February 2007
Slowly, test by test, the clinical laboratory industry is entering the field of pharmacogenomics, or what is often called "personalized medicine" or "predictive medicine," the use of advanced molecular diagnostic tools to tailor therapeutics.
Although in some cases the tests have been approved by the Food and Drug Administration (FDA) and marketed, laboratories have been rather slow to adopt the tests. "The whole emphasis on personalized medicine has been way over-hyped," says Jeffrey A. Kant, M.D., Ph.D., professor of pathology and human genetics and director of molecular diagnostics at the University of Pittsburgh Medical Center. "Eventually we’ll get there, but in regard to the promise of pharmacogenetics, the clinicians don’t know what to do with it. Clinicians are not, by and large, asking for this."
Although market penetration seems relatively sluggish, it seems that new pharmacogenomic tests are hitting the market every week. Two tests that pioneered this niche of esoteric testing are the Affymetrix AmpliChip Cytochrome P450 Genotyping Test and Third Wave Technologies’ Invader UGT1A1 Test.
Affymetrix AmpliChip Cytochrome P450 Genotyping Test
Manufactured and commercialized jointly by Roche Molecular Systems (Pleasanton, CA) and Affymetrix (Santa Clara, CA), the Roche AmpliChip Cytochrome P450 Genotyping test, which runs on the Affymetrix GeneChip Microarray Instrumentation System, was approved by FDA on Dec. 23, 2004. At its simplest, the CYP450 test helps to determine a patient’s susceptibility and tolerance for a wide range of drugs.
The test screens a patient’s genome for two specific genes, Cytochrome P450 2D6 and 2C19, which are implicated in the body’s ability to metabolize many commonly prescribed drugs. Approximately 25% of all drugs are primarily metabolized by CYP2D6 and CYP2C19. Drugs in this category include antidepressants, antipsychotics, beta-blockers, proton Pump Inhibitors, and anti-epileptics.
There are 29 known polymorphisms (variations in the gene) in the 2D6 gene and two significant polymorphisms of the C19 gene. The CYP450 test distinguishes these polymorphisms in both genes and provides the associated predictive phenotype (poor, intermediate, extensive, or ultra-rapid metabolizer). Detection of CYP2D6 polymorphisms results in the identification of 33 unique alleles, including seven CYP2D6 gene duplication alleles.
The test is performed on a standard blood sample. The laboratory first performs PCR amplification on selected segments of DNA extracted from the blood sample. Amplified and labeled DNA segments, or "PCR products," are then applied to the AmpliChip CYP450 microarray. The microarray is placed into the Affymetrix hybridization chamber. Once completed there, the PCR products that have bound to the microarray are stained with a fluorescent dye. The entire microarray is moved to the Affymetrix scanner, in which a laser scans the hybridization pattern and software analyzes it to determine which specific genetic information is present.
Third Wave Technologies’ Invader UGT1A1 TestThird Wave Technologies (Madison, WI) has a collaborative agreement with Genzyme Corporation (Cambridge, MA) to manufacture and provide testing using the Invader UGT1A1 Molecular Assay. The Invader UGT1A1 test is used for colorectal cancer patients who are being considered for the chemotherapy agent irinotecan, manufactured by Pfizer under the trade name Camptosar. The Invader UGT1A1 identifies patients who may be at increased risk for adverse reactions to Camptosar. The FDA approved the Invader UGT1A1 Molecular Assay on Aug. 22, 2005.
While irinotecan is an effective treatment for metastatic colorectal cancer, irinotecan-associated toxicity can result in both neutropenia (reduced white blood cell count) and severe diarrhea. The UGT1A1*28 allele that the Invader UGT1A1 Molecular Assay detects, homozygous in approximately 10% of the North American population, has been shown to be an effective genetic marker for predicting irinotecan-induced toxicity. On July 7, 2005, the FDA revised the safety labeling for irinotecan, recommending that treatment be altered for individuals who are homozygous for the UGT1A1*28 allele.
The UGT1A1 gene produces the enzyme UDP-glucuronosyltransferase, which is active in the metabolism of certain drugs. Variations in the gene can affect a patient’s ability to break down irinotecan. One study showed that people with one type of genetic variation have a five times greater risk of experiencing irinotecan toxicity. Similar to the Affymetrix AmpliChip Cytochrome P450 Genotyping Test, the Invader UGT1A1 test works with a combination of PCR and Invader chemistry.
Laboratory Integration
Despite intense media attention to pharmacogenomic tests, this young, highly specialized, and expensive area of molecular-based testing has been relatively slow in its market penetration. The molecular laboratory at Dartmouth-Hitchcock Medical Center was the first to begin offering the Invader UGT1A1 test. According to Greg Tsongalis, Ph.D., director of molecular pathology at Dartmouth-Hitchcock, the lab began marketing the test in the fall of 2005, but demand for the assay has been rather low. Dartmouth-Hitchcock is selling the test at a list price of $300.
Participants in Washington G-2 Reports’s 2006 Molecular Diagnostic Test Survey were given a list of 16 molecular tests and asked which ones they currently offer, which ones they plan to offer within one to two years, which ones they plan to offer within three to five years, and which ones they have no plans to offer.
More than a third of respondents indicated they do not have plans to offer HLA-typing (67%); prenatal testing for chromosomes 13, 18, 21, X, Y (61%); UGT1A1 (57%); CYP450 (42%); or HER-2/neu (36%). Although HLA-typing is typically the domain of a flow cytometry laboratory, and HER-2/neu and prenatal testing are typically handled by cytogenetics laboratories, the relatively low interest in CYP450 and UGT1A1 is something of a puzzle, given the amount of media attention personalized medicine receives.
Of the laboratories surveyed, 11% indicated that they were currently offering CYP450, and 14% were offering the UGT1A1. A full third (33%) of laboratories surveyed indicated they had plans to offer CYP450 in the next one to two years, and 18% planned to offer UGT1A1 in the next one to two years. In terms of long-range planning, 14% planned to offer CYP450 in three to five years, and 12% planned to offer UGT1A1 in the same time period.
This test or series of tests may be too new for laboratories to be actively considering adoption, or there may as yet be difficulties in interpretation, as well as in demand. If physicians feel the CYP450 results will limit treatment options rather than fine-tune treatment options, they may be slow to require them.
New Report Questions Clinical Value of CYP450 Testing for SSRI Patients
Does testing for CYP450 polymorphisms in adults entering selective serotonin reuptake inhibitor (SSRI) treatment for depression lead to improvement in outcomes, or are testing results useful in medical, personal, or public health decision making? This was the overarching question posed by a team of investigators at the Duke Evidence-based Practice Center. The short answer, according to the team’s recently issued report, is that it’s too soon to tell.
According to the report, supported by a collaboration of the Agency for Healthcare Research and Quality (AHRQ) and the Centers for Disease Control and Prevention’s National Office of Public Health Genomics, there is insufficient evidence to determine if CYP450 testing intended to personalize dosing of SSRIs, the most commonly prescribed class of drugs for treatment of depression, improves patient outcomes or aids in treatment decisions in the clinical setting.
This report is the first step in the two-step process of CDC’s Evaluation of Genomic Applications in Practice and Prevention (EGAPP) pilot project to evaluate and make recommendations regarding the use of gene-based tests.
Although the report found that CYP450 testing was largely accurate in evaluating differences in genes that affect the rate at which a person metabolizes SSRIs, the researchers did not find any evidence that such tests led to improved patient outcomes or affected treatment decisions for patients with depression. The report also noted that other genetic and non-genetic factors, such as diet and other medical conditions, may affect therapeutic response.
The researchers’ literature review turned up no well-designed studies that evaluated clinical outcomes of tests to detect differences in genes belonging to the CYP450 family. They found that the majority of studies included a small number of people, did not test for all variations of the enzymes, and were poorly designed. Most studies also reported the rate of metabolism after just one SSRI dose or were conducted in patients without depression.
SSRI dosing has been considered a particularly good candidate for pharmacogenomic testing, because patient response to this class of drugs is known to vary widely. By sorting out the ultra-rapid metabolizers from the poor metabolizers of SSRIs, CYP450 testing could theoretically prevent side effects and help clinicians to optimize dosing without having to resort to trial and error. The likelihood that a person will experience relief from all symptoms of depression after one year of SSRI treatment is about 40%, and side effects cause 12% to 15% of those who start treatment to stop taking the drug.
"This report emphasizes that well-designed observational studies and clinical trials are needed to clearly establish the clinical validity and utility of the many emerging genomic tests for treatment and prevention of common diseases of public health significance," said Muin Khoury, M.D., Ph.D., director of CDC’s National Office of Public Health Genomics. "Early availability of the evidence base is key to the effective use of genomics for the benefit of population health."
Within the next couple of months, the EGAPP working group will issue recommendations on the use of CYP450 tests in the treatment of depression based on the evidence report and other considerations. Future reports that are part of the AHRQ/CDC collaboration will evaluate the use of genomic tests for specific diseases or conditions, such as a rare type of inherited colorectal cancer.
The report, Testing for CYP450 Polymorphisms in Adults With Non-Psychotic Depression Treated With SSRIs, can be downloaded from the following Web site:
www.ahrq.gov/downloads/pub/evidence/pdf/cyp450/cyp450.pdf.
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