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

Exclusion Criteria28

• Unclear molecular subtype or refusal to undergo molecular subtyping;
• p53-abnormal molecular subtype;
• ER-negative confirmed by pathological immunohistochemistry;
• L1CAM-positive confirmed by pathological immunohistochemistry (L1CAM ≥ 10% positive cells);
• Received any of the following treatments within 6 months before enrollment: high-dose potent progestins (megestrol acetate or medroxyprogesterone acetate) for consecutive ≥ 3 months; GnRHa ± letrozole for consecutive ≥ 3 months; immune checkpoint inhibitors for consecutive ≥ 3 months; levonorgestrel-releasing intrauterine system (Mirena) for consecutive ≥ 3 months; other treatments that may affect efficacy evaluation;
• Contraindications to therapeutic drugs (immune checkpoint inhibitors, progestins, GnRHa, letrozole);
• Complicated with severe medical diseases or severe liver dysfunction;
• History of major organ transplantation;
• History of severe mental illness or cerebral functional disorders;
• History of autoimmune diseases requiring immunosuppressant therapy;
• History of substance abuse or drug addiction;
• Request for hysterectomy or other treatments except conservative drug therapy;
• Inability to comply with the study protocol;
• POLE-mutant/NSMP endometrial cancer: Complicated with other gynecological malignancies; For non-gynecological malignancies, enrollment is permitted if MDT evaluation confirms no impact on fertility-preserving treatment, and excluded if it affects fertility-preserving treatment or efficacy evaluation;
• dMMR/MSI-H endometrial cancer (non-Lynch syndrome): Complicated with other malignancies, and MDT evaluation confirms impact on the selection of fertility-preserving treatment regimens or efficacy evaluation.
• Previous treatment with anti-PD-1, anti-PD-L1, or anti-PD-L2 agents, or drugs targeting other stimulatory or co-inhibitory T-cell receptors (e.g., CTLA-4, OX-40, CD137);
• Received or planned to receive live vaccines within 30 days before the first dose of study intervention. Note: Inactivated vaccines are permitted;
• Known intolerance to study interventions (or any excipients);
• Diagnosed with immunodeficiency or receiving chronic systemic steroid therapy (≥ 10 mg prednisone per day or equivalent dose) or any other form of immunosuppressive therapy within 7 days before the first dose of study intervention;
• Severe hypersensitivity reaction (≥ Grade 3) to PD-1/PD-L1 monoclonal antibodies and/or any of their excipients;
• Active autoimmune diseases requiring systemic treatment (e.g., disease-modifying drugs, corticosteroids, or immunosuppressants) within the past 2 years. Replacement therapy (e.g., thyroxine, insulin, or physiological corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered systemic treatment and is permitted;
• History of (non-infectious) pneumonitis requiring steroid treatment or current pneumonitis;
• Active infection requiring systemic treatment;
• Known history of HIV infection;
• Known history of hepatitis B (defined as HBsAg-positive) or active hepatitis C virus infection (defined as detectable HCV RNA \[qualitative\]); a. Chronic hepatitis B virus (HBV) carriers: HBV carriers with normal liver function and low HBV DNA load (e.g., below the lower limit of detection or at a low level) may be considered for PD-1 treatment after comprehensive evaluation. During PD-1 treatment, close monitoring is required, and appropriate antiviral prophylaxis should be administered if necessary to ensure treatment safety and efficacy; b. Patients with well-controlled hepatitis B: Patients with hepatitis B who have achieved good disease control through long-term standardized antiviral treatment, with mild liver inflammation and fibrosis, basically normal liver function, and no obvious complications such as cirrhosis or liver failure may receive PD-1 treatment;
• Any history or current evidence of diseases, treatments, or laboratory abnormalities that the researcher believes may confound study results, interfere with the patient's ability to complete the study, or make trial participation not in the patient's best interest;
• Known mental illness or substance abuse disorder that may interfere with the patient's ability to comply with study requirements;
• Currently breastfeeding.