Deleterious mutations in the BRCA1 and BRCA2 genes are associated with a markedly elevated risk of early-onset breast and ovarian cancer. Mutation carriers have up to a 70% risk of breast cancer and an 11% to 40% risk of ovarian cancer by age 70 years.1–3 Germline testing for these genes provides an opportunity to reduce morbidity and mortality by allowing for appropriate integration of risk reduction and screening options. Studies evaluating the efficacy of these prophylactic strategies in patients with BRCA1/2 mutation have confirmed that risk-reducing bilateral salpingo-oophorectomy (RRSO) is associated not only with a reduction in cancer risk but, most importantly, with a significant reduction in cancer-specific and all-cause mortality. Compared with women who did not undergo RRSO, those who had the surgery had lower all-cause mortality (10% vs 3%; hazard ratio [HR], 0.40; 95% CI, 0.26–0.61), breast cancer–specific mortality (6% vs 2%; HR, 0.44; 95% CI, 0.26–0.76), and ovarian cancer–specific mortality (3% vs 0.4%; HR, 0.21; 95% CI, 0.06–0.8).4 Markov modeling suggests that a healthy 30-year-old woman with the mutation would gain 0.2 to 1.8 years in life expectancy with RRSO and 0.6 to 2.1 years from risk-reducing mastectomies.5,6
Additionally, risk-reducing surgeries have been shown to be the most cost-effective measures. Using costs, life-years (LY), and quality-adjusted life-years (QALY) as outcomes, a study that compared preventive surgery, chemoprevention, MRI, and mammography showed that prophylactic surgeries were associated with the lowest overall cost and the longest survival in LYs, dominating all other strategies.5 Thus, testing for BRCA1/2 mutations meets the ultimate goal of a screening test: it saves lives.
Unfortunately, many mutation carriers are only identified after their first cancer diagnosis. This is often because they have few female relatives or because their family history was not striking enough to warrant testing. However, it is clear that for genetic testing to have its greatest impact, it should occur before a carrier develops cancer. This argument forms the basis for considering population-based genetic testing.7 Concerns about this approach have focused on an expected increase in the rate of identification of variants of unknown significance (VUS) causing anxiety and uncertainty; a lack of clarity regarding the cancer risks in carriers without a strong family history of cancer; the accuracy of interpretation of negative results; the ability of the current model of genetic counseling practices to deal with the increase in patient volume; and the cost-effectiveness of such an approach.8,9
One way of minimizing the identification of VUS, the impact of false-negatives, and financial concerns is to focus population-based testing on groups with known founder mutations, such as individuals of Ashkenazi Jewish (AJ), Icelandic, or French-Canadian descent.10–13 The advantage of such an approach is that, in these populations, the founder mutations often account for the majority of mutations identified. Additionally, this more narrowed testing reduces cost and decreases the likelihood of detecting a VUS. For example, in Ashkenazi Jews, 2 BRCA1 mutations (185delAG and 5382insC) and 1 BRCA2 mutation (6174delT) have been found in approximately 1 in 40 individuals (2.5%). Importantly, these account for 90% of the mutations identified in this ethnic group.14–18
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