Beyond BRCA: Promising results with multigene testing for breast cancer

Results of a multicenter observational study suggest that testing for a panel of genes may be the wave of the future for hereditary breast and ovarian cancer and alter the course of clinical management. The findings, published in JAMA Oncology, showed that detection of mutations in genes beyond BRCA1 and 2 would be likely to lead to recommendations for more cancer screening and/or preventive measures for women at risk of breast cancer and their family members unaffected by the disease. 

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The goal of the research, conducted between 2001 and 2014 at 3 academic centers, was to determine the potential clinical effect of multigene panel testing for hereditary breast and ovarian cancer in a clinical representative cohort. A total of 1046 women were enrolled and testing at Stanford University and Massachusetts General Hospital was with the 29-gene Hereditary Cancer Syndromes test (Invitae) and at Beth Israel Deaconess Medical Center was with the 25-gene MyRisk test (Myriad Genetics).

Forty of the women who were BRCA1/2-negative (3.8%; 95% CI, 2.8%-5.2%) harbored deleterious genetic mutations, most often in moderate-risk breast and ovarian cancer genes (CHEK2, ATM, and PALB2) and Lynch syndrome genes. Most of the mutations (92%) found in these women and 23 other mutation-positive women enrolled from the clinics were consistent with the spectrum of cancer(s) observed in those patients or their families, leading the authors to conclude that their results were clinically significant.

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For 33 of the 63 women (52%) with mutations, under current guidelines, the results of the testing would trigger a recommendation for additional disease-specific screening or preventive measures beyond what would be standard based on personal and family history alone. Additional familial testing also would be considered for those with first-degree relatives (42 [72%] of 58; 95% CI, 5.8%-82.2%) based on potential management changes for mutation-positive relatives. The clinical effect was not restricted to a few of the tested genes because most identified genes could change management for some patients.

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The authors noted that of the mutations found with the multigene panel testing, only 3 were in high-risk breast cancer genes other than BRCA1/2 (CDH1) and 4 were in genes that do not have a well-established link to hereditary breast and ovarian cancer (2 in CDKN2A, 1 biallelic in MUTYH, and 1 in APC).

While indicating that their study provides “key new information regarding the utility of multigene testing,” the researchers noted some limitations. The clinical effect of the testing is likely to apply only to an appropriately selected cohort. The findings do not apply to population screening for mutations because the cancer risk estimates and probability that an identified mutation would change clinical management are influenced by ascertainment. Management recommendations for hereditary breast and ovarian cancer also are likely to change in the future.