Clinical Management of BRCA Mutation Carriers
Furthermore, a clinically useful test must have a high PPV (a parameter derived from sensitivity, specificity and disease prevalence in the screened population). Practically speaking, a biomarker with a PPV of 10% implies that ten surgical procedures would be required to identify one case of ovarian cancer; the remaining nine surgeries would represent false-positive test findings. In general, the ovarian cancer research community considers biomarkers with a PPV less than 10% to be clinically unacceptable, given the morbidity related to bilateral salpingo-oophorectomy. Finally, it is important to keep in mind that while novel biomarkers may be present in the sera of women with advanced ovarian cancer (which comprise the vast majority of cases analyzed in the early phases of biomarker development), they may or may not be detectable in women with early stage disease, which is essential if the screening test is to be clinically useful.
It has been suggested that there are five general phases in biomarker development and validation:
Phase I - Preclinical exploratory studies
- Identify potentially discriminating biomarkers.
- Usually done by comparing gene over- or under-expression in the tumor compared with normal tissue.
- Since many exploratory analyses in large numbers of genes are performed at this stage, one or more may seem to have good discriminating ability between cancers and normal tissue by random chance alone.
Phase 2 - Clinical assay development for clinical disease
- Develop a clinical assay that can be obtained on noninvasively obtained samples (e.g., a blood specimen).
- Often the test targets the protein product of one of the genes found to be of interest in phase I.
- The goal is to describe the performance characteristics of the assay for distinguishing between subjects with and without cancer. At this point, the assay should be in its final configuration and remain stable throughout the following phases.
- IMPORTANT: Since the case subjects in a phase 2 study already have cancer, with assay results obtained at the time of disease diagnosis, one cannot determine if disease can be detected early with a given biomarker.
Phase 3 - Retrospective longitudinal repository studies
- Compare clinical specimens collected from cancer case subjects before their clinical diagnosis with specimens from subjects who have not developed cancer.
- Evaluate, as a function of time before clinical diagnosis, the biomarker's ability to detect preclinical disease.
- Define the criteria for a positive screening test in preparation for phase 4.
- Explore the influence of other patient characteristics (e.g., age, gender, smoking status, medication use) on the ability of the biomarker to discriminate between those with and without preclinical disease.
Phase 4 - Prospective screening studies
- Determine the operating characteristics of the biomarker-based screening test in a population for which the test is intended.
- Measure the detection rate (number of abnormal tests among all those with the disease) and the false-positive rate (the number of abnormal tests among all those who do not have the disease).
- Evaluate whether the cancers detected by the test are being found at an early stage, a point at which treatment is more likely to be curative.
- Assess whether the test is acceptable in a population of persons for whom it is intended. Will subjects comply with the test schedule and results?