The National Comprehensive Cancer Network (NCCN) has issued updated clinical guidelines that now recommend considering DPYD genotyping before initiating fluoropyrimidine-based chemotherapy, marking a significant advancement in the personalization of cancer treatment.
The updated guidelines, released in Version 3.2025 for colon, rectal, anal, and small bowel cancers on April 24, 2025, acknowledge that genetic variants in the DPYD gene significantly increase the risk of severe or fatal toxicity from fluoropyrimidines such as 5-fluorouracil (5-FU) and capecitabine (Xeloda).
The Science Behind DPYD Testing
Dihydropyrimidine dehydrogenase (DPD) deficiency, first linked to fluoropyrimidine toxicity in 1988, can cause catastrophic reactions in patients receiving standard chemotherapy doses. The enzyme, encoded by the DPYD gene, is responsible for metabolizing approximately 80% of administered fluoropyrimidines.
In the United States, approximately 6% of individuals carry a pathogenic DPYD variant. These genetic variations are estimated to underlie 40% to 60% of severe or fatal fluoropyrimidine toxicity cases, making genetic screening a potentially life-saving intervention.
"For those in the field who have worked tirelessly to translate pharmacogenetic evidence into clinical practice, this NCCN update is a welcome step toward improving safety in cancer treatment," noted Ryan S. Nelson, PharmD, medical director of precision medicine at ARUP Laboratories, and Daniel L. Hertz, PharmD, PhD, associate professor of clinical pharmacy at the University of Michigan College of Pharmacy.
Clinical Evidence Supporting Testing
The recommendation follows substantial clinical evidence demonstrating the benefits of genotype-guided dosing. In a prospective cohort study of DPYD variant carriers, genotype-guided fluoropyrimidine dose adjustments significantly reduced severe toxicity (grade ≥3) from historical rates of approximately 73% to 28%, and eliminated treatment-related mortality, which previously occurred in about 10% of cases.
Importantly, research has shown that dose reduction in variant carriers does not compromise treatment effectiveness. A matched-pair study comparing DPYD*2A carriers receiving approximately 50% reduced doses to wild-type patients receiving standard doses showed no significant differences in overall survival (median 27 vs 24 months; P = .47) or progression-free survival (median 14 vs 10 months; P = .54).
Regulatory Alignment
The NCCN guideline update aligns with recent FDA actions. In December 2022, the FDA approved updated labeling for capecitabine (Xeloda), advising clinicians to "consider testing for genetic variants of DPYD to reduce the risk of serious adverse reactions." Similarly, in March 2024, the FDA approved comparable labeling changes for fluorouracil injection products.
However, the European Medicines Agency has taken a stronger stance, recommending pre-emptive testing for DPD deficiency before starting treatment with fluoropyrimidines.
The Human Cost of Missing Variants
The human impact of fluoropyrimidine toxicity is devastating. David McIntyre, a 73-year-old patient from Oregon who was cancer-free following surgery for stage I cholangiocarcinoma, received a high dose of capecitabine despite recommendations for reduction. Within days, he developed severe toxicity that progressed to strokes, pneumonia, and ultimately death. Posthumous testing confirmed severe DPD deficiency.
Similarly, Kerrie Prettitore, a 42-year-old mother of three from New Jersey, experienced severe toxicity shortly after beginning 5-FU chemotherapy. Tests revealed complete DPD deficiency, and despite intensive care, she remained minimally conscious until her passing.
Implementation Challenges
Despite the clear benefits, widespread adoption of DPYD genotyping has been slow due to several factors:
- Early evidence limitations in study design
- Implementation barriers including turnaround time and insurance coverage
- Fragmented stakeholder engagement across regulatory, clinical, and payer groups
Pharmacists as Implementation Leaders
The updated guidelines create a significant opportunity for pharmacists to lead implementation efforts. "Pharmacists are ideally positioned to lead DPYD implementation by ensuring testing is offered, interpreting test results, and educating providers," according to Nelson and Hertz.
They further emphasize that "with the FDA and NCCN recommending clinicians discuss testing with patients, pharmacists in the United States have a professional, ethical, and likely legal responsibility to ensure testing was offered and completed, or refused by the patient, before approving fluoropyrimidine treatment orders."
Additional Guideline Changes
Beyond DPYD testing, the NCCN has made other notable updates to the colon cancer guidelines:
- Added a dedicated section on pharmacogenetics, highlighting its growing importance in oncology practice
- Removed the recommendation for referral to an enterostomal therapist for preoperative site marking and teaching as part of the standard workup for resectable colon cancer
Looking to the Future
The MetaCensus initiative is addressing implementation challenges by enabling real-time inter-institutional collaboration, converting emerging data into focused clinical updates through blockchain-secured infrastructure and open-access living meta-analyses.
As pharmacogenetic testing becomes more integrated into standard oncology care, these guidelines represent an important step toward reducing preventable adverse events and improving patient outcomes through personalized medicine approaches.
The NCCN's embrace of DPYD testing reflects decades of work toward safer chemotherapy administration and signals a broader shift toward support for integrating genetic testing into routine oncology care.
