Evidence Builds for Multigene Testing for Hereditary Cancers

Publication
Article
Oncology Live®October 2015
Volume 16
Issue 10

The use of multigene assays to screen patients for hereditary breast and ovarian cancer risk yields clinically valuable information beyond single-gene BRCA testing, but confusion about accurately interpreting the results presents a challenge for clinicians even as panel testing becomes more widely adopted.

Leif W. Ellisen, MD, PhD

The use of multigene assays to screen patients for hereditary breast and ovarian cancer risk yields clinically valuable information beyond single-gene BRCA testing, but confusion about accurately interpreting the results presents a challenge for clinicians even as panel testing becomes more widely adopted.

Those were among the conclusions that Leif W. Ellisen, MD, PhD, reached after leading a research team that investigated the clinical utility of multigene panel risk assessment in more than 1000 patients. The researchers found that broader knowledge of deleterious mutations beyond BRCA1/2 in known cancer-causing genes suggested changes in management strategies, which they concluded supports the use of such assays.1

At the same time, Ellisen said in an interview with OncologyLive, testing for additional genes increases the number of variants of unknown significance (VUS) that will be found, making the results more difficult to interpret.

“It’s actually more common to find a VUS than it is to find something definitively wrong,” said Ellisen, program director of breast medical oncology at Massachusetts General Hospital and professor of medicine at Harvard Medical School. “There’s no doubt that in general you should not act on variants of unknown significance because the overall likelihood is that, as time goes by and we learn more about them, they turn out to be benign.

Rapid Growth of Multigene Testing

“But, in the provider community there is confusion and continues to be confusion, and those of us in the genetics profession see that every day,” said Ellisen. “And that’s where providers, oncologists need to look to their genetics professionals to clearly interpret what this finding means and whether or not it’s actionable.”The research by Ellisen and colleagues comes at a time when the use of multigene assays to assess hereditary cancer risk is increasing rapidly in oncology practice, Elizabeth M. Swisher, MD, noted in a commentary that accompanied Ellisen’s research report in JAMA Oncology in August.2

Swisher said testing for BRCA1 and BRCA2 mutations quickly spread beyond the research settings where it initially was recommended in the mid-1990s into community practice resulting in millions of women getting screened worldwide and the accumulation of vast amounts of data. She sees a similar phenomenon unfolding now with multigene testing.

“The advent of next-generation sequencing has opened the door to broader evaluation of cancer risk genes without additional cost,” wrote Swisher. “… Multigene testing is rapidly becoming the norm for genetic cancer risk assessment.” Indeed, the market for such testing has exploded since the US Supreme Court ruled in June 2013 that human genes cannot be patented.

Today, there are at least a dozen companies offering either a variety of BRCA tests or multigene panel assays that include BRCA genes.3

Ellisen said several market forces are driving the trend toward multigene testing. “In many cases, that’s the major test that the companies are offering now,” he said. “Secondly, many payers will only pay for one test, so you can’t do BRCA1/2 and then go back and test for more genes if that one’s negative. If you’re going to have to test for anything, you have to do it all up front. And then finally, the actual costs, because of the way sequencing is done in the modern era, it basically costs the same regardless of how many genes you’re doing.”

Two Assays Examined

Additionally, clinical evidence is mounting about genes other than BRCA with the potential to confer a heightened cancer risk. “One of the main reasons why these panels have become popular is that when we see patients with family cancer histories, often it’s a mixed history,” Ellisen said.In their observational study, Ellisen said researchers sought to answer two main questions about multigene risk testing: “If you do a much broader panel with more genes, how often do you find [mutations] in addition to BRCA1 and BRCA2? And most importantly, does finding these other genes actually change what you would do for the patient?”

Genes Selected for Hereditary Risk Screening Study1

To answer those questions, investigators recruited patients who had been referred for genetic counseling and/or testing between 2001 and May 2014 from Massachusetts General Hospital Center for Cancer Risk Assessment, Stanford University Clinical Cancer Genetics Program, and Beth Israel Deaconess Breast/Ovarian Cancer Genetics Clinic. Patients with a known deleterious BRCA1/2 mutation were excluded. Blood samples from each enrolled patient were then tested using either a 29-gene Hereditary Cancer Syndromes test from Invitae, a genetics company based in San Francisco, or the 25-gene MyRisk test from Myriad Genetics, the Salt Lake City molecular diagnostics company that had patented the BRCA gene. The researchers previously established that next-generation sequencing techniques can produce similar sensitivity and specificity results as traditional BRCA1 and BRCA2 tests.4

Overall, the study accrued 1046 patients, a group that included nine men; notably, more than 70% of the participants with a personal history of cancer were younger than 50 years at the time of their diagnosis. The patients’ histories showed five different tumor types, and the genes selected for screening reflected a variety of hereditary cancers.

In all, the researchers found that 63 patients— all BRCA1/2 negative—harbored mutations in other genes. Of these, 40 patients (3.8%) had deleterious mutations in moderate-risk breast and ovarian cancer genes such as CHEK2, ATM, and PALB2, and/or Lynch syndrome genes. The other 23 patients exhibited mutation profiles similar to the rest of the cohort.

Significantly, one-third of the participants with mutations—described in the report as “a substantial subset of individuals”—had mutations in high-risk genes for which the National Comprehensive Cancer Network (NCCN) has developed guidelines, an indication of the actionable nature of the study’s findings.

Specifically, the multigene profiling indicated that 52% of those with mutations (33 patients) were candidates for additional disease-specific screening and/or prevention measures beyond those based on personal or family history and that additional testing would be suggested for 72% (42 patients) with first-degree family members.

“We did a patient-by-patient analysis of the people who were found to have those mutations and said, according to current guidelines, what would that mutation mean for their cancer risk? Should you manage them differently?” said Ellisen. “The answer was that in more than half the cases you should make a management change for that patient based on finding the mutation as opposed to just what you would do for them based on personal and family history alone.

Screening Questions Persist

“And it was also true that for the majority, you would recommend testing to other family members because it would certainly change what you should recommend to family members if they were found to have that mutation,” he said.The question of which individuals should be screened for hereditary breast and ovarian cancer risks has become a subject of debate within the oncology community, with some experts calling for broader population-based screening.

The NCCN guidelines recommend genetic risk evaluation for individuals in two broad categories— those diagnosed with cancer and those with a family history of cancer—with detailed criteria in each circumstance.5

For example, the criteria for patients with a cancer diagnosis include early-age onset breast cancer, a breast cancer diagnosis and a close blood relative age 50 years or younger with breast cancer or invasive ovarian cancer at any age. The family history criteria detail the numbers of breast cancers and other malignancies and whether the family members are first- or second-degree relatives.

In their paper, Ellisen and colleagues said their findings concerning potential changes in patient management approaches due to mutations was a “conservative analysis” based on the current guidelines.

Ellisen said in the interview that the guidelines currently are “very limited and rather general for people with mutations other than BRCA1/2, outside of these very rare, high-risk mutations,“ but that the recommendations would evolve as new evidence becomes available.

“I think that the bigger challenge is not so much what the guidelines say but educating practitioners about how to spot people who would fit the guidelines,” said Ellisen. “Where the guidelines make perfect sense, the problem is that applying them to an individual patient is rather complex and that tends to be an obstacle because it leads to both under and over referral of patients for genetic testing.

“In many centers, including ours, there’s a relatively long waiting line for genetic testing and nonetheless, we do miss some people who should be referred,” he added. “So there’s both overreferral, underreferral because it’s rather complex to do a full and complete assessment of family history and then apply the guidelines to determine who should be referred. There’s no doubt about that and that’s a challenge for practitioners.”

References

  1. Desmond A, Kurian AW, Gabree M, et al. Clinical actionability of multigene panel testing for hereditary breast and ovarian cancer risk assessment [published online August 13, 2015]. JAMA Oncol.
  2. Swisher EM. Usefulness of multigene testing: catching the train that’s left the station. [published online August 13, 2015]. JAMA Oncol.
  3. deLartigue J. The new BRCA1/2 landscape [published online December 13, 2014]. OncologyLive. 2014;15(12): 50-55. www.OncLive.com.
  4. Lincoln SE, Kobayashi Y, Anderson MJ, et al. A systematic comparison of traditional and multigene panel testing for hereditary breast and ovarian cancer genes in more than 1000 patients. J Mol Diagn. 2015;17(5):533-544.
  5. Genetic/familial high-risk assessment: breast and ovarian. NCCN Clinical Practice Guidelines in Oncology. Version 2.2015. Published June 25, 2015. Accessed October 4, 2015.

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