The future of laboratory testing moves toward pharmacogenomics.(SPECIAL FEATURE)(Interview)

We met Drs. Moyer and Yeo at this year's CLMA/MLO panel in Tampa, FL. The two of them agreed to answer some of our questions. Here are their responses.

MLO: The advent of pharmacogenomics has opened up the prospect of a new world of personalized medicine, one in which the clinical laboratory will surely be involved. How long will it take for pharmacogenomics (PGx) and all it stands for to become the standard in medicine?

Thomas P. Moyer, PhD: Clinical adoption of pharmacogenomic testing has been slow and non-uniform. There are some drugs recently approved with companion diagnostics that have been well accepted by clinicians; the best example is Herceptin and HER2 testing. Such testing directs very expensive therapy to the patients most likely to respond to that therapy. There are other pharmacogenomics tests that have been mandated by the Food and Drug Administration (FDA); testing for the HLA-B*5701 allele for those taking abacavir and HLA-B*1502 for patients taking carbamazepine to identify patients most likely to develop hypersensitivity reactions and Stevens-Johnson Syndrome are good examples. Such tests will decrease adverse drug events.

And, there are some pharmacogenomic tests with significant associations between nucleotide polymorphisms and adverse drug events that have not been adopted; the best examples here are UGT1A1 and Irinotecan, CYP2C9 and VKORC1, and warfarin. In these cases, there seems to be a major concern that the cost of testing would overwhelm the healthcare system without demonstrable benefit. Several academic groups are addressing these issues at this time. The short answer is that pharmacogenomics will be adopted slowly as risk-benefit data demonstrate the value of testing.

Jerry Yeo, PhD: Despite widespread interest in pharmacogenomic biomarkers--the examples Dr. Moyer mentions--clinical adoption has been slow. The major issues facing most clinicians' readiness to order pharmacogenomic tests currently include a lack of evidence that such testing improves clinical outcomes and is cost-effective. Other non-trivial barriers include the lack of a) specific CPT codes for individual pharmacogenomic panels, b) physician education, c) wider array of FDA-approved tests on automated platforms, d) consensus guidelines on appropriate PGx panels for a given drug, and e) the need for development of a special interpretive service/ program for laboratory results (Wu, et al. Personalized Med. 2009;6:315-327). Currently, there is a National Heart, Lung and Blood Institute (NHLBI) sponsored multicenter randomized trial underway for genotype-guided dosing for warfarin therapy (www.genome.gov/27530277) asking the fundamental question, "Can genotyping improve warfarin dosing?" On the flipside, the Center for Medicare and Medicaid Services (CMS) issued an announcement on May 5, 2009, that as it currently stands, pharmacogenetic testing for warfarin responsiveness has not been shown to improve health outcomes and, thus, should not be reimbursable under Medicare unless it is done for the purpose of a trial to prove such an outcome. So, the controversy continues for a little longer, awaiting the publication of various randomized trials and, until then, adoption will be cautious and slow in the next few years.

[ILLUSTRATION OMITTED]

[ILLUSTRATION OMITTED]

MLO: We already know that the mapping of the human genome has made it possible to test for certain extremely serious genetic disorders. Do we have some "feel" for what other tests for what types of genetic diseases will follow once the most crucial of them have been covered?

Moyer: Limiting the view to tests for genetic diseases based on germ line cells, such as classical medical genetics, pharmacogenomics represents the next major group of tests coming down the pipeline. But if you open up that question to include genetic variances derived from somatic differences, there are many more investigators focused on identifying genetics patterns to detect or guide treatment of neoplasm; BCR-Abl, BRCA1 or 2, HER2, EGFr, Oncotype, and Mammaprint are just a few examples. And, of course, if you open the question even wider to include non-human genetic variances that affect human disease, detection of various microorganisms by genetic testing has exploded in volume; the recent outbreak of H1N1 influenza is but one example of a recently developed genetic test.

Yeo: Speaking specifically regarding pharmacogenomic testing, I think it will be very interesting to observe what barriers need to be overcome before wider adoption can happen. I do not think the problem is a current lack of a pipeline for new biomarkers of PGx; the problem is finding the funding to run large randomized trials to prove the clinical utility and cost-effectiveness of PGx testing. If CMS will not reimburse due to lack of such trials, then the third-party payers may pick up on this and deny coverage for patients with private insurance as well. Thus, it will be interesting to see what is going to happen with warfarin genotyping testing--the "poster child" PGx test--whether the FDA relabeling to promote adoption of PGx is going to be "negated" by the recent CMS announcement of lack of evidence for better health outcomes for genotyping and, therefore, recommending no reimbursement for Medicare patients. Until such issues are resolved, PGx diagnostic companies will be very reluctant to develop and validate more PGx assays on their platforms because of the unknown risks of the return on such investments, especially in the current economic climate. It is encouraging, however, that the National Institutes of Health has taken the lead to fund the current multicenter NHLBI warfarin genotyping randomized trial.

MLO: A medical laboratory consultant recently indicated to us that molecular testing training might be one of the new skills that lab managers look for in new hires. In what ways would the medical laboratory technician/technologist need to be trained to handle the new testing that will surely become part and parcel of his/her career in short order. Where today can a medical laboratory professional get such training, if at all?

Mover: I disagree with this laboratory director from an historical context. Laboratories have been seeking and rewarding molecular testing training in new hires for many years. Demonstration of this skill makes a new graduate instantly employable. I have watched with interest recent newscasts showing new college graduates who cannot find work. I suspect that those new graduates with molecular diagnostics skills are not standing in job recruitment lines because they have already been hired. In other words, this is not "soon to be"; it has been happening for years.

Yeo: While molecular diagnostic testing is not a brand new discipline in laboratory medicine, what I think is meant is that the newer generation of medical technologists will have to become more competent with molecular techniques in their training to remain relevant in a changing laboratory environment where such skill sets will be expected. Additionally, as molecular tests become more robust and automated, they will become integrated into their natural domains of expertise, such as molecular tests for infectious diseases that are now largely done in microbiology labs; and I predict pharmacogenomics testing will be done in clinical chemistry labs which traditionally perform therapeutic drug monitoring testing. As these tests become more "routine," so will molecular diagnostics become a routine part of the medical technology training program.

MLO: Will interpreting genetic tests be more complicated than some of the tests lab professionals currently perform--why or why not? Will even more complex laboratory equipment be required to perform such testing or to aid in interpreting results?

Moyer: Clinicians are overloaded with information. It is very difficult to keep up with the plethora of diagnostic information coming out each week; 1 do not know how a general practitioner can keep up with this. Therefore, interpretation of genetic tests will be essential. Clinicians will need guidance from the laboratory regarding how best to use the information contained in any genetic test.

The technology used by the laboratory to perform these new genetic tests is different from the classical genetic testing performed by chromosome evaluation; if anything, the technology is less complex than chromosome analysis. The technology has matured dramatically in the past decade such that it is within the realm of all hospital laboratories to acquire and integrate into their laboratory practice. I teach in my lectures that if the community hospital lab is not doing some form of molecular diagnostic analysis now or in the near future, they may as well start cleaning out the drawers in anticipation of closing due to obsolescence.

Yeo: In general, interpretation of genetic tests is a complex task since the presence of a particular variant or mutation may or may not always translate to a specific predicted phenotypic effect. While the laboratory may be fascinated by cutting-edge technology that can interrogate "gazillions" of alleles using advanced microarrays, translating this complex information into clinical actionable data is a different matter. For example, genotyping will not provide all the answers to account for an individual's variability in handling a drug; other non-genetic factors like age, sex, ethnicity, drug-drug interactions, and health status can have equally large effects. For genotyping to be useful for a particular drug, the genotype-phenotype relationships must be well understood and characterized. In the case of cytochrome P450-2D6-the enzyme responsible for metabolizing - 20% of the drugs used today--this is a highly polymorphic (>70 allelic variants) entity, and combinations of duplications and single nucleotide polymorphisms can result in a complex genotype in an individual that may be hard to predict the ultimate phenotype. Throw in non-genetic factors like compromised renal function, co-medication with known CYP2D6 inhibitors, like fluoxetine or inducers like rifampin, the final interpretation becomes even more complex. I would predict one would need to measure some type of phenotypic marker(s) in addition to genotyping so as to facilitate proper interpretation of such complex genotype, as in parent drug and metabolites.

Print Get the Mag Weekly Updates