Multigene Panel Test Finds Mutations in BRCA-Negative Individuals

Roxanne Nelson

August 14, 2015

For people at risk for hereditary breast or ovarian cancer, multigene panel testing might provide more actionable information than screening for only BRCA1 and BRCA2 mutations, according to a new study.

"We found that 3.8% of individuals referred for hereditary breast/ovarian cancer testing who were negative for BRCA1/2 had mutations in these other genes," said senior author Leif W. Ellisen, MD, PhD, program director of breast medical oncology at Massachusetts General Hospital and professor of medicine at Harvard Medical School in Boston.

"Since the typical proportion of such patients expected to have BRCA1/2 mutations is about 9%, this represents a substantial increase in the proportion of patients with cancer risk gene mutations," he told Medscape Medical News.

"Identifying such mutations is likely to change management for the majority of these individuals and their families in the near term, and in the long term, should lead to the development of effective management guidelines and improved outcomes for at-risk individuals," Dr Ellisen and his colleagues conclude.

For the 52% of people who are mutation-positive, this would amount to cancer screening and/or preventive measures over and above what would be recommended on the basis of personal and family cancer history alone. He pointed out.

The study was published online August 13 in JAMA Oncology.

Lingering Concerns

However, multigene testing is not without concerns. A major argument against it is the need to avoid harm by providing information on mutated genes for which guidelines about care management are not well defined, writes Elizabeth M. Swisher, MD, from the University of Washington Medical Center in Seattle, in an accompanying commentary.

"In many high-risk families, we already are harming patients by having inadequate knowledge about who is at risk," Dr Swisher notes.

As an example, she describes the case of two sisters with ovarian cancer who have tested negative for BRCA1/2 mutations. "Most physicians would offer age-appropriate risk-reducing salpingo-oophorectomy to first-degree female relatives, half of whom are really not at risk," she says.

But a more comprehensive genetic assessment might identify the cause of the ovarian cancer in the affected women, such as the RAD51C mutation. "By identifying the cause of ovarian cancer in the family, at-risk relatives can be tested, eliminating unnecessary interventions in women without the familial risk," she notes. "In this case, nontesting is more harmful than multigene testing."

She notes that multigene testing is rapidly becoming the norm for genetic cancer risk assessment, and that "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."

Dr Ellisen agrees that uncertainty can be a concern, particularly when the risks associated with many of the genes are less than those with BRCA1/2.

Another level of uncertainty is in the interpretation of the test itself; so-called "variants of unknown significance" are found in any genetic test. "Most of these turn out to be benign, but the uncertainty can be troublesome and needs to be appropriately conveyed to patients and other practitioners," he explained. "The levels of uncertainty need to be balanced against the ability of these tests to provide additional information about cancer risks that can help patients and providers make well-informed decisions about cancer screening and prevention."

"Our study suggests that this information is likely to change management for many mutation-positive patients even under current guidelines," he added.

Changes in Management

Dr Ellisen's team notes that a number of published studies from various groups have looked at the prevalence of non-BRCA1/2 mutations. However, they believe that their study is distinct because of the size of the cohort and the availability of detailed personal and family history data collected directly from the participants. This study also looked at the patient management implications of these prevalent mutations — an issue that has not been thoroughly addressed.

The 1046 study participants had been referred for genetic testing/counseling for hereditary breast or ovarian cancer risk assessment to three academic centers — the Massachusetts General Hospital Center for Cancer Risk Assessment, the Stanford University Clinical Cancer Genetics Program, and the Beth Israel Deaconess Medical Center Breast/Ovarian Cancer Genetics Clinic — and their community affiliates from 2001 to 2014.

The majority of the participants were women, and 83% had a personal history of breast and/or ovarian carcinoma. All had been tested and none had BRCA1 or BRCA2 mutations.

In the study, 669 of the participants underwent testing with the 29-gene Hereditary Cancer Syndromes test (Invitae) and 377 underwent testing with the 25-gene MyRisk Test (Myriad Genetics). Both panels included established high-risk and low- or moderate-risk hereditary breast and/or ovarian cancer predisposition genes.

Of the 1046 study participants, 3.8% (95% confidence interval [CI], 2.8% - 5.2%) harbored deleterious mutations other than BRCA1 and BRCA2, most commonly in moderate-risk hereditary breast and/or ovarian cancer genes (CHEK2, ATM, and PALB2) and Lynch syndrome genes. In 10 of these 40 participants, change in management would have been recommended and would have involved increased screening or preventive surgery, the researchers report.

Twenty participants had mutations in high-risk genes. In each case, identification of the mutation would have changed pretest recommendations for screening and/or preventive surgery.

The 23 participants who harbored non-BRCA genetic mutations were analyzed in combination with the 40 participants who had mutations other than BRCA1 and BRCA2.

Of there 63 participants with cancer risk mutations, 52% would have received a post-test management recommendation for additional screening and/or prevention, in accordance with current consensus practice guidelines.

Dr Ellisen and his colleagues found that the consequences of identifying these genes were more pronounced for family members than for the participants themselves. A positive mutation would have prompted a recommendation to test first-degree family members in 72% of cases.

Guidelines Needed and Counseling

Currently, multigene testing is not standard practice; the cancer genetics community is somewhat divided on the role of these tests, Dr Ellisen explained.

"The consensus practice guidelines for some of the additional genes on these multigene panels are less specific than those for BRCA1/2, and for other genes there are no guidelines," he said. "In those cases, the recommendation needs to be based on what is known about the cancer risks associated with these particular genes."

"Our study showed that even with this increased uncertainty, finding such gene mutations in people appropriately referred for genetic testing for hereditary breast and/or ovarian cancer would lead to different recommendations for cancer screening and/or prevention than would be recommended based on their personal and family cancer history alone," he added.

But multigene testing adds to the complexity of data that patients are already dealing with, and clarification is needed to help them understand what these results mean, and the associated implications. "This is a key point," emphasized Dr Ellisen. "Genetic testing is getting more complex, and patients should have access to experts to help them decide whether to be tested, what test is appropriate, and how to interpret the results. This includes genetic counselors, physicians, and other providers who are versed in the nuances of the testing."

This study was funded by unrestricted philanthropic gifts from the MGH Friends Fighting Breast Cancer, the Tracey Davis Memorial Fund, and the Breast Cancer Research Foundation. Dr Ellisen reports consultancy for Biorefernce/GeneDx Laboratories. Two of his coauthors report receiving research funding from Myriad Genetics, four are Invitae employees, and one is a paid member of Invitae's advisory board. Dr Swisher has disclosed no relevant financial relationships.

JAMA Oncol. Published online August 13, 2015. Abstract, Commentary


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.
Post as: