PREFACEMolecular Classification in Fertility-Sparing Treatment for Endometrial Cancer

Endometrial cancer is the most common gynecologic malignancy in high-income countries, with an increasing incidence among women of reproductive age. In 2024, over 65,000 new cases were diagnosed in the United States alone. The prevalence of endometrial cancer in younger women who desire to preserve their fertility presents a significant clinical challenge. Traditional treatment for endometrial cancer involves hysterectomy, which precludes future pregnancies. However, fertility-sparing treatments, primarily using hormonal therapies, have emerged as a viable option for select patients with low-grade, early-stage endometrial cancer. Despite reported complete response (CR) rates of approximately 80% with fertility-sparing therapy, the outcomes vary significantly among patients. Molecular classifications have revolutionized the understanding of endometrial cancer by identifying four distinct subtypes: POLEmut (ultramutated), p53abn (TP53-mutant), MMRd/MSI-H (mismatch repair deficiency/microsatellite instability-high), and NSMP (no specific molecular profile). These classifications have demonstrated prognostic value in predicting oncologic outcomes in endometrial cancer. For instance, the NSMP subtype is associated with higher CR rates (78.4%) and lower recurrence rates (18.4%), whereas MMRd/MSI-H and p53abn subtypes show significantly poorer outcomes, including lower CR rates (48.8% and 50%, respectively) and higher recurrence rates (42.8% and 33%). However, the role of these molecular subtypes in guiding fertility-sparing treatment remains underexplored. A recent meta-analysis synthesized data from eight studies involving 363 patients who underwent fertility-sparing treatment for endometrial cancer. This analysis highlighted significant differences in complete response to treatment and in oncologic outcomes among the molecular subtypes, emphasizing the potential utility of molecular classification in personalizing treatment strategies. This study aims to build on these findings by prospectively evaluating the prognostic role of molecular classifications in a well-defined cohort of endometrial cancer patients undergoing fertility-sparing treatment.