Evaluation of 5-fluorouracil degradation rate and Pharmacogenetic profiling to predict toxicity following adjuvant Capecitabine.

Abstract

On account of the lack of predictive biomarkers of toxicity, we investigated whether polymorphisms of genes involved in fluoropyrimidine metabolism and 5-fluorouracil (5-FU) degradation rate were associated with outcomes of adjuvant capecitabine in patients with early stage gastrointestinal cancers. Genotyping of DPYD GIVS14A, MTHFR C677T and A1298C SNPs were performed by pyro-sequencing technology. PCR analysis was used for genotyping TYMS-TSER. We also evaluated the 5-FU degradation rate, which determines the amount of drug consumed by PBMC in a time unit. Association of these variables with clinical outcome was evaluated using multivariate logistic regression analysis. One hundred forty-two patients with early stage colon (39%), rectal (28%), stomach (20%) and pancreatic (13%) cancer, treated with adjuvant capecitabine, were included in this retrospective analysis. Seventy and 20% of the patients suffered from at least one G1-4 and G3-4 adverse events, respectively. According to the 5-FU degradation rate, three and 13 patients were assigned as poor (<0.86ng/mL/106 cells/min) and ultra-rapid (>2.1ng/mL/106 cells/min) metabolizers, respectively. At a multivariate logistic regression analysis, an altered 5-FU degradation rate (values<0.86 or >2.10ng/mL/106 cells/min) was associated with grade 3-4 adverse events (OR=2.09, 95% CI: 1.14-3.82, P=0.01). No correlation was reported between toxicity and gene polymorphisms except for hand-foot syndrome that was more frequent in the MTHFR 1298CC homozygous variant genotype (OR=2.03, 95% CI 1.04-3.96, P=0.03). 5-FU degradation rate may be regarded as possible predictive biomarker of capecitabine toxicity in early stage gastrointestinal cancer.