Removal of the Ovaries/Fallopian Tubes and CA-125 Screening to Reduce the Risk of Ovarian Cancer in Women at Increased Genetic Risk

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.

- INCLUSION CRITERIA:

To be considered at increased genetic risk of OC, subjects must have:

Age greater than or equal to 30;

No prior history of OC, including low malignant potential cancers (LMP), or primary
papillary serous carcinoma of the peritoneum;

At least one intact ovary:

Satisfied one of the following additional criteria:

The family of the subject has a documented deleterious BRCA1 or BRCA2 mutation - either:

- the subject herself has tested positive for a deleterious BRCA1 or BRCA2 mutation; OR

- the subject has a first- or second-degree relative with a deleterious BRCA1 or BRCA2
mutation

OR

The family contains at least two ovarian and/or breast cancers among the subject or first-
or second-degree relatives of the subject within the same lineage. This condition is
satisfied by multiple primary cancers in the same person. Where breast cancer is required
to meet this criterion, at least one breast cancer must have been diagnosed prior to
menopause (age at diagnosis less than or equal to 50 if age at menopause is unknown); OR

The subject is of Ashkenazi Jewish ethnicity with one first-degree or two second-degree
relatives with breast and/or OC. Where breast cancer is required to meet this criterion, at
least one case must have been diagnosed prior to menopause (or at age less than or equal to
50, if age at menopause is unknown).

OR

The subject is of Ashkenazi ancestry and has had breast cancer herself. To meet this
criterion, her breast cancer must have been diagnosed prior to menopause (age at diagnosis
less than or equal to 50 if age at menopause is unknown).

OR

The probability of carrying a BRCA1/2 mutation given the family pedigree of breast and OCs
exceeds 20% as calculated by BRCAPRO.

Note: BRCAPRO does NOT need to be calculated on everyone who enters the study. Patients are
eligible based on a family history which meets one of the specific patterns described in
this protocol, regardless of BRCAPRO results. BRCAPRO assessment is valuable in families
where genetic testing has not been done, and the family history does not fit one of the
specific patterns described, but the pattern of cancers leads you to believe that the
family might still be considered high-risk. At that point, if the BRCAPRO estimate of being
a mutation carrier is greater than 20 percent, then the patient IS eligible.

Signed an approved informed consent and authorization permitting release of personal health
information.

EXCLUSION CRITERIA:

A first- or second-degree relative has a deleterious BRCA1/2 mutation, and the subject has
tested NEGATIVE for the exact same mutation.

Women who are currently pregnant or planning pregnancy during the study.

Women who are participating in another OC early detection trial (except for the ROCA study
being run by the Cancer Genetics Network. Women who have enrolled in the ROCA study and who
subsequently choose to undergo surgery may enroll in the surgical cohort of GOG 0199).

Women with psychiatric, psychological or other conditions which prevent fully informed
consent.

Women with current untreated malignancy (excluding non-melanoma skin cancer).

Women with adjuvant radiation therapy or chemotherapy within the past 1 month (31 days).
For purposes of this study, any biologic agent administered with an anti-cancer therapeutic
intent (e.g., Herceptin) will also not be permitted.

Women who have been treated for prior metastatic malignant disease within the past 5 years.

Women who have undergone intraperitoneal surgery within the prior 3 months (includes
laparoscopy).

Women who have had both ovaries removed prior to study entry.

Women with a history of any medical condition which places the subject at risk related to
the need for donating blood for research purposes, e.g., chronic infectious diseases,
severe anemia, hemophilia.

Note: Enrollment of women in whom there is a significant pre-operative clinical suspicion
that there might exist ovarian or fallopian tube caner should be avoided. The intent of the
study is to ascertain subjects who are contemplating a risk-reducing, rather than a
therapeutic, procedure. Women with findings of uncertain significant on baseline TVUS
remain eligible.