DPYD Testing Makes Fluoropyrimidine Chemotherapy Safer

Pharmacists say testing patients for DPYD gene variants before starting fluoropyrimidine chemotherapy is the right thing to do — even though U.S. clinical practice guidelines don’t yet recommend the practice.

“It’s important for the pharmacy team to understand that this is a patient safety issue,” said Daniel Hertz, associate professor of pharmacy at the University of Michigan College of Pharmacy. “And I think there’s an opportunity for pharmacists to lead on this issue and work with their medical oncologists to make sure they are aware” of the benefits of testing.

DPYD testing identifies alleles that result in impaired metabolism of dihydropyrimidine dehydrogenase (DPD). Patients with DPD deficiency can have serious adverse reactions to standard doses of 5-fluorouracil (5-FU) or capecitabine.

Hertz noted that the risk of serious toxicity can exceed 70% in patients with certain DPYD variants. Of greatest concern, he said, are DPYD variant carriers for whom standard dosing regimens may prove deadly.

The Institute for Safe Medication Practices announced in 2021 that it was aware of several reports of serious fluoropyrimidine-related reactions, including deaths, in patients who were later found to be DPD deficient. And in 2022, a U.S. hospital agreed to pay $1 million to settle a lawsuit related to the death of a DPD-deficient patient who did not undergo pharmacogenetic testing before starting fluoropyrimidine treatment.

The Clinical Pharmacogenetics Implementation Consortium (CPIC) lists several genetic variants that result in DPD deficiency. CPIC defines DPD metabolizer phenotypes as normal, intermediate, and poor on the basis of alleles identified through pharmacogenetic testing. The organization’s guideline on DPYD-guided fluoropyrimidine dosing recommends a reduced starting dosage for patients whose genotype indicates a DPD deficiency, with subsequent dose escalations as tolerated.

That’s the strategy adopted by Wentworth-Douglass Hospital in Dover, New Hampshire, where a patient who was later found to be DPD deficient had a bad outcome after receiving a standard 5-FU regimen, said oncology pharmacy manager Suzanne Stevens.

Stevens said the DPYD screening program — the pharmacy’s first official pharmacogenomics service — was implemented in 2022 and targets all patients who are expected to start a new 5-FU–based regimen. Patients provide a cheek swab sample during the pretreatment consultation. The test panel, which covers DPYD and other pharmacogenes, is analyzed by an outside laboratory.

“We’ve been finding that about 10% of our patient population are intermediate DPD metabolizers,” Stevens said. For these patients, the pharmacy team follows CPIC’s guidance and recommends reducing the starting dose by 25% or 50% and then increasing it as tolerated.

Pretreatment DPYD screening is the norm in Europe but has not been incorporated into guidelines from the American Society of Clinical Oncology (ASCO) or the U.S. National Comprehensive Cancer Network (NCCN) — despite calls for the organizations to do so.

Jai Patel, associate vice president and associate director of basic science research at the Levine Cancer Center in Charlotte, North Carolina, said the lack of ASCO and NCCN endorsement is a major barrier to implementing DPYD screening in the United States.

Patel said the main concern oncologists voice about DPYD screening is that reducing the starting dose in patients with DPD deficiency will lead to cancer treatment failures. But he said clinical studies haven’t borne out this fear.

And Hertz, in a 2022 special report published in ASCO’s Journal of Clinical Oncology, found no direct evidence that pretreatment testing for pathogenic DPYD variants reduces the effectiveness of chemotherapy. He also found similar fluoropyrimidine exposure and toxicity risks between variant carriers who undergo DPYD-guided dosing and patients without pathogenic variants who receive a standard regimen.

“There ... should be minimal concern for reduced efficacy,” Hertz said in an interview. He also noted that any patient treated with a fluoropyrimidine, regardless of genotype, may require a dose reduction.

“When we did an analysis here, we saw rates of treatment modifications due to toxicity in the neighborhood of 15–20%,” Hertz said.

Patel described 5-FU as the backbone of chemotherapy regimens for gastrointestinal (GI) and colorectal cancers. So, when the Levine Cancer Center rolled out DPYD testing, it started with a pilot program in the GI service — which still accounts for about 90% of patients who underwent testing through last fall.

“The first step was just clearly educating our physicians and oncologists, clinical pharmacists, nurses ... on the potential value of doing DPYD testing,” Patel said. The educational outreach included a review of clinical trial data, CPIC recommendations, and information about newly identified genetic variants that affect toxicity.

Patel said five or 10 years ago, fewer than 1% of patients were thought to have a genetic variation associated with increased fluorouracil toxicity.

“But now, with the growing list of genetic variants that we’re identifying, it’s more like 5–7% of patients. And so that was actually a big thing for our physicians,” he said. “If we’re treating 1,000 of these patients every year, we’re bound to find 50–70 patients that could be at risk for very severe toxicity, hospitalizations, and even potentially drug-related fatality by receiving standard dosing.”

In addition to establishing the clinical benefits of DPYD testing, Patel’s team had to consider existing clinic workflows and make testing as easy as possible for frontline staff.

“We really had to figure out how do we make it the least disruptive and ensure that physicians are actually going to be ordering the tests — and that we can return those results in time,” he said.

Patel noted that his organization does its own pharmacogenomic testing instead of sending samples to a commercial laboratory. When the DPYD service was first rolled out, testing was optional for physicians, and the costs were covered by a grant, so patients weren’t billed for the tests.

Nowadays, some insurers cover the cost of the tests, but others don’t — and that’s a problem, Patel said.

“Financial toxicity is a big concern in patients with cancer,” he said. “A $200 or $300 test can still be significant for a patient if that’s not being covered by their insurance.”

Stevens said insurance coverage of the tests for her cancer center’s patients also varies. She noted that the commercial test panel includes genes in addition to DPYD that can help guide drug therapy for multiple conditions. Some patients have found that information valuable enough to pay for the test out of pocket.

When a patient lacks insurance coverage and can’t afford the test, the cancer center orders a DPYD-specific test instead of the usual 25-gene panel.

Stevens, who participated in the inaugural cohort of the ASHP Pharmacogenomics Accelerator program, said pharmacogenomics fits well with her organization’s focus on optimizing patient care through precision medicine. Her team is working on a referral process to offer additional pharmacogenomic tests.

“We’re trying to expand our services to focus on patients who have maybe polypharmacy, patients who are having a hard time tolerating medications. Maybe even employees who are just interested in understanding their pharmacogenomics,” she said.

Patel said his organization’s well-established pharmacogenomics service aligns with a larger focus on precision oncology and individualized dosing and medication management.

He said clinical pharmacists are involved in almost every step of the pharmacogenomics service. They identify patients, work with nurses to collect and transfer test specimens, and counsel patients about their test results.

“This entire program really wouldn’t be possible, I think, without our incredible pharmacist champions here doing a lot of the frontline clinical work,” he said.