Researchers look at pharmacogenomics

Sep 28 2005

When patients receive chemotherapy, 15 percent will have severe side effects while 85 percent will not - even though they're given the same relative dose.

What determines this reaction? It’s all in your genes and the way in which each individual’s body processes the drugs.

“Traditionally, we’ve given drugs based on patient size - how big they are, how tall they are, how much they weigh. But we’ve ignored how people metabolize those drugs - once you take them, how you change them,” says Daniel Hayes, M.D., clinical director of the Breast Oncology Program at the University of Michigan Comprehensive Cancer Center.

“You don’t metabolize a drug based on how big you are. You metabolize a drug based on what’s going on in your liver and your kidneys that changes the drug into inactive products and excretes it. Much of the reason Mrs. Jones does it differently than Mrs. Smith is because of the genes she’s inherited from her parents,” Hayes says.

Researchers at the U-M Comprehensive Cancer Center are studying a field called pharmacogenomics, which looks at the ways in which drugs interact with genes and metabolism.

There are two issues involved in giving a drug: how well it works and what side effects it causes. How you metabolize a drug will affect both of those. For some drugs, such as aspirin, it’s easier to determine a dose. A standard dose of aspirin is actually more than what most people need because there’s a big window between where aspirin becomes active and where it becomes toxic.

But for chemotherapy and other cancer drugs, there’s often a small window between active and toxic. Doctors therefore must balance giving enough of the drug to kill the cancer cells without giving too high a dose that harms the patient.

By looking at the small differences in people’s genes, researchers can identify abnormalities, or polymorphisms, that play a role in how individuals metabolize drugs. Using this information, doctors can determine the best dose to prescribe for each individual patient, based on how that patient’s body will process it.

Already, in studying the breast cancer drug tamoxifen, researchers have found some women carry an abnormality on their genes that turns the drug into an inactive metabolite that is excreted. For these patients, the drug might not be as effective. Also, these patients are less likely to experience side effects.

Even among women without this abnormality, if tamoxifen is combined with certain other drugs, it will not be metabolized correctly. Hayes and his colleagues have found the antidepressant Paxil, given to treat the hot flashes that are a side effect of tamoxifen, prevents tamoxifen from converting into an active drug. Meanwhile, the antidepressant Effexor does not have that effect.

“If you’re going to take one of these drugs for hot flashes, we believe you’re probably better off to take Effexor if you’re taking tamoxifen, than to take Paxil,” Hayes says. Other studies are looking at a class of breast cancer drugs called aromatase inhibitors. There are several different aromatase inhibitors available for doctors to prescribe, but no evidence that one is better than another. Researchers hope that looking at a woman’s genes may help determine which drug will work best for her.

Hayes envisions pharmacogenomics eventually playing a key role in every doctor’s office. The doctor will swab the inside of the patient’s mouth or run a blood test to look at the patient’s DNA. Then he or she can use that information to determine which particular drug to prescribe and in what dose, based on how that patient will metabolize it.

“It’s still a colossal research undertaking. It’s going to take a lot of hard work, a lot of dedication, a lot of money frankly, but we have the technologies now,” Hayes says. “I believe the field of pharmacogenomics is going to fundamentally revolutionize the way doctors take care of patients.”