title: The TYMS-TSER polymorphism is associated with toxicity of low-dose capecitabine in patients with advanced gastrointestinal cancer.
abstract: Low doses of drugs delivered at close, regular intervals are increasingly being used to manage patients with different neoplasms. Despite the good tolerability, treatment-related adverse events still occur following metronomic protocols. The aim of this study was to retrospectively investigate whether polymorphisms of different genes involved in fluoropyrimidine metabolism and 5-fluorouracil (5-FU) degradation rate were associated with the outcome of a low-dose capecitabine schedule. Genotyping of DPYD IVS14+1 G>A, MTHFR C677T, and A1298C single-nucleotide polymorphisms was performed by pyrosequencing technology. A PCR technique was used for genotyping TYMS-TSER. Using peripheral blood mononuclear cells, we also evaluated the 5-FU degradation rate, which determines the net result of all the enzymatic transformation of 5-FU, in terms of the amount of drug consumed by the cells in a time unit. The association of these variables with clinical outcome was evaluated using multivariate logistic regression analysis. Eighty-four patients with metastatic gastrointestinal cancer, who had been treated with a low-dose fluoropyrimidine schedule, as a rescue therapy were included in the study. The TSER 2R/2R genotype was significantly associated with both hematologic (odds ratio=7.90, P=0.002) and gastrointestinal toxicity (odds ratio=3.24, P=0.009). Because DPYD IVS14 G>A single-nucleotide polymorphism was not observed in the cohort, it was excluded from the statistical analysis. No significant association was detected between clinical outcome and both MTHFR polymorphisms and the 5-FU degradation rate. In the advanced setting of cancer care, high attention should be paid toward avoiding toxicity and worsening of quality of life. Although metronomic chemotherapy is generally well tolerated, treatment toxicity nonetheless does occur. Our data suggest a possible role of the TSER 2R/2R polymorphism as a predictive marker of toxicity in patients treated with low-dose capecitabine.
authors.affiliation: aClinical and Molecular Medicine Department bAdvanced Molecular Diagnostics Unit cDepartment of Neurosciences, Mental Health and Sensory Organs, Sant'Andrea Hospital, Sapienza University dGenetic Epidemiology Unit, National Centre for Epidemiology, Surveillance and Health Promotion, National Institute of Health, Rome, Italy.
authors.forename: Adriana
authors.initials: A
authors.lastname: Romiti
authors.forename: Michela
authors.initials: M
authors.lastname: Roberto
authors.forename: Chiara
authors.initials: C
authors.lastname: D'Antonio
authors.forename: Concetta E
authors.initials: CE
authors.lastname: Onesti
authors.forename: Viola
authors.initials: V
authors.lastname: Barucca
authors.forename: Annalisa
authors.initials: A
authors.lastname: Milano
authors.forename: Giovanna
authors.initials: G
authors.lastname: Gentile
authors.forename: Luana
authors.initials: L
authors.lastname: Lionetto
authors.forename: Emanuela
authors.initials: E
authors.lastname: Medda
authors.forename: Federica
authors.initials: F
authors.lastname: Mazzuca
authors.forename: Andrea
authors.initials: A
authors.lastname: Botticelli
authors.forename: Rosa
authors.initials: R
authors.lastname: Falcone
authors.forename: Maurizio
authors.initials: M
authors.lastname: Simmaco
authors.forename: Paolo
authors.initials: P
authors.lastname: Marchetti
mesh_terms: D000069287:Capecitabine / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004742:Enhancer Elements, Genetic; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D006801:Humans; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D012189:Retrospective Studies; D013940:Thymidylate Synthase / Q000235:genetics*
chemical_list: D000069287:Capecitabine; C573423:MTHFR protein, human; D042965:Methylenetetrahydrofolate Reductase (NADPH2); C000600377:TYMS protein, human; D013940:Thymidylate Synthase