NEW YORK (GenomeWeb) – A recent study by Myriad Genetic Laboratories adds to a growing body of evidence that shows that gene panels can catch variants outside of BRCA1 and BRCA2 in breast cancer patients referred for genetic testing, although there are still unanswered questions about appropriate clinical implementation of such panels.
Researchers at Myriad, the Beth Israel Deaconess Medical Center, and Harvard School of Medicine reported in a study published online this month in Cancer that Myriad's 25-gene next-generation sequencing-based test found variants in BRCA1 and BRCA2 in 9.3 percent of 1,781 breast cancer patients, and mutations in other cancer susceptibility genes in an additional 4.3 percent of patients.
The study highlights the fact that "panel testing identifies more mutations in cancer-causing genes than testing for one gene at a time," Anne-Renee Hartman, vice president of clinical development at Myriad, told Clinical Sequencing News.
Myriad launched myRisk last September to a limited number of customers in an early access program, and plans to enter full commercial launch this fall. By summer 2015, it will transition all of its hereditary cancer testing to myRisk. The company uses the RainDance Thunderstorm platform to amplify the 25 genes and sequencing is done primarily on the Illumina HiSeq 2500. The test has a list price of $4,000 to $4,500 and an average turnaround time of 14 days, which it aims to reduce to 10 days.
During a conference call in August discussing its fiscal year fourth-quarter results, Myriad said that by the end of its fourth quarter about 30 percent of the firm's hereditary cancer incoming orders were for myRisk. In FY 2015, Myriad projects it will test over 100,000 patients with myRisk.
The researchers tested the panel on two different patient cohorts. The first cohort consisted of 1,781 patients with breast cancer that were referred to Myriad for BRCA1 and BRCA2 testing and were not of Ashkenazi Jewish heritage. A second cohort consisted of 377 breast cancer patients referred to Beth Israel Deaconess Medical Center for genetic testing, but who tested negative for BRCA1 and BRCA2.
In the first cohort, 241 individuals, or 13.5 percent, had a mutation in at least one gene. BRCA1 and BRCA2 mutations were the most common, present in 165 individuals, or 9.3 percent. There were 76 individuals, or 4.3 percent, with mutations in at least one of the other 23 genes.
In the second cohort that had already tested negative for BRCA1 and BRCA2 mutations, the researchers found mutations to other breast or ovarian cancer genes in 2.9 percent of patients and mutations in other cancer susceptibility genes in 0.8 percent of patients.
A number of patients had incidental mutations, which the researchers defined as mutations in genes associated with cancers for which there was no family history. For instance, in the first cohort, five individuals had mutations in Lynch syndrome genes despite having no family history of ovarian cancer, and one individual had a mutation in a gene associated with colon cancer. In cohort 2, three individuals had incidental mutations in genes associated with hereditary melanoma and colon cancer.
Hartman said that such incidental findings were not necessarily a surprise, but they "reconfirm our thoughts that there's overlap between the spectrum of cancers that mutations in these genes cause." In addition, she said, these mutations have implications not just for the individual being tested, but also for family members. Some of the mutations will "trigger preventative and surveillance measures," she said.
Around 41 percent of individuals in each cohort had variants of unknown significance. Hartman said that this number, while high, is in line with expectations and will drop as more individuals are tested. Already, she said, the rate has dropped to about 30 percent in Myriad's clinical myRisk testing. "Over time, with large volumes of testing, and experience in categorizing and classifying variants, we anticipate that number to go down into the single digit range," she said.
Kami Schneider, a pediatric oncology genetic counselor at Children's Hospital Colorado and the University of Colorado, Denver, who was not affiliated with the study, told CSN that the high rate of variants of unknown significance would be a hurdle toward clinical adoption. "Especially because you have a 40 percent chance of a VUS and a 13 percent chance of finding a [pathogenic] mutation," she said. Just doing BRCA1/2 testing, there is a 9 percent chance of finding a mutation and only a 2 percent chance of finding a VUS.
"The cost-effectiveness is unclear," Schneider said. From a clinical perspective, it may make more sense to do the standard BRCA1/2 testing, and then reflex to an NGS panel only if a patient is negative for mutations in those genes. But that kind of cost-benefit analysis has yet to be performed. "Cost effectiveness is more than just the price the lab charges," she said, adding that it's also about the energy spent on analyzing and trying to make sense of the variants of unknown significance, as well as the genetic counseling and explaining the complexities and nuances of the test to the patient.
Harry Ostrer, a professor at the Albert Einstein College of Medicine, who was not affiliated with the study, told CSN that he thinks that such NGS-based panel tests will continue to gain acceptance in the community. "The field is really going to shift," he said. Nonetheless, he said that there are still a lot of unanswered questions about panel testing.
Like Schneider, he noted that there are risks associated with NGS-based panel testing that still need to be addressed, specifically when it comes to making risk predictions based on the findings. "There's a real difference with regards to how you counsel a patient depending on if they have an increased risk of 20 percent, 40 percent, or 80 percent," he said.
Hartman added that Myriad is currently doing research on many of the variants of unknown significance that were found in the study in order to better classify them and to understand in better detail how mutations in the various genes influence cancer risk. Although one criterion for including a given gene on the panel was that there had to be at least four peer-reviewed studies linking it to an increase in cancer risk, the exact risk increase for each gene is not perfectly understood, Hartman said. "We can give a ballpark or estimate, but we want to refine that number to help inform patients on what to do to manage that risk," she said.
Hartman said that Myriad is also considering a second version of the panel with additional genes in the near future. In addition, she said the firm has completed studies of its myRisk panel in colon cancer and other cohorts of patients that will be published in the next several months.