ASCO 2025: Pretreatment DPYD Testing for Fluoropyrimidines Can Improve Patient Safety and Lower Cost

The landscape of pharmacogenomics in oncology is rapidly evolving, and recent findings presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting underscore the critical role of DPYD genotyping in optimizing the safety of fluoropyrimidine (FP)–based chemotherapy. Two abstracts from the Atrium Health Levine Cancer Institute provide compelling evidence on both the clinical outcomes and economic impact of pre-treatment DPYD testing in routine oncology practice.^1,2

Patient receiving chemotherapy. Image Credit: © VectorBum - stock.adobe.com

These studies by Nguyen et al and Morris et al coupled with insights from lead investigators Grace Nguyen, PharmD, BCPS, and Sarah Morris, PharmD, in interviews with Pharmacy Times^®, reinforce the central role pharmacists play in implementing and refining pharmacogenomics-guided care pathways.^1-4

DPYD Variants and Fluoropyrimidine Toxicity: The Clinical Context

Fluoropyrimidines such as 5-FU and capecitabine remain foundational therapies in gastrointestinal (GI) and other solid tumors. However, a subset of patients—estimated at 3% to 8% in European and US populations—carry loss-of-function or decreased-function DPYD gene variants, significantly impairing DPD enzyme activity. This impairment leads to an increased risk of severe and sometimes fatal FP-related toxicities, including myelosuppression, mucositis, and GI adverse events (AEs).^1,2

Despite longstanding awareness of this risk, routine pre-treatment DPYD genotyping has been slow to gain traction in US clinical practice, in part due to concerns around cost-effectiveness, logistical barriers, and variable payer reimbursement. The ASCO 2025 abstracts from the Levine Cancer Institute address these challenges, providing real-world data that supports the integration of DPYD testing into standard oncology workflows.^1,2

Dosing Tolerability and AEs in DPYD Variant Carriers

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.

In her ASCO presentation, Nguyen, a clinical pharmacogenomics specialist in the Division of Pharmacology & Pharmacogenomics at Atrium Health Levine Cancer Institute, and her team reported on a retrospective cohort study evaluating 49 patients with DPYD variants who received genotype-guided FP dosing across a multisite cancer center network. All patients underwent routine in-house DPYD testing covering 5 key variants—c.1236G>A (HapB3), c.557A>G, c.2846A>T, c.1905+1G>A, and c.1679T>G—before initiating FP chemotherapy.

Key findings include:

• Initial dose reductions: All patients started with a 50% reduced FP dose, following Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines.
• Dose escalation patterns: 37% of patients underwent cautious dose escalations (typically 5%-15% increases) in later cycles, with only 10% (5 patients) achieving full standard dosing without severe toxicity.
• Toxicity profiles: Overall, 27% experienced grade 3 or higher AEs, 18% required hospitalization, and 22% discontinued therapy due to AEs.
• Variant-specific trends: Patients with no-function variants (c.1905+1G>A, c.1679T>G) had higher toxicity rates (75%) than those with decreased-function variants (22%).

Nguyen highlighted the need for variant-specific titration protocols, as current CPIC guidelines recommend uniform 50% dose reductions but provide limited guidance on individualized escalation strategies.³

Cost Analysis of Pre-Treatment DPYD Genotyping

Sarah Morris, PharmD, is a clinical pharmacogenomics specialist at Atrium Health Levine Cancer Institute in Charlotte, North Carolina.

Complementing the clinical findings, Morris, a clinical pharmacogenomics specialist at Atrium Health Levine Cancer Institute, and her team conducted a health-system–level cost analysis of implementing routine DPYD genotyping.² This decision-tree model compared 2 strategies over a 3-month horizon²:

1. Pretreatment genotyping with dose adjustments: Testing all patients, reducing doses in variant carriers.
2. No pretreatment testing: Treating all patients at standard FP doses.

Key findings include²:

• Per-patient cost savings: DPYD testing reduced per-patient costs by $36.98 on average, primarily through avoiding hospitalizations for severe AEs.
• Hospitalization rate reduction: Among variant carriers, hospitalization rates decreased from 64% (without testing) to 25% (with genotype-guided dosing).
• Testing costs: At approximately $175 per test (CMS 2023 fee schedule), the testing program yielded net savings, even before accounting for indirect costs like outpatient AE management or patient productivity loss.
• Broader implications: Savings were amplified when insurance reimbursement for testing was assumed, supporting broader payer engagement.

Morris emphasized the importance of integrating DPYD genotyping into treatment workflows and advocated for making testing an "opt-out" rather than "opt-in" process to ensure consistency.⁴

Pharmacists at the Forefront of DPYD Genotyping Implementation

Both abstracts underscore the pivotal role of pharmacists in the successful deployment of DPYD testing^1,2:

• Patient identification: Pharmacists facilitate test ordering during treatment planning, ensuring preemptive testing rather than reactive testing after toxicity occurs.
• Dose optimization: Pharmacists interpret genotype reports, recommend initial dose reductions, and guide cautious dose escalations tailored to individual patients and variants.
• Toxicity monitoring: Pharmacists provide close surveillance during therapy, identifying emerging AEs and advising on necessary interventions.
• Advocacy and education: Pharmacists champion the value of pharmacogenomics with payers, prescribers, and patients, addressing barriers like inconsistent insurance coverage and prior authorization delays.

Nguyen noted the need for real-time clinical decision support tools and collaborative protocols that empower pharmacists to make proactive, evidence-based recommendations.³

“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,” Nguyen said. “Pharmacists play a central role in ensuring these dose adjustments, when appropriate, are timely, safe, and evidence-based.”

Conclusion

The findings from the ASCO abstracts provide compelling real-world evidence for integrating DPYD genotyping into standard oncology practice. Such evidence aligns with recent changes in National Comprehensive Cancer Network (NCCN) clinical guidelines. On April 23, 2025, NCCN updated its guidelines to recommend pre-treatment DPYD genotyping for patients initiating fluoropyrimidine-based chemotherapy, reflecting a growing consensus on its clinical utility.

These developments underscore the momentum toward a more personalized, pharmacogenomics-informed approach to chemotherapy, positioning pharmacists at the forefront of implementing related testing protocols, optimizing dosing strategies, and advocating for equitable access to DPYD genotyping. As the oncology landscape continues to evolve, expertise in pharmacogenomics will remain critical to ensuring safe, effective, and individualized patient care.

REFERENCES

1. Nguyen G, Morris S, Kwange S, et al. Dosing tolerability and adverse events (AEs) in dihydropyrimidine dehydrogenase (DPYD) variant carriers receiving genotyping-guided fluoropyrimidine (FP) dosing. American Society of Clinical Oncology. 2025. Accessed May 28, 2025. https://meetings.asco.org/abstracts-presentations/249391

2. Morris S, Nguyen G, Verbyla A, et al. Cost analysis of pre-treatment dihydropyrimidine dehydrogenase (DPYD) genotyping to reduce hospitalizations at a cancer center in the United States (U.S.). American Society of Clinical Oncology. 2025. Accessed May 28, 2025. https://meetings.asco.org/abstracts-presentations/253106

3. Nguyen G, Hippensteele A. ASCO 2025: Real-World Strategies for DPYD-Variant–Guided Fluoropyrimidine Dosing. Pharmacy Times. May 28, 2025. Accessed May 28, 2025. https://www.pharmacytimes.com/view/asco-real-world-strategies-for-dpyd-variant-guided-fluoropyrimidine-dosing

4. Morris S, Hippensteele A. ASCO 2025: Cost Savings and Clinical Outcomes of Pre-Treatment DPYD Genotyping Before Fluoropyrimidine Therapy. Pharmacy Times. May 28, 2025. Accessed May 28, 2025. https://www.pharmacytimes.com/view/asco-2025-cost-savings-and-clinical-outcomes-of-pre-treatment-dpyd-genotyping-before-fluoropyrimidine-therapy

5. Nelson RS, Hertz DL. DPYD Testing Gains Ground: NCCN Guideline Update Reflects Decades of Work Toward Safer Chemotherapy. Pharmacy Times. April 25, 2025. Accessed May 28, 2025. https://www.pharmacytimes.com/view/dpyd-testing-gains-ground-nccn-guideline-update-reflects-decades-of-work-toward-safer-chemotherapy