Performance of molecular classification in predicting oncologic outcomes of fertility-sparing treatment for atypical endometrial hyperplasia and endometrial cancer

Objective: Endometrial cancers can be classified into 4 molecular sub-groups: (1) POLE mutated (POLEmut), (2) mismatch repair deficiency/microsatellite-instable (MMRd/MSI-H), (3) TP53-mutant or p53 abnormal (p53abn), and (4) no specific mutational profile (NSMP). Although molecular classification is increasingly applied in oncology, its role in guiding fertility-sparing treatments for endometrial cancer remains unclear. This study examines the prognostic role of molecular classification in fertility-sparing treatment and its potential to guide treatment decisions. Methods: We conducted a systematic review and meta-analysis of studies applying molecular classifiers in patients with endometrial cancer or atypical hyperplasia who underwent fertility-sparing treatment (International Prospective Register of Systematic Reviews, identification CRD42024555559). A literature search was performed across Scopus, PubMed/MEDLINE, ScienceDirect, and the Cochrane Library (2013-February 2024). Studies included full-text English articles with pre-operative assessments (histology, magnetic resonance imaging, or ultrasound) and molecular classification through next-generation sequencing or Proactive Molecular Risk Classifier for Endometrial Cancer. Both randomized controlled trials and observational studies were considered. Outcomes included complete response, partial response, stable disease, progression, and recurrence, with pooled analyses performed. Results: Eight retrospective cohort studies comprising 363 patients met the inclusion criteria. Next-generation sequencing was used in 5 studies. The distribution of molecular sub-groups was POLEmut (5.8%), p53abn (3.3%), MMRd/MSI-H (12.1%), and NSMP (78.8%). Complete response and recurrence rates were POLEmut (66.6% and 14.3%), p53abn (50% and 33%), MMRd/MSI-H (48.8% and 42.8%), and NSMP (78.4% and 18.4%). Significant differences in complete response (p <.001) and recurrence rates (p = .005) were found across sub-groups. Pairwise analysis revealed lower complete response and higher recurrence rates for MMRd/MSI-H (p <.001, p = .01) and lower response for p53abn (p = .03) than for NSMP. POLEmut did not show superior success to other groups. Conclusion: Molecular classification indicates prognostic value in fertility-sparing treatment for endometrial cancer. NSMP had the highest response rates, whereas MMRd/MSI-H and p53abn were associated with poorer outcomes.