Fluoropyrimidine Toxicities and DPYD Genotyping: A Clinical Case

Area of Science:

• Pharmacogenomics
• Oncology
• Clinical Chemistry

Background:

• Fluoropyrimidines are essential chemotherapeutic agents, primarily metabolized by dihydropyrimidine dehydrogenase (DPD).
• Genetic variations in the *DPYD* gene can impair DPD function, leading to severe drug toxicity.
• Current guidelines recommend testing for specific *DPYD* variants before initiating fluoropyrimidine therapy.

Observation:

• A patient experienced significant capecitabine toxicity despite not carrying the four routinely screened *DPYD* variants.
• Subsequent *DPYD* gene sequencing revealed three heterozygous variants with potential deleterious effects on DPD.
• Treatment was discontinued due to observed toxicity and the presence of uncharacterized *DPYD* variants.

Findings:

• This case underscores that toxicity can occur even in patients negative for common *DPYD* variants.
• The presence of multiple, less-characterized heterozygous *DPYD* variants may contribute to fluoropyrimidine-induced toxicity.
• The interpretation of novel or multiple *DPYD* variants requires careful consideration, potentially including haplotype analysis.

Implications:

• Broader *DPYD* genotyping or alternative screening methods may be necessary for comprehensive toxicity risk assessment.
• Further research into the functional impact of various *DPYD* variants and their combinations is warranted.
• Understanding the complete genetic landscape influencing DPD activity is crucial for personalized cancer treatment strategies.