title: Evaluation of 5-fluorouracil degradation rate and Pharmacogenetic profiling to predict toxicity following adjuvant Capecitabine.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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 (<0.86 ng/mL/106cells/min) and ultra-rapid (>2.1 ng/mL/106cells/min) metabolizers, respectively. At a multivariate logistic regression analysis, an altered 5-FU degradation rate (values <0.86 or >2.10 ng/mL/106cells/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).
  
  
  CONCLUSIONS
  5-FU degradation rate may be regarded as possible predictive biomarker of capecitabine toxicity in early stage gastrointestinal cancer.
authors.affiliation: Clinical and Molecular Medicine Department, Sapienza University of Rome - Sant'Andrea Hospital, Via di Grottarossa 1035, 00189, Rome, Italy. Mikiroberto@hotmail.it.
authors.forename: Michela
authors.initials: M
authors.lastname: Roberto
authors.affiliation: Clinical and Molecular Medicine Department, Sapienza University of Rome - Sant'Andrea Hospital, Via di Grottarossa 1035, 00189, Rome, Italy.
authors.forename: Adriana
authors.initials: A
authors.lastname: Romiti
authors.affiliation: Clinical and Molecular Medicine Department, Sapienza University of Rome - Sant'Andrea Hospital, Via di Grottarossa 1035, 00189, Rome, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Botticelli
authors.affiliation: Clinical and Molecular Medicine Department, Sapienza University of Rome - Sant'Andrea Hospital, Via di Grottarossa 1035, 00189, Rome, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Mazzuca
authors.affiliation: Advanced Molecular Diagnostics Unit, Sant'Andrea Hospital, Rome, Italy.
authors.forename: Luana
authors.initials: L
authors.lastname: Lionetto
authors.affiliation: Advanced Molecular Diagnostics Unit, Sant'Andrea Hospital, Rome, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Gentile
authors.affiliation: Clinical and Molecular Medicine Department, Sapienza University of Rome - Sant'Andrea Hospital, Via di Grottarossa 1035, 00189, Rome, Italy.
authors.forename: Ida
authors.initials: I
authors.lastname: Paris
authors.affiliation: Clinical and Molecular Medicine Department, Sapienza University of Rome - Sant'Andrea Hospital, Via di Grottarossa 1035, 00189, Rome, Italy.
authors.forename: Rosa
authors.initials: R
authors.lastname: Falcone
authors.affiliation: Clinical and Molecular Medicine Department, Sapienza University of Rome - Sant'Andrea Hospital, Via di Grottarossa 1035, 00189, Rome, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Bassanelli
authors.affiliation: Clinical and Molecular Medicine Department, Sapienza University of Rome - Sant'Andrea Hospital, Via di Grottarossa 1035, 00189, Rome, Italy.
authors.forename: Francesca Romana
authors.initials: FR
authors.lastname: Di Pietro
authors.affiliation: Clinical and Molecular Medicine Department, Sapienza University of Rome - Sant'Andrea Hospital, Via di Grottarossa 1035, 00189, Rome, Italy.
authors.forename: Concetta Elisa
authors.initials: CE
authors.lastname: Onesti
authors.affiliation: Clinical and Molecular Medicine Department, Sapienza University of Rome - Sant'Andrea Hospital, Via di Grottarossa 1035, 00189, Rome, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Anselmi
authors.affiliation: Clinical and Molecular Medicine Department, Sapienza University of Rome - Sant'Andrea Hospital, Via di Grottarossa 1035, 00189, Rome, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Macrini
authors.affiliation: Advanced Molecular Diagnostics Unit, Sant'Andrea Hospital, Rome, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Simmaco
authors.affiliation: Clinical and Molecular Medicine Department, Sapienza University of Rome - Sant'Andrea Hospital, Via di Grottarossa 1035, 00189, Rome, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Marchetti
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D000069287:Capecitabine / Q000009:adverse effects / Q000627:therapeutic use; D017024:Chemotherapy, Adjuvant; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics; D005260:Female; D005472:Fluorouracil / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D005838:Genotype; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D013940:Thymidylate Synthase / Q000235:genetics
chemical_list: D000964:Antimetabolites, Antineoplastic; D000069287:Capecitabine; D042943:Dihydrouracil Dehydrogenase (NADP); C573423:MTHFR protein, human; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D013940:Thymidylate Synthase; D005472:Fluorouracil
keywords: Adjuvant capecitabine; Gene polymorphisms; Oral fluoropyrimidines; Personalized medicine; Predictive biomarkers; Toxicity