Multigene panel tests may identify less common harmful mutations in moderate-risk genes

Multigene testing of women negative for BRCA1 and BRCA2 found some women harbored other harmful genetic mutations. These were most commonly moderate-risk breast and ovarian cancer genes and Lynch syndrome genes, which increase ovarian cancer risk, according to an article published by JAMA Oncology (2015; doi:10.1001/jamaoncol.2015.2690).

Multigene panel genetic tests are increasingly recommended for patients evaluated for a predisposition to hereditary breast/ovarian cancer (HBOC). However, the rapid introduction of these tests has raised concerns because many of the tested genes are low- to moderate-risk genes for which consensus management guidelines have not been introduced or were introduced only very recently, according to the study background.

Leif W. Ellisen, MD, PhD, of Massachusetts General Hospital Cancer Center in Boston, and coauthors wanted to determine how often multigene panel testing would identify mutations that warranted some clinical action among women appropriately tested but lacking BRCA1 and BRCA2 mutations.

The authors enrolled 1,046 women and carried out multigene panel testing on all the participants. Among the women, 3.8% of them (40 women) who were negative for BRCA1 and BRCA2 had harmful mutations in other moderate-risk genes.

The authors included an additional 23 patients in the study's clinical management analysis and results indicate that among 63 women positive for mutations, the majority of them (33 women [52%]) would be considered for additional disease-specific screening and/or prevention measures beyond those based on personal and family history alone. Additional family testing also would be considered for first-degree relatives, according to the results. In the large majority of mutation-positive cases (58 of 63 [92%]), personal and/or family histories included cancer associated with the mutant genes.

“Multigene panel testing for patients with suspected HBOC risk identifies substantially more [people] with relevant cancer risk gene mutations than does BRCA1/2 testing alone. Identifying such mutations is likely to change management for the majority of these [people] and their families in the near term, and in the long term should lead to development of effective management guidelines and improved outcomes for at-risk [persons],” the study concluded.

In a related commentary in JAMA Oncology (2015; doi:10.1001/jamaoncol.2015.2699), Elizabeth M. Swisher, MD, of the University of Washington Medical Center in Seattle, wrote: “I applaud Desmond et al. for tackling this important and challenging question. Multigene testing is rapidly becoming the norm for genetic cancer risk assessment. We must continue to assess the effect of such testing on clinical care and patient experience and work to provide meaningful guidelines for cancer-preventive care for those with less common genetic findings.”

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