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Ovarian Cancer

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200 participants scheduled for surgery for suspected ovarian cancer due to a pelvic mass but without a confirmed tissue or cytology diagnosis.

50 participants with an inherited BRCA1 or BRCA2 deleterious mutation without suspected ovarian cancers who are scheduled for risk-reducing salpingo-oophorectomy (RRSO) to remove ovaries and fallopian tubes.

Uterine lavage is performed during surgery using a flexible, 3-way balloon tipped catheter. The catheter is inserted through the cervix, the balloon expanded and the uterine cavity lavaged using 10 cc of sterile saline which is collected, processed and stored for later analysis.

Uterine lavage, or a wash of the womb

Participants undergo two blood draws (one required, one optional) up to 31 days before surgery

Blood sample

Participants undergo a standard Papanicolaou smear to collect cells and fluid from the cervix.

Pap smear

Jackie Dahlgren

Beth Scanlan

Kristin Zorn, MD

Isabel Perez

Christine Garcia, MD

Jaci Miller

Monica Jones, MD

Rebecca Stone, MD

Tina Colella

Amy Bregar, MD

Robert Pearhill

Charles Drescher, MD

Christos Patriotis, PhD

The study aims to develop a test for early detection of ovarian cancer using DNA from a growth involving the ovary found in a washing of the uterus (womb), and proteins found in the blood. The samples of the wash and the blood will be taken before surgery. After surgery, doctors will determine whether the participant had ovarian cancer or a benign disease of the ovaries. The tests of the washings and the blood will be examined to see how much the participants with ovarian cancer can be separated from the participants with a benign ovarian disease by the tests. Small amounts from the washing and the blood samples will be sent to four sites for analysis.

Statistical analyses of these data will compare tumor DNA found in the washing of the uterus with proteins in the blood to detect cases of ovarian cancer. The primary goal is to find tests that are mostly positive for cases of ovarian cancer and mostly negative for patients with benign disease. It is hoped that if the tests work for participants with symptoms of the disease that these tests will also work when testing women who have no symptoms. A new study would be needed to see if the tests worked in this situation. If the tests work, this could lead to increasing the number of cases detected in early stage disease and decreasing the number of cases detected in late stage disease. If this change in late stage is large, it will likely reduce deaths due to ovarian cancer.

The study aims to elucidate the relative contributions to detection of ovarian cancer from tumor DNA in uterine lavage (UL) and protein biomarkers from blood using newly available detection and sample collection technologies. In this document, the term "ovarian cancer" includes fallopian tube cancer. In the first cohort, the study will enroll 200 participants. Enrolling participants prior to surgical diagnosis (e.g. laparoscopy or paracentesis) ensures the study will be "Prospective Collection of Samples, Blinded Evaluation" (PRoBE) compliant. The expectation is that \~50 of these participants will have pathologically confirmed ovarian cancer. In a second cohort, 50 participants will be enrolled. Based on published reports, it is expected that \~5 participants will have microscopic or low volume ovarian cancer. In each cohort, the participants with a pathologic invasive epithelial ovarian cancer diagnosis will be defined as Cases and participants without any ovarian cancer, primary peritoneal cancer (PPC), or other cancer identified due to the surgery, will be defined as Controls. Other cancer groups are: (i) PPC, (ii) non-invasive serous tubal intraepithelial carcinoma (STIC) lesions, (iii) non-epithelial ovarian cancers, and (iv) non-ovarian cancers.

Two sites will sequence DNA obtained from uterine lavages to detect tumor-derived DNA (tDNA): one will carry out Duplex Sequencing of TP53 and the second site will carry out Haloplex sequencing of an 18-gene panel. Two other sites will assay serum proteins: the first will use clinical grade assays for CA125 and HE4, and the second will use research grade assays for these two proteins plus four additional protein biomarker candidates. Statistical analyses of these data will evaluate the relative utility of tDNA and plasma proteins to detect Cases (sensitivity) while limiting detection of Controls (specificity) in these two cohorts. Remaining DNA from UL and blood based biospecimens in form of plasma, serum, and buffy coat will be stored at a biorepository at NCI Frederick for future biomarker investigations which include (but are not limited to) other methods of detecting tDNA from UL, tDNA from plasma, exosomal markers, and additional blood-based and UL biomarker candidates.

Primary objectives:

1. To collect samples from 200 participants with suspected ovarian cancer (of which \~50 or more are expected to have pathologically confirmed ovarian cancer) and 50 participants undergoing a risk-reducing salpingo-oophorectomy (of which \~5 are expected to have microscopic or low volume ovarian cancer).
2. To test the tDNA from uterine lavage samples for tumor-derived TP53 mutations, using Duplex sequencing, and for potential abnormalities in an 18-gene panel, using Haloplex sequencing
3. To test the serum proteins with two assays: the first will use clinical grade assays for CA125 and HE4, and the second will use research grade assays for these two proteins plus four additional protein biomarker candidates.

Outline: Participants undergo two blood draws (one required, one optional) up to 31 days before surgery and a uterine lavage at the time of planned surgery. The tDNA and serum proteins are then extracted from the samples and sent for analysis.

* Serum (red-top tubes)
* EDTA plasma (purple-top tubes)
* Uterine Lavage supernatant (conical tube)
* Uterine Lavage filter (conical tube)
* Uterine Lavage cell pellet (conical tube)
* Buffy coat (purple-top tubes)
* Tissue sections

Developing a Test for the Detection of Ovarian Cancer

Ovarian Cancer Detection by Uterine Lavage DNA and Serum Proteins: a Phase 2 Biomarker Study

Individual participant data is not anticipated to be shared.

Biomarkers that distinguish between ovarian cancer and benign ovarian disease

Johns Hopkins University

Fred Hutchinson Cancer Center

Anne Arundel Health System Research Institute

University of Arkansas

National Cancer Institute (NCI)

Kaiser Permanente

McGill University

M.D. Anderson Cancer Center

Swedish Medical Center

TwinStrand Biosciences

Massachusetts General Hospital

Principal Investigator

Fallopian Tube Cancer

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.

Patients with non-malignant gynecological conditions indicating surgical procedure, either salpingo-oophorectomy, hysterectomy or hysteroscopy.

Healthy women with genetically high risk for developing ovarian cancer, who have not undergone risk reducing procedure.

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.

Uterine lavage

5-10mL of blood will be drawn from participants.

Uterine lavage catheter

Keren Levanon, MD, PhD

Shunit Armon, MD

Yfat Kadan, MD

Ram Eitan, MD

Ariella Jakobson-Setton, MD

Tamar Perri, MD

Keren Levanon, MD,PhD

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.

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:

1. Proof-of-principle cohort - patients with either established ovarian cancer or other, non-malignant, gynecological conditions.
2. 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.

Biomarkers for Early Detection of Ovarian Cancer Using Uterine Lavage

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

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

Assessment of complications rate based on patient's questionnaire and medical records

Assessment of cost-effectiveness of uterine lavage-based diagnostic test for high risk population, including direct and indirect costs

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Developing a Test for the Detection of Ovarian Cancer	NCT04794322	Ovarian Neoplas... Ovarian Epithel... Fallopian Tube ... High Grade Ovar... Stage I Ovarian... Stage II Ovaria... Stage III Ovari... Stage IIIA Ovar... Stage IIIA1 Ova... Stage IIIA2 Ova... Stage IIIB Ovar... Stage IIIC Ovar... Stage IV Ovaria... Stage IVA Ovari... Stage IVB Ovari...	Uterine lavage,... Blood sample Pap smear	30 Years -	Massachusetts General Hospital
Developing a Test for the Detection of Ovarian Cancer	NCT04794322	Ovarian Neoplas... Ovarian Epithel... Fallopian Tube ... High Grade Ovar... Stage I Ovarian... Stage II Ovaria... Stage III Ovari... Stage IIIA Ovar... Stage IIIA1 Ova... Stage IIIA2 Ova... Stage IIIB Ovar... Stage IIIC Ovar... Stage IV Ovaria... Stage IVA Ovari... Stage IVB Ovari...	Uterine lavage,... Blood sample Pap smear	30 Years -	Massachusetts General Hospital
Biomarkers for Early Detection of Ovarian Cancer Using Uterine Lavage	NCT03150121	Ovarian Cancer Ovarian Carcino... Fallopian Tube ... Primary Periton... Serous Cystaden...	Uterine lavage Blood sample Uterine lavage ...	18 Years - 80 Years	Sheba Medical Center

Spots Global Cancer Trial Database for uterine lavage