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

## TL;DR

This study finds that specific POLE gene mutations in endometrial cancer are linked to better survival rates, suggesting a shift in how patients are classified and treated.

## Contribution

The study provides a meta-analysis confirming that POLE exonuclease-domain mutations are strongly associated with improved survival outcomes in endometrial cancer.

## Key findings

- POLE-mutant endometrial cancer patients have a 65% lower risk of death compared to non-mutant patients.
- Disease-free survival is significantly better in POLE-mutant patients with a pooled hazard ratio of 0.22.
- Cancer-specific survival rates are exceptionally high in POLE-mutant patients, often with zero events reported.

## Abstract

Endometrial cancer, a common gynecological malignancy, has traditionally been classified by its appearance under the microscope. Still, this approach often misses key biological details that predict disease progression. Specific mutations in the POLE gene, which helps proofread DNA during cell division, create highly unstable tumors, yet surprisingly lead to better patient outcomes. This study reviews existing research and combines data from multiple studies to clarify the actual survival benefits of these patients with POLE mutations. The findings could help doctors better classify patients based on risk level, potentially allowing safer reductions in aggressive treatments for those with favorable mutations, improving care, and guiding future clinical trials.

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.