The future of laboratory testing moves toward pharmacogenomics

July 1, 2009
Thomas P. Moyer, PhD Jerry Yeo, PhD

e 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

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 (
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.

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? 

Moyer: 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; I 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

MLO: Where (country) has the concept been most
favorably supported, and why?  Are there groups of scientists
competing (as was the case, to some degree, in the mapping of the human
genome) to design tests for some of the most important of the genetic

Moyer: Molecular diagnostics has been broadly
accepted in North America, Europe, and Asia. Some of the best molecular
diagnostic work is coming out of European labs, and we frequently see
outstanding studies published by Japanese and Chinese scientists. I
visited China in 2004 and observed very modern molecular diagnostic
laboratories. Other Eastern countries such as Singapore and Australia
are also heavily engaged in molecular testing. The simple answer —- any
country in the G20 group has adopted molecular diagnostics.

Yeo: I agree with Dr. Moyer that diagnostics
tests — molecular and other tests — are more widely available to the
clinical community overseas, probably due to a less stringent regulatory
environment; companies do not need to jump through the “FDA hoops” to
sell their tests to the clinical community. So, in a sense one could
view this as “more broadly accepted.” If there is a hot novel molecular
test or panel, I assume there will be competition in developing this for
the diagnostic marketplace; but if there is intellectual property
already awarded to the discoverer, it can also limit the competition,
for example, the PGx test, thiopurine methyl transferase, or TMPT, and
limit adoption in clinical practice.

MLO: What two or three major changes will occur
in the way medicine is practiced when “personalized medicine” is finally
realized?  What impact will this change make in healthcare
generally? Will the healthcare system become more complicated,
costly, or not … and why or why not?

Moyer: Personalized medicine, if adopted
correctly, should improve patient outcome while reducing the cost of
care. Treating an individual patient based on that patient’s unique
genetic trait as defined by molecular diagnostics will allow a clinician
to better advise a patient what he or she can do to maintain good
health, and to identify disease at and earlier stage and treat it
appropriately. These new diagnostics will allow a clinician to manage a
patient with fewer procedures and apply the most appropriate therapies.
These attributes are highly likely to improve outcome and decrease
overall cost. If you will allow me to editorialize on two related
topics, I would like to do so.

First, we hear continuously from Washington
bureaucrats of the need to reduce cost of healthcare by eliminating
“useless” laboratory testing; I heard these exact words on a national
news broadcast recently. It is important to keep in mind that laboratory
testing represents less than 3% of all healthcare dollars spent, yet it
is estimated that 80% of all documented healthcare information derives
from laboratory results. Adoption of personalized medicine will result
in increased laboratory testing, maybe to 4%, but will dramatically
improve a clinician’s ability to make highly informed decisions about a
patient’s treatment. Yes, we need to eliminate duplicate testing — an
electronic patient record can accomplish this — but that should not
translate to fewer dollars spent on lab testing. More dollars spent on
appropriate lab testing will reduce overall healthcare spending.

Second, the news media continuously reports public
concern about maintaining strict privacy of genetic information. The
concern about abuse of genetic information by insurance companies or
employers is appropriate. But the public must come to learn that genetic
information represents the future of medicine, the basis for better
healthcare delivery. It will be important that the medical care system
be allowed to perform genetic testing for the patient’s benefit. If the
healthcare system is not allowed to do this, the cost of care will
continue to rise. Stated another way, if patients are allowed to
suppress genetic testing based on their fears that it will affect their
lives, then who is going to pay for the additional cost of healthcare
associated with that? I see this as a serious roadblock to the
implementation of personalized medicine.

Yeo: Personalized medicine promises to deliver
the “right drug/therapy to the right patient at the right time,” which —
if done correctly — should be cost-effective. One should not, however,
underestimate the complexity needed to build a system that must be in
place to realize that goal, ranging from having timely access to
complete patient medical records, medications, and lab and other testing
results, and so forth. The hope is that when such a system is realized,
it will result in timely assessment and treatment of an individual
patient which should, ultimately, reduce the total costs of healthcare.

Although there is a danger of healthcare becoming
more complicated and costly with access to “high tech” discoveries of
the future, these are solvable issues with better access to medical
informatics to avoid information overload causing the inability to make
sense out of large amounts of data. While it is true that molecular
tests tend to be more expensive as a group, I believe with advances in
automation systems to handle these testing, pricing as a whole will
decrease with time for any test that is clinically useful due to
increased requests. I predict in the future we might envision that a
physician will, in addition to the usual workup, order a targeted set of
genetic tests to help decide on what drug or therapy will be optimal for
the patient. So a patient might have to show the pharmacist his or her
pharmacogenotype profile before being given the prescribed drug and
appropriate dosing information.

MLO: Thank you Dr. Moyer and Dr. Yeo for
contributing to our knowledge about genetic testing and the future of

Thomas P. Moyer, PhD,
is professor of Laboratory Medicine at the Mayo College of Medicine,
Mayo Clinic, Rochester, MN. He served as director of the Drug Laboratory
and the Metals Laboratory, as chair of the division of Clinical
Biochemistry and Immunology, and as vice chair of the Department of
Laboratory Medicine and Pathology at Mayo Clinic. His area of academic
interest is metal toxicity, therapeutic drug monitoring, and
pharmacogenomics. Jerry Yeo, PhD,
is currently the director of Clinical Chemistry Laboratories, Clinical
Pharmacogenomics Program, and professor of Pathology at the University
of Chicago, IL. Dr. Yeo is the current chair of Molecular Pathology
Division of AACC and is involved in efforts to translate
pharmacogenomics into the clinical labs.