Clinical Trial to Screen Participants Who Are at High Genetic Risk for Ovarian Cancer

OBJECTIVES:

- Determine the feasibility of prospective ovarian cancer screening studies within the
Cancer Genetics Network and other NCI ovarian programs for participants who are at high
genetic risk for developing ovarian cancer.

- Identify the logistical issues of screening these participants and their solutions
within this framework.

- Establish normal ranges and distributions of CA 125 values over time within and between
high-risk participants, with subclassification by pre- or post-menopausal status,
estrogen-replacement therapy usage, and prior prophylactic oophorectomy.

- Estimate the specificity and positive predictive value of the "risk of ovarian cancer
algorithm" (ROCA) suitable for designing a definitive trial of screening for ovarian
cancer in high-risk participants.

- Establish a longitudinal serum and plasma biorepository for retrospective evaluation of
other promising biomarkers with special relevance to inherited ovarian and breast
cancer risk.

OUTLINE: This is a multicenter study. Participants with 1 or 2 ovaries are assigned to group
A, whereas participants with prior prophylactic bilateral oophorectomy are assigned to group
B (closed to accrual as of 10/18/04).

At baseline, participants who are not eligible by BRCA mutation criteria or family history
criteria undergo BRCAPRO evaluation. Participants in both groups complete a questionnaire
requesting demographic information and a personal and family health history at baseline and
a questionnaire requesting hospitalization or cancer diagnosis information after each blood
test. Participants in both groups also complete health status questionnaires once every 3
months for 6 months-7 years. Participants undergo blood draws for measurement of CA 125
levels once every 3 months for 6 months-7 years. For each CA 125 measurement, the risk of
ovarian cancer algorithm (ROCA) is calculated.

Group A (1 or 2 ovaries at baseline):

- Participants are assigned to 1 of 2 subgroups based on ROCA.

- Subgroup A1: Participants with normal-risk for ovarian cancer (ROCA less than 1%)
continue CA 125 screening as above.

- Subgroup A2: Participants with intermediate-risk for ovarian cancer (ROCA more
than 1% but less than 10%) or elevated-risk for ovarian cancer (ROCA more than
10%) undergo transvaginal sonography (TVS). Participants with elevated-risk
undergo an additional blood draw for a confirmatory CA 125 level prior to TVS.
Participants with normal TVS continue CA 125 screening as above. Participants with
abnormal TVS are referred to a gynecologic oncologist who decides whether standard
clinical intervention for potential ovarian cancer is needed. Participants who are
not referred for standard clinical intervention continue CA 125 screening as
above. Participants who are referred for standard clinical intervention, have at
least 1 ovary remaining, and are found to have no malignancy continue CA 125
screening as above. Participants who are referred for standard clinical
intervention, are found to have no malignancy, and then undergo prophylactic
bilateral oophorectomy proceed to CA 125 screening as in group B below.
Participants who are referred for standard clinical intervention and are found to
have malignancy are taken off study.

Group B (no ovaries at baseline) (closed to accrual as of 10/18/04):

- Participants are assigned to 1 of 2 subgroups based on ROCA.

- Subgroup B1: Participants with normal-risk for ovarian cancer (ROCA less than 5%)
continue CA 125 screening as above.

- Subgroup B2: Participants with elevated-risk for ovarian cancer (ROCA more than
5%) undergo an additional blood draw for a confirmatory CA 125 level and are then
referred to a gynecologic oncologist who decides whether standard clinical
intervention for potential ovarian cancer is needed. Participants who are not
referred for standard clinical intervention continue CA 125 screening as above.
Participants who are referred for standard clinical intervention and are not found
to have malignancy continue CA 125 screening as above. Participants who are
referred for standard clinical intervention and are found to have malignancy are
taken off study.

Patients are followed for clinical diagnosis for 1 additional year.

PROJECTED ACCRUAL: Approximately 2,430 participants will be accrued for this study within 12
months.

DISEASE CHARACTERISTICS:

- Participant meet the criteria for one of the following conditions:

- Participant has tested positive for BRCA1 or BRCA2 mutation or has a first- or
second-degree relative with a BRCA1 or BRCA2 mutation

- At least 2 ovarian or breast cancers (including ductal carcinoma in situ) have
occurred among the participant and her first- and second-degree relatives within
the same lineage

- Condition may be satisfied by multiple primary cancers in the same person

- Where breast cancer is required to meet this criterion, at least 1 breast
cancer patient must have been pre-menopausal (age 50 and under at diagnosis
if age at menopause unknown)

- Participant is of Ashkenazi Jewish ethnicity and either has had breast cancer or
has 1 first-degree or 2 second-degree relatives with breast cancer (including
ductal carcinoma in situ) or ovarian cancer

- Where breast cancer is required to meet this criterion, at least 1 breast
cancer patient must have been pre-menopausal (age 50 and under at diagnosis
if age at menopause unknown)

- Probability of carrying a BRCA1 or BRCA2 mutation exceeds 20% as calculated by
BRCAPRO, given family pedigree of breast cancer (including ductal carcinoma in
situ) and ovarian cancer

- Participant must have no prior or concurrent ovarian cancer (including low malignant
potential (LMP) cancers) or primary papillary serous carcinoma of the peritoneum

- Participant must not be negative for the same BRCA1 or BRCA2 mutation for which a
first- or second-degree relative has tested positive

- Participants who test negative for BRCA1 or BRCA2 mutation are still eligible if the
pedigree or BRCAPRO criteria are satisfied, including Ashkenazi women who test
negative for the three founder mutations

- Documentation of family history is by participant's self-report

- In relatives, ovarian cancer is defined as invasive ovarian epithelial cancers,
fallopian tube cancers, or primary papillary serous carcinoma of the peritoneum

- Germ cell or granulosa tumors or LMP ovarian cancers do not qualify

- First- and second-degree relatives include half siblings of the participant or her
first-degree relative

PATIENT CHARACTERISTICS:

Age:

- 30 and over

Performance status:

- Not specified

Life expectancy:

- Not specified

Hematopoietic:

- No hemophilia or other bleeding disorders

- No serious anemia

Hepatic:

- Not specified

Renal:

- Not specified

Pulmonary:

- No emphysema

Other:

- Not pregnant

- Fertile patients must use effective contraception

- No psychiatric, psychological, or other conditions that would preclude informed
consent

- No concurrent untreated malignancy except nonmelanoma skin cancer

- No medical conditions that would preclude blood draws during study

- No chronic infectious disease

PRIOR CONCURRENT THERAPY:

Biologic therapy:

- Not specified

Chemotherapy:

- At least 3 months since prior adjuvant anticancer chemotherapy

Endocrine therapy:

- Prior or concurrent adjuvant hormonal therapies (e.g., tamoxifen, leuprolide, or
goserelin) allowed

- Concurrent hormonal therapies (e.g., tamoxifen) for prevention allowed

Radiotherapy:

- At least 3 months since prior adjuvant anticancer radiotherapy

Surgery:

- At least 3 months since prior intraperitoneal surgery (laparoscopy or laparotomy)

- No prior prophylactic oophorectomy

Other:

- At least 5 years since prior non-hormonal treatment for metastatic malignancy

- No concurrent participation in other ovarian cancer early detection trials