Molecular and Clinicopathological Characteristics Predict Fertility‐Sparing Treatment Outcomes in Endometrial Atypical Hyperplasia and Endometrioid Endometrial Cancer

Rising incidence of endometrial cancer among young women has increased the demand for fertility-sparing treatment (FST) in patients with endometrial atypical hyperplasia (EAH) and endometrioid endometrial cancer (EEC). However, approximately 20%-30% of patients exhibit progesterone resistance, and reliable predictive biomarkers remain inadequately defined. Therefore, we aimed to identify biomarkers associated with treatment response and prognosis in patients undergoing FST. In this retrospective study, we analyzed 161 patients undergoing mainly progestin-based FST, including 125 with EAH and 36 with G1 EEC. Molecular classification, pretreatment pathological morphology, hormone receptor expression, oncological outcomes, recurrence, and reproductive outcomes were evaluated. According to molecular classification, the cohort included POLEmut (n = 2), NSMP (n = 143), MMRd (n = 11), and p53abn (n = 5). Over a median treatment duration of 7 months, molecular classification significantly stratified complete response (CR) rates (p = 0.027), with distinct cumulative CR curves (p = 0.034). Patients with EEC showed lower CR rates than those with EAH (p < 0.001). Reduced CR was associated with extensive lesions, larger lesion diameter, proliferative endometrial background, papillary structure, and squamous metaplasia, whereas morular metaplasia and high estrogen receptor (ER)/progesterone receptor (PR) expression predicted higher CR rates. Multivariate analysis identified MMRd and squamous metaplasia as independent predictors of recurrence. Within the NSMP subgroup, pathological morphology and PR expression further refined risk stratification. Pregnancy outcomes were comparable across molecular subtypes. These findings suggested that integrating molecular classification with clinicopathological characteristics can improve prognostic assessment and support individualized management for patients undergoing FST.