ASCO 2025: Real-World Strategies for DPYD-Variant–Guided Fluoropyrimidine Dosing

Pharmacogenomics-guided dosing is reshaping the landscape of fluoropyrimidine (FP) chemotherapy, particularly for patients with DPYD genetic variants that put them at heightened risk for severe toxicity. At the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting, Grace Nguyen, PharmD, BCPS, presented an abstract titled “Dosing tolerability and adverse events (AEs) in DPYD variant carriers receiving genotyping-guided FP dosing,” providing insight on the real-world implementation of DPYD genotyping in oncology practice.

In this interview, Nguyen discusses her institution’s experience with DPYD genotype-guided dosing, including observed patterns in AEs, emerging strategies for dose escalation in variant carriers, and the critical role of pharmacists in supporting individualized patient care.

Pharmacy Times®: How does DPYD genotyping currently influence initial FP dosing strategies at your clinical practice?

Grace Nguyen, PharmD, BCPS, is a clinical pharmacogenomics specialist in the Division of Pharmacology & Pharmacogenomics at Atrium Health Levine Cancer Institute and is a member at Atrium Health Wake Forest Baptist Comprehensive Cancer Center in Charlotte, North Carolina.

Grace Nguyen, PharmD, BCPS: DPYD genotyping is available to order by providers as a standard of care test at our institution across over 20 oncology clinics and has become routine at most clinics. When patients undergo pretreatment testing and results are available before FP chemotherapy initiation, our providers consistently follow Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines by reducing the initial FP dose in DPYD intermediate metabolizers by up to 50%.

Pharmacy Times: Which DPYD variants are most commonly associated with increased risk of FP-related toxicity, and how do they impact dosing decisions?

Nguyen: CPIC categorizes DPYD variants by their function: decreased-function variants (eg, c.1236G>A [HapB3 haplotype], c.557A>G, c.2846A>T) and no-function variants (eg, c.1905+1G>A, c.1679T>G). We conducted an analysis of 49 DPYD variant carriers (6% frequency of all patients who received testing) who received pretreatment testing, and results were available before treatment start. Though limited by a small sample size, we observed that patients with no-function variants had more severe AEs (75%) compared to those with decreased-function variants (22%) despite initial dose reductions. Interestingly, few patients with decreased-function variants tolerated cautious dose escalations up to the full standard dose, suggesting there may be room for more individualized titration strategies based on variant and patient factors.

Pharmacy Times: How do you assess and monitor tolerability in patients receiving reduced initial FP doses due to DPYD variants?

Nguyen: In addition to standard monitoring for treatment-related toxicity by the treating oncologists and pharmacists, our pharmacogenomics-trained pharmacists closely follow patients with DPYD variants and make recommendations when a dose escalation may be appropriate. All clinical outcomes and dosing adjustments are tracked under an institutional review board–approved research protocol, which supports ongoing quality improvement and research efforts.

Pharmacy Times: Do you follow a specific protocol for dose escalation in intermediate metabolizers once treatment begins, and how successful has that been in maintaining efficacy while minimizing toxicity?

An intravenous drip set up in a hospital room. Image Credit: © Pitchy - stock.adobe.com

Nguyen: Currently, we do not have a formal institutional protocol for dose escalation, which is also lacking from CPIC guidelines (albeit, updated CPIC guidelines are being developed and may address this more clearly). Based on our data, we are in the process of developing a variant-specific dose escalation protocol to standardize this approach. Our general approach involves cautious dose escalations of 5% to 15% after 1 to 2 cycles if patient is tolerating treatment or no significant toxicities have occurred to maintain efficacy. Specific dose increases are tailored to the individual patient's variant, clinical status, and toxicity profile. In patients who tolerate treatment well, we continue gradual escalations to reach the maximum tolerated dose. We did not evaluate survival outcomes in this analysis, though a survival analysis by Knikman et al has demonstrated that survival outcomes were not compromised with DPYD genotype-guided dosing approach.

Pharmacy Times: What has been your experience with dose adjustments in DPYD variant carriers? Are these patients generally able to tolerate dose escalations over time?

Nguyen: Our experience shows considerable variability in dose tolerability and toxicity among identified DPYD variant carriers. While some patients, especially those with decreased-function variants, can tolerate dose escalations, others experience severe toxicity even at reduced doses. Provider practices regarding dose escalation can also vary, which is why pharmacist involvement and clinical decision support tools are so important. As our data set grows, we hope to perform additional statistical analyses to identify factors associated with dose tolerability, including specific variants and patient factors.

Pharmacy Times: What is your takeaway from this study?

Nguyen: After initial dose reduction, carriers of certain decreased-function variants may tolerate greater dose escalations than those with no-function variants. Pharmacists play a central role in ensuring these dose adjustments, when appropriate, are timely, safe, and evidence-based.