Entire Article From USA Today by Rita Rubin.
Genetic testing may yield personalized health treatments
Heart disease patient Terence Gooding and breast cancer survivor Kathy Negro live 2,000 miles apart, but they stand shoulder-to-shoulder in the burgeoning field of personalized medicine.
They are among a small but growing number of American patients who have sought genetic testing to help guide their treatment. The genes in question, passed from parent to child, carry the blueprints for liver enzymes involved in processing many medications.
Scientists expect that in the not-too-distant future patients will be tested routinely for a variety of genes that affect their response to drugs. The results should help doctors decide what and how much to prescribe, a major step forward in personalizing treatments for a range of ailments.
In the next three to five years, the cost of sequencing a person’s genome will drop below $1,000 — less than the price of a colonoscopy, says National Institutes of Health director Francis Collins, who led the Human Genome Project to completion in 2003. Says Collins: “I think that will finally make pharmacogenomics” — the study of how variations in the human genome affect a person’s responses to medications — “really practical.”
Gooding and Negro illustrate both the promise and the problems of using pharmacogenomics in treating patients.
Gooding, 75, whose medical history could fill a cardiology textbook, took a saliva test last fall to see whether he had inherited fully working copies of a gene involved in converting Plavix — the blockbuster drug given to reduce heart patients’ risk of lethal blood clots — to its active form.
Negro, 41, who already had had nearly every type of breast cancer treatment since her diagnosis at age 39, took a blood test to see whether she had inherited working copies of a gene involved in converting tamoxifen — prescribed to reduce the risk of a recurrence — to its active form.
Some health care organizations already offer pharmacogenomic testing to select patients, such as Gooding, and some test manufacturers are marketing directly to consumers, such as Negro, through the Web. As the cost of sequencing the genome drops, doctors can expect to see more patients who already know their genetic status when it comes to metabolizing certain drugs.
But before they pay for pharmacogenomic testing, some insurers want more evidence that it leads to better patient care, says Robert Epstein, chief medical officer of Medco Health Solutions, a pharmacy benefit manager that in January acquired DNA Direct, which sells such tests.
In late January, a Centers for Medicare and Medicaid Services advisory panel concluded that there was insufficient evidence to determine whether testing for the gene involved in processing tamoxifen leads to better outcomes for breast cancer patients.
Who would fund such research isn’t clear, Epstein says. Meanwhile, he says, “we believe that you have to look at the weight of the evidence that’s out there, the seriousness of the (health) problem and whether there is an alternative therapy.”
Some scientists, echoing insurers, also question whether the tests are ready for prime time.
“We’re having genetic tests commercially available and reasonably affordable before the evidence has fully matured,” Duke University breast cancer specialist Jeff Peppercorn says.
One problem, Peppercorn and others say, is the lack of research into what to do with test results. And genetic variations aren’t the only factors that affect drug metabolism, which also can be inhibited by obesity, older age and interactions with other medications and dietary supplements.
“Genes don’t act by themselves,” notes University of Maryland endocrinologist Alan Shuldiner.
Another issue is doctors’ inexperience with genetic testing. “I don’t think they are anywhere near prepared for it,” Collins says. “They are so buffeted about by other demands on their time.”
Treatments need body’s help
As it comes out of a pill bottle, neither Plavix nor tamoxifen is an active drug, ready to battle blood clots or breast cancer. Each needs something to flip its switch into the “on” position: a molecule in the liver called an enzyme.
Specific enzymes convert Plavix and tamoxifen into their active forms. When medications are active to begin with, these enzymes can turn them off, preventing the accumulation of too much in the body.
Genes carry the blueprints for these enzymes, and genetic variations can cause a shortage. The two enzymes involved with Plavix and tamoxifen also play a role in processing about a quarter of all drugs, says Issam Zineh of the Food and Drug Administration’s clinical pharmacology office. Many drugs have such a wide safety and effectiveness window, he says, it probably doesn’t matter if you’re a poor metabolizer.
But with Plavix, studies consistently have shown that poor metabolizers might as well be taking a sugar pill than the standard dose, because their risk of heart attacks and strokes is much higher than that of other Plavix users.
More than 2 million Americans taking Plavix — 5% of the 48 million in total — are poor metabolizers, because they didn’t inherit any fully functioning copies of CYP2C19, the gene involved in converting the drug into its active form. Most don’t know it, because they haven’t been tested.
“How can we leave these people in the lurch any longer?” asks cardiologist Eric Topol, chief academic officer of Scripps Health, a health care delivery network in San Diego.
In September, Scripps Health began offering CYP2C19 testing to Gooding and others who get coronary stents at Scripps Green Hospital.
Each year, about 1 million Americans get such stents, and afterward they’re usually prescribed Plavix, now the second-best-selling drug in the world, behind only the statin Lipitor.
Gooding, a San Diego resident who had been on Plavix for more than two years, learned that neither of his parents had passed on working copies of the gene, so he’s a poor metabolizer. His doctor doubled his Plavix dose, an approach that hasn’t yet been studied.
Blood tests show Gooding seems to be responding well. He has a brother and a son on Plavix who plan to be tested to determine whether they also are poor metabolizers.
But how best to treat such patients isn’t clear, says David Flockhart, clinical pharmacology chief at the Indiana University School of Medicine.
“Do you double the dose of Plavix?” he asks. “Do you take Effient (a competing drug)? Or do you give them aspirin (which also trims blood clot risk) and pray?”
Still, despite the uncertainty about what to do with the results, Flockhart says, “if I was a patient who’d been stented after a heart attack, I’d want to know.”
The question of how well a patient metabolizes Plavix will carry more weight if, as expected, it goes off patent next year, paving the way for cheap generic versions. Then, many patients now on Effient, an expensive brand-name drug, probably will be switched to generic Plavix.
Studies sponsored by Effient’s co-marketers, Daiichi Sankyo and Eli Lilly, indicated that among Plavix users, poor metabolizers didn’t do as well as normal, or “extensive,” metabolizers. Genetic status didn’t appear to affect Effient metabolism, but in the studies, 2.4% of Effient users experienced the side effect of serious internal bleeding, compared with 1.8% of Plavix users.
‘Opening a can of worms’
Negro, a Detroit resident, had been on tamoxifen for a year. The former pharmaceutical sales rep hoped testing would provide peace of mind and show that she, like most, had two working CYP2D6 genes. Her cancer doctor warned that “you could be opening a can of worms, because we’re not sure what to do” with the results, but went along with her desire to be tested last fall.
Research about whether having no working CYP2D6 genes raises tamoxifen users’ breast cancer recurrence risk has been mixed, although some scientists blame the lack of clarity on flawed studies, not on the absence of a real connection.
If she had no fully working copies of the gene, Negro figures she’d have her ovaries removed, an aggressive move to put her into menopause and make her eligible for an aromatase inhibitor — tamoxifen alternatives that can be taken only by postmenopausal women. Premenopausal, she had no choice but tamoxifen.
But the test showed she has one working copy and one non-working copy of the gene, putting her in the gray area of “intermediate,” or so-so, metabolizers.
“Now I’m kind of standing still,” she says, explaining she’ll probably stay on tamoxifen for now because she’s not ready to have her ovaries removed.
One concern about pharmacogenomic testing of breast cancer patients is that the results might spur some to quit taking tamoxifen, says Vered Stearns, a Johns Hopkins breast cancer specialist. Even for premenopausal poor metabolizers, she says, “tamoxifen is the drug of choice.”
In postmenopausal women, studies have found aromatase inhibitors to be slightly more effective than tamoxifen in reducing recurrence risk, although some scientists say that may be a result of including poor tamoxifen metabolizers in the studies.
By pooling results from various studies, Mayo Clinic breast cancer researcher Matthew Goetz hoped to settle the debate about whether CYP2D6 status affects tamoxifen users’ recurrence risk.
Goetz’s own study had seemed to answer that question. In December 2008, he reported at the annual San Antonio Breast Cancer Symposium that tamoxifen users who didn’t have any fully working copies of the gene were nearly four times as likely to have an early recurrence as those with two copies.
In a press release at the time, Goetz said his results “strongly suggest” that postmenopausal patients considering tamoxifen be tested first to see whether they’re poor metabolizers.
But at the same meeting a year later, Goetz reported that when he lumped his findings with those of other studies, he didn’t find a link between CYP2D6 status and tamoxifen users’ recurrence risk. “It’s a little bit disappointing,” he says, noting that many studies lacked important information such as dose size.
For now, Goetz says, he tells postmenopausal patients who are considering tamoxifen that some studies have shown CYP2D6 status to be important, while others haven’t.
Most, he says, choose to be tested.
Gentris is presenting at the 40th anniversary of the Environmenal Mutagen Society in St. Louis, MO. CSO, Scott Clark, will be speaking on “CYP2D6*16 testing to accurately test poor metabolizers”. Gentris will be discussing its toxicogenomics program with attendees.