title: Correlation of cytidine deaminase polymorphisms and activity with clinical outcome in gemcitabine-/platinum-treated advanced non-small-cell lung cancer patients.
abstract: BACKGROUND
  The aim of this study was to evaluate whether cytidine deaminase (CDA) polymorphisms 79A>C and 435C>T and/or CDA enzymatic activity influenced clinical outcome in 126 advanced non-small-cell lung cancer patients treated with gemcitabine-platinum-regimens.
  
  
  METHODS
  CDA polymorphisms and activity were analysed by PCR and high-performance liquid chromatography, respectively. Univariate and multivariate analyses compared biological/clinical parameters with response, clinical benefit, time to progression (TtP) and overall survival (OS) using Pearson's χ(2) test, log-rank test and Cox proportional hazards model.
  
  
  RESULTS
  Patients with CDA A79A/A79C genotypes had significantly longer TtP (6.0 versus 3.0 months; P = 0.001) and OS (11.0 versus 5.0 months; P = 0.001) than patients with C79C genotype. Patients harbouring CDA C435C/C435T genotypes also had a longer OS (P = 0.025), but no correlations were observed with TtP. Conversely, patients with low-CDA activity had a significantly higher response rate (37.7% versus 13.8%; P = 0.006), clinical benefit (91.8% versus 51.7%; P < 0.001), as well as longer TtP (8.0 versus 3.0 months; P < 0.001) and OS (19.0 versus 6.0 months; P < 0.001). Furthermore, enzymatic activity emerged as an independent predictor for death/progression risk at multivariate analysis.
  
  
  CONCLUSIONS
  CDA enzymatic activity appears to be the strongest candidate biomarker of activity and efficacy of platinum-gemcitabine-based chemotherapy and should be validated in a prospective study.
authors.affiliation: Division of Oncology, Department of Oncology, Azienda USL-6 of Livorno, Livorno, Italy. Electronic address: tiby@katamail.com.
authors.forename: C
authors.initials: C
authors.lastname: Tibaldi
authors.affiliation: Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: E
authors.initials: E
authors.lastname: Giovannetti
authors.affiliation: Division of Oncology, Department of Oncology, Azienda Ospedaliero-Universitaria of Parma, Parma, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Tiseo
authors.affiliation: Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: L G
authors.initials: LG
authors.lastname: Leon
authors.affiliation: Division of Oncology, Department of Oncology, Azienda USL-6 of Livorno, Livorno, Italy.
authors.forename: A
authors.initials: A
authors.lastname: D'Incecco
authors.affiliation: Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: N
authors.initials: N
authors.lastname: Loosekoot
authors.affiliation: Division of Oncology, Department of Oncology, Azienda Ospedaliero-Universitaria of Parma, Parma, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Bartolotti
authors.affiliation: Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: Honeywell
authors.affiliation: Division of Oncology, Department of Oncology, Azienda USL-6 of Livorno, Livorno, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Cappuzzo
authors.affiliation: Division of Oncology, Department of Oncology, Azienda Ospedaliero-Universitaria of Parma, Parma, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Ardizzoni
authors.affiliation: Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: G J
authors.initials: GJ
authors.lastname: Peters
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D019540:Area Under Curve; D014408:Biomarkers, Tumor / Q000032:analysis / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics*; D002851:Chromatography, High Pressure Liquid; D003564:Cytidine Deaminase / Q000235:genetics*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005838:Genotype; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics*; D009367:Neoplasm Staging; D017671:Platinum Compounds / Q000008:administration & dosage; D011110:Polymorphism, Genetic; D016016:Proportional Hazards Models; D012372:ROC Curve; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000093542:Gemcitabine
chemical_list: D014408:Biomarkers, Tumor; D017671:Platinum Compounds; D003841:Deoxycytidine; D003564:Cytidine Deaminase; D000093542:Gemcitabine