Chemo Safety Test Is Finally Gaining Ground in the US

 It’s been known for decades that certain gene variants put patients at high risk for severe toxicity from fluoropyrimidine chemotherapy — yet pretreatment testing for those variants never caught on in the US. That is finally changing.

In October 2025, the FDA added a boxed warning to the 5-fluorouracil (5-FU) prodrug capecitabine telling clinicians to test for genetic variants in the DPYD gene that reduce the ability to metabolize capecitabine. Then in February, the agency clarified that its mandate also applies to 5-FU itself.

The warning marked a dramatic shift for a test that had been largely overlooked. Despite years of evidence that testing prevents serious and sometimes fatal toxicity, and the European Medicines Agency recommending routine testing in Europe in 2020, testing was stalled in the US.

Now, following the FDA’s action — and the National Comprehensive Cancer Network (NCCN) subsequent recommendation to test patients with colon cancer — centers across the US are adding DPYD testing to their protocols.

“We are seeing a dramatic increase in implementation in the United States,” said University of Michigan pharmacist Daniel Hertz, PharmD, in Ann Arbor, who has advocated for routine screening for over a decade.

However, the extent to which testing has been incorporated into routine practice is unclear because centers aren’t required to report compliance, and uptake is not tracked in a central database. A commercial lab that offers the screening — Quest Diagnostics — told Medscape Medical News that it’s seen more than a doubling of tests ordered in 2026.

One Enzyme Makes a Big Difference

Fluoropyrimidines are the backbone of colorectal cancer treatment, and they’re also used in treating patients with pancreatic, breast, and other tumors.

The DPYD gene codes for dihydropyridine dehydrogenase (DPD), an enzyme responsible for most fluoropyrimidine metabolism. Approximately 6% of the population have variants in the gene that reduce DPD function, whereas fewer than 1% have variants that lead to little or no DPD activity.

Those genetic glitches cause fluoropyrimidines to build up in the system, greatly increasing the likelihood of severe side effects. The general population runs about a 30% risk for grade 3 or higher toxicity with fluoropyrimidines, but DPD-deficient patients are at a 70% or higher risk. Adverse events include myelosuppression, gastrointestinal toxicity, hand-foot syndrome, and death — sometimes after just one or two standard doses in deficient patients.

About 35-40 patients need to be genotyped to prevent one case of severe toxicity, and roughly 1000 need to be tested to prevent one fatal reaction, according to Hertz, who presented on the topic at the 2026 American Society of Clinical Oncology (ASCO) annual meeting.

Dose Reductions and Up Titrations

In its warning, the FDA said to avoid fluoropyrimidines in patients with DPYD variants that lead to complete DPD deficiency and to individualize doses for those with partial DPD deficiency unless immediate treatment is necessary.

In practice, initial doses are reduced to 25%-50% depending on what variant patients carry, according to guidance from the Clinical Pharmacogenetics Implementation Consortium (CPIC), which are followed by most oncologists.

For patients with little or no DPD activity with no other options, dose reductions of 99% appear to be tolerated, but efficacy is unknown. In theory, Hertz said, miniscule doses could still lead to meaningful systemic exposure in poor metabolizers.

If patients do well on the first two cycles, doses are titrated upwards to tolerance, to optimize efficacy.

“Doing that is logistically somewhat challenging, but it’s absolutely essential for patients,” Hertz said.

Although there are scores of DPYD variants, just over 10 have been validated to affect fluoropyrimidine metabolism; others are being investigated. CPIC director Kelly Caudle, PharmD, PhD, said the group will incorporate the latest information in a guideline update slated for early 2027, and provide more detail on up-titration and using extremely reduced doses in poor metabolizers.

Several studies have shown that DPYD-guided dosing normalizes fluoropyrimidine toxicity rates, but only a few studies have examined how well it works.

A 2023 Dutch investigation, for instance, matched 156 patients with DPYD variants who were slated for fluoropyrimidine chemotherapy with 775 patients who were DPYD wild-type carriers. Dosing was reduced by 25%-50% for variant carriers. Over roughly 5 years, there was no difference in overall survival (HR, 0.95; P = .698), though there was a trend toward reduced progression-free survival among patients with variant (HR, 1.23; P = .053).

Very few variant carriers in the study were up-titrated to tolerance, so there is a chance many were undertreated. And Hertz said, “some efficacy reduction is preferable to severe/fatal toxicity from standard doses.”

The Long Road to Routine Testing

Although DPD deficiency was first recognized in 1988, it took years for screening to become standard of care.

The move toward routine screening got a boost when families who lost members to fluoropyridine toxicity started to organize and lobby policymakers for change. They formally launched the nonprofit Advocates for Universal DPYD/DPD Testing (AUDT) in 2022. Hertz is a clinical advisor.

At the same time, families sued cancer centers for the wrongful deaths of patients who weren’t screened for DPD deficiency. In 2022, Oregon Health and Science University agreed to a $1 million settlement, and various other suits are pending, according to AUDT co-founder Karen Merritt, who lost her mother to fluoropyrimidine toxicity in 2014.

AUDT members petitioned the NCCN eight times starting in 2014 to recommend pretreatment DPYD screening, but there was pushback from key panelists, including Alan Venook, MD, vice-chair in the colon/rectal/anal cancer guidelines panel and a gastrointestinal oncologist at the University of California, San Francisco.

“We did not believe it should be in the guidelines,” Venook told Medscape Medical News.

His concerns included lower efficacy with reduced dosing, delays in treatment while waiting for test results, and uncertainty about what to do with unvalidated DPYD variants.

Venook, Hertz, Merritt, and others met to discuss the issues at a January 2025 workshop jointly sponsored by the FDA and the American Association for Cancer Research. 

“It was clear after the workshop that death from toxicity to 5-FU and capecitabine was underreported and patient safety precautions were necessary,” said Merritt, who represented patient families at the meeting.

A week afterwards, the FDA issued a safely alert about DPD deficiency, urging clinicians to tell patients about the potential for serious and life-threatening toxicities due to DPD deficiency and discuss testing options with them.

The FDA box warning followed 8 months later, and now “places are ramping up” to get testing done, Venook said.

He is still concerned about underdosing but does test his own patients. “It’s reasonable to do,” Venook said. “It’s true that you can avoid severe toxicity in the occasional patient.”

In a December 2025 commentary seeking common ground, Venook and Hertz wrote they are now both “supportive of all patients undergoing testing, with rare exceptions for patients who must start treatment immediately or make an informed decision to opt out.”

For Venook, the fact that an advocacy group “helped move the field” on this issue is noteworthy. AUDT is now focusing on facilitating DPYD testing across the US through outreach and education. The group also continues to connect families with legal assistance, according to Merritt.

Implementing Testing

DPYD testing is straightforward. Patient blood samples are sent to Quest, LabCorp, Mayo Diagnostics, or another commercial lab if testing isn’t done in house. Results take about 5-12 days, which can coincide with the time needed for chemotherapy planning, authorization, port placement, and other matters. Out-of-pocket costs are typically $250-$500.

Most centers are incorporating testing by adding an alert to the electronic medical record (EMR) system or adding testing to routine chemotherapy order sets.

“Each site has to figure out what works for their workflow,” Hertz said. “At what point is testing going to be ordered? Where does the sample get drawn? Who gets the results? Who interprets them?”

Although there can be challenges, “we haven’t heard of any site that couldn’t figure this out,” added Hertz, who co-authored a guide to help practices get up and running.

Intermountain Healthcare in Murray, Utah, opted for an EMR alert, according to Mark Lewis, MD, a gastrointestinal oncologist there.

“We got a new EPIC medical record system last September, and it was very easy to incorporate,” Lewis said. “We are now testing everybody for DPYD to comply with the FDA label. It works great.”

Testing is approximately cost-neutral when offset against treating fluoropyrimidine toxicities, including treatment with the rescue medication uridine triacetate (Vistogard). To be effective, fluoropyridine toxicity must be recognized and the drug infused within 96 hours of the last dose. The costly drug isn’t routinely stocked at many cancer centers and must be special ordered.

Concern About Community Oncology Uptake

Although the exact uptake is uncertain, routine DPYD testing is rolling out across the US. MD Anderson, Duke, Yale, and the Cleveland Clinic are among the many centers that have implemented system-wide screening, according to AUDT. Memorial Sloan Ketting Cancer Center in New York City implemented system-wide testing in November 2025 following a fluoropyrimidine death earlier in the year.

Although screening is gaining momentum at academic centers, Jai Patel, PharmD, a cancer pharmacology and pharmacogenetics researcher at Atrium Health Levine Cancer Institute in Charlotte, North Carolina, is concerned that uptake may be lagging in community settings, where the majority of patients with cancer are treated.

Atrium Health was ahead of the curve, implementing pretreatment DPYD testing in 2020 and adding an alert to the EMR system in 2022. Patel and his colleagues subsequently showed that the measures substantially reduced severe toxicities and hospitalizations.

Patel is now launching a randomized trial to assess whether the implementation strategies that worked at Atrium — EMR alerts and provider education — work at other community practices in the National Cancer Institute Community Oncology Research Program.

As a result, he’s been in touch with community practices, and found that earlier in 2026, most had no systematic process in place for DPYD testing. “A lot of it is physician awareness, if they know about the new changes with the FDA and NCCN,” Patel said.

Kalyani Narayan, MD, an oncologist at John Peter Smith Hospital in Fort Worth, Texas, illustrated that point at this year’s ASCO meeting.

“I just heard of this testing about 2 weeks ago,” she said after Hertz’s talk. As a physician who prides herself on staying ahead of the curve, it was humbling not to have heard of it earlier, Narayan told Medscape Medical News.

A patient brought it to her attention after Narayan suggested capecitabine for metastatic breast cancer. The patient called back the next day and wanted to be screened for DPD deficiency. Narayan turned to a pharmacist at her hospital for an explanation.

She now tests her own patients and has talked with other oncologists at Peter Smith about the issue. They are working to implement routine screening at the hospital.

“It will take somebody from the top to say, ‘OK, this is our standard protocol now,’ and then it will get percolated downstream,” said Narayan, whose patient with breast cancer turned out to have normal DPD function.

The story line is familiar to Patel. What’s happening at Peter Smith, he said, “is true for many community cancer centers.”

At this point, uptake is variable, Patel said, noting that guideline updates can take years to broadly change clinical practice.

Echoing Narayan, he added that “it’s very rare that we see significant change when it’s just one or two oncologists who are periodically ordering the test. There really needs to be more of a systematic change in standard operating procedures.”

The sources cited in this article had no relevant disclosures.

https://www.medscape.com/viewarticle/chemo-safety-test-finally-gaining-ground-us-2026a100169t