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Myriad Highlights Benefits of Multi-Gene Hereditary Cancer Testing at SABCS; Outlines MyRisk Plan

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At the San Antonio Breast Cancer Symposium last week, Myriad Genetics presented new data on its myRisk Hereditary Cancer panel, which the firm believes will help it convince physicians, patients, and payors of the advantages of multi-gene panels over single disease testing.

Myriad Genetics presented data at the conference from a large prospective study that found its 25-gene, next-generation sequencing myRisk Hereditary Cancer panel was able to identify 51 percent more patients with a heightened risk for familial breast and ovarian cancer compared to testing just the BRCA1 and BRCA2 genes. Previously, the firm had shown that the myRisk test picked up 61 percent more patients at risk for hereditary colon cancer compared to standard genetic testing for the disease.

The firm currently gauges BRCA1/2 mutations associated with increased risk of hereditary breast and ovarian cancer with its BRACAnalysis test, Myriad's best-selling product. However, the firm launched the myRisk test to a group of early-access customers in September. By the summer of 2015, Myriad plans to transition customers using its hereditary cancer tests, including BRACAnalysis, to its myRisk panel, which gauges a panel of genes associated with eight hereditary cancers with 99.99 percent accuracy.

Separately at the conference, InVitae announced the global launch of its NGS-based 29-gene panel hereditary cancer test, which includes BRCA1/2 genes and a number of other genes that play a part in hereditary cancers. Although InVitae hasn't garnered as much validation data on its test as Myriad has on myRisk, the company is aiming to attract customers by competitively pricing its service while steadily working to increase the evidence backing its test and the markers it gauges. In contrast to the $4,000 for Myriad's myRisk panel, InVitae has priced its test at $1,500, regardless of whether the physician wants information just on BRCA genes, a custom set of genes, or the full panel (see related story, in this issue.).

The emergence of multi-gene diagnostic panels, like those being marketed by Myriad and InVitae, signal a sea change in the way doctors screen and diagnose patients for diseases, particularly cancer. Today, healthcare providers commonly test for variants in BRCA1/2 when a patient has a family and medical history of breast and ovarian cancer. But they do not readily test for a slew of other genes that occur more infrequently, even though emerging clinical data increasingly suggest these genes are associated with multiple inherited cancers that they wouldn't test for using current treatment guidelines.

"One of the key things about myRisk and one of the major advances that we found — and [clinical] data are clearly bearing out — is the overlap in these syndromes," Elizabeth Garner, VP of medical affairs, preventive care at Myriad, told PGx Reporter. "Patients may have a family history for a particular syndrome, but in fact … a particular patient may be eligible for testing for a number of other genes."

At an investor meeting at SABCS, Larry Geier, assistant professor at Kansas University Medical School and a dedicated user of Myriad's tests, said that healthcare providers are fairly comfortable at the moment performing genetic testing for hereditary breast, ovarian, and colon cancers. To determine whether a patient needs testing, physicians typically look for family clustering of certain types of cancers, multiple cancers in one person, or the evidence of cancer at a younger age. Still, there is much room for improvement, he believes.

"We've had BRCA testing available to us for 17 or 18 years, and we're not very good at this. To date, fewer than 10 percent of all Americans with BRCA mutations and fewer than 3 percent of all those with Lynch Syndrome have actually been diagnosed," said Geier. "That's not Myriad's fault, that's our fault on the doctor's side. We need better tools to help us know what to do." Geier has previously received honoraria from Myriad Genetic Laboratories.

"It makes you wonder," Geier noted, "if we're performing that badly on these straight-forward symptoms, how badly are we doing on these other syndromes and on these newer genes?"

Besides InVitae and Myriad, there are a number of other companies performing NGS-based, multigene hereditary cancer testing, including GeneDx and Ambry Genetics. However, the increasingly competitive landscape in the hereditary cancer testing space is currently complicated by a crosshatch of lawsuits and countersuits between Myriad and its competitors.

In late November, Myriad sued InVitae, alleging that the firm is infringing its patents related to BRCA1/2 genetic testing. InVitae is one of six firms that Myriad has sued after the US Supreme Court over the summer ruled that several of its patent claims on isolated BRCA1/2 sequences were patent ineligible, while several claims on cDNA were patent eligible. InVitae promptly countersued Myriad in Northern California District Court seeking declaratory judgment that certain patent claims held by Myriad on BRCA1/2 and MUTYH genes are invalid and not infringed by the company.

Myriad has also sued Ambry Genetics, Gene by Gene, GeneDx, Quest Diagnostics, and Labcorp. Like InVitae, Ambry, Gene by Gene, and Quest have launched their own legal challenges against Myriad. The outcome of these lawsuits will play a part in shaping the future of the hereditary cancer testing space, Mark Capone, president of Myriad Genetic Laboratories, told investors at a SABCS. "There are a number of genes on these panels that Myriad has exclusive rights to," and the outcome of litigation "will dictate a lot of what happens in that post-2015 time frame," he said.

Gathering evidence

Before the Supreme Court reached its decision regarding Myriad's patent claims in June, the company had been the sole provider of BRCA mutation testing for nearly two decades. On the strength of that experience, the company has managed to analyze approximately 10,000 patients' samples to date on the myRisk panel.

A company spokesperson told PGx Reporter recently that Myriad is receiving around 1,000 samples per month across various cancers from early-access physicians for myRisk. Before ordering myRisk, doctors first gauge whether a patient's family and medical histories fit the profile for hereditary breast and ovarian cancer syndrome or for Lynch syndrome. "One of those is our ticket into the process," Geier said, noting that he hasn't experienced problems with insurance coverage using this method for directing testing to myRisk.

The 25 genes on the panel are highly penetrant genes, which according to the published literature, have significant risk of cancer associated with them. Additionally, 18 of the 25 genes are included in clinical guidelines for cancer as being clinically actionable.

List priced at approximately $4,000, myRisk has been investigated in multiple studies involving 5,000 patients in total. The study presented at SABCS adds to the growing body of evidence that Myriad is cultivating in order to convince its existing customer base to switch to the myRisk panel from individual hereditary cancer tests and maintain its market leadership.

This latest investigation, involving approximately 2,300 patients, was split into two cohorts – one group of nearly 2,000 patients referred for BRCA1/2 mutation testing, not including patients from the high risk Ashkenazi Jewish population; and a second group of more than 300 patients, including Ashkenazi Jews, who had a family history of hereditary breast and ovarian cancer but had tested negative for BRCA1/2 mutations previously.

The researchers, led by Nadine Tung of Beth Israel Deaconess Medical Center, reported than in the first cohort, 14 percent of patients had a mutation in at least one of the 25 genes on the myRisk panel; 9 percent had a BRCA1/2 mutation; and nearly 5 percent had a mutation in a non-BRCA gene. In this group, 275 patients were identified by myRisk as carrying deleterious cancer mutations, while testing for only BRCA1/2 genes would have picked up 182 patients as carriers.

In the second cohort of BRCA1/2 negative patients, more than 4 percent had a mutation in at least one of the 23 other non-BRCA genes in the myRisk panel. Overall, researchers found the most common non-BRCA mutations were CHEK2 (32 percent), NBN (15 percent), ATM (13 percent), and PALB2 (13 percent). Tung and colleagues also observed that using traditional risk factors such as age of breast cancer diagnosis and family history, they were unable to predict which patients would harbor non-BRCA mutations.

Mutations in genes other than BRCA, however, tended to be less prevalent in the Ashkenazi population, but more prevalent in patients with multiple breast cancers. In particular, in the second cohort, three breast cancer patients with NBN mutations had a family history of pancreatic cancer, which the researchers said needs to be confirmed.

Using the 25-gene panel in his practice, Geier noted he is "much more likely to find a [pathogenic] mutation if there is one," and if the test result is negative, "that's much more likely to be a true negative." He further observed that counseling his patients about their myRisk results has been easier than he thought. "I certainly did expect it to be harder. You have to talk about more genes. It's more complex," Geier said. "But the reality is that that's overshadowed by the fact that we're doing such comprehensive testing."

Commercialization plans

Myriad plans to continue its early-access program for myRisk until the end of this month, but then offer the test through an expanded access program for its last two fiscal quarters of 2014. MyRisk testing currently comprises 5 percent of Myriad's testing volume, but Capone expects that approximately 20 percent of the firm's hereditary cancer testing volume will come from the NGS panel by the end of the current fiscal year. Starting in the summer of 2014, the company will begin commercial launch efforts around myRisk, and aim to have its hereditary cancer testing customers transitioned to the NGS panel by summer of 2015.

Ahead of commercial launch, Myriad will continue to improve the testing process, focusing particularly on reducing the rate of variants of unknown significance (VUS) for myRisk. After testing 10,000 patients' samples on myRisk, Myriad has been able to reduce its BRCA VUS rate from 3.2 percent down to 0.4 percent. Company officials told investors that it achieved this low VUS rate with the help of its million-sample in-house variant database, and two proprietary variant classification algorithms the firm uses to assess whether a marker is benign or pathogenic. According to Myriad, the firm classifies 60 percent of variants from testing using the proprietary methods, while 40 percent of variants are classified using techniques commonly used in the field.

Capone noted that payors seem particularly keen on gauging the quality differences between multi-gene platforms for determining coverage, and the VUS rate will likely play a key part of determination. "We've built economic models … [showing that] testing with Myriad will save over $2,600 per patient because of the more accurate test," he said. "Incorrect tests are extraordinarily expensive."

Geier, who has tested 100 patients on myRisk over three months during the early-access period, provided examples of the costs he racked up using genetic tests specifically indicated for individual hereditary cancer syndromes. For example, Geier discussed one of his patients who was diagnosed with breast cancer at a very young age, and although various family members had had different cancers, including colon cancer, breast cancer, uterine cancer, there was no clear pattern of inheritance for a particular cancer type.

Given this history, this patient was considered for testing for BRCA, PTEN, TP53, Lynch Syndrome genes — and Geier assessed this patient for all these mutations through separate tests before identifying a variant in PTEN. But by then, the total cost for all this sequential testing was more than $10,000 and the process took 14 weeks. "But what if we had myRisk available?" posited Geier. "She would have qualified for BRCA testing based on her age [and] for $4,000 [she would have] gone right into the 25-gene panel and boom, we find the PTEN mutation in one step … in three weeks."

According to Myriad, the average turnaround time for myRisk results is approximately 20 days, but the firm aims to reduce that down to two weeks. "We're learning more and more that these cancers are biologically distinct, and that may have an impact on the prognosis of that cancer, the surgical management, and the sensitivity to chemotherapy," Geier said. "This is stuff we have to know in real time. I can't make surgical decisions or decisions about chemotherapy based on a test I'm going to get back in three or four months."

Other labs have a comparatively longer turnaround time for their NGS cancer panels. Myriad claims that some of its competitors are taking longer than 80 days to return results. And while these labs may be offering cheaper NGS-based analysis, Myriad's Capone explained that MyRisk is currently priced at a premium to BRACAnalysis because additional variant classification and counseling work is necessary with a larger, more complex panel.

"While sequencing costs may continue to decrease," he noted, "there are still significant costs associated with delivering these high-quality test results. So, we continue to believe panel testing will have a premium price relative to single syndrome testing."

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