DPYD genotype-guided dose individualization to improve patient safety of fluoropyrimidine therapy: call for a drug label update

Abstract

The fluoropyrimidine anticancer drugs, especially 5-fluorouracil (5-FU) and capecitabine, are frequently prescribed for several types of cancer, including breast, colorectal, head and neck and gastric cancer. In the current drug labels of 5-FU and capecitabine in the European Union and the United States, no adaptive dosing strategies are incorporated for polymorphic metabolism of 5-FU. Although treatment with fluoropyrimidines is generally well tolerated, a major clinical limitation is that a proportion of the treated population experiences severe, sometimes life-threatening, fluoropyrimidine-related toxicity. This toxicity is strongly affected by interindividual variability in activity of dihydropyrimidine dehydrogenase (DPD), the main metabolic enzyme for inactivation of fluoropyrimidines, with an estimated 3%-8% of the population being partially DPD deficient. A reduced functional or abrogated DPD enzyme is often caused by genetic polymorphisms in DPYD, the gene encoding for DPD, and heterozygous carriers of such DPYD polymorphisms have a partial DPD deficiency. When these partially DPD deficient patients are treated with a full dose of fluoropyrimidines, they are generally exposed to toxic levels of 5-FU and its metabolites, and the risk of developing severe treatment-related toxicity is therefore significantly increased.Currently, functional and clinical validity is well established for four DPYD variants (DPYD*2A, c.2846A>T, c.1679T>G and c.1236G>A), as those variants have retrospectively and in a large population study prospectively been shown to be associated with increased risk of fluoropyrimidine-associated toxicity. Patient safety of fluoropyrimidine treatment can be significantly improved by pre-emptive screening for DPYD genotype variants and dose reductions in heterozygous DPYD variant allele carriers, thereby normalizing 5-FU exposure. Based on the critical appraisal of currently available data, adjusting the labels of capecitabine and 5-FU by including recommendations on pre-emptive screening for DPYD variants and DPYD genotype-guided dose adjustments should be the new standard of care.

Influence of DPYD*9A, DPYD*6 and GSTP1 ile105val Genetic Polymorphisms on Capecitabine and Oxaliplatin (CAPOX) Associated Toxicities in Colorectal Cancer (CRC) Patients

“…(Toffoli et al, 2015;Deenen et al, 2016) However, the major limitation of DPYD*2A of being used as a predictive marker for toxicity is its lower minor allele frequency varying from 0.1 % to 1% in different ethnic groups. (Henricks et al, 2017) A recent study states that only a 50 % patients with DPYD*2A carriers actually develop toxicity with 5-FU treatment and reported that novel DPYD variants, DPYD*9 and DPYD*6 carry 2 fold higher risk for toxicities with 5 -FU treatment when compared to DPYD*2A polymorphism alone (Gentile et al, 2016). This emphasizes the search for novel genetic toxicity predictive markers for capecitabine treatment.…”

A Novel DPYD Variant Associated With Severe Toxicity of Fluoropyrimidines: Role of Pre-emptive DPYD Genotype Screening

“…Current evidence supports upfront DPYD screening for four DPYD variants ( DPYD * 2A, c.2846A>T, c.1679T>G, and c.1236G>A), followed by genotype-guided dosing, based on dosing recommendations by the CPIC. This clinical utility has been confirmed by two recent large-scale studies ( 20 , 21 ) and drug label update has been called ( 22 ).…”

Polymorphisms of xenobiotic-metabolizing and transporter genes and the risk of gastric and colorectal cancer in an admixed population of Brazil.

“…Additionally, the rs17116806 has been also associated to an increased susceptibility to colorectal carcinogenesis, demonstrating that the same polymorphism can act on tumorigenesis in different tissues. International regulatory agencies, such as the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA), strongly recommend the monitoring of polymorphisms on the DPYD gene for evaluation of therapeutic response in fluoropyrimidine-based treatment [29] [30]. Nevertheless, few investigations have studied genetic variations in the DPYD gene regarding cancer susceptibility, thus, the variety of clinical manifestations resulting by mutations in DPYD is still not well understood [31].…”