In a journal article published online last week in The Lancet Oncology, Henricks et al. reported that DPYD genotype-based dose reductions of fluorouracil and capecitabine in cancer patients resulted in improved safety outcomes and was feasible in clinical practice.
The authors prospectively genotyped four DPYD variants: rs3918290 (1905+1G>A; DPYD*2A), rs55886062 (1679T>G; DPYD*13), rs56038477 (1236G>A; haplotype B3) and rs67376798 (2846A>T). Heterozygous DPYD variant allele carriers for rs3918290 and rs55886062 received an initial dose reduction of 50%. Heterozygous variant allele carriers for rs56038477 and rs67376798 received an initial dose reduction of 25%, since these variants result in moderately reduced DPYD activity. Wild-type patients were treated according to the current standard of care, and homozygous or compound heterozygous variant allele carriers were excluded.
Results showed that the genotype-guided dosing reduced the risk of severe fluoropyrimidine-related toxicity in patients carrying the rs3918290, rs55886062 and rs67376798 variants, though patients carrying the rs67376798 variant still had an increased risk for toxicity compared with wild-type patients. Carriers of the rs56038477 variant did not have a reduction in severe toxicity. The authors concluded that a dose reduction of 25% in patients with rs56038477 and rs67376798 variants was not sufficient to lower the risk of severe toxicity, and suggested that a larger dose reduction may be required.
Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for DPYD genotype-guided fluoropyrimidine dosing recommend a dose reduction of 50% in heterozygous carriers of the rs3918290 and rs55886062 variants. However, they do not recommend an exact dose reduction for heterozygous carriers of the rs56038477 and rs67376798 variants, rather, they suggest a range of 25-50%. This lack of specificity was due to limited evidence for genotype-guided dosing of these variants. However, Amstutz and Largiadèr, in their accompanying commentary, suggest that the Henricks et al. study provides evidence to support a recommendation for a 50% dose reduction in all heterozygous variant allele carriers. Amstutz and Largiadèr also note that 8% of white patients carry one of these four variants, meaning that the benefits shown in this study affect a substantial proportion of patients treated with fluoropyrimidines.
Read the CPIC dosing guideline for DPYD and fluoropyrimidine dosing