More progress, fewer barriers for PGx testing

Even more helpful, Dr. Moyer says, is the FDA Table of Pharmacogenetic Associations (https://bit.ly/FDA-PGxAssn), which summarizes the information contained in the drug labels.

The table is divided into three sections. The first shows the PGx associations for which data support therapeutic management recommendations. The second section shows associations for which data indicate a potential impact on safety or response, while the third section looks at potential impact on pharmacokinetic properties only.

Though the data in section one are clinically actionable, the other two sections are useful as well, says Dr. Scott. Section two is considered emerging evidence, while the information in section three can help temper unchecked enthusiasm. Explains Dr. Scott: “There’s a lot of literature that shows very robust association between genetic variants and drug phenotype. But if the drug phenotype is only the drug levels in your blood system, but it has no actual clinical outcome change, then that’s not really high enough evidence to suggest that people should do genetic testing in that context.”

The FDA has been crucial in promoting the use of pharmacogenomics, Dr. Scott says. The agency has essentially been doing its own scientific curation and evidence review, leading to those three tables. And for all of CPIC’s strengths, he says, the FDA carries with it a more formal authority.

Professional societies have also been using their influence to bring more clarity to the field.

The Association for Molecular Pathology pharmacogenomics working group, which Dr. Weck co-chairs (Drs. Moyer and Scott are members), has been working for five or six years to help push labs out of the starting blocks. Many labs want to set up PGx tests but don’t know what alleles to include, Dr. Weck says.

To date the group has published six papers in The Journal of Molecular Diagnostics, with a seventh—a recommendation for DYPD genotyping assays—set to be submitted for publication soon, says Dr. Weck. The group includes the CAP as well as CPIC, Pharm­GKB, the Dutch Pharmacogenetics Working Group (“which has been very active in the field,” Dr. Weck says), and the European Society of Pharmacogenomics and Personalized Therapy.

To develop their guidance, Dr. Scott says, “We went gene by gene, looking at the common PGx genes, including CYP2C19, CYP2C9, CYP2D6, TPMT, NUDT15, and others.” They looked to see whether each variant occurred at a high enough frequency in the general population, their functional impact, and whether reference materials are available to support validation—the group considers only alleles with such material to be tier 1 recommendations.

(Along those lines, the Centers for Disease Control and Prevention GeT-RM program, which characterizes reference materials, including for PGx, is another useful resource. Says Dr. Moyer: “This is helpful to laboratories when they are trying to validate their assay, so they can obtain samples that are known to have variants of interest, as well as to use as controls once their assays are live.”)

Though the recommendations of the AMP pharmacogenomics working group have been well received by clinical laboratories conducting PGx testing, Dr. Weck says, she acknowledges there often remains a disconnect between laboratory recommendations and offerings, and clinical recommendations and uptake.

“At least at my institution, that has historically limited the clinical utilization of pharmacogenomic testing,” she says. Nevertheless, the recommendations from the AMP and other groups, particularly CPIC, “have really moved the needle in terms of uptake of pharmacogenomic testing.”

And while CPIC might be seen by some as primarily aimed at end users, says Dr. Moyer, laboratories can incorporate that information into their electronic reports. CAP proficiency testing incorporates CPIC guidelines, she says. “We cite them regularly in the participant summary report discussions because we do want labs and lab directors to look at those.” Even if not every lab is providing medication recommendation information in its reports, laboratory directors and other lab professionals need to know about CPIC, she says, and be able to help users understand how to use PGx and direct users to the right resources.

Even as next-generation sequencing becomes more common, it’s not the only option in PGx testing, “which surprises people,” Dr. Moyer says.

“We still do a lot of targeted genotyping for pharmacogenetics, so it’s important how the lab designs its test.” Simply put, a specific gene variant won’t be detected unless it’s included.

That’s why the efforts to bring order to test design are so critical. “It used to be all over the map,” Dr. Moyer says, with different laboratories testing for different alleles. Published recommendations for what alleles to include in a clinical test, she adds, “are really helpful, because we need to be inclusive of the whole American population, which includes people of many different ancestral backgrounds.”

CPIC has also pushed the field to standardize nomenclature. “If different labs are using different nomenclature, that makes it hard for the end user to have any hope of understanding this information,” Dr. Moyer says.

As clinicians have become more familiar with PGx testing, Dr. Moyer says she and her colleagues are now receiving fewer calls from clinicians needing help in interpreting results. Mayo has its own PGx pharmacist specialists. But for institutions that don’t, she says, laboratories should know that even general pharmacists are being educated in pharmacogenomics. “They can handle a lot of questions.”

In a similar vein, she’d like to improve laboratory director education. Currently pharmacogenomics is a relatively niche field, Dr. Moyer says. But as the field expands, “We may need more labs that can handle it.”

Laboratories will also need to handle turnaround times for PGx testing. “We try to be quick about getting results back,” says Dr. Moyer. And ideally turnaround times will become less important in PGx, assuming preemptive testing becomes the norm. “People would get the testing before you really need it,” she says.

But new devices may also help speed matters along. At Mayo, “the cardiac cath lab has been really interested in rapid turnaround times for CYP2C19,” to help guide use of clopidogrel, Dr. Moyer says. The Cube CYP2C19 testing system (Genomadix), which offers rapid genotyping for antiplatelet therapy, might be an option, she says. “It’s a limited number of alleles, but for places where there’s a quick turnaround time indication,” such devices may prove useful.

Dr. Scott and his colleagues at Stanford are also looking at rapid testing; they set up the Cube system this past summer. “We’re hoping to go live in January,” he says. “Our neurology colleagues are interested in having rapid testing results—the same day—to help them with their platelet prescribing decisions in the context of minor stroke and TIA.”

Even as the barriers to pharmacogenomic testing tumble, progress isn’t always swift or straightforward.

Dr. Moyer is quick to weigh in. “For the last I-don’t-know-how-many years, I have been saying, ‘Oh, we’re going to switch to sequencing soon,’ instead of still using targeted genotyping. But at least at our institution, targeted genotyping is still faster and cheaper, and it makes it a lot more accessible to patients.”

Long term, however, she hopes that as pharmacogenomic testing as a whole turns to more sequencing, laboratories will be able to layer pharmacogenomics onto other testing. For example, might it be possible to add DPYD onto tumor sequencing, given its importance for metabolizing fluoropyrimidines? The only caveat, Dr. Moyer says, would be that when sequencing tumor tissue for the genes that are specific to the chemotherapy metabolism, labs need to be aware that the tumor could have additional mutations not present in the germline. “You’d have to confirm your findings if you found that someone had reduced metabolism.”

Dr. Weck and her UNC colleagues have performed PGx testing for a number of clinical trials looking at the clinical utility of genotype-guided dosing, including for warfarin, tamoxifen, and irinotecan. But those efforts haven’t been adopted in clinical practice, primarily because the results of the clinical trials have not demonstrated improved outcomes.

In contrast, CYP2C19 genotyping has had the greatest uptake by UNC clinicians. “Cardiologists who are involved in placing coronary artery stents have ordered CYP2C19 genotyping in every patient to identify poor and intermediate metabolizers who should receive an alternative platelet inhibitor. Therefore, we perform CYP2C19 genotyping three times a week to identify patients who are at risk of thrombosis due to lack of clopidogrel response in the setting of coronary artery stents or atrial fibrillation.”

The UNC molecular genetics lab has also worked with Epic and its genomics module to provide clinical decision support tools for any patient who is prescribed clopidogrel. If clopidogrel is ordered in a patient known to be a CYP2C19 poor or intermediate metabolizer, a best-practice alert pops up to suggest the patient receive a different drug or alternative dose. They use Epic’s genomics module to include a genomic indicator specifying a patient’s genotype information up front, for various genetic information, including PGx. “So if the information is available, it can be part of the electronic medical record as a discrete result, and ideally pharmacogenomic information would be available preemptively” if the patient ever needs a drug. Dr. Weck says routine, preemptive PGx genotyping as part of annual medical visits is “the dream of pharmacogenomics, but that’s still not happening.”

They also have clinical decision support in place for TPMT and NUDT15 genotyping, which is recommended for patients who are prescribed thiopurine drugs.

Dr. Weck is a champion of clinical decision support. “CDS does help drive the practice” of pharmacogenomics, she says, and is likely to keep gaining traction in medicine in general. CDS can also be helpful in another sense, she adds, by blurring the distinction between primary care physicians and specialists: “It doesn’t matter who orders the drug if an alert pops up in the electronic medical record.” CDS tools at her institution have to be approved by a clinical decision support committee, which includes clinicians and, if relevant, pharmacists.

On a related note, she says the FDA package insert for lecanemab, a recently approved drug for treating Alzheimer’s disease, recommends APOE genotyping. “We’re bringing up this testing at UNC—the pharmacy requires APOE genotyping before the release of the drug and considers it to be contraindicated in APOE4 homozygotes” who are at high risk of amyloid-related imaging abnormalities, or ARIA. This is a fairly new application of PGx testing associated with drug toxicity, she says.

As pharmacogenomics spreadsits wings, what else should individual laboratories be doing?

“You have to partner,” says Dr. Moyer. A good place to start is to let clinicians know testing is available, “and that you’re willing to partner with them—if they’re interested.”

The more labs can do to make PGx testing seamless for their colleagues, the better, she continues. Noting that short and shrinking appointment times hinder most physicians, “If those of us in lab medicine can make it as easy as possible for our colleagues, that’s a good role for us to be playing.”

Dr. Scott agrees. “The lab can build the best test we want, but if providers are uncomfortable with it, then it’s not going to take off anywhere.”

While he and his lab colleagues are used to working with numerous specialties with an interest in PGx testing—cardiovascular medicine, behavioral health, pain management, and oncology—“We’ve also enjoyed working with primary care physicians. They’re quite open to this type of information, with the caveat that they’re very busy. If we can deliver the results efficiently, without adding extra work for them, we’ve found this group to be fairly open to leveraging that information for their clinical decisions.”

But, he cautions, “It’s already hard enough for primary care physicians and specialists to manage what they have now. To add another layer of burden on top of it usually makes them shy away.” Ideally, labs will understand the operational barriers well in advance, as opposed to finding them out after a test launches. “That does a disservice to the whole thing if it’s found out too late.” 

Karen Titus is CAP TODAY contributing editor and co-managing editor.