The variations affecting treatment response may involve a single gene (and the protein it encodes) or multiple genes/proteins. For example, some painkillers work only when body proteins convert them from an inactive form to an active one. How well these proteins do their jobs varies considerably between people. As another example, tiny genetic differences can change how statin drugs work to lower blood cholesterol levels.
Biotechnology researchers are interested in the use of gene-based tests to match patients with optimal drugs and drug dosages. This concept of personalized medicine-also called targeted therapy-is beginning to have a powerful impact on research and treatment, especially in cancer.
The biotech breast cancer drug Herceptin® is an example of a pharmacogenomic drug. Initially approved in 1998, Herceptin® targets and blocks the HER2 protein receptor, which is overexpressed in some aggressive cases of breast cancer. A test can identify which patients are overexpressing the receptor and can benefit from the drug.
New tests have been launched recently that identify patients likely to respond to Iressa®, Tarceva®, Gleevec® and Campath®, and patients developing resistance to Gleevec®. Tests are available to choose the correct dosage of a powerful chemotherapy drug for pediatric leukemia-the tests have saved lives by preventing overdose fatalities.
One of the most exciting new tests is Genomic Health's Oncotype DXTM, which examines expression of 21 genes to quantify risk of breast cancer recurrence and predict the likelihood that chemotherapy will benefit the patient. Impressed with the product's results in recent studies, the NIH in May 2006 launched a large new study called TAILORx (Trial Assigning Individualized Options for Treatment [Rx]) that will utilize Oncotype DXTM to predict recurrence and assign treatment to more than 10,000 women at 900 sites in the United States and Canada.
Many more pharmacogenomic cancer products-both medicines and tests-are in development. In fact, oncology may be entering an era when cancer treatment will be determined as much or more by genetic signature than by location in the body.
The idea is simple, but the project is monumental, given the variety of genetic tools cancer cells use to grow, spread and resist treatment. The National Institutes of Health in December 2005 announced it was taking on this challenge through The Cancer Genome Atlas. The project aims to map all gene variations linked to some 250 forms of cancer, not only the variations that help cause cancer, but also those that spur growth, metastasis and therapeutic resistance.
In December 2004, the FDA approved Roche and Affymetrix's AmpliChip® CYP450 Genotyping Test, a blood test that allows physicians to consider unique genetic information from patients in selecting medications and doses of medications for a wide variety of common conditions such as cardiac disease, psychiatric disease, and cancer.
The test analyzes one of the genes from the family of cytochrome P450 genes, which are active in the liver to break down certain drugs and other compounds. Variations in this gene can cause a patient to metabolize certain drugs more quickly or more slowly than average, or, in some cases, not at all. The specific enzyme from this family that is analyzed by this test, called cytochrome P4502D6, plays an important role in the body's ability to metabolize some commonly prescribed drugs including antidepressants, anti-psychotics, beta-blockers, and some chemotherapy drugs.
AmpliChip® was the first DNA microarray test to be cleared by the FDA. A microarray is similar to a computer microchip, but instead of tiny circuits, the chip contains tiny pieces of DNA, called probes.
RACE- AND GENDER-BASED MEDICINE
In 2005, the FDA for the first time approved a drug for use in a specific race: BiDil®, a life-saving drug for heart failure in black patients. In the 1990s, the drug had failed to beat placebo in a broad population but showed promise in African Americans. Further testing confirmed those results.
Although BiDil® thus far is the only drug to win a race-based approval, it's far from unique in its differential effects across populations. Many drugs, including common blood-pressure medicines and antidepressants, exhibit significant racially correlated safety and efficacy differences.
For example, in a large study of one of the most common blood pressure medications, Cozaar®, researchers found a reduced effect in black patients-a fact that has been added to the prescribing information for the drug. Interferon, likewise, appears to be less effective in blacks with hepatitis than non-Hispanic white patients (19 percent vs. 52 percent response rate), according to a recent study in the New England Journal of Medicine.
One such study found Japanese cancer patients are three times more likely to respond to Iressa®, apparently because of a mutation in a gene for the drug's target, epidermal growth factor receptor.