A Key Test For Genetic Testing

This has been a banner year for Mark H. Skolnick. Last fall, a team led by the University of Utah geneticist beat out 12 others in an epic battle to find a key gene that is implicated in up to 10% of all cases of breast cancer. Then, on Oct. 6, Skolnick's company, Myriad Genetics Inc., went public at $18 a share, and the stock has since almost doubled. As co-founder and executive vice-president for research, Skolnick holds a 12% stake in Myriad that is now worth $22 million.

Myriad's exuberant reception on Wall Street makes it one of the hottest genetics companies going. It has alliances with three major drug companies: Eli Lilly, Bayer, and Ciba-Geigy. And investors are betting that Skolnick's DNA sleuthing skills will give Myriad an edge in finding more genes related to common genetic diseases, including heart disease, hypertension, and melanoma (table). But the short-term payoff is in the potential--both economic and medical--for the breast cancer test Myriad plans to introduce next fall. "This is the first genetic test that can tell someone's predisposition to getting a major common cancer," says Skolnick.

MUTANT MYSTERIES. But before it can become Myriad's golden egg, the breast cancer test faces some tough problems. Perhaps the biggest is deciding who should get the test, which could cost $850. Unlike most genetic tests available now, the BRCA1 gene test does not definitively say whether a person has or will get a certain disease. Therefore, some doctors--including one of Myriad's own advisers--favor giving the test only under a narrow set of circumstances. The outcome of the debate over who should be tested could have a big impact on the acceptance of future genetic predisposition tests.

Scientists do agree that the discovery of the BRCA1 gene is important. Women with breast cancer who have a family history of it and test positive for the mutant BRCA1 gene are more likely to have an aggressive form of the disease that could spread to the ovaries. Patients who test negative, on the other hand, may be spared from radical treatments such as a mastectomy plus radiation, and they may need less rigorous follow-up monitoring.

But questions remain about what role the gene plays in cancer. In the several generations studied by Skolnick's group--mainly white Mormons from Utah and other Caucasians--some 86% of the women with the mutant gene had breast cancer. Yet an additional 14% who inherited mutant BRCA1 genes did not get cancer during their lifetimes. Another mystery is how the 100 different mutations found so far in the BRCA1 gene lead to cancer.

Scientists also aren't sure whether women in all ethnic groups who have the defective gene carry the same 86% risk of getting breast cancer as the women in the original families studied. And they don't know how to determine the cancer risk for women who have the defective gene but no family history of the disease.

DOCTOR'S CALL. These uncertainties could limit the market for Myriad's test. One influential group, the American Society of Human Genetics, recommends that only those patients diagnosed with breast cancer who have a clear family history of the disease be tested. That's the group that would most obviously benefit from the costly test.

Even Dr. Barbara Weber, a University of Pennsylvania breast cancer specialist who sits on Myriad's board of clinical advisers, is cautious about the BRCA1 test. Unlike the genetics society, she thinks it can be offered to women who do not have breast cancer. But she says the women should have a strong family history of breast cancer to be tested. Indeed, a recent study by the University of Texas showed that women with nonfamilial cases of breast cancer have normal BRCA1 genes. "Outside the setting of families with a history of breast cancer, we're not sure what to tell people" about the meaning of a BRCA1 test, she says.

Skolnick disagrees. He thinks the test can be given to anyone diagnosed with breast cancer, not just those with a clear family history. He believes that it will be valuable for deciding on a course of treatment as well as providing valuable information to other family members.

For Myriad, the outcome of the debate will have a big impact on its potential market. It's the difference between offering the test to 180,000 diagnosed breast cancer patients annually, or to just 18,000 or so patients with known family histories of breast cancer and possibly their immediate relatives.

Ultimately, doctors will make their own decisions on whether to make the BRCA1 test available to their patients. Historically, they have proved reluctant to recommend genetic tests when they can't give patients a clear interpretation of the results--as would be the case with women who have no family history of breast cancer.

REACHING OUT. Myriad faces still another hurdle: competition. By being the first to discover BRCA1, the company is likely to receive broad patent protection covering products related to the gene. But that has not scared off Oncormed Inc. in Gaithersburg, Md. The genetic-testing startup has been offering a BRCA1 test for the last six months at a handful of research centers. The test is targeted to a narrow patient population: It compares the BRCA1 gene in a known cancer patient with the same gene in other family members.

Myriad Chief Executive Peter D. Meldrum maintains that Myriad's test will be much more accurate than Oncormed's--and more useful. A key difference is that Myriad is compiling a huge database documenting the relationship between BRCA1 mutations and different ethnic groups to help in patient counseling. Myriad hopes the information will give the test a broader reach than the largely Mormon population already tested. Still, until Myriad's test becomes available, Oncormed could chip away at Myriad's business. "I'm missing the advantage of Myriad's test," says Dr. Kevin Hughes, coordinator of the breast cancer treatment center at the Lahey Clinic outside Boston.

HYPERTENSION TEST. David K. Stone, a biotech industry analyst with Cowen & Co., which served as Myriad's investment banker, estimates that revenues from the BRCA1 test will reach $17 million in 1997 and $67 million in 1998. But that depends on several assumptions. Myriad must conduct tests on 4% of patients worldwide diagnosed with breast cancer in 1997, rising to 11% the next year. That's a high percentage, given that only 5% to 10% of women with breast cancer have strong family histories of the disease.

Stone is also assuming that Myriad scientists will isolate a second breast cancer gene also implicated in the hereditary form of the disease--called BRCA2--and will incorporate it into its BRCA1 test. That would boost the test price from $850 to $1,000 a pop. That's not a given. Myriad is involved in a three-way race to find the BRCA2 gene, and there's no guarantee it will win this time.

Luckily for Myriad, it has other tests in the pipeline. One, for salt-induced hypertension, could be introduced next year if the results of a National Institutes of Health study confirm the link between the gene and the disease. And a test for heart disease holds enormous potential. Myriad thinks it is close to finding the gene, called CHD1, which is believed to be carried by an estimated 6% of the U.S. population.

If Myriad succeeds--and if Stone's revenue prediction is right--its breast cancer test alone will more than double the size of the $10 million DNA testing market in just one year. At that prospect, Skolnick doesn't balk. "No one's done anything like this before," he says. Indeed, it is a significant leap forward for genetics. But it's also a leap into the unknown.


Myriad Genetics aims to develop tests for genetic abnormalities that lead to disease. Here are its prime targets:


Breast Cancer

A white woman in the U.S. has a 10% lifetime risk of developing breast cancer. But if she has a mutation in BRCA1, the odds rise to 86%. Myriad is expected to sell a test next fall for $850.


Breast Cancer

Myriad thinks this gene accounts for nearly all cases of genetically related breast cancer in women under 50 that aren't caused by the BRCA1 gene. Myriad is in a three-way race to find the gene.



A defect in this gene may account for as many as one-third of the 55 million cases of salt-induced hypertension in the U.S. If a study confirms the gene's role, Myriad could have a test out next year.



An abnormality in this gene may play a role in melanoma and other cancers. Myriad has cloned MTS1 and two related genes and is studying their function. It says a test could be launched in 1997.


Heart Disease

A flaw in CHD1 that's carried by about 6% of the population is associated with increased risk of heart disease. Myriad has not yet cloned the gene but has determined its approximate chromosomal location.


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