Capecitabine is an oral
prodrug of
5-fluorouracil with a relevant role in the treatment of
breast cancer. Severe and unexpected toxicities related to
capecitabine are not rare, and the identification of
biomarkers is challenging. We evaluate the relationship between
dihydropyrimidine dehydrogenase,
thymidylate synthase enhancer region and
methylenetetrahydrofolate reductase polymorphisms,
5-fluorouracil degradation rate and the onset of G3-4 toxicities in
breast cancer patients. Genetic polymorphisms and the
5-fluorouracil degradation rate of
breast cancer patients treated with
capecitabine were retrospectively studied.
Genetic markers and the
5-fluorouracil degradation rate were correlated with the reported toxicities. Thirty-seven patients with a median age of 58 years old treated with
capecitabine for stages II-IV
breast cancer were included in this study. Overall, 34 (91.9%) patients suffered from at least an episode of any grade toxicity while nine patients had G3-4 toxicity. Homozygous
methylenetetrahydrofolate reductase 677TT was found to be significantly related to haematological toxicity (OR = 6.5 [95% IC 1.1-37.5], P = 0.04). Three patients had a degradation rate less than 0.86 ng/mL/106 cells/min and three patients greater than 2.1 ng/mL/106 cells/min. At a univariate logistic regression analysis, an altered value of
5-fluorouracil degradation rate (values < 0.86 or >2.10 ng/mL/106 cells/min) increased the risk of G3-4 adverse events (OR = 10.40 [95% IC: 1.48-7.99], P = 0.02). A multivariate logistic regression analysis, adjusted for age, comorbidity and CAPE-regimen, confirmed the role of
5-fluorouracil degradation rate as a predictor of G3-4 toxicity occurrence (OR = 10.9 [95% IC 1.2-96.2], P = 0.03). The pre-treatment evaluation of
5-fluorouracil degradation rate allows to identify
breast cancer patients at high risk for severe
5-FU toxicity.