As revenue falls, a pioneer of cancer gene testing slams rivals with overblown claims

No company has had a more profound impact on inherited breast and ovarian cancer than Myriad Genetics. Its DNA test to identify women with a sharply increased chance of developing these cancers changed millions of lives: Many women who learned they had a cancer-causing mutation had their breasts and ovaries removed in an effort to dodge the genetic bullet.

The pioneering genetic test, introduced in 1996, was also good for Myriad, which won a patent on the “BRCA” cancer genes and has collected more than $2 billion from its BRCA tests. But its fortunes changed in 2013, when the US Supreme Court invalidated the company’s key patents and Myriad lost its monopoly on BRCA testing. Other labs began offering the tests for as little as a few hundred dollars, a small fraction of Myriad’s $4,000.

Revenue slid  — even after Angelina Jolie raised awareness of Myriad’s BRCA tests by publicizing her results and her decision to therefore undergo a double mastectomy. The company’s stock price today is about half what it was the day before the court’s unanimous ruling.

Desperate to protect its business, Myriad embarked on an aggressive strategy to undermine its new competitors, STAT has found. In interviews, genetic counselors, physicians, and competitors said the company deployed its national sales force to stoke fears that other companies’ BRCA tests are so faulty they miss potentially deadly mutations.

More recently, Myriad went further, reaching out to reporters at major national publications to paint its competitors’ BRCA tests as a “public health crisis,” as spokesman Ron Rogers told STAT last month.

Although Myriad still has about 85 percent of the US market for BRCA testing, a dozen or so companies now offer the tests and, Rogers said, they “are coming up short, providing doctors and patients with what we believe are inaccurate results.” He added, “We don’t know how many patients are being affected, but we believe it’s probably in the hundreds or thousands.”

The company’s assertions about its competitors themselves come up short, however. Scientists whose work Myriad cited as supporting its contentions said it did not. Some genetic counselors agreed that Myriad’s BRCA test is superior, but others did not. And competitors pushed back strongly against Myriad’s claims that their tests often produced disastrously incorrect results, as did experts not connected to any company.

“It’s shocking that Myriad is disparaging other labs’ tests when, for nearly 20 years, it used its patents to keep other labs and academic scientists from making BRCA testing as accurate and accessible as possible,” said law professor Lori Andrews, of Chicago-Kent College of Law, who specializes in the legal and ethical issues surrounding genetics.

Myriad emphasizes the size and accuracy of the proprietary database it has built over 20 years of testing, which indicates the medical consequences — cancer-causing or not — of just over 17,000 variants of the BRCA genes. A variant is any deviation in the long chain of molecular “letters” — A, T, C, and G — that make up the healthy version of a gene. Myriad’s database is more extensive than its competitors’, but it’s unclear how much of an advantage this provides because the company refuses to share its data. That prevents independent researchers from comparing Myriad’s BRCA interpretations to others’.

The consequences of the battle between Myriad and its new competitors go well beyond who profits. Ultimately, it’s about whether patients can get reliable test results while paying far less. A consortium of patient groups, universities, companies, and others, called “Free the Data,” recently began collecting Myriad test results from patients and physicians. So far, there is a high degree of agreement between Myriad’s and its major competitors’ readings, and most experts say patients need not worry about using cheaper non-Myriad tests.

“I see it not as Myriad vs. non-Myriad labs but as reputable vs. non-reputable labs,” said Mary Freivogel, a genetic counselor in Denver, president-elect of the National Society of Genetic Counselors, and a former Myriad employee. “I feel like Myriad thinks it’s the gold standard [for BRCA testing], and they do do things very, very well. But there are many labs that are just as good, and I don’t worry about the ones that have been around for a while.”

Myriad disputed that, arguing that even labs that have done other forms of genetic testing are simply not as expert when it comes to testing cancer genes. “To say that because you’re good at testing very specific sites in specific genes, like cystic fibrosis, you’re also good at hereditary cancer testing is flawed,” said Dr. Johnathan Lancaster, a gynecological oncologist and Myriad’s chief medical officer.

‘Patients are being harmed’

Myriad transformed how women and doctors think about hereditary breast and ovarian cancer when it began selling its BRACAnalysis molecular test in 1996. For the first time, women who inherited dangerous forms of the BRCA1 or BRCA2 genes could change their medical destiny.

Studies by scientists who helped found the company in 1991, as well as others, had shown that if either gene is mutated, a woman’s risk of developing breast and ovarian cancer soars to as high as 85 percent and 40 percent, respectively. That compares with a risk of 12.7 percent and 1.4 percent in the general population. Women with a strong family history of breast and ovarian cancer clamored for the test: Those carrying a cancer-causing mutation could undergo risk-reducing surgery, while those with no dangerous mutations could breathe a sigh of relief.

Myriad patented the sequence of the BRCA genes, angering many in the scientific and medical community because it seemed to prevent even academic labs from conducting genetic tests. Geneticists, patient advocacy groups, and individual patients sued, resulting in the landmark Supreme Court decision that genes cannot be patented.

During the 17 years that Myriad had its US monopoly on BRCA testing, it tested DNA from some 2 million patients. After it lost all of its post-Supreme Court lawsuits trying to keep rivals out of the BRCA market in the United States, its main competitive edge was its proprietary database. It lists which BRCA variants are cancer-causing, and which are benign spelling differences that don’t affect the gene’s function – like “baptise” vs. “baptize” doesn’t affect meaning. For some variants, there is too little information to make a call, so these rare variants are described as having unknown or uncertain significance.

Competitors, which entered the BRCA testing market in 2013 or later, have much smaller databases and rely in part on public ones. The public databases get their information in different ways, but in general it comes from published studies, genetic testing labs, and committees of medical experts.

Myriad highlights its database — along with its exemplary handling of samples and its team of PhD scientists — to stock analysts, reporters, and customers by, among other things, denigrating public databases. In a presentation to analysts last year, Myriad called public databases of BRCA variants “fraught with errors” and said interpreting BRCA variants accurately is “impossible with public databases.”

With BRCA testing by other companies, “patients are being harmed,” Myriad’s Lancaster said. “Patients are walking around today who believe they tested negative” when in fact their BRCA mutation causes cancer. “They will die of an avoidable cancer,” he added. Meanwhile, patients who are mistakenly told a benign BRCA mutation is cancer-causing might never know that the mastectomy or ovary removal they underwent was unnecessary.

Labs that perform genetic testing are required to have certification that covers the basics, such as whether they use quality-controlled chemicals to run tests. There is no requirement to publicly vet their interpretation of variants.

There are no published studies directly comparing the accuracy of Myriad’s BRCA interpretations to those of its competitors. But for two months this year, Myriad collected data on what happened when physicians, nurses, or genetic counselors asked about a suspicious interpretation of a cancer-linked gene from another company. The list included 55 BRCA requests: 58 percent agreed with Myriad’s classification of variants and 42 percent did not, according to data that Myriad sent STAT.

Myriad also provided names of clinicians who it said had contacted the company about incorrect BRCA test results. STAT attempted to contact all of them, but only a few responded or agreed to talk. Of the latter, some offered examples of testing more than a decade ago (by an academic lab testing BRCA despite Myriad’s patents) or of genes other than BRCA, and none would identify the Myriad competitor that allegedly made the mistake.

In one example, a woman with a family history of breast cancer underwent BRCA testing through one of Myriad’s competitors in 2014. It classified her BRCA2 variant as cancer-causing, said genetic counselor Sara Carroll of Cleveland Clinic Florida. The woman was considering a prophylactic mastectomy, but a few months later the lab reclassified the variant as of uncertain clinical significance. She needed only to undergo frequent cancer screenings (based on her family history), not radical surgery.

Such cases of Myriad’s competitors stumbling in their BRCA testing “are rare but becoming more common,” said Carroll, who participated in the woman’s case in her previous job at a New England hospital.

Another woman had a confusing experience when Myriad found that she had a cancer-causing BRCA mutation but her sister, tested by a lab that does not specialize in genetic analysis, was told she had a different mutation, one whose meaning was supposedly unclear. But the first sister’s genetic counselor, Whitney Ford of Saint Luke’s Health System in Kansas City, Mo., knew that Myriad classified the other sister’s variant as benign, providing some peace of mind in a situation that could have led to unnecessary surgery.

Outside experts urged caution in interpreting such anecdotes. “The truth is, Myriad probably does have a better database because they’ve done more than 2 million [BRCA] tests and they’re a pretty good lab,” said Robert Cook-Deegan of Arizona State University, a longtime scholar of genetics and science policy. “But they are way overstating how bad the public databases are. No one knows Myriad’s rate of false positives or false negatives. There is no way of knowing, but there is clear corporate spin.”

Even Ford said that while she was concerned about the quality of testing at labs that don’t focus on genetics, and uses Myriad “frequently,” she feels no qualms about using other genetic testing companies that she has learned to trust.

Are public databases inferior?

Myriad points to several lines of evidence, including three recent papers, to support its argument that competitors’ interpretations of BRCA variants are wrong.

A 2015 analysis of ClinVar, a database of genetic variants that is run by the National Institutes of Health, concluded that of the 12,895 variants submitted by more than one source, 17 percent had different interpretations (pathogenic vs. benign, for instance).

But it is misleading to imply from this, as Myriad does, that other genetic testing companies rely on interpretations in ClinVar and are therefore giving patients mistaken interpretations of their BRCA variant or are flummoxed by the existence of conflicting interpretations of a variant, said geneticist Heidi Rehm of Brigham and Women’s Hospital in Boston and lead author of the paper, which was published in the New England Journal of Medicine.

“None of us takes a claim [in a database] and assumes it’s correct,” Rehm said. “So why would a genetic testing lab?”

They don’t, said scientists at three leading rivals of Myriad’s.

Directors of genetic testing labs know that ClinVar and other public databases contain many incorrect variant calls, said Steve Lincoln, a bioinformatics expert at Invitae. They therefore also know not to accept a variant call uncritically, he said, but to make sure it’s based on recent research and to follow American College of Medical Genetics and Genomics (ACMG) guidelines for what constitutes compelling evidence that a variant is benign or pathogenic.

No responsible lab director “just cuts-and-pastes variant calls from a database,” Lincoln said. When lab directors sign a genetic testing report, he added, “they put their license, reputation, and the patient’s health on the line,” and therefore know they must scrutinize the underlying data.

Another 2015 study that Myriad said supports its claims compared how five public databases (three in Europe and two in the United States maintained by the NIH) interpreted 1,327 BRCA variants. The authors, all employees of Myriad, found “substantial disparity of variant classifications,” they wrote. For instance, a Dutch database lists a “well-characterized” pathogenic BRCA variant as benign, while a Welsh one lists as pathogenic 61 of 63 variants that others call benign or unknown. Of 116 variants found in all five databases and called pathogenic in at least one, only four were so characterized in all five.

“Overall, for four or more databases, there was zero agreement for variants classified as uncertain significance, and very little agreement with any other classification,” said Myriad’s Rogers.

As with the ClinVar study, however, it’s misleading to think that disagreements between databases mean that patients are getting incorrect interpretations of their variants, scientists said. GeneDx, for instance, employs more than 95 MD and PhD scientists and more than 100 genetic counselors to interpret every variant that the DNA sequencing machines spit out, said Rachel Klein, a genetic counselor and co-director of the company’s inherited cancer program. If the interpretation isn’t clear, a panel of scientists discusses and resolves it, she said, based on molecular biology, information in multiple public and company databases, and a “deep dive” into published papers.

“Nobody, and certainly not GeneDx, is typing a variant into ClinVar and automatically reporting that classification” as a BRCA test result, Klein said.

Based on data they submit to ClinVar, GeneDx and other clinical testing labs disagree on the meaning of a BRCA1 variant enough to affect patient care for only 0.15 percent of BRCA1 variants, and 0.17 percent of BRCA2 variants. The top companies, with the exception of Myriad, compare and share such data.

When databases disagree on the meaning of a BRCA variant, said Ambry Genetics CEO and geneticist Aaron Elliott, “we call one another and figure it out. You have to be collaborative to understand this stuff.”

Spurred by Myriad’s 2015 study, scientists at Invitae and the University of California compared how seven labs classified just over 2,000 BRCA variants from roughly 20,000 patients. The labs substantially agreed on 97.9 to 99.7 percent of the variants and 99.7 percent of patients, Lincoln reported in June at the 2016 annual meeting of the American Society of Clinical Oncologists. (The patient agreement is higher because labs disagree more often on rare variants — which, by definition, few people carry.) He said Myriad “did a number of things that greatly overstated the discordance” between databases on the meaning of variants.

Myriad does not participate in calls among competitors, and called the claim that its competitors do not rely on the flawed public databases disingenuous. “Our competitors together have done [many] fewer” BRCA tests than Myriad has, Rogers said. “They have no choice but to use these databases.”

Free the data

Anger over Myriad’s refusal to make its database public led some physicians, breast cancer patients, and scientists to devise a creative solution. In 2012 Rehm, Dr. Robert Nussbaum of the University of California, San Francisco, and others launched the Sharing Clinical Reports Project to gather BRCA reports that Myriad had sent to health care providers. Soon after, the Free the Data consortium was launched to allow patients to directly share their BRCA results from Myriad. Those results offer a snapshot of the Myriad database, with 2,361 BRCA variants and counting.

Testing companies such as GeneDx, Counsyl, Ambry, and Invitae agreed with those Myriad calls for between 98.7 percent (Ambry) and 99.5 percent (GeneDx) of variants, according to a study that Invitae’s Lincoln presented this year to the ACMG meeting. Most of the disagreements are in variants found in very few patients. Of the 27 variants that the study found to be interpreted differently by at least two labs, for instance, all are found in fewer than 1 in 2,000 patients.

Thanks to the free-the-data effort, Lincoln said, scientists know that “Myriad’s data is highly concordant with other labs that don’t have access to its magic database. Our friends at Myriad have made some strong statements, but the data to back them up is not available for public scrutiny. If you keep your database proprietary, you can make unverifiable claims about accuracy.”

Even its critics believe that Myriad’s two-decade monopoly on BRCA testing in the United States gave it one lasting advantage: Its database includes fewer question marks, for the simple reason that it has seen more variants than its competitors have. Myriad reported in a 2016 presentation to financial analysts that “variants of uncertain significance” — the misspellings whose consequences for cancer are unclear — now account for only 0.5 percent of BRCA1 variants and 1.1 percent of BRCA2 variants.

“It’s fair to say they do know more than anybody else” about variants of uncertain significance, said cancer geneticist Fergus Couch of the Mayo Clinic.

Patients concerned about the higher percent of variants that Myriad’s competitors say are of uncertain significance can nevertheless use one of those less expensive labs, said ASU’s Cook-Deegan. “If you’re one of the 2 to 4 percent who get a VUS result, only then turn to Myriad and pay the $4,000.”

Myriad said its position against sharing its data is in the best interest of patients. Although genetic data are stripped of identifying information, the company argues that big-data tools can be used to identify patients. “The primary reason for us not depositing our genetic data is out of respect for our patients and their privacy,” Lancaster said. He acknowledged, however, that its proprietary database can be a selling point for its tests, and “we don’t want to cut ourselves off at the knees.”

The edge that Myriad gets from its database of BRCA variants may nevertheless be coming to an end.

Last year, scientists and physicians launched the BRCA Exchange, an online database of BRCA variants from multiple sources. As of mid-November, it had 8,578 BRCA1 variants and 9,192 BRCA2 variants. An expert panel reviews the evidence on variants and “a single result is put out” for clinicians and others to use, Couch said. Ambry and GeneDx, as well as newcomers such as Color Genomics, “all have representatives on the committee to resolve differences in interpretation,” he said. Myriad does not participate.

Given the pace at which BRCA variants and their interpretation are being added to the BRCA Exchange, Couch said, “it won’t be long before it has as much information as Myriad does.”

Correction: An earlier version of this story incorrectly quoted Myriad spokesman Ron Rogers’s estimate of how many patients might be affected by competitors’ incorrect BRCA test results. He said “hundreds or thousands.”