This phase II trial tests compares the effect of progestins, megestrol acetate to micronized progesterone, in treating patients with endometrial cancer and precancers of the uterus (atypical endometrial hyperplasia) before surgery. Progestins, similar to the natural hormone progesterone, are approved drugs used in birth control and hormone replacement pills, and some can treat uterine endometrial cancers. In the initial comparison of this rotating umbrella trial, megestrol acetate, a progestin, will be compared to micronized progesterone, a form of natural progesterone that is a hormone produced by body normally. Hormone therapy using megestrol acetate and micronized progesterone may be effective in treating patients with endometrial cancer or atypical endometrial hyperplasia before surgery, and understanding the tissue effects of each agent on the malignant endometrium will uncover novel mechanistic and biomarker data to understand how best to advanced hormone therapy for endometrial cancer.

PRIMARY OBJECTIVES:

I. Perform an adaptive, master protocol, surgical window of opportunity rotating umbrella trial to assess the effectiveness of progestins in tissues from women with newly diagnosed endometrial cancer or atypical endometrial hyperplasia.

II. Establish biomarkers and molecular signatures of progestin efficacy in patients with endometrial cancer.

OUTLINE: Patients are randomized to 1 of 2 arms in the initial comparison.

ARM I: Patients undergo biopsy or curettage and then receive megestrol acetate orally (PO) twice daily (BID) 21-24 days prior to standard of care (SOC) hysterectomy on study.

ARM II: Patients undergo biopsy or curettage and then receive micronized progesterone PO once daily (QD) beginning 21-24 days prior to SOC hysterectomy on study.

After completion of study treatment, patients are followed up at 30-45 days after surgery.

Inclusion Criteria:

• Patients must have a histologically proven diagnosis of endometrioid endometrial adenocarcinoma by endometrial curettage or biopsy within 8 weeks prior to registration. Pathology reports should document adequate tissue from the biopsy and slides should be reasonable determined to be obtainable by the study team for study use
• History/physical examination within 42 +/- 5 days of planned surgical procedure (18-21 days from day 1)
• Age ≥ 18
• The trial is open only to women with primary endometrioid adenocarcinoma of the uterine corpus (all histologic grades and stages) who are planned and appropriate for primary surgical treatment to include removal of the uterine corpus via any surgical modality. The patient must be considered a suitable surgical candidate
• Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, 2, or 3 within 28 days prior to registration
• Formalin-fixed, paraffin-embedded tumor tissue from the biopsy or curettage must be reasonably deemed available for submission along with the corresponding pathology report
• Platelets ≥ 100,000/μl
• Granulocytes (absolute neutrophil count [ANC]) ≥ 1,500/μl
• Creatinine ≤ 1.6 mg/dl
• Serum glutamic-pyruvic transaminase (SGPT) (alanine transaminase [ALT]) ≤ 3 x upper limits of normal
• Bilirubin within institutional normal limits
• The patient must provide study-specific informed consent and authorization permitting release of personal health information prior to study entry
• Any patients of childbearing potential must have a negative pregnancy test

Exclusion Criteria:

• Patients with any non-endometrioid histology (such as serous, clear cell, or carcinosarcoma or mixed)
• Patients who have received prior progestin or anti-estrogen therapy during the 3 months before the diagnosis of endometrioid adenocarcinoma of the uterine corpus is established. Estrogen therapy alone is allowed
• Patients with ECOG performance status of 4
• Patients with history of deep venous thrombosis or pulmonary embolism within the past 2 years or ongoing thromboembolic disorders
• Patients who have previously received systemic, radiation or other treatment for uterine cancer
• Patients for whom formalin-fixed, paraffin-embedded tumor tissue from the biopsy or curettage is scant or unavailable
• Patients with a suspected or known peanut allergy
• Patients with serious comorbidities or gastrointestinal obstruction that precludes taking oral medications or have malabsorptive disease