Developing a Test for the Detection of Ovarian Cancer

Study Overview
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Brief Summary
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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.

Detailed Description
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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: 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). 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 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.

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

Conditions
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Ovarian Neoplasms, Ovarian Epithelial Carcinoma, Fallopian Tube Neoplasms, High Grade Ovarian Serous Adenocarcinoma, Stage I Ovarian Cancer, Stage II Ovarian Cancer, Stage III Ovarian Cancer AJCC v8, Stage IIIA Ovarian Cancer AJCC v8, Stage IIIA1 Ovarian Cancer AJCC v8, Stage IIIA2 Ovarian Cancer AJCC v8, Stage IIIB Ovarian Cancer AJCC v8, Stage IIIC Ovarian Cancer AJCC v8, Stage IV Ovarian Cancer AJCC v8, Stage IVA Ovarian Cancer AJCC v8, Stage IVB Ovarian Cancer AJCC v8

Intervention / Treatment
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* Diagnostic Test: Uterine lavage, or a wash of the womb
* Diagnostic Test: Blood sample
* Diagnostic Test: Pap smear


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has intact uterus (no history of uterine ablation, tubal ligation or bilateral salpingectomy) Cohort 1 (n=200 participants): Women scheduled for surgery or diagnostic laparoscopy for suspected but undiagnosed ovarian/fallopian tube cancer Cohort 2 (n=50 participants): Known BRCA1 or BRCA2 mutation carrier scheduled for risk-reducing salpingo-oophorectomy Exclusion Criteria: Current tissue or cytology diagnostic procedure positive for ovary cancer or any cancer Inability to provide informed consent Age less than 30 years Inability to obtain the minimum amount of blood Inability to obtain the minimum amount of uterine lavage sample At risk if blood were drawn (e.g. hemophilia, serious anemia- Hb less than 8.0 gm/dL) Prior history of known ovarian or endometrial cancer Treatment less than 1 year (excluding hormonal therapy) for cancer that spread beyond its origin History of untreated high-grade cervical dysplasia (CIN3) History of treated high grade cervical dysplasia (CIN3) with a cytologically abnormal pap smear within the past year. If there is no post treatment Pap smear in the medical record, perform a Pap smear prior to the day of surgery. If this Pap smear is abnormal, the participant is ineligible. Currently pregnant Known Lynch syndrome

Ages Eligible for Study
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Minimum Age: 30 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Pelvic Mass Cohort (cohort #1)<br>200 participants scheduled for surgery for suspected ovarian cancer due to a pelvic mass but without a confirmed tissue or cytology diagnosis. | Diagnostic Test: Uterine lavage, or a wash of the womb<br>* 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.<br>Diagnostic Test: Blood sample<br>* Participants undergo two blood draws (one required, one optional) up to 31 days before surgery<br>Diagnostic Test: Pap smear<br>* Participants undergo a standard Papanicolaou smear to collect cells and fluid from the cervix.<br>|
| BRCA1/2 Carriers Cohort (cohort #2)<br>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. | Diagnostic Test: Uterine lavage, or a wash of the womb<br>* 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.<br>Diagnostic Test: Blood sample<br>* Participants undergo two blood draws (one required, one optional) up to 31 days before surgery<br>Diagnostic Test: Pap smear<br>* Participants undergo a standard Papanicolaou smear to collect cells and fluid from the cervix.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Genomic biomarkers assessing mutations and methylation of tumor DNA, and protein biomarkers measured as the concentration of a protein in pg/mL, both types of biomarkers measured in the collected biospecimens. | Biomarkers that distinguish between ovarian cancer and benign ovarian disease | Through study completion, an average of three years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Uterine Lavage, Tumor DNA, Serum proteins, Ovarian neoplasms, Ovarian epithelial carcinoma, Ovarian cancer, Ovarian epithelial cancer, Neoplasms, Ovarian diseases, Early detection