Study of Megestrol Acetate in Grade 2 Endometrioid Endometrial Cancer

This is a single centre, single arm, open label, preoperative window of opportunity study. Grade 2 endometrioid endometrial carcinoma patients awaiting surgery will be prospectively recruited to receive a pre-operative progestin therapy course. Therapy response will be histologically evaluated and correlated with clinical and molecular data by comparison of responders vs. non-responders pre- and post-treatment tumor samples.

The incidence of endometrial cancer is increasing due to the rising rates of obesity. Further, the average age at onset is decreasing. As a result, there is a growing interest in fertility-sparing treatments, such as progesterone-based therapy. While the role of progestins for the conservative management of atypical hyperplasia and with Fédération Internationale de Gynécologie et d'Obstétrique (FIGO) grade 1 endometrial endometrioid carcinomas (EEC), assigned on preoperative endometrial biopsy, is well established, there is limited clinical experience in patients FIGO grade 2 EECs (EEC2) for whom the current standard therapy is hysterectomy. However, there are case reports of successful progestin treatment of patients with preoperative biopsy EEC2, suggesting that progestin response mechanisms are functional in select EEC2s and that hormonal treatment may be a viable option if the responsive patients could be safely identified.

In this study, the investigators will prospectively recruit EEC2 patients for pre-operative progestin treatment. Participants will be given high-dose progestin from day of consent for a minimum of 21 days. This will allow investigators to generate a unique cohort of matched pre-progestin treatment biopsies and post-treatment surgical specimens for each participant. The investigators intend to analyze clinical, pathological and transcriptomic data of EEC2 that histologically respond to progestin therapy versus their counterparts that do not, with the goal of identifying candidate predictive biomarkers and clinical parameters that would supplement pathological screening of these lesions to better stratify patient classification to good and poor responders. Once good responders are successfully characterize, this will enable the investigators to identify patients with biopsy EEC2 that could be safely managed conservatively with oral progestin therapy. For young patients, who have not completed their family planning, this could mean the difference between undergoing a hysterectomy versus retaining their fertility.

Eligibility Criteria:
Inclusion Criteria:

* Adult female patient 18 years of age or older.
* Confirmed diagnosis of FIGO grade 2 endometrioid endometrial cancer on preoperative endometrial biopsy read by a pathologist with a subspecialty in gynecologic pathology.
* Stage 1 endometrioid endometrial cancer on preoperative endometrial biopsy.
* P53 wild type immunohistochemistry on preoperative endometrial biopsy.
* Patients eligible for primary staging surgery for definitive treatment for their cancer.
* Eastern Cooperative Oncology Group (ECOG) performance status 0-2
* Required Initial Laboratory Values obtained within 3 days of enrolment following standard of care protocols: Absolute Neutrophil Count (ANC) ≥ 1,500/mm3; Platelet Count ≥ 100,000/mm3; eGFR ≥ 60 mL/min/1.73m2; Total Bilirubin ≤ 1.5 x upper limit of normal (ULN); AST / ALT ≤ 2.5 x upper limit of normal (ULN).
* Informed consent for this study is obtained and signed by the participant or have an acceptable Substitute Decision Maker (SDM) capable of signing the informed consent form on behalf of the participant.

Exclusion Criteria:

* Patients cannot be receiving systemic or hormonal therapy for treatment of the endometrial cancer.
* Prior radiation therapy for treatment of the endometrial cancer is not allowed.
* Stage 2 or 3 endometrioid endometrial cancer on preoperative endometrial biopsy.
* Abnormal p53 immunohistochemistry on preoperative endometrial biopsy.
* History of an allergic reaction to medroxyprogesterone acetate.
* History of venous thromboembolic event (including previous deep vein thrombosis or pulmonary embolism).
* Family history of venous thromboembolic event.
* Have a \>20 pack-year smoking history.
* Patients unwilling or unable to follow the study protocol schedule.