title: Cross-validation study of class III beta-tubulin as a predictive marker for benefit from adjuvant chemotherapy in resected non-small-cell lung cancer: analysis of four randomized trials.
abstract: BACKGROUND
  The IALT, JBR.10, ANITA and Cancer and Leukemia Group B 9633 trials compared adjuvant chemotherapy with observation for patients with resected non-small-cell lung cancer (R-NSCLC). Data from the metastatic setting suggest high tumor class III beta-tubulin (TUBB3) expression is a determinant of insensitivity to tubulin-targeting agents (e.g. vinorelbine, paclitaxel). In 265 patients from JBR.10 (vinorelbine-cisplatin versus observation), high TUBB3 was an adverse prognostic factor and was associated (nonsignificantly) with 'greater' survival benefit from chemotherapy. We explored this further in additional patients from JBR.10 and the other three trials.
  
  
  METHODS
  TUBB3 immunohistochemical staining was scored for 1149 patients on the four trials. The original JBR.10 cut-off scores were used to classify tumors as TUBB3 high or low. The prognostic and predictive value of TUBB3 on disease-free survival (DFS) and overall survival (OS) was assessed by Cox models stratified by trial and adjusted for clinical factors.
  
  
  RESULTS
  High TUBB3 expression was prognostic for OS [hazard ratio (HR)=1.27 (1.07-1.51), P=0.008) and DFS [HR=1.30 (1.11-1.53), P=0.001). TUBB3 was not predictive of a differential treatment effect [interaction P=0.20 (OS), P=0.23 (DFS)]. Subset analysis (n=420) on vinorelbine-cisplatin gave similar results.
  
  
  CONCLUSIONS
  The prognostic effect of high TUBB3 expression in patients with R-NSCLC has been validated. We were unable to confirm a predictive effect for TUBB3.
authors.affiliation: Department of Medicine, Dalhousie University and Department of Oncology, Saint John Regional Hospital, Saint John. Electronic address: Anthony.Reiman@HorizonNB.ca.
authors.forename: T
authors.initials: T
authors.lastname: Reiman
authors.affiliation: Department of Laboratory Medicine and Pathology, Cross Cancer Institute and University of Alberta, Edmonton, Canada; Departments of.
authors.forename: R
authors.initials: R
authors.lastname: Lai
authors.affiliation: Biostatistics and Epidemiology.
authors.forename: A S
authors.initials: AS
authors.lastname: Veillard
authors.affiliation: Biostatistics and Epidemiology.
authors.forename: E
authors.initials: E
authors.lastname: Paris
authors.affiliation: Medicine, Institut Gustave-Roussy, Paris, France.
authors.forename: J C
authors.initials: JC
authors.lastname: Soria
authors.affiliation: Department of Medicine, Institut Catala d'Oncologia, Hospital Germans Trias i Pujol, Badalona, Barcelona, Spain.
authors.forename: R
authors.initials: R
authors.lastname: Rosell
authors.affiliation: Department of Medicine, Institut Catala d'Oncologia, Hospital Germans Trias i Pujol, Badalona, Barcelona, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Taron
authors.affiliation: Department of Medicine, State University of New York, Upstate Medical University, Syracuse.
authors.forename: S
authors.initials: S
authors.lastname: Graziano
authors.affiliation: Department of Medicine, University of Minnesota, Minneapolis, USA.
authors.forename: R
authors.initials: R
authors.lastname: Kratzke
authors.affiliation: NCIC Clinical Trials Group, Kingston.
authors.forename: L
authors.initials: L
authors.lastname: Seymour
authors.affiliation: Department of Medicine, Princess Margaret Hospital, University Health Network, Toronto, Canada.
authors.forename: F A
authors.initials: FA
authors.lastname: Shepherd
authors.affiliation: Biostatistics and Epidemiology.
authors.forename: J P
authors.initials: JP
authors.lastname: Pignon
authors.affiliation: Department of Internal Medicine, Hopital de la Croix Rousse.
authors.forename: P
authors.initials: P
authors.lastname: Sève
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000032:analysis*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D017024:Chemotherapy, Adjuvant; D018572:Disease-Free Survival; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D011379:Prognosis; D016016:Proportional Hazards Models; D016032:Randomized Controlled Trials as Topic; D014404:Tubulin / Q000096:biosynthesis*
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C498585:TUBB3 protein, human; D014404:Tubulin