Issues and limitations of available biomarkers for fluoropyrimidine-based chemotherapy toxicity, a narrative review of the literature

Abstract

Fluoropyrimidine-based chemotherapies are widely used to treat gastrointestinal tract, head and neck, and breast carcinomas. Severe toxicities mostly impact rapidly dividing cell lines and can occur due to the partial or complete deficiency in dihydropyrimidine dehydrogenase (DPD) catabolism. Since April 2020, the European Medicines Agency (EMA) recommends DPD testing before any fluoropyrimidine-based treatment. Currently, different assays are used to predict DPD deficiency; the two main approaches consist of either phenotyping the enzyme activity (directly or indirectly) or genotyping the four main deficiency-related polymorphisms associated with 5-fluorouracil (5-FU) toxicity. In this review, we focused on the advantages and limitations of these diagnostic methods: direct phenotyping by evaluation of peripheral mononuclear cell DPD activity (PBMC-DPD activity), indirect phenotyping assessed by uracil levels or UH2/U ratio, and genotyping DPD of four variants directly associated with 5-FU toxicity. The risk of 5-FU toxicity increases with uracil concentration. Having a pyrimidine-related structure, 5-FU is catabolised by the same physiological pathway. By assessing uracil concentration in plasma, indirect phenotyping of DPD is then measured. With this approach, in France, a decreased 5-FU dose is systematically recommended at a uracil concentration of 16 ng/ml, which may lead to chemotherapy under-exposure as uracil concentration is a continuous variable and the association between uracil levels and DPD activity is not clear. We aim herein to describe the different available strategies developed to improve fluoropyrimidine-based chemotherapy safety, how they are implemented in routine clinical practice, and the possible relationship with inefficacy mechanisms.

Keywords: 5-FU; dihydropyrimidine dehydrogenase; genotype; phenotype; toxicity; uracil.

Figure 1

5-FU mechanisms of action and pyrimidine metabolism. 5-FU is converted to FdUMP which inhibits the enzyme thymidylate synthase (TS). Other cytotoxic mechanisms of action of 5-FU include the conversion of FUDP and FdUDP to FUTP and FdUTP that are incorporated into RNA and DNA, respectively. All this mechanism overwhelms DNA repair mechanisms and eventually leads to cell death. 5-FU catabolism consists of three consecutive steps. Firstly, 5-FU is catalysed to 5,6 dihydrofluorouracil (DHFU) by the dihydropyrimidine dehydrogenase (DPD). Secondly, DHFU is catalysed to fluoro B-ureidopropionate by dihydropyrimidinase. And then fluoro B-ureidopropionate is catalysed to fluoro B-alanine by the ureidopropionase. 5-FU, 5-flourouracil; CMP, cytidine monophosphate; CTP, cytidine triphosphate; DHU, dihydrouracil; dTMP, deoxythymidine monophosphate; dUMP, deoxyuridine monophosphate; FdUDP, fluorodeoxyuridine diphosphate; FdUMP, fluorodeoxyuridine monophosphate; FdUTP, fluorodeoxyuridine triphosphate; FUDP, fluorouridine diphosphate; FUDR, fluorodeoxyuridine; FUMP, fluorouridine monophosphate; FUTP, fluorouridine triphosphate; UMP, uridine monophosphate; UTP, uridine triphosphate.

Figure 2

Impact of exogenous factor on 5-FU metabolism. Leucovorin (LV) treatment and uridine metabolism are presented in two mechanisms of 5-FU action. The FdUMP, TS, and 5,10, methylene-THF ternary complex is stabilised by the administration of LV (A). Administration of uridine lowers UMP catabolisation; higher amounts of UMP, UDP, and UTP facilitate UTP on FUTP RNA incorporation (B). FdUMP, 5-fluoro-deoxyuridine monophosphate; FUTP, fluorouridine triphosphate; TS, thymidylate synthase; UMP, uridine monophosphate; UDP, uridine diphosphate; UTP, uridine triphosphate.