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With New BRCA Testing Options, Patient Groups Advise Women to Speak to Genetics Expert, Share Reports


Women with a family history of breast and ovarian cancer who are interested in getting genetically tested to gauge whether they have a heightened risk for the diseases should speak to a genetic counselor before getting tested, patient groups are advising their members.

These groups are also encouraging women to obtain their test reports from their healthcare providers and anonymously submit data on the gene variants they harbor to a public repository to advance researchers' collective knowledge about the links between genetic markers and cancer.

This advice from entities like Facing our Risk of Cancer Empowered, also known as FORCE, and Genetic Alliance comes as a number of labs have announced they would begin testing for BRCA mutations after the Supreme Court last week invalidated five patent claims held by Myriad Genetics on isolated BRCA1/2 gene sequences. These patents underlie Myriad's $4,000 BRACAnalysis test, which determines whether a patient harbors BRCA mutations linked to familial breast and ovarian cancer risk. Helped by its patent portfolio, for nearly two decades Myriad was the only company providing BRCA testing in the US.

The case started in 2009 and quickly became emotionally charged, as several plaintiffs ─ Genae Girard, Lisbeth Ceriani, and Runi Limary ─ submitted testimony asserting that Myriad's monopoly on BRCA testing was keeping them from being able to get a second opinion on their test results, receiving testing due to insurance issues, and getting the most accurate information about BRCA variants that have uncertain links to cancer. These women held that if there were other labs providing BRCA testing, then they would have more access to testing, prices would be lower spurring greater insurance coverage, and researchers could collaborate on identifying new BRCA variants and their links to disease.

Several labs have interpreted the Supreme Court's ruling on Myriad's gene patents as essentially ending Myriad's control over the BRCA testing market and believe they are now free to launch competing tests that gauge BRCA mutations. Immediately after the court released its decision, a number of labs announced that they would begin testing for BRCA alterations, including GeneDx, Pathway Genomics, Ambry Genetics, and Gene by Gene. Quest has also expressed an interest in providing BRCA testing later this year.

While patient groups aren't advising women to get testing from a particular lab, they are recommending women turn to a genetic counselor for guidance. "We don't really make a recommendation around where women should get tested," said Sharon Terry, CEO of Genetic Alliance, an advocacy organization for patients with genetic disorders. "Although some labs have announced that they will be testing [for BRCA mutations], I think it still remains moderately unclear as to whether or not that testing can happen."

In invalidating Myriad's patent claims, the Supreme Court reasoned that isolated gene fragments are products of nature, and by simply discovering the location of these genes and their association to disease, Myriad didn't transform that knowledge into a patent-eligible invention. Additionally, the court upheld Myriad's patents on complementary DNA, synthesized in a lab and used as probes and primers in diagnostic testing, noting that cDNA is not naturally occurring and therefore is patent eligible under 35 USC Section 101 of the patent law (see related story, in this issue).

Indeed, questions remain as to whether labs will be able to perform accurate testing without using cDNA as part of their diagnostic methodology, and whether Myriad will enforce its 24 remaining method patents still underlying BRACAnalysis to thwart competition. Some market observers have argued that cDNA is "unavoidable" in current testing processes, while many lab directors remain confident that cDNA can be worked around. Still others believe that even if competing labs use patent protected cDNA to test for BRCA mutations, a lawsuit challenging their use won't be successful (see related story, in this issue).

In the immediate aftermath of the court ruling, Terry told PGx Reporter that Genetic Alliance "doesn't feel really qualified to make any determination as to where quality testing can happen right now" from competing labs,. "That'll sort itself out in the marketplace," she added.

Similarly, FORCE is also advising women to see a genetics expert. As a non-profit that supports individuals and families affected by hereditary breast and ovarian cancer, FORCE advises women to make sure that they are getting the most up to date and accurate information, "now more than ever, as different labs are offering testing for BRCA [alterations] as part of a large panel of genes," said Executive Director and Founder Sue Friedman.

Myriad officials have maintained that in addition to its remaining patent suite, the company will be able to compete with other providers of BRCA testing on the strength of its customer service and the quality of its test. The firm certainly has the most market experience with BRCA testing and has a large proprietary database that contains information on numerous gene variants and their links to cancer.

When BRACAnalysis was first launched, more than 40 percent of patients' test results included one or more variants that had unknown or uncertain links to breast or ovarian cancer risk. Now, after testing more than one million patients and collecting information from their test reports into its proprietary database, Myriad reported last year that it had lowered its rate of variants of unknown significance down to around 3 percent (PGx Reporter 6/27/2012).

Plaintiff Limary, who was diagnosed with breast cancer when she was 28 years old, got tested through Myriad but got a report stating that she had a mutation that may or may not be linked to heightened risk of cancer. In the course of this lawsuit, other women have publicly discussed receiving a report from Myriad stating that they harbored a variant of uncertain significance. Myriad has said that the rate of uncertain variants will likely be much higher for these newer labs offering BRCA testing.

During a conference call to discuss Myriad's quarterly earnings, Mark Capone, president of Myriad Genetics Laboratories said, "Any competitor that comes out with a new [BRCA] test is going to face the same journey that we've faced over the last 15 years."

In a more crowded market, however, women considering BRCA testing may find it difficult to judge which lab to go with. "I think the issue for women deciding to get tested elsewhere," at a lab other than Myriad's, "is they need to know to ask what methods they're using, what kind of coverage they have, what technology they're using. That's a lot to assess," Terry said. "I'm moderately well educated on these things and I'd have a hard time understanding all that and [determining if] a test is going to be as good as what Myriad will offer."

In Friedman's view, women are in a better situation now that they have a choice in terms of labs performing BRCA testing, particularly since it's bringing down testing costs. "These are CLIA-approved labs, many of which have a track record and history of being able to do gene sequencing," she said of labs that have announced they will be performing BRCA testing. "So, it's not surprising that they're able to offer the test so quickly, and it's also not surprising that they are offering testing less expensively." For example, Gene by Gene said its BRCA testing service would cost around $1,000.

Noting that Mary-Claire King's lab at the University of Washington will be offering a multi-gene panel test for hereditary breast and ovarian cancer that will gauge BRCA1/2 alterations, Friedman said, "I have absolutely no concerns that they know what they're doing."

King first described the link between BRCA1 mutations and heightened risk of breast cancer in 1990. She also led a research team that reported in 2006 in the Journal of the American Medical Assocation that 12 percent of women with a strong family history of cancer who test negative for BRCA1/2 mutations have large genomic duplications or deletions in these genes. Following publication of this paper, Myriad launched the BRACAnalysis Large Rearrangement Test.

The 40-gene panel test, called BROCA, which UW will perform for hereditary breast and ovarian cancer risk will be priced competitively to Myriad's test, according to industry experts. A spokesperson for UW couldn't provide an exact price for the test, noting the university is still figuring that out, but said that the cost of adding analysis of BRCA1 and BRCA2 genes to the panel will not be significant.

"Ultimately, it will come down to payors and the labs that they will contract with," Friedman said. "If people want their genetic testing to be covered by an insurance company, they will probably have to go with a lab that their insurance company will approve of."

Market analysts have noted that as newer labs offering BRCA testing establish the clinical validation for their tests, it might lead insurance companies to favor tests that are performed at a discount to Myriad's BRACAnalysis. But it may take some time before other labs can convince payors that their BRCA tests are comparable to Myriad's not just in terms of cost, but also in terms of accuracy and validation.

"We encourage patients to speak with their physicians if they have questions about their health or genetic testing," said Myriad spokesperson Ron Rogers.

Encouraging data sharing

The rate-limiting factor for labs newly offering BRCA testing is their comparatively limited knowledge about variants of unknown significance. Myriad in 2006 stopped sharing information on BRCA1 and BRCA2 variants with the open-access international database Breast Cancer Information Core. Many researchers interpreted this to be an unethical move on Myriad's part to keep critical knowledge about gene-disease association as a trade secret (PGx Reporter 11/2/2012).

Even though the Supreme Court case against Myriad has been highly publicized, Terry said that most women still probably don't know that the company doesn't share BRCA variant information publicly. "They would be appalled if they knew that," Terry said. "They would want to share it so that the next person who comes along can see whether or not their variation is [associated with cancer] or not."

Following the court's decision on Myriad's patents, Genetic Alliance announced an effort called Free the Data!, through which the group is urging patients to get their BRCA test report from their healthcare provider or counselor and submit that information to an open database called ClinVar, hosted by the National Center for Biotechnology Information.

The Free the Data! effort is an extension of Sharing Clinical Reports, a project being spearheaded by Robert Nussbaum, head of the medical genetics division at the University of California, San Francisco. InVitae, a diagnostics firm that offers a $1,500 next-generation sequencing test for hereditary conditions is also participating in the effort. Through Sharing Clinical Reports, Nussbaum and other volunteers have been reaching out to cancer clinics and asking them to submit de-identified data from BRCA test reports.

A 2004 NCI survey of state regulations on research use of biological data, including genetic data, found that cancer clinics can release test data once they are de-identified or for institutional review board-approved research. Furthermore, federal laws under the Health Insurance Portability and Accountability Act include provisions that give people control over their healthcare information. Under these provisions, "you can do whatever you like," with your healthcare information, "including putting it on a billboard in Times Square," Terry said.

ClinVar currently houses a small percentage of the data on BRCA1/2 variations compared to what Myriad's database holds, but researchers are betting that the submissions will come more quickly with the engagement of clinics and patients. So far, NCBI has collected and mapped data on close to 2,000 BRCA1 and BRCA2 observed variants and uploaded it to ClinVar. Sharing Clinical Reports has collected information on an additional 2,000 BRCA variants in the past six months. Project volunteers have sent this data to NCBI for mapping, but it is not yet known how many of these variants are unique. Since the Supreme Court's decision on gene patents, Sharing Clinical Reports has received 13 reports from BRCA tests from three clinics, a project spokesperson said.

With the collaboration of patients and cancer clinics, researchers and labs are hopeful that it won't take a decade to amass a robust database of information on BRCA1/2 variants. While initially some labs performing BRCA testing may not have as much experience as Myriad, Heidi Rehm, chief laboratory director of the Laboratory for Molecular Medicine at Partners HealthCare Center for Personalized Genetic Medicine, predicted that these competing labs will catch up quickly and improve their knowledge with the data being shared through ClinVar.

"We're in a really bad situation right now with lack of transparency in variant interpretation that would be improved with data sharing. Even researchers cannot get access to these variants so they can study them," Rehm told PGx Reporter. Her lab is supporting the data collection and submission work for the Sharing Clinical Reports Project, and she noted that the project has "already uncovered hundreds of variants of unknown significance" that Myriad has been reporting, but that no one has been able to study because the firm stopped sharing that data.

ClinVar stores information on many genes linked to a variety of conditions, not just on BRCA1/2 genes. In a recent pilot project through ClinVar between Rehm's lab, Emory University, and diagnostics firm GeneDx, researchers found a 20 percent discrepancy in variant interpretations in the RAS family genes linked to developmental syndromes and this finding has allowed labs to resolve those inconsistencies. "Unfortunately, with only one laboratory offering BRCA1/2 testing today, such opportunities to improve patient care are lacking," Rehm said.

Privacy concerns

The American Medical Association during its annual meeting this week issued a policy encouraging healthcare providers, regulators, and payors "to make clinical variant data and their interpretation publicly available through a system that assures patient and provider privacy protection." The AMA policy encourages labs "to place all clinical variants and the clinical data that was used to assess the clinical significance of these results, into the public domain," noting that this would "allow appropriate interpretation and surveillance for these variations that can impact the public’s health."

Although the information submitted to ClinVar is scrubbed of identifying information, the prospect of sharing healthcare data in a public database raises questions about privacy.

Specifically, with regard to genetic data, recently published studies have illustrated the challenges of keeping de-identified genetic information truly private. In a study published in Science earlier this year, researchers from the Whitehead Institute for Biomedical Research, Baylor College of Medicine, and Tel Aviv University used genetic demographic information from publicly accessible internet resources to re-identify anonymized data in public sequencing projects (BI 1/18/2013). In response to this study, the National Human Genome Research Institute and the National Institute of General Medical Sciences relocated study participants' age information from a publicly accessible repository to a controlled access location.

While Genetic Alliance's Terry is supportive of clinics submitting de-identified reports from BRCA tests to Sharing Clinical Reports, she acknowledged that clinics have a responsibility to inform patients that this is being done. "Do the individuals know their data is being shared?" posited Terry. "I would want to ask permission, not so people can deny submissions and stop this data-sharing process, but so they themselves become engaged and become part of the process, because after all it is their data."

Genetic Alliance's Free the Data! portal allows patients to anonymously submit their BRCA test reports, as well as share other details about their health. The site includes privacy measures allowing submitters to control who will have access to the report and how the information may be shared.

Rehm pointed out that the data being collected in ClinVar is aggregated variant data and individual variant data, as opposed to a complete genomic data set that was used in the re-identification exercise published in Science. "By storing only individuals' variants, it doesn't allow that type of security breach," she said.

Eventually, researchers are planning to submit people's complete genomic data sets to ClinVar. However, at that point that data will be available for researchers through a controlled-access portal.

In an effort to encourage women to share their test reports and "fill the public information gap" about BRCA1/2 variants, Genetic Alliance is also providing educational materials and videos to inform people about the Supreme Court case, about BRCA testing, and about privacy issues related to data sharing.

But the Free the Data! movement has much bigger goals than just educating patients about BRCA testing and data sharing. "We're going to actually motivate them to say, 'This is outrageous. This can't continue. And we're going to be part of the solution,'" Terry said.

This story has been corrected to note that the Supreme Court invalidated five patent claims on isolated gene sequences held by Myriad, not five patents.