DPYD Testing Before Fluoropyrimidine Therapy Strengthens Oncology Safety and Personalization

In a move to improve patient safety within oncology, the FDA updated the labeling for capecitabine and fluorouracil (5-FU) to include new requirements for dihydropyrimidine dehydrogenase (DPD) deficiency testing prior to initiating therapy.

The change is supported by growing evidence showing reduced activity of the DPD enzyme—caused by genetic variants of the DPYD gene—leads to patients being hypersensitive to fluoropyrimidine. Some cases can be fatal.

In line with the FDA Safety Labeling Update, clinicians are advised to carry out DPYD genotype testing to help identify poor or intermediate metabolizers and thus be able to adjust dosing or consider alternative therapies accordingly.¹

Predictable Toxicity Through Pharmacogenomic Screening

Fluoropyrimidines, such as capecitabine and 5-FU, are key components of a number of chemotherapy regimens used to treat colorectal, breast, and other types of solid tumors. Although these drugs have very broad utility, a significant number of patients undergoing treatment with these agents are affected by early severe toxicities such as neutropenia, mucositis, diarrhea, and cardiotoxicity.²

Traditionally, toxicities are addressed in a reactive manner and only after the patients have gone through profoundly negative adverse events (AEs). However, pharmacogenomic data indicate that certain DPYD variants are associated with markedly lowered DPD enzyme activity and elevated systemic drug levels, resulting in these toxicities.²

Individuals with complete DPD deficiency metabolize fluoropyrimidines so poorly that exposure accumulates to toxic levels rapidly. The FDA Safety Labeling Update points out that these patients can experience "life-threatening toxicity or death" if they receive the usual standard of care, which underscores the importance for safety of determining these patients prior to therapy.¹ Intermediate metabolizers, who possess partial deficiency, are also at elevated risk and require substantially lowered starting doses.^1,3

Evidence Supporting Routine DPYD Testing

Multiple studies support the clinical utility of DPYD genotyping in reducing severe AEs. A recent systematic pharmacogenomic analysis underscores the value of incorporating DPYD screening into clinical practice, noting that genotype-guided dosing strategies can reduce hospitalizations related to toxicity without compromising antitumor efficacy.² Based on such evidence, international standards for chemotherapeutic safety have increasingly incorporated DPYD testing, and regulatory guidance in Europe and Canada has long advocated preemptive genotyping.³

The National Community Oncology Dispensing Association (NCODA) also issued strong recommendations for universal testing before fluoropyrimidine therapy, pointing to increased safety outcomes. NCODA points out that DPYD testing "helps clinicians identify patients who may require dose reductions or alternative treatment approaches" as a way of avoiding serious toxicity.⁴

Clinical Perspectives on Implementation

In a Pharmacy Times interview, Serena Mitaly, PharmD—a system clinical pharmacogenomics pharmacist with Ochsner Health—described the scientific rationale for the label update and the operational role pharmacists play in DPYD testing implementation.

“The new capecitabine boxed warning reflects a growing recognition that severe fluoropyrimidine toxicity is not a random event—it’s often biologically predictable. Fluorouracil [5-FU] and capecitabine remain staples in many cancer regimens, yet a significant portion of patients still experience serious, sometimes life-threatening, toxicities early in treatment,” Mitaly stated.⁵

She highlighted how identifying poor metabolizers before treatment enables clinicians to avoid unsafe dosing altogether and how intermediate metabolizers can be safely started at reduced doses.⁵

Operational challenges continue to be an obstacle to the universal implementation of pharmacogenomics, including inconsistent insurance reimbursement, integration of test results into electronic medical records, and clinician familiarity with pharmacogenomic data interpretation.

However, Mitaly points out that pharmacists can play a key role in overcoming these challenges through developing workflow processes, advocating for smart clinical decision support, and educating providers.⁵

Workflow Integration and Patient Counseling

When properly integrated into clinical workflows, preemptive DPYD testing adds minimal delay to treatment initiation. Ordering the test at the planning stage typically ensures that results return before the first chemotherapy cycle, allowing oncologists to make informed dosing decisions without delaying care.³ Embedding DPYD results into electronic medical records as discrete, searchable data allows pharmacists and clinicians to leverage clinical decision support tools that flag patients who need dose modification or alternative therapy.⁵

DPYD testing enhances patient counseling by reframing dose adjustments as personalized care rather than arbitrary reductions.

As Mitaly explained, “Preemptive testing actually improves the quality of our conversations with patients. Instead of reacting to toxicity after it occurs, we can explain upfront that we’re using a genetic test to help tailor their chemotherapy dose for safety. When a patient has a decreased-function variant, the conversation shifts from ‘why are we lowering the dose?’ to ‘we’re personalizing this dose to reduce your risk of severe side effects.’ Patients understand that message immediately—it feels proactive, thoughtful, and individualized.”⁵

Toward a Personalized Oncology Future

The FDA's DPYD testing mandate is just one aspect of the larger transition to precision oncology, moving away from the use of a single treatment model for all patients to genetically guided care that offers the highest efficacy and least harm. By leading implementation efforts, participating in interdisciplinary governance, and educating colleagues and patients alike, pharmacists help ensure that pharmacogenomic testing becomes a routine component of oncology care.

REFERENCES

1. Safety labeling update for capecitabine and fluorouracil (5-FU) on risks associated with dihydropyrimidine dehydrogenase (DPD) deficiency. FDA. Published February 5, 2026. Accessed February 9, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/safety-labeling-update-capecitabine-and-fluorouracil-5-fu-risks-associated-dihydropyrimidine

2. Glewis S, Senthil Lingaratnam, Krishnasamy M, et al. Pharmacogenetics testing (DPYD and UGT1A1) for fluoropyrimidine and irinotecan in routine clinical care: Perspectives of medical oncologists and oncology pharmacists. Journal of Oncology Pharmacy Practice. 2023;30(1):30-37. doi:10.1177/10781552231167554

3. Gordan L, Mehring K, Ciarrocchi R. Universal DPYD Testing Prior to 5-FU and Capecitabine Therapy. NCODA. Published October 6, 2025. Accessed February 9, 2026. https://www.ncoda.org/news/universal-dpyd-testing-prior-to-5-fu-and-capecitabine-therapy/

4. Bankhead C. FDA Calls for Testing Before Treatment With Widely Used Chemotherapies. Published February 6, 2026. Accessed February 9, 2026. https://bit.ly/4rA602E

5. Mitaly S. From Warning to Action: Implementing DPYD Testing Following the FDA-Approved Capectiabine Label Update. Pharmacy Times. Published January 15, 2026. Accessed February 9, 2026. https://www.pharmacytimes.com/view/from-warning-to-action-implementing-dpyd-testing-following-the-fda-approved-capecitabine-label-update