title: Final 10-year results of the Breast International Group 2-98 phase III trial and the role of Ki67 in predicting benefit of adjuvant docetaxel in patients with oestrogen receptor positive breast cancer.
abstract: OBJECTIVE
  Breast International Group (BIG) 2-98 is a randomised phase III trial that tested the effect of adding docetaxel, either in sequence to or in combination with anthracycline-based adjuvant chemotherapy, in women with node-positive breast cancer (BC). Here, we present the 10-year final trial safety and efficacy analyses. We also report an exploratory analysis on the predictive value of Ki67 for docetaxel efficacy, in the BIG 2-98 and using a pooled analysis of three other randomised trials.
  
  
  METHODS
  2887 patients were randomly assigned in a 2×2 trial design to one of four treatments. The primary objective was to evaluate the overall efficacy of docetaxel on disease free survival (DFS). Secondary objectives included comparisons of sequential docetaxel versus sequential control arm, safety and overall survival (OS). Ki67 expression was centrally evaluated by immunohistochemistry.
  
  
  RESULTS
  After a median follow-up of 10.1years, the addition of docetaxel did not significantly improve DFS or OS (hazard ratio (HR)=0.91, 95% confidence interval (CI)=0.81-1.04; P=0.16 and HR=0.88, 95% CI=0.76-1.03; P=0.11, respectively). Sequential docetaxel did not improve DFS compared to the sequential control arm (HR=0.86, 95% CI=0.72-1.03; P=0.10). In oestrogen receptor (ER)-positive tumours with Ki67⩾14%, the addition of docetaxel resulted in 5.4% improvement in 10-year OS (P=0.03, test for interaction=0.1). In a multivariate model, there was a trend for improved DFS and OS in ER-positive patients with high Ki67 and treated with docetaxel (HR=0.79, 95% CI=0.63-1.01; P=0.05 and HR=0.76, 95% CI=0.57-1.01; P=0.06, respectively). A pooled analysis of four randomised trials showed a benefit of taxanes in highly proliferative ER-positive disease but not in low proliferating tumours (interaction test P=0.01).
  
  
  CONCLUSIONS
  The DFS benefit previously demonstrated with sequential docetaxel is no longer observed at 10years. However, an exploratory analysis suggested a benefit of docetaxel in patients with highly proliferative ER-positive BC.
authors.affiliation: Department of Medicine, BrEAST Data Centre, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Amir
authors.initials: A
authors.lastname: Sonnenblick
authors.affiliation: Peter MacCallum Cancer Centre, Melbourne, Australia; Australia and New Zealand Breast Cancer Trials Group Newcastle, Australia; International Breast Cancer Study Group, Bern, Switzerland.
authors.forename: Prudence A
authors.initials: PA
authors.lastname: Francis
authors.affiliation: Department of Medicine, BrEAST Data Centre, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Hatem A
authors.initials: HA
authors.lastname: Azim
authors.affiliation: Department of Medicine, BrEAST Data Centre, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Evandro
authors.initials: E
authors.lastname: de Azambuja
authors.affiliation: Swedish Breast Cancer Group, Universitetssjukhuset, Linkoping, Sweden.
authors.forename: Bo
authors.initials: B
authors.lastname: Nordenskjöld
authors.affiliation: Grupo Oncologico Cooperativo Chileno De Investigacion, Clinica Las Condes, Santiago, Chile.
authors.forename: Jorge
authors.initials: J
authors.lastname: Gutiérez
authors.affiliation: International Drug Development Institute, Louvain-La-Neuve, Belgium.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Quinaux
authors.affiliation: University of Milan School of Medicine, and Department of Pathology, European Institute of Oncology, Milan, Italy.
authors.forename: Mauro G
authors.initials: MG
authors.lastname: Mastropasqua
authors.affiliation: Data Management Unit, Institut Jules Bordet, Université Libre de Bruxelles, Belgium.
authors.forename: Lieveke
authors.initials: L
authors.lastname: Ameye
authors.affiliation: Department of Oncology, Copenhagen University Hospital Rigshospitalet, and Danish Breast Cancer Cooperative Group, Copenhagen, Denmark.
authors.forename: Michael
authors.initials: M
authors.lastname: Anderson
authors.affiliation: Department of Hematology and Medical Oncology, Hospital Clínico Universitario de Valencia/INCLIVA, Universidad de Valencia, Spain(1).
authors.forename: Ana
authors.initials: A
authors.lastname: Lluch
authors.affiliation: Department of Surgery and Comprehensive Cancer Center, Medical University of Vienna, Austrian Breast and Colorectal Cancer Study Group, Vienna, Austria.
authors.forename: Michael
authors.initials: M
authors.lastname: Gnant
authors.affiliation: European Institute of Oncology, Milan, Italy; International Breast Cancer Study Group (IBCSG), Bern, Switzerland.
authors.forename: Aron
authors.initials: A
authors.lastname: Goldhirsch
authors.affiliation: Sandro Pitigliani' Medical Oncology Department, Hospital of Prato, Istituto Toscano Tumori, Prato, Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: Di Leo
authors.affiliation: Medical Oncology Department, Hospital Santa Creu i Sant Pau, Medicine Department, Universitat Autònoma, Barcelona, Spain(1).
authors.forename: Agusti
authors.initials: A
authors.lastname: Barnadas
authors.affiliation: Department of Medical Oncology, University Hospital 12 de Octubre, Madrid, Spain.
authors.forename: Hernan
authors.initials: H
authors.lastname: Cortes-Funes
authors.affiliation: Department of Medicine, BrEAST Data Centre, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Martine
authors.initials: M
authors.lastname: Piccart
authors.affiliation: St Vincet's University Hospital, Dublin 4, Ireland. Electronic address: john.crown@icorg.ie.
authors.forename: John
authors.initials: J
authors.lastname: Crown
mesh_terms: D000328:Adult; D000368:Aged; D018943:Anthracyclines / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D017024:Chemotherapy, Adjuvant; D018572:Disease-Free Survival; D000077143:Docetaxel; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000378:metabolism*; D008875:Middle Aged; D011237:Predictive Value of Tests; D011446:Prospective Studies; D043823:Taxoids / Q000008:administration & dosage / Q000627:therapeutic use*
chemical_list: D018943:Anthracyclines; D014408:Biomarkers, Tumor; D019394:Ki-67 Antigen; D043823:Taxoids; D000077143:Docetaxel
keywords: Adjuvant taxanes; Breast cancer; ER positive; Ki67; Pooled analysis