Refining Fertility-sparing Treatment in Endometrial Carcinoma Based on Molecular Classification

Endometrial cancer (EC) stands among the most common gynecological malignancies in developed countries and regions, with a notable trend toward younger age at onset. Correspondingly, the demand for fertility-sparing treatment (FST) has been increasingly prominent among young EC patients. High-potency progestogens remain the sole therapeutic option recommended by international guidelines for this patient population; however, approximately 30% of patients exhibit no response to such treatment. The concept of EC molecular subtyping, proposed by The Cancer Genome Atlas (TCGA) in 2013, has revolutionized the diagnosis and management of EC. EC subtypes with distinct molecular features demonstrate substantial differences in biological behaviors and responses to pharmacotherapeutic interventions. Nevertheless, the role of molecular subtyping in guiding FST decision-making-both in terms of its applicability and specific mechanisms-remains an unmet research need worldwide. Notably, the POLE-mutant and microsatellite instability-high (MSI-H) subtypes display the highest sensitivity to immune checkpoint inhibitors, underscoring the clinical value of exploring their utility in FST. The no specific molecular profile (NSMP) subtype is sensitive to progestogens but lacks reliable predictive biomarkers-accurate pre-treatment prediction would enable tailored treatment selection, shorten treatment duration, and enhance therapeutic outcomes. In contrast, the p53-abnormal (p53abn) subtype is associated with a poor prognosis, and FST is therefore not recommended for this subgroup. Building on the aforementioned background and our research team's preliminary clinical findings, this project focuses on the field of FST for EC. To address the current challenges-including narrow indications, limited treatment options, suboptimal efficacy, and the absence of precise personalized regimens-we aim to conduct the world's first prospective multicenter umbrella trial based on EC molecular subtyping. Optimal novel diagnostic and therapeutic protocols will be developed for each molecular subtype, with the goals of optimizing existing FST strategies, improving FST efficacy and reproductive outcomes, expanding eligible indications, and providing high-quality clinical evidence for molecular subtype-guided FST in EC, thereby advancing the overall effectiveness of FST for EC patients.