Clinical Management of BRCA Mutation Carriers
Phase 5 - Cancer control studies
- Ideally, conduct randomized controlled clinical trials in clinically relevant populations, in which one arm is subjected to screening and appropriate intervention if screen-positive, while the other arm is not screened.
- Determine whether the death rate of the cancer being screened for is reduced among those who use the screening test.
- Obtain information about the costs of screening and treatment of screen-detected cancers.
Finally, for a validated biomarker test to be considered appropriate for use in a particular population, it must have been evaluated in that specific population without prior selection of known positives and negatives. In addition, the test must demonstrate clinical utility, that is, a positive net balance of benefits and risks associated with the application of the test. These may include improved health outcomes and net psychosocial and economic benefits.
Ovarian cancer poses a unique challenge relative to the potential impact of false-positive test results. There are no reliable noninvasive diagnostic tests for early stage disease, and clinically-significant early stage cancer may not be grossly visible at the time of exploratory surgery. Consequently, it is likely that some patients will only be reassured that their abnormal test does not indicate the presence of cancer by having their ovaries and fallopian tubes surgically removed and examined microscopically. High test specificity (i.e., a very low false-positive rate) is required to avoid unnecessary surgery and induction of premature menopause in false positive women.
Variations on CA 125
CA 125 plus an ovarian cancer symptom index
An ovarian cancer symptom index for predicting the presence of cancer was evaluated in 75 cases and 254 high-risk controls (BRCA mutation carriers or women with a strong family history of breast and ovarian cancer). Women had a positive symptom index if they reported any of the predefined symptoms (bloating or increase in abdominal size, abdominal or pelvic pain, and difficulty eating or feeling full quickly) more than 12 times per month occurring only within the prior 12 months. CA 125 values greater than 30 U/mL were considered abnormal. The symptom index independently predicted the presence of ovarian cancer, after controlling for CA 125 levels (P < .05). The combination of an elevated CA 125 and a positive symptom index correctly identified 89.3% of the cases. The symptom index correlated with the presence of cancer in 50% of the affected women who did not have elevated CA 125 levels, but 11.8% of the high-risk controls without cancer also had a positive symptom index. The authors suggested that a composite index including both CA 125 and the symptom index had better performance characteristics than either test used alone, and that this strategy might be used as a first screen in a multi-step screening program. Additional test performance validation and determination of clinical utility are required in unselected screening populations.