Biomarkers for Early Detection of Ovarian Cancer Using Uterine Lavage

Study Overview
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Brief Summary
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Screening programs for high-grade ovarian carcinoma failed to reduce disease-specific mortality, since they do not offer early enough detection of the disease. Most cases of high grade ovarian cancer develop in the fallopian tubes, hence the universal recommendation for high-risk populations (e.g., BRCA1/2 mutation carriers) is to undergo risk-reducing bilateral salpingo-oophorectomy (RRBSO) around the age of 40. The aims of this trial are: (1) to identify novel early-stage disease biomarkers using liquid biopsies obtained through uterine lavage, and (2) to optimize the technique a of uterine lavage and the processing of the samples for ultimate implementation as a routine diagnostic test for high risk populations.

Detailed Description
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Brief Summary: Screening programs for high-grade ovarian carcinoma failed to reduce disease-specific mortality, since they do not offer early enough detection of the disease. Most cases of high grade ovarian cancer develop in the fallopian tubes, hence the universal recommendation for high-risk populations (e.g., BRCA1/2 mutation carriers) is to undergo risk-reducing bilateral salpingo-oophorectomy (RRBSO) around the age of 40. The aims of this trial are: (1) to identify novel early-stage disease biomarkers using liquid biopsies obtained through uterine lavage, and (2) to optimize the technique a of uterine lavage and the processing of the samples for ultimate implementation as a routine diagnostic test for high risk populations. The end point of the study is sensitivity and specificity of a liquid biopsy test based on uterine lavage for detection of ovarian cancer. The study enrolls two cohorts: Proof-of-principle cohort - patients with either established ovarian cancer or other, non-malignant, gynecological conditions. High risk cohort - healthy women at genetically high-risk for ovarian cancer who have not undergone RRBSO. Inclusion criteria include age over 18, ability to read, understand and sign informed consent form, and planned surgical procedure with general anesthesia (for the proof-of-principle cohort), or planned regular gynecological examination due to high-risk for developing ovarian cancer (high risk cohort). Exclusion criteria include pregnancy or current attempts to conceive, any prior condition that precludes washing of the entire fallopian tubes. Patients will provide signed informed consent and will undergo uterine lavage which will be performed by a surgeon before surgery, after induction of anesthesia (proof-of-principle cohort), or by a gynecologist during gynecological examination in an office setting (high risk cohort). Uterine lavage is performed using an intrauterine insemination catheter or rigid pipelle uterine sampler. The catheter is inserted into the cervical canal. 10mL of saline are infused into the uterine cavity and fallopian tubes and immediately retrieved. 5-10mL of blood is also collected from each participant. Patients who have undergone the procedure without anesthesia are requested to complete a pain and stress score questionnaire. All patients are asked to allow access of their medical records and pathology reports from past, present and future gynecologic surgeries. The uterine lavage liquid biopsy samples are centrifuged to eliminate cells and cell debris. Supernatants were aliquoted within 6 hours from the procedure. Microvesicles, total RNA and DNA are isolated according to previously published protocols. The samples of the proof-of-principle cohort will be used to define an optimized set of assays, measuring either protein-based or nucleic acid-based biomarkers. The samples of the high risk cohort will be used to test the sensitivity and specificity of the previously defined biomarkers, and to evaluate confounding factors that may affect the accuracy of the test, such as menopausal status and breast cancer endocrine therapy. Each participant will be asked to consent to uterine lavage procedure on subsequent follow-up visits.

Official Title
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Identification of Novel Biomarkers for Early Detection of Ovarian Cancer in High-risk and Normal-risk Populations Using Uterine Lavage

Conditions
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Ovarian Cancer, Ovarian Carcinoma, Fallopian Tube Cancer, Primary Peritoneal Carcinoma, Serous Cystadenocarcinoma

Intervention / Treatment
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* Procedure: Uterine lavage
* Procedure: Blood sample
* Device: Uterine lavage catheter


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject must be at least 18 years of age. Subject must have all gynecological organs, including: vagina, cervix, uterus, fallopian tubes and ovaries. For the proof-of-principle cohort: Subject must have been evaluated for a gynecologic condition, for which the treating physician has determined that a surgical intervention is required. The surgical procedure may be either: hysterectomy, surgical hysteroscopy, or salpingo-oophorectomy. The eligible gynecological diagnoses include: high grade ovarian, fallopian tube or primary peritoneal carcinoma, or any non-malignant gynecologic condition. For the high risk cohort: Subject must have an increased risk for developing ovarian cancer, as determined by genetic testing for BRCA1 or BRCA2 mutations, or by family history of at least one first degree relative that has been diagnosed with high grade ovarian cancer. Exclusion Criteria: Subject is pregnant or is currently attempting to conceive. Subject has undergone resection of the uterus, fallopian tubes or ovaries. Subject is unable to read, understand and sign the informed consent form. Subject refuses to allow access to medical records or pathology reports.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ovarian cancer patients<br>High grade ovarian/fallopian tube/primary peritoneal carcinoma patients with current active disease, at any stage and histological type, who have not yet undergone debulking surgery. | Procedure: Uterine lavage<br>* Uterine lavage is performed using an intrauterine insemination catheter or rigid pipelle uterine sampler. The catheter is inserted into the cervical canal. 10mL of saline are infused into the uterine cavity and fallopian tubes and immediately retrieved.<br>* Other names: Tubo-uterine lavage;Procedure: Blood sample<br>* 5-10mL of blood will be drawn from participants.<br>Device: Uterine lavage catheter<br>* Uterine lavage is performed using an intrauterine insemination catheter or rigid pipelle uterine sampler. The catheter is inserted into the cervical canal. 10mL of saline are infused into the uterine cavity and fallopian tubes and immediately retrieved.<br>* Other names: Intrauterine insemination catheter;|
| Active Comparator: Non-malignant controls<br>Patients with non-malignant gynecological conditions indicating surgical procedure, either salpingo-oophorectomy, hysterectomy or hysteroscopy. | Procedure: Uterine lavage<br>* Uterine lavage is performed using an intrauterine insemination catheter or rigid pipelle uterine sampler. The catheter is inserted into the cervical canal. 10mL of saline are infused into the uterine cavity and fallopian tubes and immediately retrieved.<br>* Other names: Tubo-uterine lavage;Procedure: Blood sample<br>* 5-10mL of blood will be drawn from participants.<br>Device: Uterine lavage catheter<br>* Uterine lavage is performed using an intrauterine insemination catheter or rigid pipelle uterine sampler. The catheter is inserted into the cervical canal. 10mL of saline are infused into the uterine cavity and fallopian tubes and immediately retrieved.<br>* Other names: Intrauterine insemination catheter;|
| Experimental: High risk population<br>Healthy women with genetically high risk for developing ovarian cancer, who have not undergone risk reducing procedure. | Procedure: Uterine lavage<br>* Uterine lavage is performed using an intrauterine insemination catheter or rigid pipelle uterine sampler. The catheter is inserted into the cervical canal. 10mL of saline are infused into the uterine cavity and fallopian tubes and immediately retrieved.<br>* Other names: Tubo-uterine lavage;Procedure: Blood sample<br>* 5-10mL of blood will be drawn from participants.<br>Device: Uterine lavage catheter<br>* Uterine lavage is performed using an intrauterine insemination catheter or rigid pipelle uterine sampler. The catheter is inserted into the cervical canal. 10mL of saline are infused into the uterine cavity and fallopian tubes and immediately retrieved.<br>* Other names: Intrauterine insemination catheter;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ability of uterine lavage-based biomarkers to detect early stage ovarian cancer | Sensitivity and specificity of proteomic and genomic biomarkers measured in uterine lavage liquid biopsies. The samples will be analyzed in a blinded fashion. The pathological data of the patients will be reviewed and the sensitivity/specificity of each biomarker will be calculated | 7 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complications rate of uterine lavage procedure in high risk population | Assessment of complications rate based on patient's questionnaire and medical records | 7 years | 
| Burden of uterine lavage procedure as routine diagnostic test for high risk population | Assessment of cost-effectiveness of uterine lavage-based diagnostic test for high risk population, including direct and indirect costs | 7 years |