MLH1 promoter hypermethylated endometrial cancer survival outcomes: A systematic review and meta-analysis

Mismatch repair deficient (MMRd) endometrial carcinomas (EC) constitute 30 % of ECs and emerging evidence suggests that MLH1 promoter hypermethylated (MLH1ph) tumours may be more aggressive than previously recognized. This study aimed to evaluate overall survival (OS) and progression-free survival (PFS) in MLH1ph ECs compared to non-MLH1ph MMRd ECs.

A systematic review and meta-analysis was conducted following PRISMA guidelines. Five bibliographic databases and three clinical trial registries were searched from inception to January 10, 2025. Eligible studies included randomized/quasi-randomized clinical trials and prospective/retrospective cohort studies evaluating OS or PFS in MLH1ph ECs versus non-MLH1ph MMRd ECs. Data were extracted independently by two authors. Fixed-effect and random-effects meta-analyses estimated pooled HRs, and risk of bias was assessed using the Newcastle-Ottawa Scale.

Of 15,659 studies identified, 11 cohort studies (2007-2023) from six countries included 3980 MMRd EC patients (3176 MLH1ph cases [80 %] and 804 non-MLH1ph MMRd cases [20 %]). Eight studies (n = 2524) were included in the OS meta-analysis and nine studies (n = 1968) in the PFS meta-analysis. Random-effects meta-analyses demonstrated significantly higher risk of (1) death (OS HR 1.34, 95 %CI 1.16-1.56) and (2) disease progression or death (PFS HR 1.33, 95 %CI 1.12-1.58) in MLH1ph ECs compared to non-MLH1ph MMRd ECs.

MLH1ph ECs represent a higher-risk molecular subgroup with significantly poorer survival. Our findings support routine MLH1ph testing when MLH1/PMS2 protein loss is identified. Improved recognition of this subgroup is crucial for refining molecular risk stratification and will enable more personalized and effective oncologic management strategies based on tumour biology.