The study goal is to investigate a non-invasive approach to predict endometrial cancer (EC) risk, better understand disease progression and identify opportunities for intervention.

This two-part case-cohort prospective study will recruit patients whose abnormal uterine bleeding is being evaluated via endometrial biopsy. Participants will complete an online health questionnaire, and a subset will be invited to self-collect vaginal samples for sequencing.

Selected sequenced participants will be invited for longitudinal monitoring (questionnaires, wearable fitness tracker) and an additional vaginal self-collection to identify persistent genetic mutations or microbiome alterations 6-8 months later.

Purpose:

To improve the prediction of EC and its precursors by integrating data from questionnaires and biological biomarkers obtained from non-invasive tests (vaginal DNA and microbiome swabs, vaginal pH). We also want to better understand pre-malignant disease progression and identify opportunities for earlier intervention.

Hypotheses:

1. Risk factors in combination with ultrasound data, and patterns of abnormal bleeding are associated with endometrial cancer and its precursors.
2. Prediction of pathology is improved by including mutation and microbiome data from noninvasive tests combined with traditional risk factors.
3. Persistence of mutations and microbiome alterations is more common in patients with endometrial hyperplasia than other benign diagnoses and is associated with lifestyle factors.

Justification:

Non-invasive tests and questionnaires may be used to predict onset of endometrial carcinoma or its precursors and can be used to triage those participants with abnormal bleeding who require an endometrial biopsy.

Objectives:

To enhance understanding of the progression of EC and propose non-invasive methods for detection in patients who are experiencing abnormal uterine bleeding and have already been referred to a gynecologist for an endometrial biopsy.

Research Design:

This is a prospective case-cohort study that will recruit n=1000+ participants over the age of 35 years whose abnormal uterine bleeding is being evaluated via endometrial biopsy. Prospective participants will consent to access the information in their medical records, including access to their pathology report. A subset of participants (n=450) will be invited to self-collect vaginal DNA and microbiome samples using swabs and vaginal pH using a litmus kit for sequencing and analysis. A subset of those who retain their uterus (i.e. are not directed to a hysterectomy per standard clinical management) (n=200+), will be invited to take part in longitudinal monitoring using a wearable fitness tracker (Fitbit) and questionnaires, and an additional vaginal self-collection.

Inclusion Criteria:

Study Part A:

• 40 years and older
• Experiencing unexplained abnormal uterine bleeding (i.e., not from IUD, etc.)
• Have an intact uterus
• Referred for an endometrial biopsy

Study Part B/Longitudinal monitoring:

• Those selected for sequencing (from Part A) and who retained their uterus.

Exclusion Criteria:

Study Part A:

• Endometrial sampling, pelvic radiation, or vaginal infection (vaginosis, yeast) in the past 3 months
• Started hormone therapy (HRT, birth control, IUD) in the past year (with the exception of tamoxifen)
• Intercourse, vaginal product use, or douching in the past 48 hours

Study Part B/Longitudinal monitoring:

• Same as Study Part A
• EC or EIN, or anyone who is recommended a hysterectomy

The study investigators will have 10-15 study gynecologists across British Columbia, Canada, who will be recruiting study participants from patients who are referred to them for an endometrial biopsy due to abnormal uterine bleeding. The investigators aim to recruit ~1000 participants in Study Part A in order to achieve their target sample size of n=50 EIN/EC and n=150 EH.

Sequenced participants will be invited to participate in Study Part B/ Longitudinal monitoring and provide additional samples.