Genetic Testing for Medicating Patients

Genetic Testing for Medicating Patients

For millions of people who rely on a daily dose of the blood thinner warfarin to prevent blood clots, staying healthy is a precarious balancing act. Too much of the drug may cause excessive bleeding. Too little can lead to a heart attack or stroke. Even eating such foods as garlic, cranberry, leafy greens or ginger can affect the way the medicine works and provoke a bad reaction. More people wind up in the emergency room because of warfarin than almost any other drug, according to the U.S. Food and Drug Administration.

So it came as good news when, last August, the FDA updated its prescribing information for warfarin. Now, the label recommends that doctors use genetic testing to determine an appropriate dosage for patients. That's because negative reactions depend on a patient's variants of two genes, CYP2C9 and VKORC1. (Health Canada labels for warfarin highlight how CYP2C9 may affect dosage, but don't yet include information about VKORC1.) "[This] is one step in our commitment to personalized medicine," said Dr. Andrew C. von Eschenbach, the FDA commissioner, at the time. Modern science, he continued, would "get the right drug in the right dose for the right patient."

Warfarin (brand name Coumadin) is just one example of how personalized medicine - the use of genetic tests to determine an individual's risk level for disease, and the most appropriate treatments - is the new frontier of health care. Every day, it seems, there are reports of discoveries: a variant in the DPP6 gene may lead to Lou Gehrig's disease. A test examining the activity of 21 genes may determine if a woman should receive chemotherapy for breast cancer. Drugs known as TKIs are best for lung cancer patients with a mutation in the gene EGER. "It's the most exciting area of medicine," says Dr. Albert Chudley, president of the Canadian College of Medical Geneticists (CCMG), and professor of GENETICS at the University of Manitoba. "It impacts every part of life."

And yet, for most Canadians, information about and access to genetic tests and targeted therapy is limited. (The warfarin genetic test is one that is not accessible.) Of the thousands of genetic tests available in the world, "at most, a clinic will offer several hundred," says Chudley, whose Winnipeg centre provides only "about a hundred." That's partly due to a severe shortage of geneticists to administer tests and analyze risk factors. It's also because of a lack of money: "[Demand for] testing has gone up about 25 per cent a year for 15 years," says Dr. Peter Ray, head of molecular genetics at Toronto's Hospital for Sick Children and a professor at the University of Toronto, of his experience. "The funding for testing has gone up about four or five per cent a year." So it's no surprise wait times for some tests can be as long as half a decade.

And the deficiency isn't unique to Canada. "The bad news," read a report in the Harvard Business Review last October, "is that progress in realizing the promise of personalized medicine has been slow and uneven." The authors characterize the gap between science and medical practice as "inexcusably large." That sentiment was echoed in a Science article from last September observing that "emerging technologies have only had marginal impact on health care to date."

Even if demand for personalized medicine plateaued where it is today, Canada wouldn't have enough geneticists: there are about 245 who are members of the CCMG, according to Chudley. Less than half of them are clinical or medical geneticists - that is, doctors trained to administer tests and deal with patients. The other half are laboratory geneticists, who do analysis and conduct research. (By comparison, there are 450 plastic surgeons in Canada.) "We are having a hard time fulfilling that minimum need," because each patient visit takes several hours, says Dr. Micheil Innes, a member of the Royal College of Physicians and Surgeons (RCPSC) medical genetics specialty committee, and a professor at the University of Calgary. "That's our short-term bottleneck. The bigger thing that we're thinking about is when it comes to genetic tests for everyone." That couldn't be done now for lack of resources and technology, he says.

There's a shortage of genetic counsellors too - only about 250 nationwide. They work with clinical geneticists, and focus on the emotional and psychological needs of patients, says Jennifer Fitzpatrick, director of the genetics counselling program at McGill University in Montreal, and a past president of the Canadian Association of Genetic Counsellors (CAGC). "There's a strange paradox," she observes, "that you have more advances in research but there are no greater numbers of health professionals for patients."

Partly to blame for the shortage are Canadian universities, which "have been lurching, if not stumbling, forward to embrace the genomification of medicine," criticized a 2003 editorial in the Canadian Medical Association Journal (CMAJ). Only seven are accredited by the RCPSC to offer genetics programs - which take up to five years to complete on top of medical school - and each accepts only a handful of applicants a year; in 2007 just seven doctors graduated. Genetic counselling, meanwhile, is a two-year master's program offered by four Canadian universities. But one in 10 students is accepted, says Fitzpatrick. As Innes says, there needs to be "more buy-in from medical schools and clinical centres to employ these geneticists."

If not, patients will suffer, the experts say. Already, there are legions waiting between two months and five years to see a clinical geneticist, depending on the province. "[Patients are] astounded when you say they've come up to the top," says Chudley, but occasionally "it's too late." Some family doctors aren't referring patients for genetic testing because of the long wait, according to a CMAJ article from last January. "That's frustrating and unacceptable for some families," says Innes, who need genetic information to make decisions about prophylactic surgery, family planning or appropriate schooling for a child who may develop a particular disorder. The wait times partly reflect how laborious genetic testing is, says Fitzpatrick. But improvements must be made, because the demand for it will grow as the genetic components of more illnesses are discovered, and as people with these conditions live longer and need ongoing care, predicts the CMAJ.

The simultaneous geneticist shortage and growing demand for tests and drugs adds to the burden of already overworked doctors. "Taking a family history [is] the bread and butter of family medicine," says Dr. June Carroll of the Granovsky Gluskin medical centre at Toronto's Mount Sinai Hospital, and a professor at the University of Toronto. But some GPs "don't have the tools or the time to explain predisposition," says Timothy Caulfield, professor and research director of the Health Law Institute at the University of Alberta. "It's one of the fastest- growing areas of medicine, so the knowledge base is changing rapidly," adds Ray. "There's a huge need for improved education" for family physicians.

And doctors may be reluctant to take on this additional work without some compensation, says Mara Aspinall, co-author of the Harvard report and president of diagnostic testing giant Genzyme Genetics, based in Cambridge, Mass. She says physicians are rewarded "for action, activity, for doing a surgery, for prescribing a drug. There is very little or no reward for spending an extra half-hour to diagnose a patient, or to suggest a test be done that says one drug should be used over another," Aspinall continues, "There's no financial incentive." In Canada, for example, the money for genetic testing goes to the lab rather than to the physician, says Fitzpatrick.

Even when patients do get tested for a genetic condition, usually there is no targeted medicine or therapy for them. "That's our big stumbling block: we can identify sequence changes in DNA that will lead to disease, but [then] we grind to a halt," says Fitzpatrick. The science, adds Aspinall, has gotten ahead of the drug development. That's partly because research and approval takes years. Companies are also reluctant to invest in drugs perceived to be expensive to produce - and marketable to only a fraction of people. "You may need more [money] early to understand the difference between populations," says Aspinall. But the FDA has recognized that highly specific drugs may undergo shorter clinical trials than "blockbuster" ones. And, she adds, "targeted drugs tend to be priced higher because they don't have side effects."

Until genetic tests and tailored treatments are available to everyone who wants them, though, patients make perfect customers for new companies offering genetic mapping. One company in Iceland called deCODE Genetics is set to offer a personal genome assessment for dozens of common diseases, physical characteristics and ancestry. In the U.S., there is 23andMe, financed by Google; and Navigenics, which essentially operates a mail-order service - customers send away US$2,500 and saliva, and in return their genetic profile is posted online (password required).

Many in the medical community are skeptical of such commercial enterprises. But for patients desperate for information and unable to access services within the public system, these offers are their only option. "Given the dearth of geneticists, how can we block this?" asks Fitzpatrick. "That's not ethical either."

See also PHARMACEUTICAL INDUSTRY; MEDICAL ETHICS.

Maclean's February 18, 2008