Screening for DPD: Q&A with Kristine Ashcraft

Kristine Ashcraft
Founder and CEO
YouScript

FDA recently announced new safety requirements for DPD screening in cancer patients. Kristine Ashcraft, founder and CEO of YouScript, spoke with Pharmaceutical Executive about these updates and the impact it will have on oncology.

Pharmaceutical Executive: How significant an issue is DPD deficiency?
Kristine Ashcraft: Patients with DPD variations are 25.6X more likely to experience treatment related death on standard‐dose fluoropyrimidine chemotherapy (5‐fluorouracil or capecitabine).¹ Although complete loss of activity is rare, reduced activity impacts up to 8% of patients² and simple dose reductions can reduce risk without negatively impacting long-term or progression free survival.³ CPIC, the guidelines body for gene-drug interactions, has provided evidence-based guidance on medication adjustments for Fluoropyrimidines based on DPYD genotyping since 2017.⁴ In 2024, a joint consensus recommendation from leading genetic, lab and pharmacogenomic expert groups on must test and optional variants for DPYD genotyping was published.⁵

PE: What prompted FDA to issue the safety announcement?
Ashcraft: The safety announcement highlighted labeling changes for Capecitabine and fluorouracil issued by the FDA Oncology Center of Excellence under Project Renewal, an FDA initiative that aims to update prescribing information for certain older oncology drugs. Many years prior to this change, representatives of Advocates for Universal DPD/DPYD testing petitioned the FDA to update fluoropyrimidine chemotherapy product inserts to recommend testing. A testing recommendation wouldalign with European guidance in place since 2020. While the FDA made several updates to point out the risks in March of 2024, it stopped shy of a recommendation. In January of 2025, the FDA and AACR convened a workshop to discuss whether to test or not, where all participants seemed to agree that testing for DPD variations should be discussed with all patients.

PE: What further guidelines are needed?
Ashcraft: Translating the momentum from the FDA safety alert into an FDA requirement would strengthen adoption.Furthermore, DPYD testing recommendations in the NCCN guidelines are a critical next step. Although NCCN acknowledges CPIC guideline existence, they do not recommend that providers consider testing in alignment with the recent FDA safety communication. An FDA requirement would also be useful, but the NCCN guidelines are often cited by oncologists as a reference in determining standard of care, and will help to mitigate real and avoidable patient harm for patients.

PE: What are the benefits of performing comprehensive PGx panel tests?
Ashcraft: In an assessment of over 30,000 patients that received panel testing and take at least one PGx impacted medication, almost 60% were taking medications with evidence-based drug or dose change guidance in more than one clinical area.⁶ A large randomized study of almost 7000 patients across different care settings in several European countries showed a 30% reduction in clinically significant adverse drug reactions in just 12 weeks with PGx panel testing.⁷ Testing provides immediate benefit, but can also provide ongoing drug and dose optimization. An assessment of almost 500,000 patients with PGx panel testing in the UK Biobank showed that patients would have an atypical response to over 10 medications on average.⁸

Think of PGx panel testing like a seatbelt for medication safety and efficacy that should be used every time medication changes are considered. One model suggested a 10.6% reduction in mortality with the use of PGx testing.⁹ PGx panel testing and a pharmacist-provided comprehensive medication review would incur a low lifetime cost of $450 averting 106 deaths per 1000. Comparatively, other preventative measures–such as mammograms for breast cancer, low-dose CT scans for lung cancer in high-risk patients, and colonoscopies for colon cancer–all cost more to prevent fewer deaths. So why are they considered the standard of care, while PGx panel testing is not, when all are worthwhile preventative interventions that have likely saved the lives of someone you care about?

Sources

1. Pathogenic DPYD Variants and Treatment-Related Mortality in Patients Receiving Fluoropyrimidine Chemotherapy: A Systematic Review and Meta-Analysis. NIH. December 26, 2021. https://pubmed.ncbi.nlm.nih.gov/34506675/
2. Population-scale predictions of DPD and TPMT phenotypes using a quantitative pharmacogene-specific ensemble classifier. NIH. December, 2020. https://pubmed.ncbi.nlm.nih.gov/32973300/
3. Survival of Patients With Cancer With DPYD Variant Alleles and Dose-Individualized Fluoropyrimidine Therapy-A Matched-Pair Analysis. NIH. August 28, 2023. https://pubmed.ncbi.nlm.nih.gov/37639651/
4. CPIC® Guideline for Fluoropyrimidines and DPYD. CPIC. https://cpicpgx.org/guidelines/guideline-for-fluoropyrimidines-and-dpyd/
5. DPYD Genotyping Recommendations. PharmgKB. https://www.pharmgkb.org/literature/15161962
6. Validation of Pharmacogenomic Interaction Probability (PIP) Scores in Predicting Drug–Gene, Drug–Drug–Gene, and Drug–Gene–Gene Interaction Risks in a Large Patient Population. MDPI. November 29, 2022. https://www.mdpi.com/2075-4426/12/12/1972
7. A 12-gene pharmacogenetic panel to prevent adverse drug reactions: an open-label, multicentre, controlled, cluster-randomised crossover implementation study. The Lancet. February 4, 2023. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(22)01841-4/abstract
8. Pharmacogenetics at Scale: An Analysis of the UK Biobank. NIH. June, 2021. https://pubmed.ncbi.nlm.nih.gov/33237584/
9. Cost-Effectiveness of Pharmacogenomics-Guided Prescribing to Prevent Gene-Drug-Related Deaths: A Decision-Analytic Model. NIH. June, 2022. https://pubmed.ncbi.nlm.nih.gov/36120299/