<i>DPYD*7</i> as a Predictor of Severe Fluoropyrimidine-Related Adverse Events.

Abstract

Around 20%-30% of patients treated with fluoropyrimidines develop severe treatment-related adverse events (AEs). These are mainly caused by deficiency of dihydropyrimidine dehydrogenase, its main metabolizing enzyme. The <i>DPYD</i>*7 variant allele contains a frameshift mutation that leads to absence of dihydropyrimidine dehydrogenase. Clinical studies on this variant in patients treated with fluoropyrimidines are lacking because of its low minor allelic frequency. However, the <i>DPYD</i>*7 minor allelic frequency is 56-times higher in the Dutch compared with the global population. This allowed us to evaluate fluoropyrimidine tolerability in <i>DPYD</i>*7 variant allele carriers. Patients treated with standard-of-care fluoropyrimidine who were pretreatment <i>DPYD</i> genotyped for <i>DPYD*2A</i>, <i>*13</i>, <i>2846A>T</i>, and <i>1236G>A</i> single-nucleotide polymorphisms were included for analyses. Patients were additionally screened for the <i>DPYD</i>*7 allele (rs72549309, 295-298delTCAT). AEs were graded if they worsened from baseline, according to Common Terminology Criteria for Adverse Events version 5.0. AEs ≥ grade 3 were considered severe. From 3,748 patients, we found 13 patients carrying heterozygous <i>DPYD*7</i>. Relevant clinical data were available for 11 patients. All patients developed fluoropyrimidine-related AEs, of which five patients developed severe AEs (46%). From these five patients, three patients were started with 65% or 50% of standard dose, but apparently still developed severe toxicity. Because of severe AEs, three patients discontinued treatment prematurely (one patient already started with 50% of standard dose) and one patient who started with 50% of standard dose was further reduced to 35% of standard dose. In this study, the clinical consequences of carrying the <i>DPYD</i>*7 variant allele were confirmed as 46% of the patients developed severe AEs, even in the presence of initial dose reductions. This underlines the need for prospective studies investigating the required fluoropyrimidine dose for <i>DPYD</i>*7 carriers.