Building the case for PGx testing

“We are continuing to collect that data. I suspect we are going to get enough numbers over a year. We realize we need to prove it works to get paid.”

For the third analyte on the pharmacogenomic panel, genotyping of the SLCO1B1 gene may help reduce myopathy from the 80-mg dose of simvastatin. Evaluation of thiopurine methyltransferase (TPMT) genotype is the most recent introduction to the PREDICT program. Severe TPMT enzyme deficiency can sometimes cause life-threatening myelosuppression in patients on azathioprine.

Adding new analytes is not technically difficult because, like the University of Florida/Shands group, Dr. Laposata is working with a highly multiplexed assay platform, Illumina’s VeraCode ADME Core Panel assay, which genotypes 184 common polymorphisms in 34 genes associated with drug absorption distribution, metabolism, and excretion. Performing all assays on one chip does raise questions. All pharmacogenomic requests include all alleles on the panel, so, for example, a physician can order the test for clopidogrel and get a result for simvastatin. “We report out Plavix status when we get a request for simvastatin,” Dr. Laposata said in his AMP talk. “Ethical challenges abound in this area,” he noted, adding, “We can’t go backward.” In the interview with CAP TODAY, he posed the ultimate question: “What are you going to do when everybody gets a whole genome sequence?”

As for reimbursement, Dr. Lapo­sata told the AMP attendees, “For many advances in medicine, if you have to ask that question first, you’ll never get to question No. 2.”

“Some say, ‘We are not going to start unless you show how we will pay for this upfront,’” he tells CAP TODAY. “Others say, ‘We understand you will not pay money upfront. We will look for clinical value then, and if there is clinical value, we will approach you to get paid for this work.’” Vanderbilt has taken the latter stance.

Readmission cost is a major financial consideration. “If people thrombose their stent, as we understand the rules, we are not going to be paid for that readmission. So spending $150 in reagents and supplies works out to our advantage. The cost of the test is dwarfed by the cost of readmission.”

Dr. Laposata cites another cost aspect: Clopidogrel became generic in 2012. “This makes pharmacogenomics more important,” he says. “Some people were saying that the way to avoid adverse outcomes from Plavix resistance was to switch everybody to prasugrel or ticagrelor. That decision now has major financial consequences because of the higher cost of these two newer drugs.”

At the University of North Carolina, it was the clinicians who initiated pharmacogenomic testing for clopidogrel. “The cardiologists came to us and asked us to provide testing,” Dr. Weck says. “They were well aware of the FDA black-box warning.” Along with the Institute for Pharmacogenomics and Individualized Therapy, Dr. Weck set up a dose-escalation clinical trial with the cardiology group to look at whether doubling the normal dose of clopidogrel in heterozygous patients with a single LOF allele could be effective. “The results are being published now,” Dr. Weck says. Doubling the dose from 75 to 150 mg in heterozygous individuals resulted in normalization of platelet inhibition, showing that those patients do not require a medication switch. “This provided indirect evidence that pharmacogenomics testing would have clinical utility,” Dr. Weck says.

Now Dr. Weck’s laboratory does daily CYP 2C19 genotyping for percutaneous coronary intervention patients receiving a stent using a laboratory-developed PCR assay for the three most common variants (*2, *3, and *17). Turnaround time is 24 hours. “In most cases doctors have the information before the patient is discharged,” she says. An alert system is in place in which a pharmacist working with the cardiologists is paged with the result.

Patients are started on prasugrel or ticagrelor. If the patient has a normal CYP 2C19 genotype, he or she is switched to clopidogrel. This is a turnaround from the past few years when patients were started on clopidogrel and switched to an alternative drug based on pharmacogenomic information. Now that clopidogrel is generic, this algorithm is more expensive. “Maybe the cardiologists have adopted this more conservative approach partly because they are worried that treating patients with clopidogrel, even for a short time, might not be safe and effective if they have a reduced metabolism allele,” Dr. Weck says.

“Not all institutions or all physicians are doing this routinely,” she says. “There is still some controversy whether the level of evidence is enough to use pharmacogenomics clinically for CYP 2C19.”

Dr. Weck’s laboratory is not doing pharmacogenomic testing for simvastatin. “The general consensus is that there is not enough evidence that clinical decisions will be changed based on that result,” she says. “We haven’t had any requests for it.”

Based on the results of their clinical trial of pharmacogenomic testing for warfarin, Dr. Weck says, “It seems as though using a PGx-guided dosing algorithm did not result in any decrease to time to therapeutic range.” Nor was there any significant reduction in adverse events. “To have statistically significant results we would need more patients,” she says. She considers the results of the ongoing National Heart, Lung and Blood Institute trial of PGx for warfarin to be important. “My guess is that it will be several years before it’s finished, in part because the number of adverse events is rather small. That’s because the algorithm focuses on common variants that have a smaller effect.” In her view, the emphasis should be on studying rarer alleles that have greater effects on response. “In many studies rare variants are not even interrogated,” she says. Coding region variants in VKORC1, several of which are associated with extreme resistance to warfarin, are not included in dosing algorithms, she notes.

Dr. Weck and her colleagues also did a tamoxifen dose-escalation trial using genotyping of CYP 2D6. “We showed that increasing tamoxifen dose in intermediate metabolizers normalized plasma levels of the active metabolite endoxifen. But we really are going to need outcomes trials to show that pharmacogenomic dosing has clinical utility to have greater uptake.”

At the University of Florida, pharmacogenomic testing for clopidogrel is offered for all patients evaluated for coronary artery disease, not just those getting a stent. “There is going to be a fair proportion who will not have a stent placed,” Dr. Johnson, the distinguished professor of pharmacy and medicine, says. “Having a genotype available is valuable, since they may require a stent at some time in their life.” She calls this a“preemptive genotype.”

Pharmacogenomic testing is done using Life Technologies’ OpenArray on the QuantStudio PCR system with a custom-designed chip carrying 256 SNPs. Hui-Jia Dong, PhD, assistant professor of pathology and technical director for molecular pathology, says they test for the *2, *3, *4, *5, *6, *8, *10, and *17 alleles. All except *17 are nonfunctional or poor metabolizers and trigger a pop-up alert in the medical record, both in homozygous and heterozygous configurations. The laboratory report generates a specific recommendation with regard to Plavix use.

Any nonfunctional or low-function allele in combination with either *1 or *17 has this interpretation: “This patient has predicted impaired metabolism via the CYP 2C19 drug metabolizing enzyme.” For any two nonfunctional alleles in combination, the wording is “very impaired metabolism.” The clinical interpretation for all these combinations is: “This patient will not effectively convert clopidogrel to its active metabolite. Therapeutic alternatives are recommended.”

Testing for clopidogrel uses eight of the chip’s slots. “On the remaining 248, we are collecting research informed consent data,” Dr. Johnson says. “We are asking people to allow us to use other SNPs potentially in the future clinically in the medical record, and to use genomic data for research purposes going into the medical record.” As they validate additional genes, they will move them into clinical use.

Charging for this assay is awaiting clarification of new CPT codes for 2013. “New molecular codes have been published,” Dr. Clare-Salzler says. “But we don’t yet know the reimbursement amount. That still has to be set by CMS and will guide what we can charge for the test.”

“Not all insurance companies cover this,” he adds, “but at least for CYP 2C19 some do.”

Widespread adoption of pharmacogenomic testing and routine reimbursement await further validation of clinical utility. To Dr. Weck, the value and impact of data for clinical utility are underscored by one area that she says “has really taken off” in her laboratory: detecting somatic mutations in cancers, mutations such as EGFR, KRAS, and BRAF that guide the selection of specific drugs. “Most tests in our lab in the last few years have been in this area,” she says. “There has been an explosion of molecularly targeted drugs that have led to routine molecular testing. I still think of it as pharmacogenomics,” she says. They are genotyping a cancer cell to find variants that can be predictive of drug response. One big difference is that the value to patients of the tests in conjunction with the therapeutic agents has been well established—companies doing phase three trials on oncologic drugs now routinely incorporate tests for genomic markers, thus validating the drug and the biomarker test simultaneously. Pharmacogenomics outside the realm of oncology still has a way to go to generate proof that is this compelling. 

William Check is a writer in Ft. Lauderdale, Fla.

Whole exome sequencing and pharmacogenomics

A striking example of the interrelation between pharmacogenomics and next-generation sequencing is provided by a Clinical Sequencing Exploratory Research (CSER) grant awarded to Karen Weck, MD, and her colleagues at the University of North Carolina, one of six such grants awarded by the National Human Genome Research Institute. In this work, whole exome sequencing will be done on 750 patients with a likely genetic etiology to their disease to look for diagnostic results. The conditions to be included are cardiomyopathy, seizures, neuromuscular disorders, inherited or familial cancer, and microencephaly and developmental delay.

“The study is designed so we can study characteristics of genomic information that patients want and study its impact on medical treatment and behavior,” says Dr. Weck, professor of pathology and laboratory medicine and genetics at UNC and director of molecular genetics. “If you do whole genome sequencing or whole exome sequencing, what information do you find that is useful to patients?

“We will also be returning so-called incidental information not related to that patient’s disease,” Dr. Weck says. Study subjects are randomized to receive only diagnostic information or diagnostic information with the choice to receive incidental information. “I am particularly excited about pharmacogenomic information that we will glean from this study, which is a big part of personalized medicine,” Dr. Weck says. Patients can decide whether they want pharmacogenomic information along with information about their risk of future disease. “We will have the opportunity to study how patients and physicians deal with pharmacogenomic information and whether they find it useful, and to see what effect it has on medical treatment and diseases,” Dr. Weck says. “This is a huge issue. That’s why we designed the study this way.” They have divided incidental genomic information into different risk categories or “bins,” she says, based on the potential harms and benefits to the patient, including whether information is medically actionable.

Information about pharmacogenomics is considered fairly low risk, while information about diseases such as Huntington’s is fairly high risk. Information about the apolipoprotein E gene, which affects the risk for Alzheimer’s disease, would be considered intermediate risk.

For high-risk information, patients go through a series of counseling steps. “Our approach is to have a conversation with the patient upfront,” Dr. Weck says. “We will tell them, ‘This is the type of information we might get.’ And to have the patient be the driver. My guess is that most patients will say, Yes, I want to know it all, but that they haven’t thought about all the ramifications. So having a serious conversation about that is very important.”

“If information is potentially life-threatening and treatable or medically actionable, we will return it to people even in the control arm,” Dr. Weck says. A genetic variant for long QT syndrome falls into this category. It is associated with an increased risk of sudden death, and there is something you can do about it. “That’s why I think pharmacogenomic variants will be of extreme interest to patients,” she says. “By definition it will affect their response to a drug if the patient ever needs that drug.”

—William Check, PhD