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Study Assesses Management Impact of Multigene Panels in Hereditary Breast And Ovarian Cancer

NEW YORK (GenomeWeb) – A new study suggests mutations uncovered by multigene panel sequencing may alter cancer prevention and management strategies offered to a significant subset of individuals suspected of being at risk of hereditary breast or ovarian cancer but lacking mutations in BRCA1 or BRCA2 genes.

As they reported online today in JAMA Oncology, researchers from Massachusetts General Hospital, Stanford University, and elsewhere used multigene panel sequencing to search for clinically actionable risk mutations in more than 1,000 BRCA1/2 mutation-negative women with a personal or family history of breast/ovarian cancer.

The team's follow-up analyses focused on the 40 participants with gene panel mutations that were deemed deleterious, along with another 23 gene panel mutation-positive women enrolled at participating centers.

The study's authors found that within that group, the presence of genetic glitches identified using the gene panels would likely alter screening, prevention, or other patient management strategies more than half the time, compared to the type of testing that would be traditionally provided based on personal or family disease history patterns. And almost three-quarters of the mutation-positive patients' relatives would be considered for testing based on the gene panel results.

"If you actually look on a case-by-case basis, in the majority of women where you find these mutations, you really would change what you recommend to them for either screening or prevention of cancer based on finding that genetic information," senior author Leif Ellisen, program director at Massachusetts General Hospital Cancer Center's Center for Breast Cancer, told GenomeWeb.

"Either their risk was substantially higher than predicted based on personal or family history alone, or there's a risk of additional cancers that's higher than would be predicted from personal or family history alone," he explained.

The team began by enrolling 1,046 individuals who were considered appropriate candidates for genetic testing for hereditary breast or ovarian cancer risk based on personal or family medical histories.

Depending on whether participants were enrolled at Mass General or Stanford, their samples were tested with a 25-gene panel — Myriad Genetics' MyRisk test — or with Invitae's 29-gene Hereditary Cancer Syndromes test through academic collaborations with the companies.

In the group of BRCA1/2 mutation-negative women tested, the team picked up suspicious alterations involving moderate cancer risk genes in 40 participants — almost 4 percent of those tested.

A few of the deleterious mutations the researchers detected fell in the high-risk breast cancer gene CDH1, though most affected low- or moderate-risk hereditary breast and ovarian cancer genes. Eight individuals carried Lynch syndrome-related mutations, while a few had glitches in genes implicated in other types of cancer.

To look at the clinical implications of such alterations, the team added 23 more gene panel mutation-positive, BRCA1/2 mutation-negative individuals into the mix. Some 92 percent of the mutations found in this group of 63 participants appeared to match the types of cancers described in their own medical past or in their family histories.

And the authors' analyses indicated that more than half of the women in the group would be eligible for disease-specific screening and other preventative measures that exceed those typically offered to individuals with comparable breast/ovarian cancer histories.

In those with Lynch syndrome-related mutations, for example, individuals would be encouraged to get more frequent screens for colorectal cancer, they argued, while those with deleterious alterations in the moderate cancer risk gene PALB2 may get more frequent breast screening.

Ellisen said such results are also expected to impact participants' family members by providing an opportunity to alert and perhaps test close relatives at risk of carrying the same risk mutation(s).

"We calculated that about 72 percent of the time it would be recommended to test other family members," he said.

Since the current study was done through a research protocol, the participants provided consent for research testing, while stating whether they wanted to receive clinically relevant results, if any, from their tests.

The team is now contacting participants who opted to receive clinically significant findings and hope to follow such individuals over time.

In particular, the researchers are keen to find out how many participants follow recommendations generated from the multigene panel results and what impact, if any, such management decisions have on long term cancer prevention and/or survival patterns.

Ellisen emphasized that the current study does not address the consequences of using multigene panels in a population screening capacity. Rather, the results are specific to women already being considered for hereditary breast/ovarian cancer gene testing.

"You cannot interpret such a test in the same way in someone who does not have any family history that's suggestive of hereditary cancer," he explained, noting that he and his colleagues focused on appropriately referred patients, those "who would be candidates for this kind of testing."

Although multigene panel sequencing is expected to be more cost-effective and efficient than sequential tests of individual genes, Ellisen noted that there is still some debate over their widespread use and cautioned that care is needed in communicating information about variants of unknown significance.

At the moment, it appears many VUS are benign, he said, though the classification of such variants is expected to improve as more and more individuals at risk of hereditary cancer are tested using the multigene panels.

In an accompanying commentary article in JAMA Oncology, University of Washington obstetrics and gynecology researcher Elizabeth Swisher noted that "[a] major argument against multigene testing has been the need to avoid harm by providing mutation information on genes for which guidelines about care management are not well defined."

"However, in many high-risk families, we already are harming patients by having inadequate knowledge about who is at risk," Swisher argued, noting that genetic testing could uncover cancer causing mutations that make it possible to more carefully target risk-reducing interventions.

"We must continue to assess the effect of such tests on clinical care and patient experience," she concluded, "and work to provide meaningful guidelines for cancer-preventive care for those with less common genetic findings."