The goal of this clinical trial is to assess if circulating tumor DNA can guide adjuvant selection in high-intermediate risk early-stage endometrial cancer. The main question it aims to answer is:

• To evaluate if 3-year recurrence-free survival among women with Stage I, high-intermediate risk endometrial cancer who are ctDNA negative after receiving ctDNA-guided observation is non-inferior to adjuvant vaginal brachytherapy (an internal radiation therapy) Researchers will compare high-risk intermediate ctDNA negative participants who are observed to those who receive vaginal brachytherapy to see if they have similar outcomes.

Participants will be asked to:

• Receive serial ctDNA testing
• Visit their study doctor per their standard of care visits about every 3 months for 2 years
• Answer a questionnaire about their well-being

This includes a randomized, multi-center, non-inferiority trial for a biomarker-defined subgroup, alongside two parallel, non-randomized exploratory cohorts. The study utilizes a biomarker-stratified design to formally test a treatment de-escalation strategy in patients with HIR endometrial cancer.

Following surgery, patients in the HIR cohort will be stratified based on post-operative circulating tumor DNA (ctDNA) status, as determined by the Signatera Genome assay. ctDNA-negative HIR Patients, based on the first valid post-operative ctDNA result within the baseline window, will be randomized (1:1) to either:

• Arm A: Observation unless ctDNA positivity within baseline window (<12 weeks), with serial ctDNA monitoring.
• Arm B: Vaginal brachytherapy (VBT) with serial ctDNA monitoring.

Following the initial baseline test, providers will be blinded to subsequent ctDNA results unless ctDNA positive within the first 12 weeks in Arm A [in which case, the provider will be notified and treatment of physician's choice (TPC) will be initiated. Initiation of TPC following ctDNA conversion is considered part of the ctDNA-guided treatment strategy, not a protocol deviation or cross-over, and such patients remain in the intent-to-treat population in Arm A]. Providers treating patients in Arm B will remain blinded to all ctDNA results after randomization. Post-operative ctDNA-Positive HIR patients will not be randomized and will continue serial testing while receiving TPC, which may include observation, radiation and/or chemotherapy. Providers and patients will be unblinded to the initial ctDNA result and blinded to ctDNA results thereafter.

The study will also include early stage low-risk (LR) and high-risk (HR) cohorts. Patients in these cohorts will not be randomized. They will continue serial ctDNA testing while receiving TPC, which may include observation, radiation and/or chemotherapy, and during surveillance. Providers and patients will be blinded to ctDNA results during the post-operative, TPC and surveillance period.

Inclusion Criteria:

General inclusion criteria includes the following selection criteria to be eligible for inclusion in any aspect of the study. Eligibility will be assessed by the investigator:

1. Signed and dated informed consent form (ICF) obtained prior to any trial-specific enrollment procedure.

2. Patient is ≥ 18 years-old at the time of ICF signature. 3. Able to submit sufficient residual tissue obtained per standard of care procedures.

HIR patients must meet all the following selection criteria to be eligible for the randomization cohort in the study. Eligibility will be assessed by the investigator:

1. FIGO 2009 Stage I after hysterectomy and lymph node assessment by bilateral pelvic lymphadenectomy or SLND

   1. If para-aortic lymph nodes are not pathologically assessed, documentation of surgical assessment or imaging is recommended.

2. Stage I patients with endometrioid histology:

   1. Age 70 years or older with one uterine risk factor,
   2. Age 50-69 years with two risk factors,
   3. Age 18 - 49 years with three risk factors.

Uterine risk factors include:

• Grade 2 or 3 tumor.
• Outer half depth of invasion.
• Lymphovascular invasion. Note: peritoneal cytology must be negative if performed.

Patients must meet all the following selection criteria to be eligible for the observation arms of the study. Eligibility will be assessed by the investigator following hysterectomy and lymph node assessment by bilateral pelvic and para-aortic lymphadenectomy or SLND:

1. High risk cohort

a. FIGO 2009 Stage I with high risk histology i. Defined as serous, clear cell, carcinosarcoma, or mixed histology.

1. Negative peritoneal cytology, where performed (recommended)
2. If para-aortic lymph nodes are not pathologically assessed, imaging is required b. FIGO 2009 Stage II Endometrioid

2. Low risk cohort

a. FIGO 2009 Stage I patients at low risk of recurrence i. Endometriod histology ii. Absent uterine risk factors, or present but insufficient to meet HIR criteria

Exclusion Criteria:

Patients are not eligible for the study if they meet any of the following criteria, as assessed by the investigator:

1. Undifferentiated or dedifferentiated histology

2. Uterine sarcoma

3. Prior pelvic radiation therapy

4. Positive pelvic washings

5. Pelvic lymph node assessment was not performed

6. Isolated Tumor Cells (ITC) identified in the lymph node(s)

7. Prior therapy for endometrial cancer (including hormonal therapy, chemotherapy, targeted therapy, immunotherapy)

   a. Contraceptives or other hormonal management for endometrial intraepithelial hyperplasia is allowed

8. Patients with a history of other invasive malignancies, with the exception of non-melanoma skin cancer, are excluded if there is any evidence of active malignancy within the last five years.

   a. Patients are also excluded if their previous cancer treatment contraindicates this protocol therapy.

9. Patients with a history of serious comorbid illness or uncontrolled illnesses that would preclude protocol therapy.

10. Patients with a history of myocardial infarction, unstable angina, or uncontrolled arrhythmia within 3 months from enrollment.

11. Previous diagnosis of Crohn's disease or ulcerative colitis.

12. Patient is currently receiving, or plans to receive, commercial ctDNA/MRD assay for disease monitoring, excluding Signatera. Patients must agree to forego testing with assays other than Signatera Genome upon enrollment until end of study.

Following the initial baseline test, providers in Arm A will be blinded to all subsequent ctDNA results unless ctDNA positive within the first 12 weeks in Arm A (in which case, the provider will be notified and TPC will be initiated).

Providers treating participants in Arm B will remain blinded to all ctDNA results following the initial baseline test. Providers and patients enrolled in the early stage low-risk and high-risk cohorts will be blinded to all ctDNA results (post-operatively, during treatment, and during surveillance).