducted in R v3.5.1 with an alpha level of 0.05. Results: Eighteen patients were categorized into two groups based upon results of tumor MMR testing and germline genetic testing: gLS/sLS (n = 6, 33.3%) or hMLH1 (n = 12, 66.7%). The hMLH1 patients had a higher mean BMI than gLS/sLS patients (40.9 vs 28.5, p = 0.003). Demographic and tumor characteristics were otherwise well-matched between groups. Median follow-up was 9.45 months with a response rate of 55.6%. When stratified by MLH1 hypermethylation status, response rate was 83.3% in gLS/sLS patients and 41.7% in hMLH1 patients, though this did not reach statistical significance (p = 0.152). Recurrence-free survival (RFS) was significantly decreased among hMLH1 patients (p = 0.031). Similarly, overall survival (OS) was significantly decreased for these patients (p = 0.037), as shown in Figure 1. Objectives: To determine response rate, recurrence-free survival, and overall survival to pembrolizumab in recurrent endometrial adenocarcinomas based upon the classification of mismatch repair (MMR) deficiency. Methods: A retrospective study was conducted among all women with recurrent endometrial adenocarcinomas treated with single-agent pembrolizumab at our institution from 2017 to 2021. Cases were included if complete mismatch repair data were available and were categorized based upon MMR status – germline Lynch Syndrome mutation (gLS), somatic Lynch Syndrome mutation (sLS), or MLH1 promoter hypermethylation (hMLH1). Clinical and pathologic data were abstracted by chart review and included patient demographics, tumor characteristics, recurrence date, and treatment. Continuous predictors were compared between groups using two-sample t-tests. Ordinal predictors such as stage and grade were compared using Wilcoxon rank-sum tests. Categorical predictors were compared using Fisher’s exact tests due to small counts. Unadjusted differences in survival were compared with log-rank tests and visualized with Kaplan-Meier curves. Cox proportional hazards models were used to compare differences in survival between groups after adjusting for BMI. All statistical tests were conducted in R v3.5.1 with an alpha level of 0.05. Results: Eighteen patients were categorized into two groups based upon results of tumor MMR testing and germline genetic testing: gLS/sLS (n = 6, 33.3%) or hMLH1 (n = 12, 66.7%). The hMLH1 patients had a higher mean BMI than gLS/sLS patients (40.9 vs 28.5, p = 0.003). Demographic and tumor characteristics were otherwise well-matched between groups. Median follow-up was 9.45 months with a response rate of 55.6%. When stratified by MLH1 hypermethylation status, response rate was 83.3% in gLS/sLS patients and 41.7% in hMLH1 patients, though this did not reach statistical significance (p = 0.152). Recurrence-free survival (RFS) was significantly decreased among hMLH1 patients (p = 0.031). Similarly, overall survival (OS) was significantly decreased for these patients (p = 0.037), as shown in Figure 1.