Page 15 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

variants. In addition, we discuss the advantages and disadvantages of DPYD genotyping.43 In 1 chapter 3, literature is extensively checked to discuss the effect of four DPYD variants on DPD enzyme activity. This is converted into a gene activity score for each DPYD variant, which will
be used in PGx guidelines to translate the DPYD genotype into a DPD phenotype.44 Chapter
4 contains the Dutch Pharmacogenetics Working Group (DPWG) PGx guideline for DPYD and fluoropyrimidines. The guideline provides a dose reduction advice for heterozygous DPYD variant allele carriers of DPYD*2A, DPYD*13, c.2846A>T and c.1236G>A. In addition, a statement is made that DPYD genotyping should be performed for all patients prior to treatment with fluoropyrimidines, as the clinical implication score for DPYD is essential. Then, in chapter 5, DPYD genotyping is applied prospectively in a nationwide clinical trial.45 Patients with an intention to treatment with fluoropyrimidines are genotyped for DPYD*2A, DPYD*13, c.2846A>T and c.1236G>A. Heterozygous carriers are treated with an initially reduced dose of fluoropyrimidines according to the DPWG PGx guidelines at the start of the study. The goal of the study is to show that DPYD genotyping improves patient safety. In chapter 6 we show a cost analysis of prospective DPYD genotyping of four DPYD variants.46 In chapter 7, we look into severe toxicity in patients who receive fluoropyrimidines as part of chemoradiation therapy.47 Fluoropyrimidine dosages in chemoradiation therapy are substantially lower compared to fluoropyrimidine dosages in other treatment regimens. Current PGx guidelines do not distinguish fluoropyrimidine dosing recommendations between treatment regimens. Therefore, in this chapter we compare severe toxicity between wild-type patients and DPYD variant allele carriers, either treated with standard or reduced fluoropyrimidine dosages, who receive chemoradiation therapy. In chapter 8, the first 21 months of implementation of DPYD genotyping at Leiden University Medical Center is evaluated, to study the feasibility of DPYD genotyping in daily clinical care.48 Clinical acceptance of DPYD genotyping as well as adherence to the genotyping results are the main objectives of this study. In chapter 9 we look into the aspect of quality control of genotyping in the laboratory, in specific confirmation practice.49 We use DPYD genotyping as an example. We discuss if it should be required to have two independent genotyping assays to correctly determine a genotype. Implementation of DPYD genotyping in clinical practice can improve if there is consensus on laboratory requirements.
In the first part of this thesis we describe how to reduce severe fluoropyrimidine-induced toxicity by DPYD genotyping of DPYD*2A, DPYD*13, c.2846A>T and c.1236G>A. Yet, is it known that not all severe fluoropyrimidine-induced toxicity can be predicted using DPYD genotyping of these four variants. Therefore, we investigate other options, beyond genotyping of the current four DPYD variants, to reduce severe fluoropyrimidine-induced toxicity. This is shown in the second part of this thesis, entitled “beyond current DPYD pharmacogenetics”.
In chapter 10 we investigate four DPD phenotyping assays. The goal of the study is to determine the clinical value of each DPD phenotyping assay, by assessing clinical validity parameters (e.g. sensitivity and specificity) for DPD deficiency and the onset of severe fluoropyrimidine-induced toxicity. In the following chapters, we focus on future application of genetics. In chapter 11 we investigate a special group of DPYD variant allele carriers, i.e.
General introduction
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