Page 44 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

Chapter 3
Previous guidelines and recommendations
According to the US FDA and EMA capecitabine and 5-FU are contraindicated in patients with a known DPD deficiency.17,18 However, no recommendations are given for upfront screening for DPD deficiency and no distinction is made between heterozygous or homozygous DPD- deficient patients. Also the American Society of Clinical Oncology, European Society for Medical Oncology and National Comprehensive Cancer Network do not state any genotyping guidelines or recommendations prior to fluoropyrimidine treatment. In the guideline of the Clinical Pharmacogenetics Implementation Consortium (CPIC, a network that provides guidelines on the translation of genetic laboratory tests into actionable prescribing decisions) patients heterozygous for DPYD*2A, DPYD*13 or c.2846A>T are considered to have intermediate or partial DPD enzyme activity and recommended for these patients is an initial dose reduction of at least 50% (no dosing recommendations are given for other SNPs, including c.1236G>A, because evidence on these variants was considered weak or conflicting).19 Also the Pharmacogenetics Working Group of the Royal Dutch Society for the Advancement of Pharmacy (KNMP) has provided guidelines. They recently updated their online guidelines for dose adjustments for fluoropyrimidines from a 50% dose reduction for heterozygous carriers to more specified dose reductions of 25 or 50% in heterozygous carriers of a SNP in DPYD (depending on the specific SNP), and 50, 75 or 100% in patients carrying more than one SNP in DPYD.20,21 We consider the dosing guidance of the CPIC and KNMP very useful and would like to add the gene activity score to these guidelines. With the gene activity score we can facilitate in a more specific dose adjustment in fluoropyrimidine treatment using current knowledge on differences in DPD enzyme activity due to DPYD variants.
Known DPYD alleles and their effect on DPD enzyme activity
DPYD*2A (rs3918290)
DPYD*2A is the most widely studied polymorphism in DPYD. The SNP was first described by Vreken et al. in a case series of two unrelated patients.22 and McLeod et al. named it DPYD*2A in an article in which the nomenclature for a series of DPYD SNPs was defined.23 Allele frequencies of DPYD*2A have been reported to vary between ∼0.1 and 1.0% in African-American and Caucasian populations, respectively.13,19,24,25 DPYD*2A leads to skipping of the entire exon 14 and deletion of 165 base pairs which results in a truncated protein that is catalytically inactive.22,26 This was recently confirmed in a study by Offer et al. where in an in vitro model of DPD activity several DPYD variants were homozygously expressed in mammalian cells and the enzymatic activity of expressed protein was completely absent.27 This indicates that in heterozygous carriers of this variant, who have one dysfunctional allele and one functional allele, ∼50% of the normal DPD enzyme activity will remain. Furthermore, a correlation between the DPYD*2A variant and reduced enzyme activity in peripheral blood mononuclear cells (PBMCs) was found in several ex vivo studies that confirmed decreased function of DPYD*2A26,28-30 and consequently an association was also found between DPYD*2A and reduction in fluoropyrimidine clearance in patients.31,32 In numerous studies an association between DPYD*2A allele carriership and the increased risk of toxicity related to fluoropyrimidine treatment was confirmed.4,24,31,33-45 For example,
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