Prognostic Impact of POLE Exonuclease-Domain Mutations in Endometrial Cancer: A Systematic Review and Meta-Analysis

Background/Objectives: Traditional histopathological classification of endometrial cancer (EC) exhibits limited prognostic precision due to interobserver variability and incomplete reflection of tumor biology. The Cancer Genome Atlas (TCGA) introduced molecular subtypes, with POLE-ultramutated tumors showing superior outcomes. This systematic review and meta-analysis assesses the prognostic impact of pathogenic/likely pathogenic POLE exonuclease-domain mutations (EDM) on survival in EC. Methods: PRISMA 2020-compliant search of PubMed, Embase, and Web of Science (2015–2025) identified 20 studies (n = 7708 EC patients; 159 POLE-mutant, 2.1%). Eligibility: Adult EC patients with POLE EDM vs. non-POLE, reporting OS/PFS/DFS/RFS/CSS hazard ratios (HR). ROBINS-I assessed bias; random-effects meta-analysis pooled multivariable HR. Results: The meta-analysis revealed a significantly reduced risk of death in POLE-mutant endometrial cancer patients, with an OS pooled hazard ratio (HR) of 0.35 (95% CI 0.21–0.58; I2 = 17.9%) across eight studies. Disease control endpoints (DFS/PFS/RFS) from 10 studies showed an even more substantial benefit, with a pooled HR of 0.22 (95% CI 0.12–0.41; I2 = 0%). Cancer-specific survival HRs ranged from 0.00 to 0.32 across four studies, often with zero events in POLE cohorts. ROBINS-I bias was low to moderate; heterogeneity stemmed from the comparators and stages. Conclusions: POLE-EDM confers a robust, favorable prognosis across EC stages, supporting molecular risk stratification and treatment de-escalation.