Expert Q&A: How U-M research helped inform new FDA warning to protect cancer patients

Each year, more than 250,000 people in the U.S. receive chemotherapy drugs known as fluoropyrimidines, including 5-fluorouracil (5-FU) and capecitabine (brand name Xeloda), to treat several types of cancer. These medicines are tolerated by most people, but for a small group of patients who carry certain variants of the DPYD gene, the treatments can cause life-threatening side effects. In October 2025, the U.S. Food and Drug Administration (FDA) took an important step toward preventing these severe reactions by adding a Boxed Warning—the strongest it issues—to the capecitabine label, recommending that patients receive DPYD genetic testing prior to starting treatment. A similar Boxed Warning was added to the 5-FU label in February 2026.

These decisions were informed by years of research and engagement led in part by Daniel Hertz, Pharm.D., Ph.D., associate professor of clinical pharmacy at the University of Michigan College of Pharmacy and U-M Rogel Cancer Center Scholar. Hertz and his colleagues helped build the scientific case for routine DPYD genetic testing, showing that people with certain variants are far more likely to experience severe or even fatal toxicity from a standard dose of fluoropyrimidine drugs. 

In this Q&A, Hertz discusses the evidence behind the FDA’s action, the collaborative effort that made it possible, and what it means for patients and clinicians.

Why should patients be screened for DPYD variants before receiving fluoropyrimidine chemotherapy?

I started to see more and more evidence, especially out of Europe, that DPYD genetics could help predict severe, and in some cases fatal, toxicity from fluoropyrimidine chemotherapy drugs, such as capecitabine (Xeloda) and 5-fluorouracil (5-FU). These drugs are used to treat a variety of tumor types, like colorectal cancer and other cancers of the head, neck, and breast — in fact, nearly all colorectal cancer patients start with a fluoropyrimidine-containing regimen. 

The problem is that approximately 1 in 20 patients carry a DPYD genetic variant that puts them at extremely high risk of severe toxicity, even death, from just one standard dose of these drugs. Toxic reactions typically occur within the first couple days of treatment, but it can be challenging to differentiate more routine side effects from life-threatening toxicity because patients deteriorate, and in some cases succumb, over the course of a week or a month. An antidote (uridine triacetate, brand name Vistogard) is available, but it’s expensive and must be used within the first 96 hours of a toxic reaction, so many sites do not stock it. Outside of that 96-hour window, there really is not much that can be done other than standard supportive care, so it’s really important to identify whether a patient is at risk of a toxic reaction before they ever receive the drug.

What is the genetic testing process like?

For patients, the test usually requires a blood sample, which can be collected by any medical provider. The sample is then sent to a genetic testing company, with results available in approximately seven days. Some tests can be done with a cheek swab or a saliva sample, but most tests use blood. 

At the University of Michigan, we actually found that there was a large cohort of patients who already had genetic information on file from a prior research study. We were able to create a process in which we use that research-only genetic information to passively monitor patients who carry a DPYD variant. If one is diagnosed with cancer, or is going to start a fluoropyrimidine, we can then do the clinical testing needed to confirm their heightened risk of severe toxicity. In other words, we use the study’s genetic information to keep an eye on patients who carry a genetic variant and make sure they do not receive fluoropyrimidines without the proper dose adjustment. 

How will the FDA’s new Boxed Warnings protect patients?

The FDA’s new Boxed Warnings for 5-fluorouracil and capecitabine state patients should be tested for DPYD genetic variants before starting treatment, which is an evolution from previous updates to the label. Over the last 10 years, the FDA has slowly updated the labels to first include warnings about severe toxicity, then statements encouraging clinicians to discuss testing with patients, and now, as of October 2025 and February 2026, an explicit recommendation for DPYD testing before use. 

DPYD genetic testing has been standard practice in Europe and parts of Canada for a long time – not so in the U.S. I believe the FDA’s recent action is a huge step toward improving the standard of care to ensure patients in the U.S. are receiving maximally safe and effective treatment.

What partners have helped you highlight the importance of genetic testing?

I work closely with the Advocates for Universal DPD/DPYD Testing (AUDT). AUDT was founded in 2022 by Ken Surprenant, who has been working on this issue since 2012. Ken has been an invaluable partner over the last few years as we’ve worked to inform the FDA about the importance of adding a warning to these drug labels. Together with AUDT and about 20 patient advocates, we have encouraged individual sites to start testing, submitted petitions to the FDA, and communicated with patients and clinicians about the importance of genetic testing.

As a result of our efforts, I was invited to join an FDA- and American Association for Cancer Research-sponsored workshop in January 2025, where I highlighted the clinical benefits of DPYD testing. The consensus among workshop participants was that DPYD testing, while imperfect, is a clinically feasible, relatively simple way to identify patients at risk of severe and fatal toxicity, and it should be the standard of care while testing and genetics-informed dosing continues to be improved.

Are there other drugs patients should be genetically screened for prior to use? 

There is another drug called irinotecan, and patients could benefit from being genetically tested for UGT1A1 for that as well. 5-FU and irinotecan are often used together, so the nice thing is if you send a patient to be tested for one gene, you could easily test for the other at the same time.

What advice do you have for clinicians and patients who are about to start use of one of these drugs?

Clinicians should understand that DPYD testing is now the standard of care in the U.S., and by choosing not to do it they put their patients at risk of severe toxicity and themselves at risk of medical liability. Testing has been demonstrated to have clear clinical benefits for patients; it is feasible to do in practice; and hundreds of sites are now doing it for all of their patients. 

For patients and their families, I would strongly recommend that they advocate for DPYD testing before treatment begins and ensure their results are returned prior to starting fluoropyrimidine chemotherapy. It is the only way to ensure they receive safe treatment and avoid serious, potentially life-threatening, easily preventable side effects.