Fertility-Sparing Treatment of Endometrial Cancer and Atypical Endometrial Hyperplasia by Molecular Classification: A Systematic Review and Meta-Analysis Accounting for Outcome-Assessment Timing and Follow-Up Duration.

Background/

Objectives

Molecular classification (POLE-mutated, mismatch-repair-deficient [MMRd], no-specific-molecular-profile [NSMP], p53-abnormal [p53abn]) is used to stratify women receiving fertility-sparing treatment (FST) for early endometrial carcinoma or atypical hyperplasia, but reported subtype differences are inconsistent. We estimated subtype-specific complete response (CR) and post-CR recurrence and examined how outcome-assessment timing (fixed early timepoint versus best response) and follow-up duration affect subtype comparisons.

Methods

PubMed and Embase (January 2015-August 2025) were searched; overlapping reports were consolidated; proportions were pooled with binomial-normal generalised linear mixed models; late response among early non-responders was analysed in paired cohorts; recurrence was meta-regressed on follow-up; risk of bias (QUIPS) and certainty (GRADE) were assessed.

Results

Twenty reports yielded 15 cohorts (10 primary). Best CR was 85% (95% CI 70-93) for POLE, 71% (57-83) for MMRd, and 85% (77-91) for NSMP. In six paired cohorts, CR rose from the early timepoint to best response in every subtype (MMRd 44→77%, NSMP 57→90%); 55% of MMRd and 76% of NSMP early non-responders later achieved CR, and within-cohort best CR was lower for MMRd than NSMP (odds ratio [OR] 0.36, 0.17-0.79). Recurrence after CR was 34% (23-46) for MMRd, 30% (17-49) for NSMP, and 19% (4-57; 0-100% across cohorts) for POLE. NSMP recurrence tended to rise with follow-up in an exploratory study-level analysis (OR 1.02/month; p = 0.06, dependent on the few long-follow-up cohorts), whereas MMRd recurrence did not (adjusted OR vs. NSMP 1.7, 0.9-3.3). p53abn tumours (n = 28) showed variable CR (17/24) and recurrence in 9/17. Occult p53abn or MMRd tumours affected 17% (12-24%; range 7-47%) of conventionally selected candidates. Certainty was low or very low.

Conclusions

Subtype comparisons in FST depend on when outcomes are assessed and how long patients are followed. Molecular classification is prognostic, not predictive; its principal value is to identify occult higher-risk tumours and to calibrate counselling and surveillance, not to justify de-escalation.