Genetic testing may detect melanoma risk and more

Vancouver, B.C. - Applications for genetic testing in dermatology now available or under development include identifying patients at risk of developing familial melanoma, assessing effects of sun damage on skin and flagging patients at risk of adverse drug events.

"The average North American over the age of 60 is on eight different drugs," says Greg Hines, president and CEO of Tm Bioscience Corp., Toronto. "By the time they get to a dermatologist, they may already have been to a cardiologist for their cholesterol drug and an internist for blood thinner for heart problems or stroke; they also might have been put on an antibiotic, antidepressant or painkiller such as Tylenol (acetaminophen, McNeil) or codeine. All those drugs collectively are metabolized in the same way by the same enzymes in the liver. The question is, what drugs then is the dermatologist going to pile on top of that?"

FDA responds In response to such concerns, in late 2003 the U.S. Food and Drug Administration (FDA) put out draft guidelines regarding genetic testing requirements for all drug submissions. It was expected to release a final version of these guidelines the end of 2004.

The FDA's goal is to avoid situations like the recent recalls of Vioxx (rofecoxib, Merck) and Baycol (cerivastatin, Bayer).

"The reason why the FDA feels that genetic testing would help in those instances is that for about 90 percent of all the prescription drugs that are on the market today, there are approximately half a dozen cytochrome P-450 enzymes in the liver that control how those drugs are managed in the body and then excreted. So when you take a drug like Baycol or Lipitor (atorvastatin, Pfizer), they're metabolized by a cytochrome P-450 enzyme. A genetic test would tell the doctor whether the patient is capable of making a normal amount of good-quality cytochrome P-450 enzyme or not," Mr. Hines explains.

Such findings can tell physicians whether a patient will metabolize a particular drug poorly, normally or faster than normal. On one hand, genetic testing can tell up front if a drug, especially one that may take weeks to achieve clinical efficacy, is likely to work for a patient.

On the other hand, he says, "If the patient is a poor metabolizer of Lipitor or Baycol and you give them those drugs, they can accumulate in the body without being excreted, potentially causing a side effect."

Minimize interactions Genetic testing also can help minimize dangerous drug interactions. If a patient produces poor-quality P-450 enzymes but experiences no problems with a drug such as a statin, for example, he or she may have trouble if drugs such as blood thinners, erythromycin or tazarotene are added to the mix.

"All of these different doctors are prescribing all of these different medicines, and they haven't the foggiest idea whether the patient can metabolize them or not. And we wonder why 10 percent to 20 percent of all hospital admissions in North America are due to adverse drug events," Mr. Hines tells Dermatology Times.

At press time, Tm Bioscience was offering tests for three specific cytochrome P-450 enzymes, which cover up to 70 percent of prescription drugs now available. The company also is working with David Hogg, M.D., at the University of Toronto to develop a predictive test for melanoma that is scheduled for commercial launch in 2005.

"In the CDKN2A gene," Mr. Hines says, "there have been found a number of mutations that can affect a P16 enzyme, possibly leading to melanoma. These mutations occur at least 25 percent of the time in patients who have familial melanoma. Dr. Hogg has looked at all the mutations that have ever been found in the gene and built tests so that one can take a patient's sample, like a spot of blood, and run an assessment to see if the patient carries any genetic mutations that would predispose them to developing melanoma. If a patient tests positive for a mutation, then it would be wise to make sure that patient comes back approximately once a year for a dermatology consultation to see if any of the spots on their skin are getting bigger, and to perform a screen to catch melanoma earlier so the patient can have a more successful prognosis."