Page 343 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

phenotyping assays in a patient cohort which was not selected based on –or enriched for– (severe) toxicity. The goal was 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. We could not show associations with DPD deficiency or the onset of severe fluoropyrimidine-induced toxicity. To determine the clinical value of DPD phenotyping assays additional research is required.
In chapter 11 we investigated a special subgroup of DPYD variant allele carriers, i.e. the compound heterozygous patients. These patients carry multiple DPYD variants and the effect of the DPYD variants on the DPD enzyme activity cannot be predicted using the gene activity score. Without dose reductions, these patients have an increased risk to develop severe toxicity. We describe seven cases and examine diagnostic and therapeutic strategies for fluoropyrimidine treatment of patients carrying multiple DPYD variants. The additional genotyping methods investigated in this study are still in early phases of development or currently too expensive to implement in clinical care, compared to a well-established DPD- phenotyping test. Therefore, we concluded to execute a phenotype test in these patients to determine a safe starting dose.
It is expected that other enzymes besides DPD, and thus other genes besides DPYD, are involved in the onset of severe fluoropyrimidine-induced toxicity. With the genome-wide approach in chapter 12 we aimed to discover other variants, mainly outside the DPYD gene, which are associated to the onset of severe fluoropyrimidine-induced toxicity. Approximately 700,000 single nucleotide polymorphisms (SNPs) in different genes were genotyped and imputed to over four million SNPs. We identified six variants suggestive of association to the onset of severe fluoropyrimidine-induced toxicity. In addition, we present an optimistic polygenic risk score analysis, suggesting highly polygenic nature of toxicity predisposition.
With the execution of the clinical trial described in chapter 5, an increasing number
of hospitals in the Netherlands applied DPYD genotyping prior to start of therapy. An increased uptake in implementation of DPYD genotyping was thus visible, especially in the Netherlands. Outside of the Netherlands, great differences exist in the uptake of DPYD genotyping, whether or not including DPD phenotyping. In some countries initiatives to implement prospective testing for DPD deficiency are effective, where in other countries
great differences in execution of tests exist between centres within that country. Uptake of
DPYD genotyping will benefit from clear guidelines, i.e. recommendations whom and when 14 to genotype, and dosing recommendations for DPYD variant allele carriers.
Currently four DPYD variants are included in the genotyping panel, yet it is known these four variants cannot predict all patients who will develop severe toxicity. It is likely other variants are associated to the onset of severe fluoropyrimidine-induced toxicity. To further improve the predictive power of the genotyping panel DPD phenotyping tests can be used, or novel variants can be added to the genotyping panel. Novel variants can be e.g. rare variants in the DPYD gene or variants in other genes.
The future of fluoropyrimidines
5-FU has been used to treat cancer for decades. Now, capecitabine is the preferred drug of use over 5-FU in various tumour types in several countries, including the Netherlands.
Summary
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