This article, originally published May 9, has been updated with additional information from Myriad's analyst and investor day.
Myriad Genetics plans to launch a 25-gene hereditary cancer panel by the end of this year, which will replace its existing hereditary cancer tests by the summer of 2015, the company said during its analyst and investor day last week.
The test, called myRisk Hereditary Cancer, is the company's first to use a next-generation sequencing platform, primarily Illumina's HiSeq 2500.
"We really believe that this product is going to revolutionize hereditary cancer testing," said Mark Capone, president of Myriad Genetic Laboratories, during a presentation in New York, which was webcast.
The panel includes 25 clinically actionable genes, 11 of which Myriad already tests for with other products, and assesses both sequence variants and large rearrangements.
It will initially focus on melanoma, breast, colon, ovarian, endometrial, and pancreatic cancer and will be expanded to include lung, prostate, and other cancers in the future.
The turnaround time for the test will be 14 days or less, and it will have a list price between $4,000 and $4,500. Capone said the company will be able to "use the current molecular [pathology] code and the current reimbursement" already negotiated with payors for the new test, which it projects will have growth margins of about 87 percent.
For comparison, Myriad's integrated BRACAnalysis test, which analyzes the BRCA1 and BRCA2 genes, has a list price of $4,000, and its Colaris test, which covers the MHL1, MSH2, MSH6, PMS2, and MYH genes, as well as rearrangements in EPCAM, lists for $4,500.
Because myRisk contains a number of genes Myriad is currently not testing for, it will initially have a higher rate of variants of uncertain significance than its BRCAnalysis test, though that is expected to decline over time.
"Anytime you start with a new gene, you will inherently have a higher uncertain variant rate," CEO Pete Meldrum said. But given Myriad's large test volumes, "we will be in a very good position to very rapidly be able to characterize those uncertain variants and reduce the uncertain variant rate, which will then just continue to expand the size of the variant database that we have already assembled."
IP Protection
MyRisk contains eight genes for which Myriad holds intellectual property: BRCA1, BRCA2, BART, RAD51C, PALB2, PTEN, MYH, and P16.
The company is evaluating additional proprietary genes that it might add to the panel, including MITF, a gene it recently licensed exclusively from the Institute Gustave Roussy in Paris for melanoma and renal cell carcinoma testing, and ELAC2, a prostate cancer gene it discovered in house. "There will be others that we either discovered internally or licensed from the outside that will continue to be part of the evolution of this myRisk product," Capone said.
Asked whether the upcoming US Supreme Court decision regarding Myriad's BRCA1 and BRCA2 patent claims for isolated DNA or cDNA might weaken its IP position for genes included in myRisk, Meldrum said Myriad will still have strong protection, whatever the outcome.
"It’s important for investors not to think that should the Supreme Court rule against either cDNA or isolated DNA, the gene patents are no longer any good. Quite the contrary, the method of use claims are very strong and that will continue to give Myriad a very strong intellectual property competitive advantage going forward with myRisk," he said.
Myriad's goal is to replace its existing hereditary cancer tests – BRACAnalysis, Colaris, Colaris AP, Melaris, and Panexia – with myRisk by the summer of 2105, when the other tests will be phased out.
Switching to NGS
MyRisk will be Myriad's first test to run on a next-generation sequencing platform – a significant shift away from its Sanger-based platform, on which it has sequenced more than a million patients – and the company has developed a number of proprietary technologies around the test.
MyRisk will primarily run on Illumina's HiSeq 2500, with some additional sequencing on the Illumina MiSeq and by Sanger.
According to Capone, Myriad has been working with next-gen sequencing technology for six years and has used it to analyze more than 7,000 samples. Five years ago, for example, to gain experience with the new technology, Myriad helped sequence the apple and grape genomes, at the time using the 454 platform (IS 3/11/2008).
For the last three years, Myriad has been sequencing DNA from FFPE samples and has used NGS for whole-exome, whole-genome, whole-transcriptome, and methylation sequencing, Capone said.
For myRisk, it opted for a gene panel rather than the entire exome, he explained, because an internal study found that exome sequencing missed too many mutations – 12 percent of mutations at 20x average coverage and 3 percent of mutations at 100x coverage.
The test also needs to be able to identify large rearrangements effectively, requiring an average coverage of 1,000x, Capone said, which can only be reached using targeted sequencing.
"For clinical testing, the only answer that's acceptable is 100 percent accuracy," he said. "You must be able to read every single base accurately – that's the level of quality that's required and expected by Myriad."
The myRisk process starts with DNA extraction from buccal swabs, which required a "substantial amount of development" from Myriad to allow it to use this type of DNA, he said.
Myriad tracks the samples and manages its "sequencing factory" with an in-house developed LIMS system that allows for high levels of accuracy.
To amplify the 25 genes in its panel, Myriad uses the RainDance Thunderstorm microdroplet PCR platform, a partnership it revealed several weeks ago (CSN 4/17/2013).
The RainDance platform generates 1,200 amplicons, using a multiplexed primer library developed by the partners. Following the amplification, Myriad adds nanobarcodes to each sample to be able to pool several for sequencing on the HiSeq 2500.
A number of genes that have pseudogenes are sequenced separately, Capone noted, using long-range PCR followed by sequencing on the MiSeq.
Also, Myriad has validated all 1,200 amplicons by Sanger sequencing, so it can use that technology to fill any regions that are not covered by next-gen sequencing.
Finding that no commercial software package was able to call variants effectively, the company wrote its own variant calling software, Capone said.
To classify variants as disease-causing, the company works with six so-called "gene teams" that use both internal and external databases for their analysis. Significant variants are then confirmed by an orthogonal technology – Sanger sequencing for small variants, and Agilent microarrays for large rearrangements.
Finally, Myriad generates two test reports, using its own proprietary software, one listing the genetic results, the other combining the test results with a patient's family history to assess their cancer risk over their lifetime.
The latter report, called "clinical management tool," has been well received by physicians, Capone explained, as it will help them use the results of the test in patient care.
Expanding the Market
MyRisk will solve the dilemma faced by physicians today who do not know which hereditary cancer test to order for a particular patient, he said, because several genes can predispose to the same type of cancer, and the same gene can increase the risk for several types of cancer. "Because of this genetic overlap between genes and disease, it's difficult to choose for physicians what genes to order and how to manage patients," he said.
Capone presented the cases of three patients who were tested using the myRisk panel, which showed that they had mutations in a different gene than their cancer family history had suggested.
Myriad believes that myRisk will allow it to "significantly expand the market beyond where we are today," Capone said.
Specifically, the increased sensitivity of the assay will make it applicable to more patients, and the test will cover more types of cancers as more and more genes are included in the panel.
Myriad sees the time period between now and 2015 as a conversion phase, during which myRisk will start replacing its existing tests. Its own market research has shown that 86 percent of oncologists, 93 percent of OB-GYNs, and more than 90 percent of genetic counselors would convert from existing Myriad tests to myRisk.
Today, about 300,000 cancer patients per year are eligible for hereditary cancer tests, Capone said, a number that could double by 2016 as more cancer types are covered by the test and a larger percentage of patients with a particular cancer are eligible for testing. Ultimately, with improved technology and lower prices, "we do see a time where every cancer patient is going to be tested for hereditary cancers into the future," he said, about 1.6 million cancer patients per year.
Likewise, the number of patients eligible for preventative testing, due to their family history, could increase from a current 3 percent of the population to 5 percent by 2016, and Myriad hopes that everyone will eventually undergo screening for hereditary cancer.
Starting in 2018, some of Myriad's early BRCA patents will expire, but the company believes its myRisk test will ensure it stays competitive. To that end, it will seek to expand the list of proprietary genes on the panel, and to provide better turnaround times and customer service than competitors. In addition, its variant database will be superior to that of others, Capone said, with more than 16,000 variants for breast and ovarian cancer, more than 6,000 for colon cancer, and an increasing number of variants for other genes.