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

Inclusion Criteria:

1. Age ≥ 18 years and ≤ 45 years;
2. Strong willingness to preserve fertility/uterus: Patients who have fertility requirements and insist on preserving fertility; or patients who have no fertility requirements but insist on preserving the uterus;
3. Newly diagnosed endometrial cancer: Pathologically diagnosed as endometrial cancer via endometrial biopsy, diagnostic dilation and curettage, or hysteroscopic examination;
4. Recurrent patients: Patients with endometrial lesions who received conservative treatment previously and developed recurrent endometrial cancer, with an interval of more than 6 months from the last standardized treatment, or deemed eligible for enrollment by the researcher after evaluation;
5. Imaging examinations (including pelvic enhanced MRI, upper abdominal enhanced CT/MRI, chest non-contrast CT, or PET/CT-MR) performed within 2 weeks before enrollment treatment initiation to confirm that the lesions are confined to the uterus without extrauterine involvement; for patients allergic to iodine contrast agents, MRI can be used instead of CT;
6. Clear molecular subtypes: POLE-mutant, NSMP (no specific molecular profile), or MSI-H (microsatellite instability-high);
7. Provide informed consent and sign the informed consent form;
8. Good compliance and follow-up conditions, willing and able to complete scheduled follow-up visits at our hospital;
9. No significant abnormalities in major organ functions, with relevant test values meeting the following requirements:White blood cell count ≥ 3×10⁹/L or absolute neutrophil count ≥ 1.5×10⁹/L; Platelet count ≥ 100×10⁹/L; AST and/or ALT \< 2× upper limit of normal (ULN); Serum creatinine \< 2× ULN;
10. Karnofsky Performance Status (KPS) score ≥ 90; Eastern Cooperative Oncology Group (ECOG) performance status score of 0-2;
11. Concurrent use of thyroid medications, calcium tablets, vitamin D, bisphosphonates, metformin, aspirin, etc., is permitted;
12. Multidisciplinary Team (MDT) discussion is required before treatment initiation.
13. Additional Targeted Inclusion Criteria Based on Different Molecular Subtypes： 1) POLE-mutant endometrial cancer: Pathologically and radiologically evaluated as FIGO 2023 Stage IA endometrial cancer; 2). dMMR (deficient mismatch repair)/MSI-H endometrial cancer: Pathologically and radiologically evaluated as FIGO 2023 Stage I-II endometrial cancer; Patients with Lynch syndrome may have other Lynch-related tumors in other systems; 3) NSMP endometrial cancer: Pathologically and radiologically evaluated as FIGO 2023 Stage IA1 endometrioid carcinoma; Pathological grade: G1/G2; Lesions confined to the endometrial layer; Immunohistochemistry: ER-positive, L1CAM-negative (\< 10% positive cells).

Exclusion Criteria:

1. Unclear molecular subtype or refusal to undergo molecular subtyping;
2. p53-abnormal molecular subtype;
3. ER-negative confirmed by pathological immunohistochemistry;
4. L1CAM-positive confirmed by pathological immunohistochemistry (L1CAM ≥ 10% positive cells);
5. 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;
6. Contraindications to therapeutic drugs (immune checkpoint inhibitors, progestins, GnRHa, letrozole);
7. Complicated with severe medical diseases or severe liver dysfunction;
8. History of major organ transplantation;
9. History of severe mental illness or cerebral functional disorders;
10. History of autoimmune diseases requiring immunosuppressant therapy;
11. History of substance abuse or drug addiction;
12. Request for hysterectomy or other treatments except conservative drug therapy;
13. Inability to comply with the study protocol;
14. 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;
15. 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.

Exclusion Criteria for Immune Checkpoint Inhibitor Use:

1. 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);
2. Received or planned to receive live vaccines within 30 days before the first dose of study intervention. Note: Inactivated vaccines are permitted;
3. Known intolerance to study interventions (or any excipients);
4. 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;
5. Severe hypersensitivity reaction (≥ Grade 3) to PD-1/PD-L1 monoclonal antibodies and/or any of their excipients;
6. 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;
7. History of (non-infectious) pneumonitis requiring steroid treatment or current pneumonitis;
8. Active infection requiring systemic treatment;
9. Known history of HIV infection;
10. 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;
11. 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;
12. Known mental illness or substance abuse disorder that may interfere with the patient's ability to comply with study requirements;
13. Other exclusion criteria: Previous allogeneic tissue/solid organ transplantation; Failure to fully recover from surgery and/or any surgical complications;
14. Currently breastfeeding.