Non-Invasive Strategies for Early Detection of Uterine Cancer in Patients With Abnormal Uterine Bleeding
Overview
- Phase
- Not Applicable
- Intervention
- EIN/EC BIOPSY RESULT
- Conditions
- Endometrial Cancer
- Sponsor
- University of British Columbia
- Enrollment
- 1000
- Locations
- 2
- Primary Endpoint
- Association Between Risk Factor Data and Endometrial Cancer and It's Precursors.
- Status
- Recruiting
- Last Updated
- 16 days ago
Overview
Brief Summary
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.
Detailed Description
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.
Investigators
Aline Talhouk
Principal Investigator
University of British Columbia
Eligibility Criteria
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
Arms & Interventions
EIN/EC BIOPSY RESULT
Vaginal samples sequenced. Participation ends here.
EH BIOPSY RESULT
Vaginal samples sequenced. Subset invited to move on to longitudinal monitoring and samples sequenced for 6 additional months.
NEGATIVE BIOPSY RESULT
Control for natural and spontaneous changes in vaginal samples sequenced. Random subset selected to move on to longitudinal monitoring and samples sequenced for 6 additional months.
Outcomes
Primary Outcomes
Association Between Risk Factor Data and Endometrial Cancer and It's Precursors.
Time Frame: Through study completion, anticipated 1-2 years
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.
Persistence of Mutations and Microbiome Alterations in Participants With Endometrial Hyperplasia.
Time Frame: Through study completion, anticipated 1-2 years
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.
Change in Risk Prediction of Endometrial Cancer When Mutation and Microbiome Data Is Combined With Traditional Risk Factors, Compared to Traditional Risk Factors Alone.
Time Frame: Through study completion, anticipated 1-2 years
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.
Diagnostic Performance of cfDNA Mutation Detection for Endometrial Pathology
Time Frame: Through study completion, anticipated 1-2 years
Cell-free DNA (cfDNA) extracted from vaginal swabs will be sequenced to identify endometrial cancer-associated mutations. Diagnostic performance will be evaluated by calculating sensitivity, specificity, accuracy, positive predictive value, and negative predictive value for detecting endometrial pathology, using biopsy-confirmed pathology as the reference standard.
Association Between Vaginal Microbiome Profile and Endometrial Pathology
Time Frame: Through study completion, anticipated 1-2 years
Vaginal microbiome DNA extracted from swabs will be sequenced and processed into operational taxonomic units (OTUs) using an in-house bioinformatics pipeline. OTUs will be compared across biopsy-confirmed pathology groups and evaluated against previously published microbiome signatures predictive of endometrial cancer.