PHARMACOGENOMICS OF 5FU TREATMENT 

Br J Cancer. 2013 Jun 4. doi: 10.1038/bjc.2013.262. [Epub ahead of print]

Pharmacogenetic variants in the DPYD, TYMS, CDA and MTHFR genes are clinically significant predictors of fluoropyrimidine toxicity.

Loganayagam A, Arenas Hernandez M, Corrigan A, Fairbanks L, Lewis CM, Harper P, Maisey N, Ross P, Sanderson JD, Marinaki AM.

Source

Department of Gastroenterology, Guy's and St Thomas' Hospital NHS Foundation Trust, College House, St Thomas' Hospital, London SE1 7EH, UK.

Abstract

Background:Fluoropyrimidine drugs are extensively used for the treatment of solid cancers. However, adverse drug reactions are a major clinical problem, often necessitating treatment discontinuation. The aim of this study was to identify pharmacogenetic markers predicting fluoropyrimidine toxicity.Methods:Toxicity in the first four cycles of 5-fluorouracil or capecitabine-based chemotherapy were recorded for a series of 430 patients. The association between demographic variables, DPYD, DPYS, TYMS, MTHFR, CDA genotypes, and toxicity were analysed using logistic regression models.Results:Four DPYD sequence variants (c.1905+1G>A, c.2846A>T, c.1601G>A and c.1679T>G) were found in 6% of the cohort and were significantly associated with grade 3-4 toxicity (P<0 .0001="" 1.38-6.87="" 10="" 3="" 95="" a="" c.1298cc="" capecitabine="" confidence="" del="" for="" genotype="" hand-foot="" homozygous="" increased="" interval="" mthfr="" odds="" of="" patients="" predicted="" ratio="" region="" risk="" severe="" style="font-size: 0.8461em; line-height: 1.6363em; position: relative; top: -0.5em; vertical-align: baseline;" substantially="" sup="" syndrome="" the="" toxicity="" treated="" tyms="" untranslated="" variant="" with="">-6

, OR=9.99, 95% CI: 3.84-27.8). The linked CDA c.-92A>G and CDA c.-451C>T variants predicted grade 2-4 diarrhoea (P=0.0055, OR=2.3, 95% CI: 1.3-4.2 and P=0.0082, OR=2.3, 95% CI: 1.3-4.2, respectively).Conclusion:We have identified a panel of clinically useful pharmacogenetic markers predicting toxicity to fluoropyrimidine therapy. Dose reduction should be considered in patients carrying these sequence variants.British Journal of Cancer advance online publication, 4 June 2013; doi:10.1038/bjc.2013.262 www.bjcancer.com.