title: Correlation of CDA, ERCC1, and XPD polymorphisms with response and survival in gemcitabine/cisplatin-treated advanced non-small cell lung cancer patients.
abstract: OBJECTIVE
  Selecting patients according to key genetic characteristics may help to tailor chemotherapy and optimize the treatment in non-small cell lung cancer (NSCLC). Polymorphisms at the xeroderma pigmentosum group D (XPD), excision repair cross-complementing 1 (ERCC1), and cytidine deaminase (CDA) genes have been associated with alterations in enzymatic activity and may change sensitivity to the widely used cisplatin-gemcitabine regimen.
  
  
  METHODS
  Analyses of CDA, XPD, and ERCC1 polymorphisms were done on blood samples of 65 chemotherapy-naïve, advanced NSCLC patients treated with cisplatin-gemcitabine. Furthermore, CDA enzymatic activity was evaluated by high-performance liquid chromatography analysis. Association between XPD Asp(312)Asn and Lys(751)Gln, ERCC1 C118T, and CDA Lys(27)Gln polymorphisms and response, clinical benefit, toxicity, time to progression (TTP), and overall survival (OS) was estimated using Pearson's chi(2) tests, the Kaplan-Meier method, the log-rank test, and the Cox proportional hazards model.
  
  
  RESULTS
  The CDA Lys(27)Lys polymorphism significantly correlated with better clinical benefit (P = 0.04) and grade > or =3 neutropenia and thrombocytopenia, as well as with longer TTP and OS (P = 0.006 and P = 0.002, respectively), whereas no significant associations were found among ERCC1 and XPD polymorphisms and both response and clinical outcome. Finally, the enzymatic activity assay showed a significant lower mean in subjects harboring the CDA Lys(27)Lys polymorphism.
  
  
  CONCLUSIONS
  Our data suggested the role of CDA Lys(27)Lys polymorphism as a possible predictive marker of activity, toxicity, TTP, and OS in advanced NSCLC patients treated with cisplatin and gemcitabine. These results may be explained by the lower enzymatic activity associated with the Lys(27)Lys CDA and offer a potential new tool for treatment optimization.
authors.affiliation: Division of Oncology, Department of Oncology, Azienda USL-6 of Livorno, Livorno, Italy. tiby@katamail.com
authors.forename: Carmelo
authors.initials: C
authors.lastname: Tibaldi
authors.forename: Elisa
authors.initials: E
authors.lastname: Giovannetti
authors.forename: Enrico
authors.initials: E
authors.lastname: Vasile
authors.forename: Valentina
authors.initials: V
authors.lastname: Mey
authors.forename: Adrie C
authors.initials: AC
authors.lastname: Laan
authors.forename: Sara
authors.initials: S
authors.lastname: Nannizzi
authors.forename: Roberta
authors.initials: R
authors.lastname: Di Marsico
authors.forename: Andrea
authors.initials: A
authors.lastname: Antonuzzo
authors.forename: Cinzia
authors.initials: C
authors.lastname: Orlandini
authors.forename: Simona
authors.initials: S
authors.lastname: Ricciardi
authors.forename: Mario
authors.initials: M
authors.lastname: Del Tacca
authors.forename: Godefridus J
authors.initials: GJ
authors.lastname: Peters
authors.forename: Alfredo
authors.initials: A
authors.lastname: Falcone
authors.forename: Romano
authors.initials: R
authors.lastname: Danesi
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality*; D002945:Cisplatin / Q000008:administration & dosage; D003564:Cytidine Deaminase / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D018450:Disease Progression; D004720:Endonucleases / Q000235:genetics*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D012189:Retrospective Studies; D016019:Survival Analysis; D016896:Treatment Outcome; D051759:Xeroderma Pigmentosum Group D Protein / Q000235:genetics*; D000093542:Gemcitabine
chemical_list: D004268:DNA-Binding Proteins; D003841:Deoxycytidine; C071447:ERCC1 protein, human; D004720:Endonucleases; D003564:Cytidine Deaminase; D051759:Xeroderma Pigmentosum Group D Protein; D002945:Cisplatin; D000093542:Gemcitabine