Page 281 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

Compound heterozygous DPYD variant allele carriers
Introduction
Fluoropyrimidines (including 5-fluorouracil (5-FU) and capecitabine) are the cornerstone of treatment for various types of cancer, and are used by millions of patients worldwide each year.1-3 However, up to one-third of treated patients experience severe toxicity (common terminology criteria for adverse events (CTC-AE) grade ≥3), such as diarrhea, hand-foot syndrome or mucositis upon treatment with fluoropyrimidines.4,5 These adverse events can lead to mortality in approximately 1% of patients who experience severe toxicity.4,6 Dihydropyrimidine dehydrogenase (DPD) is the key enzyme in the metabolism of 5-FU and its decreased activity is strongly associated with toxicity.7,8 Variants in DPYD, the gene encoding DPD, can lead to decreased DPD enzyme activity.9-12 Prospective DPYD genotyping of four main DPYD variants followed by dose reductions in patients carrying any of these four DPYD variants is safe, cost-effective and feasible in clinical practice.13-15 These DPYD variants are DPYD*2A, rs3918290, c.1905+1G>A, IVS14+1G>A; DPYD*13, rs55886062, c.1679T>G, I560S; c.1236G>A/HapB3, rs56038477, E412E; and c.2846A>T, rs67376798, D949V. For these four variants, convincing evidence has been provided warranting implementation in clinical practice.4,5,12,15-17
An increasing number of hospitals apply prospective DPYD genotyping when treating patients with fluoropyrimidines.18 Individual dosing guidelines for the abovementioned four DPYD variants are provided by the Dutch Pharmacogenetics Working Group (DPWG) and the Clinical Pharmacogenetics Implementation Consortium (CPIC).19,20 Dosing guidelines are based on the expected remaining DPD enzyme activity and can be applied to patients who are heterozygous carriers of a single DPYD variant. For homozygous DPYD variant allele carriers (two identical variants) and compound heterozygous DPYD variant allele carriers (two or more different variants), dosing guidelines are not yet available (or treatment with an alternative drug is advised), although safe treatment with low-dose fluoropyrimidines in these homozygous DPYD patients was demonstrated by a recent case series.21
Patients who carry multiple variants (compound heterozygous) can carry the variants on a single allele (in cis) or on different alleles (in trans). In the first case, one functionally active allele remains, whereas in the latter case, both alleles are affected, which may result in a proportionally decreased enzyme activity (Figure 1). With currently used genotyping techniques, the allelic location of variants (phasing) cannot be determined. This uncertainty hampers adequate interpretation of the pharmacogenetic test result in compound heterozygous patients and makes it impossible to give an appropriate dose recommendation based on the genotype alone. Since it is likely that in the future, even more DPYD variants will be tested, the probability of finding compound heterozygous DPYD variant allele carriers will increase. The aims of this study are to examine diagnostic and therapeutic strategies for fluoropyrimidine treatment of patients carrying multiple DPYD variants and the frequency and phasing of variants of compound heterozygous DPYD patients in publicly available databases.
Methods
In this study, we present seven compound heterozygous DPYD variant allele carriers as clinical cases. In addition, we have performed in silico research in publicly available databases.
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