Evolution of Genetic Testing for Inherited Susceptibility to Breast Cancer
Authors: Susan M. Domchek
Journal: Journal of Clinical Oncology (2014)

Use of genetic testing for breast cancer susceptibility, specifically mutations in BRCA1 and BRCA2, became commercially available in the late 1990s and has expanded significantly since that time. Current debates include how low the threshold should be for consideration of genetic testing for BRCA1/2 and whether additional genes should be routinely interrogated. Clinical management options (such as risk-reducing salpingo-oophorectomy) are available and have been associated with decreased cancer risk and improved mortality. In addition, targeted therapiesarebeingdevelopedinpatientswithBRCA1/2-associatedmalignancies. Thus, identification of the best candidates for genetic testing is critically important forappropriatecare. Initially,uptakeofgenetic testing was largely in well-educated individuals with a strong family history of breast and ovarian cancer. Studies have identified groups in which the prevalence of BRCA1/2 mutations is sufficient to justify offering testing (such as those with breast cancer 40, high-grade serous ovarian cancer, male breast cancer, and individuals of Ashkenazi Jewish ancestry with breast or ovarian cancer). BRCA1 mutation–associated breast cancers are usually triplenegative([TNBC],estrogenreceptornegative,progesterone receptor negative, and human epidermal growth factor receptor 2/neu negative), and previous reports have demonstrated that approximately 10% of unselected TNBC are associated with germline BRCA1 mutations.Althoughpastunselecteddatahavebeenlimitedtosmalldatasets, TNBC diagnosed younger than age 60 years is part of the National Comprehensive Cancer Network (NCCN) guideline for consideration of BRCA1/2 testing. In the article that accompanies this editorial, Couch et al examine the frequency of BRCA1 and BRCA2 mutations in a large series of TNBC. Of 1,824 patients with TNBC unselected for family history, 11.2% had deleterious mutations in BRCA1 (8.5%) or BRCA2 (2.7%). Earlier age of onset and family history of breast or ovarian cancer were strongly associated with the presence of a BRCA1/2 mutation; however, even in the 241 women with TNBC between ages 50 to 59 with no known family history, 18 (7.5%) had detectable mutations in BRCA1/2. These data reinforce the appropriateness of the NCCN guidelines for consideration of genetic testing in individuals with TNBC younger than age 60 years. Evidence-based guidelines matter because they are often used to justify coverage of services. Even in TNBC, those with a strong family history are most likely to have a BRCA1/2 mutation. However, patients do not always know or recognize their family history (particularly on the paternal side); limited family structure (such as families in which there are few women) may obscure genetic susceptibility penetrance, and family history is often poorly captured by providers (particularly information regarding unaffected relatives, which strongly impacts many risk-prediction models). Thus, defining specific groups in which one should always consider genetic counseling and potential testing is of practical value. Women with TNBC diagnosed at younger than 60 years has been established as one of these groups. In those 60 without a family history, the frequency of BRCA1/2 mutations in the current study was 1.4%. This group is not recommended for routine testing on the basis of our current thresholds (those with at least a 5% to 10% likelihood of having a mutation), the appropriateness of which is supported by the current study. The threshold for genetic testing has fallen over time in conjunction withdataonimpactfulmanagementstrategies,patient interest, expanded insurance reimbursement, and decreasing variants of uncertain significance (VUS) rates. Recently, there have been calls to eliminate the threshold and enact population-based screening for BRCA1/2 mutations. Concerns about this approach include, among others, variability in penetrance (“What is the lifetime risk of cancer in a BRCA1 mutation carrier with a large family with many women but no breast or ovarian cancer?”), VUS, and cost. An additional consideration is the perception that a negative test result will significantly decrease a woman’s lifetime risk of breast cancer (not an accurate assumption for a woman in the general population). Population-based screening in the Ashkenazi Jewish population has fewer of these issues (cost is much lower, and there are no VUS), but appropriate implementation remains a major concern. A particular issue is how to provide effective population-based counseling for an autosomal dominant disorder with incomplete penetrance while ensuring informed decision making in an efficient manner. A second topic addressed by Couch et al was the prevalence of mutations in other genes in TNBC. The use of multigene or panel testing (in which many genes are tested simultaneously for deleterious mutations) is rapidly expanding in the assessment of breast cancer susceptibility, and the potential issues regarding their use have been elaborated. In the current study, of the 1,824 unselected patients with TNBC, 3.7% had mutations in 15 additional genes. This finding is quite similar to a study of 2,158 patients with breast cancer referred for clinical genetic testing (not restricted to TNBC), in which 4.4% had mutations, although this was lower than the reported frequencies in other studies. However, in the TNBC cohort, the gene in which mutations were most frequently detected apart from BRCA1/2 was PALB2 (1.2% of patients), and no CHEK2 mutations were detected; conversely, in an article by Tung et al, the gene most frequently mutated was CHEK2 (1.6%). This finding is consistent with the observations that CHEK2 mutations are associated with estrogen JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L