Biomarkers guiding fertility-sparing treatment in endometrial cancer

Fertility-sparing treatment is an established option for reproductive-age women with early-stage endometrioid endometrial cancer or atypical endometrial hyperplasia. Despite high initial response rates with progestin-based therapy, predicting treatment response and recurrence remains challenging. This narrative review summarizes current evidence on prognostic and predictive biomarkers for conservative management. Progesterone receptor positivity is the most consistent favorable predictor of response, while POLE ultra-mutated tumors show excellent remission and low recurrence. Mismatch repair deficiency and p53 abnormalities are strong negative predictors, associated with poor response and higher relapse risk. PTEN loss and PIK3CA mutations may contribute to hormonal resistance, especially in combination. Ki-67 and L1 neuronal cell adhesion molecule provide additional prognostic value for recurrence risk. Elevated serum human epididymis protein 4 levels predict poor response to progestin-based therapy and represent the most promising non-invasive biomarker for patient selection and monitoring. Urine metabolomics is emerging as a complementary non-invasive tool. Magnetic resonance imaging-based radiomics and apparent diffusion coefficient histogram analysis show promise in predicting complete response and identifying resistance patterns before treatment. However, no single biomarker is sufficient for clinical decision-making. Future progress requires multi-modal strategies integrating molecular, serum, and imaging data, validated in prospective multi-center studies.