Uterine Cancer Risk Reducing Strategies in Postmenopausal Women

Study Part A

Eligibility Screen 1 - REDCap questionnaire to determine absolute risk of EC: Interested participants will be directed to REDcap where they will provide informed consent for Eligibility Screen 1 and complete a questionnaire with information needed to compute their absolute risk of being diagnosed with EC in the next 10 years. This absolute risk was calculated using the Pfeiffer et al. model (PMID 23935463), and the investigators have defined the threshold of what the investigators consider higher than average risk to be 2%. The investigators have selected this number because the population lifetime risk of EC is 2%; this number also corresponds to a 15% threshold from a similar BC population. For this study any participant whose risk falls above that threshold will be eligible to participate in part B. While this risk score model is not yet validated in the British Columbia population, it considers many factors demonstrated to be highly associated with EC.

Study Part B

1. Invitation to Participate: Participants whose absolute risk is above or equal to 2% will be called by a research coordinator and invited to participate. The investigators anticipate that ~250 high-risk participants will need to be identified for Eligibility Screen 2.
2. Introduction to Primary Care Provider or Gynecologist: A member of the clinical study team will contact the participant's primary care provider to describe the study, inform them of the consent of their patient, and ask the provider if they are willing to participate by prescribing the MPA to the participant and performing any follow up as per standard of care. The primary care provider will also receive a follow-up letter confirming the participant's involvement and summarizing the phone conversation. If the participant has no physician, or if their current primary care provider is unwilling to support them in this study, our clinical study team will help direct them to a local gynaecologist to undergo the PCT and any subsequent standard of care treatment. The only exception to this would be if it was determined that the PCT was medically contraindicated. In this case, the participant would not be able to continue in the study.
3. Appointment for PCT Prescription: Participants will have either a televisit or in-person appointment with their primary care provider or gynaecologist who has agreed to prescribe the 10-day course of MPA (10mg) for the participant to undergo the PCT.
4. At-home Vaginal Swabs and Tampon Collection: Participants who have obtained a prescription for the PCT will be mailed an at-home self-sampling kit for the collection of tampons (only one is required for collection, a spare will be sent in case of error in application) and swabs along with a pH strip and a set of instructions. Participants will be asked to not have sexual intercourse, use vaginal medications, feminine sprays, douches, genital wipes or contraceptive spermicides for 48 hours before providing the self-collection. Participants will be provided with a postage paid return mailing envelope to return the samples to us. Participants will be prompted through MyCap to indicate when they receive their kits, when they complete the self-collection, and when they have mailed back their kits.

Tampons and swabs will be sent to a Research Coordinator at BC Cancer. Tampons will be processed to extract genetic material, then cell and liquid fractions will also be stored. DNA extractions and targeted sequencing of EC-associated genes will be performed. Tampon and vaginal DNA swabs will be processed and analyzed following the ADVISE study protocols. DNAgenotek OMNIgene vaginal swabs are stable at room temperature for 30 days so will be immediately treated with proteinase K and aliquoted into cryovials for storage at -80C. Samples will be sent to Microbiome Insights for DNA extraction and next- generation sequencing. 5. Eligibility Screen 2 - Progesterone Challenge Test to detect proliferative endometrium: Through the MyCap app, participants will record when they start the PCT. They will receive daily reminders to take the MPA pills and will use the app to identify withdrawal bleeding or any other symptoms. Any participant who is not responsive for two days through the MyCap app will be called by the research coordinator. Those who do not have a smartphone or choose not to use the MyCap, will be managed through email and phone correspondence.