Wednesday, October 24, 2018

DPYD genotyping implementation study published

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. 

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Read the CPIC dosing guideline for DPYD and fluoropyrimidine dosing
Read the DPWG dosing guidelines for fluorouracil and capecitabine
Read the PharmGKB annotations of the CPIC dosing guideline for fluorouracil and capecitabine
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