Symptoms and General Pathology

All Conditions

Neoplasms

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Hemorrhage

Uterine Neoplasms

Uterine Hemorrhage

Endometrial Neoplasms

Genital Neoplasms, Female

Urogenital Neoplasms

Uterine Diseases

Genital Diseases, Female

Genital Diseases

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Vaginal DNA, microbiome, pH, and saliva samples sequenced. Participation ends here.

Vaginal DNA, microbiome, pH, and saliva samples sequenced. All invited to move on to Part B and samples sequenced for 6 additional months.

Control for natural and spontaneous changes in vaginal DNA, microbiome, pH, and saliva samples sequenced.

Random subset selected to move on to Part B and samples sequenced for 6 additional months.

Aline Talhouk, PhD

Elise Abi Khalil, PhD

Anna Tinker, MD

The goal of this study is to combine information on risk factors from health questionnaires with minimally invasive biological tests (vaginal DNA and microbiome swabs, pH, hormones) to predict the risk of endometrial cancer (EC), better understand progression of the disease, and identify opportunities for intervention.

This study will recruit patients who are already scheduled to undergo diagnostic evaluation for abnormal uterine bleeding via endometrial biopsy. In Part A, consented participants will be asked to fill out an online risk factor questionnaire. Samples will be collected by the gynecologist at the biopsy appointment. After biopsy results are obtained, all samples from participants diagnosed with EC or precursors, plus a random subset with benign results, will be selected to be sequenced and analyzed.

In Part B, that subset of selected non-malignant participants, based on biopsy, will be invited to take part in lifestyle tracking using a Fitbit, questionnaires, and to provide another round of at-home vaginal samples to identify any persistent genetic mutations or microbiome alterations 6-8 months later.

Study Part A

1. Gynecologist Visit

   1. Patients over the age of 40 who are scheduled for an appointment for diagnostic evaluation of abnormal uterine bleeding (AUB) with one of the gynecologist study partners, will be invited to participate in this study. Those who consent to participate and undergo a uterine biopsy, which is the standard of care for AUB, will be enrolled in the study.
   2. If a biopsy was not anticipated when the appointment was scheduled and therefore the patient was unable to provide consent prior to their appointment, the gynecologist will explain the study and obtain verbal consent to collect the samples and provide the patient's contact information to the study coordinator. The coordinator will contact the patient as soon as possible to explain the study and obtain informed consent.
2. Primary Sample Collection

   1. During the standard biopsy procedure, the gynecologist will also collect study specific samples including: swabs for vaginal DNA and microbiome samples, a pH litmus test strip, and a saliva sample kit.
   2. Participants will consent to have their electronic medical records including biopsy results shared with the study team as part of the study. A member of the study team will further call the location where the endometrial biopsy occurred to ask for any remaining specimen that could be used for comparison to the vaginal swab DNA sequencing, as indicated on the consent form.
3. Email - REDCap Risk Questionnaire

   a. Participants will receive an email from a study coordinator with a link to a REDCap epidemiological risk questionnaire. The 5-10 minute survey will provide the information needed to compute their absolute risk of being diagnosed with EC in the next 5 years. Absolute risks will be calculated using the validated Pfeiffer et al. model (PMID 23935463).

   Study Part B
4. Selection, Consent and MyCap Enrolment

   1. After the biopsy results are reviewed, participants will be selected to have their specimen from Part A sequenced and analyzed. For budget reasons, only those participants diagnosed with endometrial cancer or hyperplasia (with or without atypia) will be sequenced and analyzed, along with twice as many randomly selected participants with benign diagnoses.
   2. Participants diagnosed with EC or endometrial intraepithelial neoplasia (EIN) will likely be recommended a hysterectomy, as per standard of care, and will be ineligible to continue in the next phase, since they will no longer be at risk for uterine cancer.
   3. All remaining participants diagnosed with endometrial hyperplasia (EH) without atypia and the non-malignant biopsy participants who were selected for sequencing will be contacted to participate in Study Part B. The study coordinator will explain this portion of the study and the procedures involved. If the participant is interested, the study coordinator will assist them in downloading MyCap, a mobile app integration for REDCap to register for the study and provide electronic consent. Participants will be mailed a Fitbit fitness tracker to monitor their lifestyle, activity and sleep patterns, along with instructions on how to set it up. They will be asked to manually report daily step counts and sleep data from their FitBit into MyCap app until the time of their second sample collection, at least 6 months later.
5. Second Sample Collection

   1. After approximately 6-8 months, participants will receive an at-home collection kit in the mail with a tampon and swab for DNA collection along with a vaginal microbiome sampling kit, a vaginal pH testing kit, and a saliva kit (n\~200). The investigators will ask that participants not have sexual intercourse, use vaginal medications, feminine sprays, douches, genital wipes or contraceptive spermicides for at least 48 hours before providing sample collection.

      * Tampon and swab #1: DNA will be collected from a tampon worn for 6-8 hours as well as by self-sample using a vaginal swab.
      * Swab #2: Vaginal microbiome samples will be obtained with a second vaginal swab using the DNAGenotek Inc. OMNIgene vaginal collection kit.
      * pH measurement: The pH kit will contain an indicator strip and a reference colour sheet; participants will be asked to take a photo of the strip next to the reference colour sheet as well as record the result in MyCap.
      * Saliva: A saliva collection kit (Affinity Diagnostics) will be used for hormone measurements and additional DNA extraction, if necessary.
   2. Participants will be provided with a postage paid return mailing envelope to send the samples. They will be prompted through MyCap to indicate when they receive their kits, when they are completed, and when they are mailed back.
6. Molecular Analysis and Results

   1. All samples will be processed and stored for follow-up investigations by batch. The investigators will prioritize genetic sequencing and screening of samples from participants in which the investigators observed cancer-associated DNA mutations in samples collected in Part A.
   2. It is important to understand that genetic mutations or alterations are fairly common in patients with abnormal uterine bleeding; and the majority will resolve on their own after shedding of the uterine lining. Because of this, and the fact that these initial analyses are experimental and are done for research purposes only, genetic results will not be communicated to participants. The significance of genetic mutations or microbiome alterations is not yet interpretable at this stage in the investigator's research.
   3. However, if the investigators discover that the same specific mutations or microbiome alterations are persistent in the second vaginal samples collected 6-8 months later, the participant and their gynecologist will be notified. The treating gynecologist will determine what, if any, follow-up or monitoring is appropriate.

8) Exit Survey

a. Participants, depending on the stage at which they exit the study, will be asked about their experience with the sample collection during biopsy, the risk questionnaire, the MyCap app, and the at-home sample collection.

Vaginal DNA Vaginal microbiome Vaginal pH Saliva

Detection of Endometrial Cancer Through Risk Modelling

Minimally Invasive Strategies for Early Detection of Uterine Cancer in Patients With Abnormal Uterine Bleeding

Participants will receive an email from a study coordinator with a link to a REDCap epidemiological risk questionnaire. The 5-minute survey will provide the information needed for the investigators to compute and assign each participant an absolute risk score of being diagnosed with endometrial cancer in the next 5 years from the time of data collection. Absolute risks will be calculated using the validated Pfeiffer et al. model, which has been externally validated.

At the time of the endometrial biopsy procedure, the study gynecologist will collect vaginal DNA using a swab, vaginal microbiome using a swab, vaginal pH using a litmus kit, and saliva for hormone analysis. Vaginal microbiome samples and pH will be collected using the DNAGenotek OMNIgene vaginal kit and GYNEX pHem-Alert vaginal kits. Saliva will be collected using saliva kit (Affinity Diagnostics).

Participants will consent to have their electronic medical records including biopsy results shared with the study team as part of the study. A member of the study team will further call the location where the endometrial biopsy occurred to ask for any remaining specimens that could be used for comparison to the vaginal swab DNA sequencing, as indicated on the consent form.

Epidemiological risk factors will be integrated with mutations and microbiome signatures from uterine/vaginal sampling to predict the presence of endometrial cancer and its precursors.

Participants will be asked to self-collect vaginal specimens for DNA and microbiome analysis, test vaginal pH using an at-home collection kit, and obtain a saliva sample. For DNA collection, participants will be asked to self-sample using a vaginal swab as well as wear a tampon for 6-8 hours. For the vaginal microbiome sampling, participants will obtain a second self-sampled vaginal swab using the DNAGenotek Inc. OMNIgene vaginal collection kit. The pH kit will contain an indicator strip and a reference colour sheet. Participants will be asked to complete a saliva kit (Affinity Diagnostics).

Approximately 6 months later, participants will be asked to repeat self-collection.

Self-collected participant data will be utilized to assess the proportion of persistent endometrial cancer-associated mutations in those with endometrial hyperplasia compared to other non-malignant conditions in females with abnormal uterine bleeding.

Canadian Institutes of Health Research (CIHR)

University of British Columbia

Principal Investigator

Patients undergo usual standard practice related to reproductive health.

Patients undergo reproductive health program comprising didactics, reproductive health assessment and navigating algorithm, and network development.

Standard practice related to reproductive heath

Training modules, algorithm, referral development

Ashlesha Patel

This clinical trial studies reproductive health program in patients with cancer. A reproductive health program may improve patients' understanding of reproductive risks and receipt of appropriate treatment to achieve their reproductive health goals.

PRIMARY OBJECTIVES:

I. To evaluate the success of the implementation of reproductive health programming (Didactics, Engendering Reproductive Health Within Oncologic Survivorship \[EROS\] Reproductive Health Assessment and EROS Trial Algorithm) among reproductive aged females (15-55) with cancer.

SECONDARY OBJECTIVES:

I. To assess the degree of discrepancy between patients and their clinicians in estimates of significance of the reproductive health goals for the patient.

II. To evaluate baseline and follow-up reproductive health assessments for trends in reproductive health choices relating to oncofertility, oncocontraception and pregnancy over the 2-year study period.

III. To identify clinical and demographic factors that predict the adequacy of reproductive health care management.

TERTIARY OBJECTIVES:

I. To perform a longitudinal study following endocrine markers of fertility in a cohort of the first 200 registered EROS trial patients who agree to participate.

II. To perform a longitudinal study of sexual function using the Patient-Reported Outcomes Measurement Information System (PROMIS) sexual function survey in all subjects participating in the EROS Trial.

OUTLINE: Participating institutions are randomized to 1 of 2 arms. Patients are assigned to a study arm depending on the institutional assignment.

ARM A: Patients undergo usual standard practice related to reproductive health. ARM B: Patients undergo reproductive health program comprising didactics, reproductive health assessment and navigating algorithm, and network development.

After completion of study intervention, patients are followed up periodically.

Reproductive Health Program in Patients With Cancer

EROS: Engendering Reproductive Health Within Oncologic Survivorship

Individual participant data may be made available upon request as per the ECOG-ACRIN Data Sharing Policy.

Reproductive health-related biomarkers, including follicle-stimulating hormone (FSH), anti-müllerian hormone (AMH), thyroid stimulating hormone (TSH) and Thyroid peroxidase (TPO), were evaluated through blood samples collected at baseline and 3, 6, 12, 24 months.

Sexual function was evaluated using PROMIS sexual function survey brief profile V1.0. All subdomain scores (except for the orgasm subdomain) are expressed as T-scores with a mean of 50 and a standard deviation of 10. A raw summed score is created for each domain. For Global Satisfaction with Sex Life, the raw summed score can range from 2 (endorsed "Not at all" to both items) to 10 (endorsed "Very" or "Very much" to both items). Higher scores indicate more satisfaction/interest/lubrication/discomfort/ability with sex life. Lower scores indicate less satisfaction/interest/lubrication/discomfort/ability with sex life.

Appropriate reproductive health management was determined using the followings: (1) Females that were pregnant or interested in immediate pregnancy (defined as within 1 year of enrollment) were given referral to obstetrician/gynecologist or counseled about pregnancy options (2) Females interested in future childbearing were counseled or given a referral for fertility preservation if requested (3) Females who were not interested in immediate pregnancy were given a referral or counseling to select family planning that was consistent with plans for sexual activity and future childbearing. If a female fell into category 1, 2, or 3, and the appropriate referral occurred within 3 months of enrollment, then appropriate reproductive health management was achieved. For patients with appropriate reproductive health management in place before the baseline visit, they were included in the analysis and counted as having appropriate reproductive health management.

The rating on the importance of fertility maintenance was assessed among patients and the corresponding treating physicians. The rating scale ranges between 1 and 10. Higher scores indicate more importance of fertility maintenance. The difference in rating was calculated by subtracting patient rating from physician's rating.

Patient's reproductive health choices relating to oncofertility, oncocontraception and pregnancy was assessed at baseline and 3 months. Patient's reproductive health status is categorized into the following categories:

* Sextually active \& childbearing not completed
* Sextually active \& childbearing completed
* Sextually not active \& childbearing not completed
* Sextually not active \& childbearing completed
* Sexuality unknown \& childbearing not completed
* Sexuality unknown \& childbearing completed
* Pregnant/Pregnancy in 1 year
* Missing/Unknown

National Cancer Institute (NCI)

ECOG-ACRIN Cancer Research Group

Serious, and Other (Not Including Serious) Adverse Events were not monitored/assessed.

Arm A (no Intervention)

Training modules, algorithm, referral development: Patients undergo reproductive health program comprising didactics, reproductive health assessment and navigating algorithm, and network development.

Arm B (Reproductive Health Program)

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Only eligible patients were included in this analysis.

Study Statistician

Only eligible patients who were evaluable for the primary endpoint were included in the analysis.

Proportion of Patients With Appropriate Reproductive Health Management

Patients with both patient rating and physician rating available were included in this analysis.

Difference in Rating Between Patients and Their Clinicians in Importance of Fertility Maintenance

Baseline

3 months

All eligible/analyzable patients were included in the analysis.

The Changes in Reproductive Health Status From Baseline to 3 Months

Completed childbearing at baseline

Childbearing not completed at baseline

Eligible patients with primary endpoint evaluated were included in this analysis.

Associations Between Clinical and Demographic Factors and Adequacy of Reproductive Health Care Management

Levels of Endocrine Markers of Fertility

Sexual Function Score by Patient-Reported Outcomes Measurement Information System (PROMIS)

Overall Study

Menopause

All Drugs and Chemicals

Antineoplastic Agents

Reproductive Control Agents

Progesterone

Medroxyprogesterone Acetate

Medroxyprogesterone

Contraceptive Agents

Contraceptive Agents, Hormonal

Contraceptive Agents, Female

Contraceptive Agents, Male

Antineoplastic Agents, Hormonal

10-day course of medroxyprogesterone acetate (Provera) 10 mg per os (po) daily.

Provera

Rachel Woima, BSc

Jessica McAlpine, MD

This study proposes to assess feasibility and acceptability of screening and risk reducing interventions in individuals at increased for endometrial cancer (EC). The investigators will use an epidemiological risk model to participants' absolute risk of developing EC in the next 10 years. Those whose absolute risk is 2% or greater or who have a Body Mass Index (BMI) higher than 34.9 will proceed to a second screening test (the Progesterone Challenge Test or the PCT) used to identify those with endometrial proliferation. The PCT consists of taking a ten-day course of medroxyprogesterone acetate (Provera) 10 mg per os daily. If withdrawal bleeding is experienced during the ten days up to two weeks since the final dose, this is considered a positive test result. PCT positive participants will receive standard of care treatment which may include endometrial biopsy and hormone therapy. As part of this project, the investigators will test the utility of self-collected vaginal sampling to measure DNA mutations and microbiome characteristics to help refine who could forego an endometrial biopsy in the future. Participants identified through the PCT will receive a lifestyle intervention through the Small Steps for Big Changes program.

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.

Participants who test positive on the PCT (estimated n\~25-50) will receive a phone call from the study coordinator at which time they will be prompted to inform their primary care provider of their withdrawal bleeding and to make a follow-up appointment. They will also be asked to complete a second round of at-home self-collection with vaginal swabs, tampon, and a pH strip.

Simultaneously, a member of our clinical study team will contact the participant's primary care provider to inform them of this positive PCT result, and request that they ensure an appointment is made with this participant. At this time, the clinical study team will also determine who will be performing an endometrial biopsy and where this will occur, as endometrial sampling is standard of care for those who tested positive on PCT. A letter will be sent after this correspondence to all treating physicians for inclusion as part of the patient's records.

7) Return of endometrial biopsy results: The study team will access the biopsy results and any hormonal intervention that may have been prescribed. They will also locate archival material of the endometrial biopsy and request any remaining specimen to be used for translational analysis to be compared to the results from tampon and vaginal swab DNA sequencing.

Study Part C

All participants who complete the PCT will be invited to participate in the final portion of the study.

Lifestyle intervention - The Small Steps for Big Changes (SSBC) program: This is a community-based program for personalized counselling on diet and exercise run by Dr. Mary Jung and her research team at UBC. The program will include six sessions of 1-on-1 exercise and dietary counselling with a trained coach over four weeks (virtually using the University of British Columbia Zoom).

Enrolling in SSBC: The study coordinator will obtain informed consent from any participants who test positive on the PCT and who remain in the study and guide them through next steps involved in the SSBC lifestyle intervention. The study coordinator will mail out a Fitbit, scale and a tape measure to all participants and confirm that the items have been received through MyCap.

Initial Coaching Appointment: A team member from the SSBC program will contact consented participants to schedule their first meeting with a coach. During the first session with the coach, participants will be instructed on how to measure their height, weight, and waist circumference using a tape measure and scale (provided as needed) and they will enter this information on REDCap. In addition, participants will be asked to create their individual health report by completing a survey through REDCap that will ask about physical activity, dietary behaviours, and utilization of healthcare.

Conforming to the SSBC program, the first and second week of the program will include two virtual sessions per week with a coach and three independent exercise sessions that participants are expected to complete on their own each week. The third and fourth week will include one virtual session with a coach and four independent exercise sessions to be completed weekly. Each week the exercise durations will become progressively longer.

Adherence to diet in SSBC is assessed weekly on REDCap using a validated food frequency questionnaire and exercise is assessed via self-report on REDCap.

Follow-up

Lifestyle Intervention: After the initial four weeks of the program, participants will have a check-in with a coach at the 3-month mark to assess progress and adherence to the program.

Exit survey: Participants, depending on the stage at which they exit the study, will be asked about their experience using the MyCap app, and with the at home vaginal sampling kits, the PCT, biopsy, SSBC program, and whether they found these acceptable.

All eligible participants will move into the various steps of the trial.

Risk Evaluation and Screening to Tailor Prevention and Reduce the Incidence of Endometrial Cancer

Uterine Cancer Risk Reducing Strategies in Postmenopausal Women

As per our consent forms IPD is only accessible to PI and research team. De-identified data may be accessible through collaborations.

Feasibility will be measured through rates of study enrollment, drop out, and adherence to intervention protocol. To be considered feasible, the study must meet all three of the following criteria: (1) enrollment and accruals: at least 80% of individuals in the top 30 percentile for risk will agree to and complete the PCT; (2) retention: at least a 50% overall retention rate after eligibility from first screen to 3 months post intervention; (3) adherence: at least 75% of participants compliant with interventions as directed (i.e. participating in at least five of the six SSBC sessions). If either accrual, retention, or adherence criteria is violated, the study will be deemed not feasible.

Acceptability will be measured through a standardized and validated survey of satisfaction with therapeutic services, the Client Satisfaction Questionnaire-8 (CSQ-8). Acceptability will be defined as a group median score ≥28 (scores range from 8 to 32) on the CSQ-8. Program evaluation items will be analyzed descriptively. The investigators will use analysis of variance to determine whether the feasibility or acceptability varied by social gender, socio demographic, ethnic, age, body size, or geographic location.

A secondary measure will be an overall program evaluation which assesses (1) the overall ease of participation and helpfulness of the program, and (2) agreement to a statement about liking the app-based format. This information will be collected through questions asked in an exit survey.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Detection of Endometrial Cancer Through Risk Modelling	NCT06268626	Endometrial Can...		40 Years -	University of British Columbia
Reproductive Health Program in Patients With Cancer	NCT01806129	Malignant Neopl...	Standard practi... Training module...	15 Years - 55 Years	Eastern Cooperative Oncology Group
Risk Evaluation and Screening to Tailor Prevention and Reduce the Incidence of Endometrial Cancer	NCT05651282	Endometrium Can...	Provera	-	University of British Columbia
Reproductive Health Program in Patients With Cancer	NCT01806129	Malignant Neopl...	Standard practi... Training module...	15 Years - 55 Years	Eastern Cooperative Oncology Group
Detection of Endometrial Cancer Through Risk Modelling	NCT06268626	Endometrial Can...		40 Years -	University of British Columbia

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