Upfront Genotyping of DPYD* 2A to Individualize Fluoropyrimidine Therapy: A Safety and Cost Analysis

Purpose
Fluoropyrimidines are frequently prescribed anticancer drugs. A polymorphism in the fluoropyrimidine metabolizing enzyme dihydropyrimidine dehydrogenase (DPD; ie, DPYD2A) is strongly associated with fluoropyrimidine-induced severe and life-threatening toxicity. This study determined the feasibility, safety, and cost of DPYD2A genotype–guided dosing.
Patients and Methods
Patients intended to be treated with fluoropyrimidine-based chemotherapy were prospectively genotyped for DPYD2A before start of therapy. Variant allele carriers received an initial dose reduction of 50% followed by dose titration based on tolerance. Toxicity was the primary end point and was compared with historical controls (ie, DPYD2A variant allele carriers receiving standard dose described in literature) and with DPYD2A wild-type patients treated with the standard dose in this study. Secondary end points included a model-based cost analysis, as well as pharmacokinetic and DPD enzyme activity analyses.
Results
A total of 2,038 patients were prospectively screened for DPYD2A, of whom 22 (1.1%) were heterozygous polymorphic. DPYD2A variant allele carriers were treated with a median dose-intensity of 48% (range, 17% to 91%). The risk of grade 3 toxicity was thereby significantly reduced from 73% (95% CI, 58% to 85%) in historical controls (n 48) to 28% (95% CI, 10% to 53%) by genotype-guided dosing (P .001); drug-induced death was reduced from 10% to 0%. Adequate treatment of genotype-guided dosing was further demonstrated by a similar incidence of grade 3 toxicity compared with wild-type patients receiving the standard dose (23%; P .64) and by similar systemic fluorouracil (active drug) exposure. Furthermore, average total treatment cost per patient was lower for screening (€2,772 [$3,767]) than for nonscreening (€2,817 [$3,828]), outweighing screening costs.
Conclusion
DPYD2A is strongly associated with fluoropyrimidine-induced severe and life-threatening toxicity. DPYD*2A genotype–guided dosing results in adequate systemic drug exposure and significantly improves safety of fluoropyrimidine therapy for the individual patient. On a population level, upfront genotyping seemed cost saving.