PGx testing wave runs uphill and down

At the same time, “You don’t want to underappreciate the work involved in the informatics piece,” Dr. Empey warns. “That really is what often takes the bulk of the time in setting up these programs.” Pharmacogenomics requires integrated information. Labs need to figure out how to transfer data in a discrete way that will feed into decision support systems—sending a coded set of fields using standard terms, for example: This person was tested for CYP2C19, their genotype was CYP2C19 *1/*2, and they are a CYP2C19 intermediate metabolizer. “We take those three database fields of information and place them in the medical record and use those fields to trigger decision support.” Flagging an entire report as normal or abnormal is virtually useless when large panels are involved because the frequencies of variants are too high.

How much interpretation might be required? Opinions vary, and it’s an area of debate in the PGx field with the FDA and laboratories. The agency seems to be suggesting that reports should be less drug based and more genetics based, Dr. Empey says, while leaders in the field suggest that this information alone might be difficult for everyone to use.

The UPMC laboratory is on site, and it reports only genotype and phenotype; there are no drug-based recommendations. “And that’s fine,” Dr. Empey says, “because those are carried out within our electronic medical records and downstream pharmacist-led clinical services.”

But that model would not work as well with an external laboratory that provides reports directly to physicians, he says, since they may not know automatically what to do with the data.

For Dr. Empey, the game is already afoot, but he knows not everyone is ready to embrace pharmacogenomics. Some people might feel burned by their previous enthusiasm. “There were people who were very passionate about it in the ‘90s, who are perhaps more jaded right now—you know, they tried this for years and it hasn’t happened.”

As with the evolution of fake meat, perhaps this time the hype is real (so to speak). No amount of wishful thinking (or numbed taste buds) were enough to convince diners that a Boca Burger and a beef patty sizzling on the grill were peers. Today, however, maybe the Impossible Burger is up to the task. “I’m really enthusiastic that we’re going to cross the threshold this time for broad-based deployment,” Dr. Empey says.

At the same time, he urges a cautious approach—no need to gobble up everything in sight. “Because sometimes we have folks who are overenthusiastic in interpreting the data, too—that if you see someone who’s a rapid metabolizer, that must mean you increase their dose.” Dr. Empey worries other aspects will be lost in such zeal. “Genetics is just one piece of the puzzle. You can override phenotypes predicted by genetics with drug interactions and other clinical factors. So we find ourselves continually championing the field but also tempering it.”

At this point, where should labs start? Should they catch another boat mid-cruise, or start flinging off lines at the dock and head out to sea on their own?

It depends, says Dr. Empey. “Know your audience,” he advises. At his institution, initial aspirations were big: a large panel for their very first test. After further reflection, they scaled back to the simple, single CYP2C19 gene. The benefits were still there, “and we learned a tremendous amount about how to effectively implement.” Though he understands the temptation to think big, he advises labs to peruse CPIC and PharmGKB data. “Testing a bunch of genes with low-quality evidence on the report doesn’t make it better.”

Educated restraint will help the field as well as individual institutions, he adds. He worries about scope creep: If testing 16 genes is good, 30 must be better. And imagine 120! “You end up with a lot of data that isn’t useful—at least not right now—and it ends up making it more difficult for clinicians and payers to see the value in the product.”

“Sometimes enthusiasm outpaces our ability to generate the data,” Dr. Empey says. He points to early excitement over pharmacogenomics-based testing for warfarin, a medication known to have genetics associations with both its metabolism and its target, VKORC1. In the late 2000s a number of institutions launched PGx testing programs, but subsequent studies offered a mixed view of its value. Some European studies were positive, but a U.S.-based trial was more equivocal, he says. “That put some cold water on reimbursement.” Several years ago, however, another large, positive, randomized controlled trial reported genotype-guided warfarin dosing, compared with clinically guided dosing, produced better outcomes after hip and knee surgeries. “So the pendulum goes back and forth.”

Michigan’s Dr. Greden knows which way he’d like the pendulum to swing. “Will this start to come into play?” he asks. “I certainly hope so. Because these tests are needed.”

Their potential for use in treating brain behavior illnesses (his preferred term) may not be fully appreciated, he says. Clinical depressions alone are ranked by the WHO as the No. 1 disabling illness worldwide, he says, with a lifetime prevalence of about 17 percent. Untreated or not adequately treated to remission, clinical depressions tend to be episodic and recurrent, worsening over time. Of patients with a well-diagnosed major depressive disorder, only about 37 to 38 percent achieve remission with the doctor’s first treatment. And treatments are incredibly costly.

The picture should not be so grim, he posits, with more than 40 antidepressants available, not to mention other interventions. “So why do we have such horrible figures?”

A large (4,041 outpatients) National Institute of Mental Health-funded study from the early 2000s, the STAR*D trial (Sequenced Treatment Alternatives to Relieve Depression), looked at treatment of patients with depression who didn’t respond to their initial medication. Of those who then tried another or added treatment, 30 percent more responded. Those still struggling were offered two additional levels of treatment, if needed. One year after treatment initiation, 30 percent were still struggling. Says Dr. Greden: “We call those treatment resistant.”

That’s Dr. Greden’s area of interest and expertise. Clearly more precise treatments were needed. “But historically we didn’t have many clues to enable us to do that better,” he says.

In treating his own patients, he observed that many couldn’t tolerate a medication’s severe side effects. “I’d say, ‘Uh-oh, we have a poor metabolizer.’” Other patients who felt no effects asked if they’d been given a placebo, indicating they were rapid metabolizers. In other cases, patients would respond well for several weeks, and then side effects would start to appear. “I’d think, We’ve got an intermediate but relatively slow metabolizer, and now it’s caught up.”

That was the state of things decades ago, when the tricyclics were being measured. “That helped, but you were targeting one medicine. And there was still nothing that told you what not to do,” he recalls. Meanwhile, he was watching oncology and other fields start to take a hard look at pharmacogenomics.

In his field, it became clear that no single gene or metabolic pathway was going to provide any answers. In about 2011, Dr. Greden, on behalf of the National Network of Depression Centers, was approached by Assurex Health (since purchased by Myriad Neuroscience) to do a large-scale study. Dr. Greden became the PI of the GUIDED study—involving eight genes and 28 medications—to guide treatment using a combinatorial model in patients who’d failed earlier treatments.

“So right away we were dealing with a difficult population,” Dr. Greden says. More than 2,000 people were screened at multiple sites, with more than 100 doctors involved. Patients were randomized into either the treatment-as-usual group, where prescribing physicians chose their favored treatment, or the guided care arm, where physicians had access to the PGx testing results and could use them to help make their treatment decision (though they weren’t required to).

The guided arm achieved better results, says Dr. Greden. “What these tests did was probably help the doctor by saying, ‘There are some medicines you do not want to use.’” Close to one in five patients had incongruent medications, Dr. Greden reports—that is, one in five people getting treatment as usual were given a medication that was a poor choice for them, given their gene composition and metabolic pattern.

Did that make a difference? The short answer is yes. Those who received congruent medications did significantly better in terms of symptom response and remission. While the test results didn’t tell physicians which drug worked best, it helped “warn you about which ones you should stay away from,” Dr. Greden says.

An equally important clinical question was, If pharmacogenomic testing information is conveyed to clinicians, do they actually change? “Basically, the answer is, doctors can, and do, change,” says Dr. Greden—to a pretty dramatic tune. Some 79 percent of patients in the guided care arm were on incongruent medications at the start of the study; at study’s end, only 10 percent were. That group responded better, as noted; moreover, their side effects decreased—6.5 percent of those who switched from an incongruent to a congruent medication reported side effects, compared with 16.5 percent of those who remained on an incongruent medication.

The study was continued for 24 weeks (though the blind rating was broken). Patients on guided therapy continued to steadily improve. “One curve goes up; the other doesn’t,” he says, noting that the latter stage was an open design, with the blind broken at eight weeks. Again, he finds this encouraging, given that these are long-term, even lifetime, illnesses. Furthermore, equally good test results were found among the aged population with major depressions. Also interesting, he says, is those who were on incongruent medications had a higher rate of discontinuation.

If PGx testing is helpful for treatment-resistant patients, could it also be used earlier? His own view has shifted from the testing being a tool for those with treatment resistance to using pharmacogenomics testing before initiating treatment. “It would likely be useful, decreasing disability, perhaps saving lives and costs. I say that simply because these are such disabling illnesses.” But “we don’t have the answer, because that study hasn’t been done yet,” Dr. Greden says. But such a study could answer the question every physician seems to ask of every lab test: What do I do?

That’s not the only study Dr. Greden would like to see. More studies—more studies! Larger studies. Longer studies. Children and adolescents. Ethnic differences. Substance misuse. Gender differences. Whether the number of episodes affects response. “And I especially want to know: Can pharmacogenomics tests actually be beneficial in helping doctors identify who’s at greatest risk of suicide? We have not addressed that adequately,” says Dr. Greden. And depression is only one focus. Bipolar and anxiety disorders, among others, are also in need of better treatment guidance, he says.

Dr. Greden is eager for the day when PGx testing in brain behavior illnesses begins to keep up with the advances being made in oncology and other fields. “But in the meantime, if you ask, Is it clinically valuable now? I would say yes.”

Like Dr. Empey, Dr. Greden encounters his share of skeptics. And like Dr. Empey, Dr. Greden plants a flag on the hill of education.

Says Dr. Greden: “The skeptics are the ones who start out with an accurate criticism, but a misunderstanding of lab test development. They say, ‘I want to know what I’m supposed to do. Don’t tell me what I’m not supposed to do.’”

“That’s got to be overcome with education,” he continues. “I’m sure lab folks have to live with this all the time.”

Dr. Greden points out that the majority of people with clinical depression are treated by nonpsychiatrists—internists, family medicine specialists, pediatricians, obstetricians, college mental health providers. Interestingly, he’s found that primary care providers often end up being more receptive to the idea of using pharmacogenomics to help them make decisions.

He’d also like to see hospital-based laboratories carve out a role in this area. “It’s really important for pathologists and laboratory directors to buy into the wisdom of the need for this testing, and take the lead to do this in a standardized way.”

He’s been engaging with the subject regularly, including at seven grand rounds and as a keynote speaker at the upcoming American Psychiatric Association meeting. The common questions he hears include: Are these tests approved? Is the FDA behind this? Is this just a research tool? What is the actual cost? Does it save money or cost money? Does insurance pay for this? Is there confidentiality? How do I choose the right test?

One area where he’s had less discussion, curiously, has been closer to home. “We have begun talking about this at the University of Michigan in family medicine, internal medicine, OB-GYN, et cetera, but have much more to do,” he says. In fact, he’s hoping to renew discussions he first tried to have a few years ago. “I tried to bring it up, but everyone said the tests weren’t very good, and there was some truth to that.”

Talking with CAP TODAY might be the right impetus, he says. “I can say, ‘Clinical pathologists are looking at these things. Maybe it’s time major medical centers do more of it in their own backyards.’”

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