Population Testing for Cancer Predisposing BRCA1/BRCA2 Mutations in the Ashkenazi-Jewish Community: A Randomized Controlled Trial

Important advances in understanding germ-line predisposition to familial cancer have led to the identification of several rare high-penetrance genes causing cancer syndromes: BRCA1/BRCA2 (familial breast and/or ovarian cancer) and mismatch-repair genes (Lynch Syndrome). BRCA1/2 carriers have a 50% to 80% risk of breast cancer, a 20% to 45% risk of ovarian cancer (OC), and a 5% to 25% risk of prostate cancer (1–5). Established management strategies for high-risk individuals include: 1) risk-reducing salpingo-oophorectomy (RRSO) to prevent tubal/ovarian cancer (hazard ratio [HR] = 0.21) (which also halves breast cancer risk in premenopausal women) (6), 2) risk-reducing mastectomy to prevent breast cancer (7–9), 3) early onset breast screening (MRI/mammograms), and 4) preimplantation genetic diagnosis. Within the UK National Health Service (NHS), genetic mutation testing is limited to individuals with cancer from high-risk families (carrier probability ≥20% in the general population and ≥10% in the Jewish population) or individuals from families with a confirmed BRCA mutation who request referral to specialist genetic clinics. This family history (FH)–based approach requires individuals/general practitioners to recognize and act on a clinically significant FH. Mutation carriers who lack/are unaware of their FH, who do not recognize the risk associated with FH or are not proactive in seeking advice, are inevitably excluded (10–12). Most of these current approach–associated limitations could be overcome by systematic population-based testing. The literature indicates that genetic counseling/testing is associated with psychological benefits in noncarriers and has no substantial adverse psychological consequences for carriers (8,13). However, available data are predominantly from trials in highly selected samples of individuals with a strong FH of cancer, and the results cannot be generalized to the general population. There is no established model for population-based testing of dominant mutations, and the best way to deliver this service on a population basis is unknown.(13) We describe results from the first phase of a novel randomized controlled trial (RCT), Genetic Cancer Prediction through Population Screening (GCaPPS). The objective was to assess the benefits/disadvantages of a population-based approach to genetic testing for high penetrance–dominant gene mutations compared with the conventional FH-based approach. The RCT design provided a basis for comparison of psychological and quality-of-life differences between population-based and FH-based testing. We based the trial in an Ashkenazi Jewish (AJ) community as a population-model and used BRCA1/2-mutations as our disease-model. These choices were guided by the higher prevalence of three BRCA1/2 founder mutations in the AJ population.