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Multigene panel testing can alter risk assessment, management for BRCA-negative women
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Multigene panel testing revealed harmful mutations that increase risk for hereditary breast and ovarian cancer in some women who are negative for BRCA1 and BRCA2, according to results of an observational study.
These findings are likely to change the clinical management for more patients and their families than BRCA1/2 testing alone, according to the researchers.
Although multigene tests are gaining in popularity for patients who may be predisposed to hereditary breast and/or ovarian cancer (HBOC), concerns remain because most of the genes tested are considered low- or moderate-risk genes for which management guidelines either do not exist or have only been recently introduced.
Leif W. Ellisen
“There is currently considerable uncertainty as to how and whether results from multigene testing will be applied in clinical practice,” Leif W. Ellisen, MD, PhD, program director at the center for breast cancer at Massachusetts General Hospital Cancer Center and a professor of medicine at Harvard Medical School, and colleagues wrote. “Furthermore, the practical clinical effect of recently introduced practice guidelines pertaining to low- and moderate-risk HBOC genes is unknown. We asked whether, under current consensus practice guidelines, finding a non-BRCA1 or -BRCA2 mutation would alter the management recommendations that would otherwise be made on personal and family history alone.”
Ellisen and colleagues evaluated data from 1,046 women who were candidates for HBOC evaluation and who were BRCA1 and BRCA2 negative.
The likelihood of a post-test management change, as well as the likelihood of an indication for additional familial testing with consideration of personal and family history, gene-associated cancer risks and gene-specific consensus management guidelines served as the primary study outcomes.
Overall, 40 (3.8%; 95% CI, 2.8-5.2) women harbored harmful mutations, most of which were moderate-risk genes such as CHEK2, PALB2 and ATM and Lynch syndrome genes.
Researchers then included an additional 23 mutation-positive women with mutations other than BRCA1/2 who were enrolled from clinics.
Among all 63 women, 92% of the mutations were consistent with the array of cancers observed in the patient or their family history.
Based on these findings, 52% (95% CI, 40.3-64.2) of the women would be considered for additional disease-specific screening or other prevention measures beyond personal and family history-based management alone. Additional familial testing would be considered for 72% (95% CI, 59.8-82.2) of those with first-degree relatives based on possible management changes for relatives who harbored mutations.
The researchers indicated that although the study data provide new key information regarding multigene testing in a clinical setting, there were some limitations to the study.
Namely, the clinical effect demonstrated may only apply to an appropriate cohort. Additionally, the clinical utility is defined based on the current consensus management recommendations, which will likely change over time. The data also are based on practice guidelines and not actual clinical practice, which means many “real world” factors could influence the clinical effect of multigene testing.
Forgoing genetic testing in this setting may be more harmful than multigene testing, Elizabeth M. Swisher, MD, professor of obstetrics and gynecology and adjunct professor of medical genetics at University of Washington, as well as medical director of the Breast and Ovarian Cancer Prevention Program at Seattle Cancer Care Alliance, wrote in an accompanying editorial.
“I applaud [Ellisen and colleagues] for tackling this important and challenging question,” Swisher wrote. “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.” – by Anthony SanFilippo
Disclosure: Ellisen reports a consultant/advisory role with Bioreference/GeneDx Laboratories. Swisher reports no financial disclosures. Please see the full study for a list of all other researchers’ relevant financial disclosures.
Perspective
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Mary B. Daly, MD, PhD, FACP
In the past 2 years, genetic testing for hereditary breast and ovarian cancer syndrome has moved from a single focus on the BRCA1 and BRCA2 genes to more comprehensive testing using multigene panels that include additional genes associated with these cancers. The commercial availability of these multigene panels expands the clinician’s ability to assess cancer risk by including additional genes with variable levels of risk for breast and ovarian cancer, and even other types of cancers. Concerns associated with these new panels include uncertainties about the actual level of risk conferred, and about the effectiveness of risk-reducing strategies that have been primarily derived from BRCA1/BRCA2-positive families.
Desmond and colleagues attempted to define the clinical utility of using multigene panels in a cohort of 1,046 individuals who met criteria for testing for hereditary breast ovarian cancer syndrome, but who did not have a deleterious BRCA1 or BRCA2 mutation. The researchers found non-BRCA1/BRCA2 mutations in 40 (3.8%) individuals. Using published clinical practice guidelines, they speculated that the discovery of these mutations would result in a change in clinical intervention for 52% of the cohort, and would result in a recommendation for testing of other family members in 72% of the cohort.
These results provide reassurance that multigene panel testing can provide information to guide clinical management in a small proportion of individuals tested. Additional studies will be needed to address the question of whether the clinical interventions recommended would afford any benefit to those testing positive for these less well-studied mutations, and the question of how to handle the significant number of variants of uncertain significance that multigene panels generate.
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