Commentary
Article
In 1988, a quiet but seismic shift began in oncology. Researchers described how inherited dihydropyrimidine dehydrogenase (DPD) deficiency could cause catastrophic reactions to fluoropyrimidines such as 5-fluorouracil (5-FU)—a mainstay in the treatment of colon, anal, rectal, and gastrointestinal cancers. It was a foundational observation published in The Journal of Clinical Investigation, connecting genotype to drug toxicity in a way that predated the formal emergence of pharmacogenetics as a clinical discipline.¹
Nearly four decades later, the National Comprehensive Cancer Network (NCCN) has issued updated clinical guidelines that embrace DPYD genotyping as a tool for tailoring fluoropyrimidine chemotherapy. 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.²
In its latest guidelines for colon, rectal, anal, and small bowel cancers, the NCCN recommends clinicians consider DPYD genotyping before initiating treatment, acknowledging that genetic variants in DPYD significantly increase the risk of severe or fatal fluoropyrimidine toxicity.²
Artificial intelligence depiction of personalized medicine and genetic testing. Image Credit: © The Gentleman - stock.adobe.com
The NCCN guideline update currently aligns with the recommendations made by the FDA: On December 14, 2022, the FDA approved updated labeling for capecitabine (Xeloda; Roche Pharmaceuticals), advising clinicians to “consider testing for genetic variants of DPYD to reduce the risk of serious adverse reactions if the patient’s clinical status permits and based on clinical judgment.”³ On March 21, 2024, the FDA approved similar labeling changes for fluorouracil injection products (5-FU), recommending clinicians “consider testing for genetic variants of DPYD prior to initiating fluorouracil to reduce the risk of serious adverse reactions if the patient’s clinical status permits and based on clinical judgment.”³ This falls short of the European Medicines Agency’s recommendation to pre-emptively test for DPD deficiency: “Phenotype and/or genotype testing is therefore recommended before starting treatment with fluoropyrimidines.”⁴
Leading pharmacogenomics guideline-producing experts go a step further in recommending dosing recommendations. In 2013, Clinical Pharmacogenetics Implementation Consortium issued its first guideline recommending reduced initial doses or avoidance of fluoropyrimidines in patients carrying certain high-risk DPYD variants. These recommendations were later updated in 2017 to reflect expanded evidence and variant interpretation.⁶ Similarly, as early as 2011, the Dutch Pharmacogenetics Working Group recommended preemptive DPYD genotyping with genotype-guided dosing strategies. For patients with a single nonfunctional allele, a 50% dose reduction was advised. In cases of biallelic deficiency, complete avoidance of fluoropyrimidines was recommended.⁷
While NCCN stops short of mandating universal testing, its recommendation underscores a shifting standard of care. Pretreatment DPYD screening is a clinically actionable consideration clinicians involved in treating patients with fluoropyrimidines (eg, pharmacists, nurse practitioners, physician assistants, and medical oncologists) should routinely discuss with patients.
Clinical data supporting genotype-guided dosing continues to accumulate. In a prospective cohort of DPYD variant carriers, genotype-guided fluoropyrimidine dose adjustments significantly reduced severe toxicity (grade ≥3) from historical rates of approximately 73% to 28%, and reduced treatment-related mortality from about 10% to 0%.⁸ A 2020 meta-analysis reaffirmed that pretreatment DPYD genotyping significantly reduces the incidence of severe toxicity, validating it as a critical tool for safer chemotherapy administration.9
Clinical data further demonstrate that dose reduction in variant carriers does not reduce clinical 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).¹⁰ In another study, DPYD variant carriers receiving reduced doses did not have reduced overall survival (hazard ratio 0.95; 95% CI, 0.75-1.51; P = .698) and only a marginal, non-significant trend toward shorter progression-free survival (HR 1.23; 95% CI, 1.00–1.51; P = .053), which was attributed primarily to carriers of the reduced activity HapB3 variant receiving 25% dose reduction.11
Personal stories vividly illustrate the human impact of fluoropyrimidine toxicity. David McIntyre, a patient aged 73 years from Oregon, underwent successful surgery for stage I cholangiocarcinoma and was cancer-free. Despite recommendations for a reduced chemotherapy dose, he received a high dose of capecitabine. Within days, he developed severe vomiting, diarrhea, mouth sores, and a facial rash. His symptoms escalated rapidly to strokes, pneumonia, and coma, leading to his death. Posthumous testing confirmed severe DPD deficiency.¹²
Patient with cancer during chemotherapy consultation. Image Credit: © tonefotografia - stock.adobe.com
Kerrie Prettitore, a patient aged 42 years and a mother of 3 from New Jersey, experienced severe toxicity shortly after beginning 5-FU chemotherapy. Hospitalized in critical condition, tests revealed complete DPD deficiency. She suffered severe mucositis, pneumonia, and entered a coma. Despite intensive rehabilitation, Kerrie remained minimally conscious until her passing. Her family now advocates for mandatory pre-treatment DPD testing.¹³
These stories underscore the urgency of routine DPYD screening. In the United States, approximately 6% of individuals carry a pathogenic DPYD variant, and DPD deficiency is estimated to underlie approximately 40% to 60% of severe or fatal fluoropyrimidine toxicity cases.¹⁴,¹⁵
Despite mounting evidence, widespread DPYD genotyping adoption has been slow due to:
Accelerating adoption now requires coordinated infrastructure to make evidence interpretation and application easier.
The MetaCensus initiative addresses this by enabling real-time inter-institutional collaboration. MetaCensus swiftly converts emerging data into focused, clinically relevant updates, enhancing transparency and expediting clinical decision-making by utilizing a blockchain-secured infrastructure and open-access living meta-analyses.21
Ryan S. Nelson, PharmD, is a medical director of precision medicine at ARUP Laboratories in Salt Lake City, Utah. Nelson is also an editorial advisory board member for Pharmacy Practice in Focus: Health Systems.
Daniel L Hertz, PharmD, PhD, is an associate professor of clinical pharmacy, University of Michigan College of Pharmacy in Ann Arbor.
Pharmacists are ideally positioned to lead DPYD implementation by ensuring testing is offered, interpreting test results, and educating providers. 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 to safeguard patients receiving fluoropyrimidine chemotherapy from severe toxicity.
