Page 14 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

Chapter 1
Personalised medicine
In order to prevent severe fluoropyrimidine-induced toxicity, interpatient differences must be overcome and treatments must be individualized (personalised medicine). As DPD is an important factor for the onset of severe fluoropyrimidine-induced toxicity, DPD deficient patients are an interesting target for personalised medicine. Yet, DPD deficient patients generally do not show specific phenotypic features and must be identified otherwise. One way to use personalised medicine, is through pharmacogenetics or pharmacogenomics (PGx). In PGx, the influence of human genetic variation in drug metabolic pathways or molecular drug targets on drug therapy response (both efficacy as toxicity) is studied.
DPD is encoded by the DPYD gene, which consists of 26 exons and is located on chromosome 1p21.3.29,30 Over 1,000 variants or single nucleotide polymorphisms (SNPs) are known in DPYD, some leading to altered DPD enzyme activity.31-33 A well-known example is the variant DPYD*2A, which is located at the intron downstream of exon 14. This point mutation at a splice donor site leads to skipping of exon 14 and results in a catalytically inactive enzyme.34
Heterozygous carriers of DPYD*2A are partially DPD deficient. Of four variants (DPYD*2A, rs3918290, c.1905+1G>A, IVS14+1G>A; DPYD*13, rs55886062, c.1679T>G, I560S; c.2846A>T, rs67376798, D949V; c.1236G>A/HapB3, rs56038477, E412E) sufficient evidence has been provided showing the association with severe fluoropyrimidine-induced toxicity.13,35-41 Other DPYD variants have been described, however evidence on the association with toxicity is limited or missing.
Previously, Deenen et al. have shown that prospective genotyping of DPYD*2A, followed by initial dose reductions in heterozygous carriers, resulted in a reduction of severe fluoropyrimidine-induced toxicity in these patients.42 In this study, 28% of the DPYD*2A variant allele carriers treated with reduced dosages experienced severe fluoropyrimidine- induced toxicity compared to 73% of DPYD*2A variant allele carriers treated with regular dosages in a historic cohort. The risk of toxicity for DPYD*2A variant allele carriers was reduced to the wild-type level of 23%. Efficacy of the treatment was not expected to be reduced, as exposure to active metabolites of 5-FU were similar in DPYD*2A variant allele carriers treated with a reduced dose and wild-types. In addition, the study showed that prospective screening was feasible and did not increase costs.
Over time, genotyping in general has become very attractive for routine diagnostics, with decreasing costs of the assays and better interpretation of the data. Yet, implementation of prospective DPYD genotyping remained limited for a substantial period, as evidence of its effectivity from a randomized clinical trial (RCT) was lacking.
Aim and outline of this thesis
The general aim of this thesis is to study how to further reduce severe fluoropyrimidine- induced toxicity, in addition to genotyping of DPYD*2A, while keeping aspects of implementation of any method in clinical practice in mind.
The first part of the thesis is entitled “DPYD genotyping: proof of principle and implementation in clinical practice”. In chapter 2 we present a review, in which we summarize the evidence on the association with severe fluoropyrimidine-induced toxicity for four DPYD
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