For Porscha Johnson, PharmD, CPGx, improving pharmacogenomics (PGx) diversity is personal. Much of the data about the genetic mutations targeted in cancer treatment come from populations with European ancestry, not people like Dr. Johnson who are of African ancestry and Native American descent. Biomarker testing for genomic variations that can inform new drug targets—whether from blood samples, tissue biopsies or cheek swabs—should be inclusive, Dr. Johnson said.
“My family, especially on my dad’s side, is riddled with cancer and we’ve never been able to pinpoint why,” noted Dr. Johnson, who spoke at the HOPA Annual Conference 2024, in Tampa, Fla. None of the mutations revealed in her family’s genetic tests matched a known pathogenic variant that was either prognostic or predictive for response to a targeted therapy, because the databases oncologists use are not comprehensive enough to contain this information.
“People are inherently built differently, which means their response to medication is different,” said Dr. Johnson, a consultant about PGx equity who previously launched a precision medicine program at the Northside Hospital Cancer Institute, in Atlanta.
If data from members of underrepresented groups were from a larger proportion of genomic databases, Dr. Johnson said, variants of uncertain significance that are not present in people of European ancestry would emerge. Most of those variants will be benign, meaning the genes encode for proteins that function normally. But over time, perhaps 10% to 20% of these variants could be reclassified as definitely or likely pathogenic (JCO Precis Oncol 2020;4:PO.20.00020).
Drug developers could target these newly discovered pathogenic variants, Dr. Johnson said. Such targeted therapies developed to counter cancer-causing mutations could still be effective in members of underrepresented groups with cancer, even if the underlying genetic data are from people of European ancestry. But this can only happen if someone knows they have the mutation, Dr. Johnson said.
“If a patient does not get genetic or genomic testing, they automatically disqualify themselves from select clinical trial opportunities because many of these trials are for targeted therapies against a biomarker,” Dr. Johnson said. Oncologists and pharmacists should encourage everyone they treat to receive biomarker testing, she stressed, adding that robust protections against misuse of genetic data are in place.
‘Everyone Benefits’ From Inclusivity
Minoli Perera, PharmD, PhD, an associate professor of pharmacology at Northwestern University Feinberg School of Medicine, in Chicago, pointed to the benefits of inclusive PGx data collection and reporting. “One example that really drives this home are PCSK9 [proprotein convertase subtilisin/kexin type 9] inhibitors, which help lower LDL [low-density lipoprotein] cholesterol,” said Dr. Perera, who heads a lab that studies PGx response in people of African ancestry. Researchers knew that mutations in the PCSK9 gene led to decreased LDL levels in people of European descent, but this mutation is much more common in people of African ancestry. “The addition of genomic data from people with African roots revealed that this gene could be a drug target,” Dr. Perera said. “Fast-forward 10 years and we have a new class of drugs. Everyone benefits when we include more people.”
In addition to influencing new drug development, PGx researchers also have explored how genetic variation influences drug response. In 2013, Dr. Perera and her colleagues showed that a mutation in the cytochrome P450 2C19 gene carried by some African American people meant they could safely receive a lower dose of warfarin than those without it (Lancet 2013;382[9894]:790-796).
She is currently leading efforts to understand why people of African ancestry disproportionately develop resistance to the antiplatelet drug clopidogrel (medRxiv [Preprint]. 2023 Dec 7. doi:10.1101/2023.12.05.23299140). That project is underway in Chicago and Puerto Rico, but is yet another example of the difficulties posed by social inequities in medicine, because many participants in the trials in both locations have transportation challenges that Dr. Perera and her collaborators bear in mind.
“Many of our patients in Chicago use city van services, and those vans are leaving at a certain time. We have to be respectful of their time,” said Dr. Perera, who added that many enrollees in her clinical trials have lower incomes and/or difficulty arranging time away from work.
A crucial part of the process is to give blood samples used for DNA analysis; Dr. Perera prefers blood samples to cheek swabs, finding the process of extracting DNA from a blood sample to be more straightforward. But a cheek swab also works. The crucial step is to motivate trial participants.
“I tell people that this is the first step in a long journey that may not help you but will hopefully help people down the road,” Dr. Perera said.
Workforce Enhancement In Rural Areas
“When I graduated from pharmacy school in 2010, there was very little pharmacogenomics education,” noted Jacob Brown, PharmD, MS, who specializes in PGx and pediatric clinical pharmacology at the University of Minnesota College of Pharmacy in Duluth. This may mean that some providers are unfamiliar with how PGx results can help them select the right drug and dosage. Dr. Brown added that this problem may be exacerbated in rural settings in which patients do not have the same level of access as those near academic medical centers or large hospital systems that offer PGx testing.
“I’ve been in Duluth for 10 years now, which is in the northern part of the state. Part of our College of Pharmacy’s Duluth campus mission is improving the health of all Minnesotans, including those in rural areas,” Dr. Brown said. To that end, he and colleagues, including his department head, Pamala Jacobson, PharmD, have conducted studies about a workforce training program for providers in rural and underserved settings (Front Genet 2023;13:1082985). The first cohort included 12 pharmacists whereas the second had 23; both studies included a mix of didactic content and cases about the interaction between drugs and gene variations in fields such as cardiology, oncology and mental health (see PGx Series box).
“The goal of the cases was to give pharmacists practical knowledge and experience about how to answer patient and provider questions when they do have pharmacogenomic test results,” Dr. Brown said.
“Sometimes the recommendation is pretty straightforward,” he pointed out. For example, if someone’s genetic composition means they are likely to metabolize a given drug slowly, the pharmacist could start with a lower dose or slower titration schedule.
Such clear-cut evidence does not exist for many potential drug–gene pairs, Dr. Brown noted, and in many cases multiple genes are involved in the drug response. Just as with any other medication management effort, some trial and error will be required to determine the optimum dose. Although this is true, Dr. Brown noted that organizations such as the Clinical Pharmacogenomics Implementation Consortium and Pharmacogenomics Knowledge Base are steadily providing more recommendations and curating PGx knowledge.
“The long-term goal of workforce training is to improve health in rural areas through better drug selection and dosage,” Dr. Brown said, adding that a longitudinal study to measure the effects of PGx education would take a while to complete.
Meanwhile, there are glimmers that PGx is moving beyond cities and into routine practice elsewhere. Dr. Brown said one of his former pharmacy students now leads PGx implementation at Cuyuna Regional Medical Center, in Crosby, Minn., a small town about two hours north of Minneapolis.
Dr. Johnson is a medical science liaison with Johnson & Johnson and has a consulting agreement with Clarified Precision Medicine. She is also a principal consultant at her own consulting firm, Clinical Pharmacy Consulting LLC. Drs. Brown and Perera reported no relevant financial disclosures.
PGx Series
This article is from the October 2024 print issue.