Removal of the Ovaries/Fallopian Tubes and CA-125 Screening to Reduce the Risk of Ovarian Cancer in Women at Increased Genetic Risk
Condition: Breast Cancer; Ovarian Cancer
MeSH terms: Ovarian Neoplasms; Carcinoma, Ovarian Epithelial
Study type: Observational

Summary: 
      This study will evaluate women who are at increased genetic risk of developing ovarian cancer
      because they or a close relative have a mutation in the BRCA1 or BRCA2 gene (the genes that
      cause most of the genetic forms of ovarian cancer) or because they have a very strong family
      history of breast and/or ovarian cancer. The study has two aspects. There will be two groups
      of subjects in this study. One group of women who will have their ovaries and fallopian tubes
      surgically removed as a prophylactic (preventive) measure against developing
      ovarian/fallopian tube cancer. These women will be studied to determine whether the surgery
      does, in fact, decrease the risk of ovarian or tubal cancer and whether it decreases the risk
      of breast and other cancers. The tissue removed at surgery will also be investigated to see
      whether a new way of examining the ovaries after they are removed provides better information
      about cancer-related tissue changes. A second group of subjects will be women who choose not
      to have preventive surgery. These women will be followed closely to see if screening with
      multiple CA-125 blood testing over time (see below) can detect ovarian or tubal cancers in
      their early stages. Both groups of women will undergo examination of the process by which
      women decide upon various options for lowering their ovarian cancer risk and a detailed
      assessment of how their choice impacts their quality of life. It will look at how those who
      opt for ovariectomy feel after their surgery and how those who choose screening feel during
      the time of screening.

      All participants will undergo the following procedures:

        -  Medical history, physical examination, and blood drawing upon entering the study,
           including blood samples for future ovarian cancer research.

        -  Screening mammogram, CA-125 blood test, and transvaginal ultrasound upon entering the
           study, with yearly repeat mammograms for all participants and yearly transvaginal
           ultrasound exams for women in the screening arm of the study. CA-125 is a protein found
           in the blood whose levels are elevated in most women with ovarian cancer. Transvaginal
           ultrasound is a way of taking pictures of the ovaries using sound waves. If the results
           of these tests are not normal, additional tests may be required to learn the reason for
           the abnormality.

        -  Questionnaires about personal, medical and family history, ovarian cancer risk factors,
           medication use, medical choices, and quality of life on entering the study, with repeat
           quality of life and medication use questionnaires every 6 months during the study
           period.

        -  Blood samples for follow-up visits and for CA-125 testing every 3 months as a screen for
           ovarian/fallopian tube cancers. Some blood from these samples will be saved for future
           ovarian cancer research.

        -  Semi-annual report during the duration of the study regarding health and quality of life
           changes that occur over the prior 6-month period.

      Researchers will use the pattern and rate of change of CA-125 levels over time in women in
      the screening group to decide if more tests are needed to test for ovarian cancer. Women in
      the surgery portion will undergo surgical removal of their ovaries and fallopian tubes. The
      removed tissues will be studied using new methods to examine the cells more closely than
      usual, and a portion of the tissues will be stored for future research on ovarian cancer.
      This study is being conducted in collaboration with the Gynecologic Oncology Group (GOG), and
      is designated GOG Protocol 0199. Subjects may join the study at any participating GOG
      institution (http://www.gog.org).
    

Detailed description: 
      Background:

      Annually, more than 25,500 women develop ovarian cancer (OC) and more than 16,000 die of this
      disease in the United States.

      Women at high genetic risk of OC have a much higher lifetime risk of developing OC than women
      in the general population.

      OC is difficult to detect using current screening methods, which include CA-125 monitoring
      and transvaginal ultrasound (TVUS); most women are diagnosed when the disease is in advanced
      stage, when survival chances are low.

      This protocol investigates a novel OC screening strategy [longitudinal CA-125 levels (using a
      mathematical algorithm known as ROCA) and TVUS] and surgical methods [risk-reducing
      salpingo-oophorectomy (RRSO)] in managing women at high genetic risk of OC.

      Objectives:

      To pool resources from intramural and extramural OC investigators and obtain the first
      prospective data from high-risk women addressing the incidence of critical cancer endpoints
      and quality of life, thus determining:

        1. . by how much RRSO reduces OC/Breast Cancer (BC) risk,

        2. . how RRSO affects quality of life,

        3. . which factors influence the decision about which management approach to choose,

        4. . how premature menopause affects the risk of developing medical problems,

        5. . if there are detectable abnormalities in ovaries which allow for early diagnosis, and

        6. . how cellular/molecular malignant processes occur.

      Eligibility:

      Women age 30 or older with no prior history of OC and at least one intact ovary.

      Must be at increased genetic risk of OC by meeting one of the following criteria:

        1. . Subject or close blood relative has tested positive for a BRCA1/2 mutation, or

        2. . Subject has family history of 2 or more close blood relatives with BC and/or OC, or

        3. . Subject has family history of 1 or more close blood relatives with BC and/or OC and
           Ashkenazi Jewish ancestry, or

        4. . Subject has had premenopausal BC and is of Ashkenazi Jewish descent, or

        5. . Subject has estimated probability of having a BRCA1/2 mutation using BRCAPRO
           evaluation.

      If the presence of BC is used for eligibility, at least one BC must be of premenopausal
      onset. If menopausal status at the time of BC diagnosis is unknown, age at diagnosis must be
      less than 50 years.

      Design:

      International, multi-institution, prospective cohort, collaborative study between NCI's
      Clinical Genetics Branch, Gynecologic Oncology Group (GOG), and Cancer Genetics Network.

      Two-arm, non-randomized study of women contemplating RRSO to diminish their OC risk.

      Women decide whether to undergo RRSO in consultation with their physicians.

        1. . Women who choose RRSO have surgery under a standardized procedure. Clinically occult
           primary cancers and precursor lesions are sought, and material is banked for molecular
           studies. CA-125 levels are measured twice yearly.

        2. . Women who decline RRSO choose OC screening with quarterly CA125/ROCA, which provides
           estimates of the likelihood that subjects have OC. TVUS and gynecologic oncology
           consultation may be arranged. TVUS is done on an annual basis, at minimum.

      Subjects from both arms complete demographic, epidemiologic, and psychosocial instruments and
      provide blood samples for research-based genetic testing (germline BRCA1/2), CA-125 testing,
      and serum/plasma/DNA storage.

      Primary outcomes are development of OC, fallopian tube cancer, primary peritoneal carcinoma,
      and BC.

      Study accrual goals include approximately 800 subjects in the RRSO arm and 2,400 subjects in
      the screening arm, each to include at least 400 BRCA1/2 mutation carriers.
    

Observational model: Cohort
Time perspective: Other
Sampling method: Non-Probability Sample
Study population: 
        Eligible study participants were at least 30 years of age (no upper age limit), had at
        least one intact ovary, had no prior personal history of ovarian cancer, and were either
        documented carriers of deleterious germline mutations in BRCA1/BRCA2 or, if not tested,
        have greater than or equal to 20% estimated probability of being a mutation carrier, based
        on their family history. Enrollees chose between participating in a novel ovarian cancer
        screening study (using ROCA, the risk of ovarian cancer algorithm) or undergoing bilateral
        salpingo-oophorectomy. Extensive biospecimens and questionnaire data were collected,
        including a major behavioral/psychosocial component. All participants were followed
        prospectively for 5 years.
      
Keywords: Screening; Oophorectomy; Hereditary; Genetics; Cancer