Is It Finally Time for a Personalized Medicine Approach for Fluorouracil-Based Therapies?

Abstract

At present, implementation of pretreatment genotypic tests to individualize fluorouracil (5-FU)-based chemotherapy is limited despite a wealth of evidence demonstrating that individuals who carry certain variants of the dihydropyrimidine dehydrogenase (DPD) gene (DPYD) are at significantly greater risk of experiencing severe and potentially lethal adverse toxicity (grade $ 3) when receiving treatment with standard dosages of 5-FU. The DPYD *2A variant—also known as rs3918290, NM_000110.3:c.190511G.A, and DPYD: IVS14_1G.A—has been reproducibly shown to result in a catalytic inactive form of DPD using a variety of methods, including the study of patient-derived clinical specimens 1 and through direct invitro study of the variant form of the protein. 2 Despite strong evidence linking this varianttotoxicity,andthemountingevidencelinkingadditionalDPYD variants to toxicity, the US Food and Drug Administration and the European Medicines Agency do not currently require pharmacogenomics testing before 5-FU administration. 3 Both agencies, however, do recommend the use of alternative drugs in individuals with known DPD deficiency. Scientific groups, such as the Clinical Pharmacogenetics Implementation Consortium and the Dutch Pharmacogenetics Working Group, provide regularly updated gene and drug clinical practice guidelines to help to translate research results into actionable treatment decisions for various drugs, including 5-FU, on the basis of peer-reviewed pharmacogenetic information. 4-6 Much of the information from these groups is disseminated by the Pharmacogenomics Knowledgebase, an actively updated, online resource for dosing guidelines, drug labels, and potentially actionable gene-drug and genotype-phenotype relationships. 7 However, it should be noted that the goal of these groups and online tools is not to direct which tests should be ordered, but, rather, to assist with the integration of test results into the decision-making process.