Page 341 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

Fluoropyrimidines, such as 5-fluorouracil (5-FU) and its oral pro-drug capecitabine, are widely used anti-cancer drugs in the treatment of several tumour types. Despite ample experience with these drugs, severe adverse drug reactions occur in up to 30% of patients treated with fluoropyrimidines. Over 80% of 5-FU is inactivated by the enzyme dihydropyrimidine dehydrogenase (DPD), which is encoded by the gene DPYD. Because of this, DPD plays an important role in the development of adverse drug reactions, mentioned here as toxicity. To prevent severe fluoropyrimidine-induced toxicity, it is important to identify patients who have an increased risk of toxicity and treat them in a personalised way. In other words, it is important to identify patients with a deficient DPD enzyme and treat them with reduced fluoropyrimidine dosages. Research has been executed on DPD deficiency, or variants in the DPYD gene, and the association with severe fluoropyrimidine-induced toxicity. This thesis focusses on reducing the risk of severe fluoropyrimidine-induced toxicity by optimising DPYD genotyping and improving implementation of DPYD genotyping in daily clinical care. In addition, we investigated DPD phenotyping and innovative genotyping techniques beyond current DPYD pharmacogenetics (PGx) to prevent severe fluoropyrimidine-induced toxicity.
DPYD genotyping: proof of principle and implementation in clinical practice
Despite substantial evidence on the association between DPYD variants and the onset of
severe fluoropyrimidine-induced toxicity, implementation of prospective DPYD genotyping
in clinical practice remained limited. Therefore, an opinion review was written (chapter
2). In this review we summarize the available evidence on the association with severe fluoropyrimidine-induced toxicity for four variants in the DPYD gene. We discuss several advantages and disadvantages of DPYD genotyping. We substantiate why arguments
against genotyping are unfounded and advocate implementation of prospective DPYD genotyping. In chapter 3 literature was extensively checked to discuss the functional effect
of four DPYD variants on the DPD enzyme activity. This is converted into a gene activity
score for each DPYD variant, which represents an expected remaining DPD enzyme activity,
and which will be used in PGx guidelines to translate the DPYD genotype into a DPD phenotype. PGx guidelines by the Dutch Pharmacogenetics Working Group (DPWG) of the
Royal Dutch Pharmacists Association (KNMP) were already present in the Netherlands for
DPYD and fluoropyrimidines. This guideline is made available outside of the KNMP network
in the Netherlands in chapter 4, and provides a dose reduction advice for heterozygous 14 DPYD variant allele carriers of the following four DPYD variants: DPYD*2A, rs3918290, c.1905+1G>A, IVS14+1G>A; DPYD*13, c.1679T>G, rs55886062, I560S; c.1236G>A/HapB3, rs56038477, E412E; and c.2846A>T, rs67376798, D949V. In addition to dosing guidelines,
the DPWG also described an implication score in which DPYD genotyping is considered ‘essential’, directing DPYD genotyping prior to treatment with fluoropyrimidines.
DPYD genotyping was applied prospectively in a nationwide clinical trial in chapter 5. Patients with an intention to treatment with fluoropyrimidines were genotyped for DPYD*2A, DPYD*13, c.2846A>T and c.1236G>A. Heterozygous carriers of a DPYD variant were treated with an initially reduced dose of fluoropyrimidine according to the DPWG PGx guidelines at the start of the study. This study showed that prospective DPYD genotyping followed by individualised dose adjustments improved patient safety by reducing the risk
Summary
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