Individualized dosing of fluoropyrimidines by genotyping and phenotyping of dihydropyrimidine dehydrogenase

Abstract

The class of fluoropyrimidine anticancer drugs includes 5-fluorouracil and capecitabine. These drugs are used by an estimated two million patients yearly worldwide and are the cornerstone of chemotherapeutic treatment of several solid tumor types, including colorectal, breast, gastric and head- and neck cancer. While fluoropyrimidine drugs are highly valuable treatment options, fluoropyrimidine-related toxicity is a major clinical limitation. Around 10-30% of the patients develops severe toxicity, which is usually associated with interruption or discontinuation of potentially effective anticancer therapy, often requires hospitalization, and is even fatal in up to 1% of patients. Although fluoropyrimidines have been on the market for over sixty years, only in the last decades it has become clear that safety of patients treated with fluoropyrimidines is strongly affected by inter-individual variability in the dihydropyrimidine dehydrogenase (DPD) enzyme, the main metabolic enzyme of fluoropyrimidines. DPD activity varies widely between patients, with an estimated 3 to 8% of the population having reduced DPD activity. DPD deficiency results in an increased risk of severe treatment-related toxicity when treated with a full dose of the fluoropyrimidine drug. DPD deficiency is often the result of genetic polymorphisms in DPYD, the gene encoding DPD. Currently there are four DPYD variants considered to be clinically relevant (DPYD*2A, c.1679T>G, c.2846A>T and c.1236G>A). Prospective screening and dose reductions in carriers of these DPYD variants is considered to be a useful strategy to improve patient safety. However, not all variation in DPD enzyme activity can be explained by one of these four DPYD variants, and therefore not all toxicity can be prevented by DPYD genotyping. Therefore, other methods to identify patients at risk of severe fluoropyrimidine-related toxicity are being investigated, mostly focusing on DPD phenotyping. The thesis of Linda Henricks describes several studies investigating DPYD genotyping and DPD phenotyping with the aim to improve patient safety of fluoropyrimidine-based chemotherapy. Despite the wealth of available evidence, DPYD genotype-guided dosing has not been implemented universally as routine clinical care. We advocate that prospective DPYD genotyping should become standard of care worldwide. Our large prospective study in 17 hospitals in the Netherlands, in which 1100 patients were included, showed that DPYD genotype-guided dosing for four DPYD variants improves patient safety and is cost-saving.