Editorials
Is Genetic Testing for Cytochrome P450 Polymorphisms Ready for Implementation?
See related article on page 391.
Individual variation in response to drugs is a problem that physicians routinely face in clinical practice. Such variation can result in lack of anticipated response, serious adverse drug reactions, or unexpected drug interactions in patients receiving multiple medications. In this issue of AFP, Lynch and Price review the clinical effects of cytochrome P450 (CYP450) metabolism on drug response, adverse effects, and interactions.1
The CYP450 isoenzyme superfamily, which catalyzes the oxidation of many drugs and chemicals, has long been on physicians' radar because of its role in many drug interactions that sometimes result in serious adverse events. A new dimension to the physician's interest is the understanding of genetic variations in the common CYP450 enzymes, which can also impact drug metabolism. Genetic polymorphisms have been identified for some of the CYP450 enzyme genes, with inactivating alleles that may decrease or eliminate enzyme activity, or multiple copies of functional genes that may increase enzyme activity. Phenotypically, this may translate into differing drug metabolism rates, with potential for toxicity, lack of effectiveness, or drug interactions.
The U.S. Food and Drug Administration (FDA) recently approved the Amplichip CYP450 test (a test that detects polymorphisms of CYP2D6 and CYP2C19) for use by physicians to make personalized prescribing decisions for their patients.2,3 The availability of an FDA-approved test for identifying CYP450 polymorphisms has brought the field of pharmacogenomics to the threshold of influencing clinical practice, which brings urgency to questions about the usefulness of such testing.
Recently, the Agency for Healthcare Research and Quality published a report that evaluated the evidence supporting the use of CYP450 genotyping in treating nonpsychotic depression with selective serotonin reuptake inhibitors (SSRIs).4 Researchers reviewed the literature for evidence regarding whether testing for CYP450 polymorphisms led to improved outcomes, and whether test results were useful in medical, personal, or public health decision making. The evidence indicated the existence of tests with high sensitivity and specificity for detecting only a few of the more commonly known polymorphisms of some of the CYP450 enzymes, namely CYP2D6, CYP2C19, CYP2C8, CYP2C9, and CYP1A1.
There was mixed evidence, mainly from a series of heterogeneous studies in small samples, regarding the association between CYP450 genotypes and SSRI metabolism, effectiveness, and tolerability in the treatment of depression. There were no data regarding whether testing for CYP450 polymorphisms in adults entering SSRI treatment for depression led to improved outcomes; if testing results were useful in medical, personal, or public health decision making; or if there were harms associated with testing or subsequent management options. There also were several limitations to the quality of evidence, which would need to be considered when designing future studies of the utility of CYP450 genotyping or of any type of genetic testing in clinical practice.
CYP450 genotyping is offered to physicians on the premise that the test accurately predicts how a patient will metabolize a "probe drug," a drug that is exclusively metabolized by a given enzyme. Several drugs, including SSRIs, are often metabolized by more than one CYP450 enzyme, which may limit the predictive value of testing for a single gene polymorphism. In the case of antidepressant effects of SSRIs, genetic factors affecting serotonin receptor proteins, membrane transporters, and signal transduction molecules have important pharmacodynamic effects.5,6 Thus, genetic factors other than pharmacokinetic factors can impact SSRI outcomes in depression, and it may be misleading to examine the effects of CYP450 polymorphisms on SSRI outcomes in isolation. Multivariable pathway analysis studies are now starting to emerge and may provide more information about SSRI treatment of depression and the proportion of risk of poor outcomes that may be attributable to a certain factor, such as CYP450 polymorphisms.7
As new genetic testing technologies are approved and made available for clinical use, it is important to emphasize that FDA approval is based on test accuracy rather than on demonstration of improved clinical outcomes. Availability of technology should ideally be paralleled by availability of evidence regarding its impact in clinical practice (through methodologically sound studies), which unfortunately has not yet happened in the case of CYP450 genotyping.
Address correspondence to David Matchar, MD, at match001@mc.duke.edu. Reprints are not available from the authors.
Author disclosure: Nothing to disclose.
REFERENCES
1. Lynch T, Price A. The effect of cytochrome P450 metabolism on drug response, interactions, and adverse effects. Am Fam Physician 2007; 76:391-6.
2. U.S. Food and Drug Administration. 510(k) Substantial equivalence determination decision summary. Assay and instrument combination template. Roche AmpliChip CYP450 microarray for identifying CPY2D6 genotype. Accessed June 4, 2007, at: http://www.fda.gov/cdrh/reviews/k042259.pdf.
3. U.S. Food and Drug Administration. 510(k) Substantial equivalence determination decision summary. Assay only template. Roche AmpliChip CYP450 microarray for identifying CYP2C19 genotype. Accessed June 4, 2007, at: http://www.fda.gov/cdrh/reviews/k043576.pdf.
4. Matchar DB, for the Duke University Evidence-based Practice Center and the Agency for Healthcare Research and Quality. Testing for cytochrome P450 polymorphisms in adults with non-psychotic depression treated with selective serotonin reuptake inhibitors (SSRIs). Rockville, Md.: Agency for Healthcare Research and Quality, 2006.
5. Serretti A, Artioli P, Quartesan R. Pharmacogenetics in the treatment of depression: pharmacodynamic studies. Pharmacogenet Genomics 2005;15:61-7.
6. Serretti A, Cusin C, Rossini D, Artioli P, Dotoli D, Zanardi R. Further evidence of a combined effect of SERTPR and TPH on SSRIs response in mood disorders. Am J Med Genet B Neuropsychiatr Genet 2004;129:36-40.
7. McMahon FJ, Buervenich S, Charney D, Lipsky R, Rush AJ, Wilson AF, et al. Variation in the gene encoding the serotonin 2A receptor is associated with outcome of antidepressant treatment. Am J Hum Genet 2006;78:804-14.
Are Some Screening Tests Doing More Harm Than Good?
As family physicians, we often face difficult decisions about ordering tests for the early diagnosis or prevention of disease in healthy-appearing persons. It is hard to convince many patients to think about prevention, and those who come in for health maintenance visits often expect to undergo tests that they have heard about from advertising on the Internet, radio, or television, or in popular magazines. For example, a colleague recently saw a healthy, asymptomatic woman who scheduled an appointment to receive the results of an ultrasound examination that had been ordered by another physician to screen for abdominal aortic aneurysm (AAA). The results were normal, but because the test was not indicated by generally accepted standards, our colleague was perplexed at what reassurance to provide the patient, if any.
Although the U.S. Preventive Services Task Force (USPSTF) recommends against performing AAA screening in asymptomatic women of any age,1 the existence of these and other evidence-based guidelines have not prevented direct-to-consumer marketing of costly screening tests of uncertain value.2 There is a striking contrast between widespread public enthusiasm for technology (e.g., whole-body computed tomography [CT], coronary calcium scans) and the paucity of evidence that performing these tests improves outcomes for patients.3,4
"Big-ticket" tests are easy targets for those seeking to reduce waste in health care. But what about the seemingly innocuous practice of performing routine tests such as a complete blood count (CBC) or urinalysis? Both are far less expensive than CT scans and can often be performed in the office at the time of the visit. More than one third of family physicians in the United States think that CBC and urinalysis should be offered routinely at health maintenance examinations,5 and these tests are ordered for 25 to 37 percent of patients who present for such visits.6
Many physicians have anecdotal recollections about detecting a serious disease with routine CBC or urinalysis. In theory, CBC can be thought of as a screening test for occult anemia, infection, and thrombocytopenia. Similarly, urinalysis might detect bladder cancer, infection, renal dysfunction, or diabetes. However, these tests would be useful only if they were "value added"-that is, if they provided additional diagnostic information that would not otherwise be obtained during a history and physical examination. In fact, large prospective studies performed in the early 1990s concluded that these tests rarely identify clinically significant problems when performed routinely in general outpatient populations.7-9
Although the majority of abnormal screening test results are false positives, their presence usually mandates confirmatory testing that causes additional inconvenience to physicians and patients. Confirmatory tests may be invasive and put patients at risk of physical harm. For example, if an unnecessary abdominal ultrasound scan in a healthy woman had detected an incidental but ultimately innocuous adrenal tumor, a needle biopsy may have been recommended.
Communicating with patients about test results consumes much of our time in the office. The time it takes to explain the results of unnecessary tests could be better spent discussing tests of proven value, such as screening for colorectal cancer. A typical U.S. physician provides slightly more than one half of effective clinical preventive services for any given patient10; time constraints are a major reason for not offering recommended tests.11
Unnecessary tests also cost money, and because these tests are performed so often, the costs rapidly add up. A recent analysis estimated that routine CBCs and urinalyses cost the U.S. health care system as much as $80 million each year.6 Because insurance companies increasingly base coverage decisions on objective evidence of benefit, many plans will not cover laboratory tests performed in the absence of a specific indication. For patients who do not have health insurance, the costs of these tests always come out of pocket. If these patients cannot afford to pay for follow-up testing for abnormal results, we are then challenged to locate resources to assist them (costing us still more time).
Like unproven big-ticket screening tests, screening CBCs and urinalyses waste time and money, interfere with providing worthwhile tests, and may end up doing more harm than good. Rather than referring patients for expensive scans or offering routine laboratory testing of dubious benefit, physicians should follow evidence-based screening recommendations. These recommendations are easily accessible at the point of care. The USPSTF recently developed a free Web-based and personal digital assistant tool, the Electronic Preventive Services Selector, to assist physicians with prevention decisions (http://epss.ahrq.gov/PDA/index.jsp). This tool is updated regularly as new evidence becomes available.
The authors thank Mary Barton, MD, MPP, and David Lanier, MD, for assistance in the preparation of this editorial.
editor's note: Dr. Lin is an assistant editor for American Family Physician.
The opinions expressed in this editorial are those of the authors and do not represent the official position of the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services.
Address correspondence to Kenneth W. Lin, MD, at kenneth.lin@ahrq.hhs.gov. Reprints are not available from the authors.
Author disclosure: Nothing to disclose.
REFERENCES
1. U.S. Preventive Services Task Force. Screening for abdominal aortic aneurysm: recommendation statement. Ann Intern Med 2005;142:198-202.
2. Lee TH, Brennan TA. Direct-to-consumer marketing of high-technology screening tests. N Engl J Med 2002;346:529-31.
3. Schwartz LM, Woloshin S, Fowler FJ Jr, Welch HG. Enthusiasm for cancer screening in the United States. JAMA 2004;291:71-8.
4. Guirguis-Blake J, Lin KW, Barton MB. Is there benefit to coronary calcium screening? [Editorial] Am Fam Physician 2007;75:1155-6.
5. Prochazka AV, Lundahl K, Pearson W, Oboler SK, Anderson RJ. Support of evidence-based guidelines for the annual physical examination: a survey of primary care providers. Arch Intern Med 2005;165:1347-52.
6. Merenstein D, Daumit GL, Powe NR. Use and costs of nonrecommended tests during routine preventive health exams. Am J Prev Med 2006;30:521-7.
7. Ruttimann S, Clemencon D, Dubach UC. Usefulness of complete blood counts as a case-finding tool in medical outpatients. Ann Intern Med 1992;116:44-50.
8. Ruttimann S, Clemencon D. Usefulness of routine urine analysis in medical outpatients. J Med Screen 1994;1:84-7.
9. Boland BJ, Wollan PC, Silverstein MD. Yield of laboratory tests for case-finding in the ambulatory general medical examination. Am J Med 1996;101:142-52.
10. McGlynn EA, Asch SM, Adams SJ, Keesey J, Hicks J, DeCristofaro A, et al. The quality of health care delivered to adults in the United States. N Engl J Med 2003;348:2635-45.
11. Yarnall KS, Pollak KI, Ostbye T, Krause KM, Michener JL. Primary care: is there enough time for prevention? Am J Public Health 2003;93: 635-41.
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