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An ingenious pharmacogenetic test from Third Wave Technologies tests for the presence of a genetic change that inhibits metabolism of irinotecan. Oncology specialists explain how it works, and why it matters.
A new test, approved by FDA on August 22, will help doctors set dosage levels for Pfizer’s Camptosar (irinotecan)-a chemotherapy drug used in the treatment of colorectal cancer. The test, the Invader Assay, developed by Wisconsin-based Third Wave Technologies, identifies a genetic mutation that causes the drug to be poorly metabolized, leading to serious toxic side effects. The company claims the Invader Assay is the first pharmacogenetic test approved by FDA for use as a companion diagnostic to a specific drug therapy.
What the Test Does:
The Third Wave detects a mutation in a gene called UGT1A1, which produces the enzyme UDP glucuronosyltransferase. The enzyme is involved in the metabolism of irinotecan, explained Howard McLeod, professor at Washington University School of Medicine. The enzyme attaches a molecule called glucuronide to the drug, making it more water soluble, so it is eliminated more rapidly from the body. This enzyme is also involved in eliminating other drugs and molecules such as estrogen and bilirubin, a by-product of breaking down hemoglobin, McLeod said.
A patient with a specific mutation in the UGT1A1 gene will not be able to eliminate irinotecan as effectively as someone without this mutation, according to McLeod. Excessive blood levels of the drug can cause dramatic side effects leading to hospitalization or death. According to Camptosar’s label, approximately 10 percent of Americans have the mutation.
How It Works:
According to Rod Hise, spokesman for Third Wave Technologies, the test contains two synthetic fragments of DNA, capable of recognizing the mutation in UGT1A1. The fragments bind with DNA in the patient’s blood sample in a way that the two probes partially overlap each other, leaving a “flap” unattached. This overlapping structure is recognized by Third Wave Technologies’ proprietary enzyme, Cleavase, which cuts the flap of overlapping DNA that is not bound to the patient’s DNA. This small fragment then binds with another DNA probe, which is also recognized by Cleavase. When the structure is cut, it releases a fluorescent signal, indicating that the mutation is present.
Setting the Dose:
Pharmacogenetic research is particularly important in cancer treatment, because chemotherapy has a narrow therapeutic window, according to Matthew Goetz, assistant professor of oncology at the Mayo Clinic in Rochester. He was the lead investigator on a study of pharmacogenetic testing for chemotherapy drugs that was presented at the American Society of Clinical Oncology meeting in May.
Pharmacogenetic tests allow physicians to maximize the amount they know about their patient’s physiology and understand how best to treat them, McLeod explained.
“It’s a whole new way of looking at patients within all fields of medicine,” he said.
Goetz predicted that in five to ten years this type of testing would be common for a variety of drugs.
McLeod was not certain that progress would be easy. He praised FDA for promoting the field of pharmacogenetic testing. But he criticized pharma companies and generics manufacturers for hesitating to embrace a more targeted, genetic approach to drug development.