Fluoropyrimidines (5-FU and capecitabine) are anticancer drugs commonly used in a range of cancers including oesophageal, gastric and colorectal cancers.  Their toxicity is unpredictable, leading to significant and sometimes life-threatening side effects.  Pharmacokinetics (steady state plasma level, area under the curve, etc.) varies between patients by a factor of 5-10, and this is also unpredictable.  Although therapeutic drug monitoring might allow better management of pharmacokinetic variability by rapid dose adjustment, it is labour-intensive and time-consuming.

Pharmacogenomics (the study of genes involved in drug metabolism and drug effect) has capacity for quicker and more precise prediction of toxicity outcomes and subsequent dose adjustment.  This has been the subject of research by our group and others over 2-3 decades.  The FU-SAFE consortium (managed from Institut Gustave Roussy, Villejuif, France) is a collaboration of 8 investigator groups including us, aimed at a meta-analysis of individual patient data across 8 separate studies done around the world addressing this issue.  Some genetic analysis needs to be completed and collated, and linked to toxicity data for all patients following which a formal statistically valid meta-analysis can be conducted.  The first meeting of the FU-SAFE consortium will occur in late June 2017.

Our study in Newcastle was undertaken between 2000-2006, and included 70 patients treated with 5-FU and leucovorin as adjuvant therapy for colon cancer. We collected detailed phenotypic data, clinical data and DNA, and published our initial analysis \.  We have recently undertaken a genetic analysis of DPYD polymorphisms (the gene encoding the main enzyme responsible for metabolism of 5-FU) and submitted this data to the FU-SAFE consortium together with all the clinical data.  What is required is a further analysis of blood samples for other SNP’s (single nucleotide polymorphisms) in DPYD, thorough cleaning of our Newcastle database, and confirmation that all data submitted to the meta-analysis is valid.  These funds will also support our participation in the meta-analysis process, including meetings, teleconferences, time spent, etc.

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