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.
“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.”
Rapid Growth of Multigene Testing
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
Swisher said testing for BRCA1
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
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.”
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.
Two Assays Examined
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?”