Diagnostic and Therapeutic Strategies for Fluoropyrimidine Treatment of Patients Carrying Multiple DPYD Variants.

Carin A T C Lunenburg,Ron H J Mathijssen,Jesse J Swen,André B P Van Kuilenburg,Jan H M Schellens,Hans Gelderblom,Linda M Henricks,Henk-Jan Guchelaar

doi:10.3390/genes9120585

Abstract

DPYD genotyping prior to fluoropyrimidine treatment is increasingly implemented in clinical care. Without phasing information (i.e., allelic location of variants), current genotype-based dosing guidelines cannot be applied to patients carrying multiple DPYD variants. The primary aim of this study is to examine diagnostic and therapeutic strategies for fluoropyrimidine treatment of patients carrying multiple DPYD variants. A case series of patients carrying multiple DPYD variants is presented. Different genotyping techniques were used to determine phasing information. Phenotyping was performed by dihydropyrimidine dehydrogenase (DPD) enzyme activity measurements. Publicly available databases were queried to explore the frequency and phasing of variants of patients carrying multiple DPYD variants. Four out of seven patients carrying multiple DPYD variants received a full dose of fluoropyrimidines and experienced severe toxicity. Phasing information could be retrieved for four patients. In three patients, variants were located on two different alleles, i.e., in trans. Recommended dose reductions based on the phased genotype differed from the phenotype-derived dose reductions in three out of four cases. Data from publicly available databases show that the frequency of patients carrying multiple DPYD variants is low (< 0.2%), but higher than the frequency of the commonly tested DPYD*13 variant (0.1%). Patients carrying multiple DPYD variants are at high risk of developing severe toxicity. Additional analyses are required to determine the correct dose of fluoropyrimidine treatment. In patients carrying multiple DPYD variants, we recommend that a DPD phenotyping assay be carried out to determine a safe starting dose.

Highlights

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 [1,2,3].Genes 2018, 9, 585; doi:10.3390/genes9120585 www.mdpi.com/journal/genesup 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]
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 [13,14,15]
We present seven compounds heterozygous DPYD variant allele carriers as clinical cases

Summary

Introduction

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%. 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 [9,10,11,12]. 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 [13,14,15]

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