Amir Sonnenblick1, Prudence A Francis2, Hatem A Azim1, Evandro de Azambuja1, Bo Nordenskjöld3, Jorge Gutiérez4, Emmanuel Quinaux5, Mauro G Mastropasqua6, Lieveke Ameye7, Michael Anderson8, Ana Lluch9, Michael Gnant10, Aron Goldhirsch11, Angelo Di Leo12, Agusti Barnadas13, Hernan Cortes-Funes14, Martine Piccart1, John Crown15. 1. Department of Medicine, BrEAST Data Centre, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium. 2. Peter MacCallum Cancer Centre, Melbourne, Australia; Australia and New Zealand Breast Cancer Trials Group Newcastle, Australia; International Breast Cancer Study Group, Bern, Switzerland. 3. Swedish Breast Cancer Group, Universitetssjukhuset, Linkoping, Sweden. 4. Grupo Oncologico Cooperativo Chileno De Investigacion, Clinica Las Condes, Santiago, Chile. 5. International Drug Development Institute, Louvain-La-Neuve, Belgium. 6. University of Milan School of Medicine, and Department of Pathology, European Institute of Oncology, Milan, Italy. 7. Data Management Unit, Institut Jules Bordet, Université Libre de Bruxelles, Belgium. 8. Department of Oncology, Copenhagen University Hospital Rigshospitalet, and Danish Breast Cancer Cooperative Group, Copenhagen, Denmark. 9. Department of Hematology and Medical Oncology, Hospital Clínico Universitario de Valencia/INCLIVA, Universidad de Valencia, Spain(1). 10. Department of Surgery and Comprehensive Cancer Center, Medical University of Vienna, Austrian Breast and Colorectal Cancer Study Group, Vienna, Austria. 11. European Institute of Oncology, Milan, Italy; International Breast Cancer Study Group (IBCSG), Bern, Switzerland. 12. Sandro Pitigliani' Medical Oncology Department, Hospital of Prato, Istituto Toscano Tumori, Prato, Italy. 13. Medical Oncology Department, Hospital Santa Creu i Sant Pau, Medicine Department, Universitat Autònoma, Barcelona, Spain(1). 14. Department of Medical Oncology, University Hospital 12 de Octubre, Madrid, Spain. 15. St Vincet's University Hospital, Dublin 4, Ireland. Electronic address: john.crown@icorg.ie.
Abstract
AIM: 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. PATIENTS AND 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). CONCLUSION: 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.
RCT Entities:
AIM: 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. PATIENTS AND 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). CONCLUSION: 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: L Buisseret; S Pommey; B Allard; S Garaud; M Bergeron; I Cousineau; L Ameye; Y Bareche; M Paesmans; J P A Crown; A Di Leo; S Loi; M Piccart-Gebhart; K Willard-Gallo; C Sotiriou; J Stagg Journal: Ann Oncol Date: 2018-04-01 Impact factor: 32.976
Authors: Amir Sonnenblick; Roberto Salgado; Sylvain Brohée; Tamar Zahavi; Tamar Peretz; Gert Van den Eynden; Ghizlane Rouas; Asher Salmon; Prudence A Francis; Angelo Di Leo; John P A Crown; Giuseppe Viale; Laura Daly; Bahar Javdan; Sho Fujisawa; Evandro De Azambuja; Ameye Lieveke; Martine J Piccart; Jacqueline F Bromberg; Christos Sotiriou Journal: Int J Oncol Date: 2017-11-27 Impact factor: 5.650
Authors: Melina L Willson; Lucinda Burke; Thomas Ferguson; Davina Ghersi; Anna K Nowak; Nicholas Wilcken Journal: Cochrane Database Syst Rev Date: 2019-09-02
Authors: Tarek M A Abdel-Fatah; Graham R Ball; Pulari U Thangavelu; Lynne E Reid; Amy E McCart Reed; Jodi M Saunus; Pascal H G Duijf; Peter T Simpson; Sunil R Lakhani; Lorinc Pongor; Balázs Gyorffy; Paul M Moseley; Andrew R Green; Alan G Pockley; Carlos Caldas; Ian O Ellis; Stephen Y T Chan Journal: JAMA Netw Open Date: 2020-07-01
Authors: Christine Desmedt; Roberto Salgado; Marco Fornili; Giancarlo Pruneri; Gert Van den Eynden; Gabriele Zoppoli; Françoise Rothé; Laurence Buisseret; Soizic Garaud; Karen Willard-Gallo; David Brown; Yacine Bareche; Ghizlane Rouas; Christine Galant; François Bertucci; Sherene Loi; Giuseppe Viale; Angelo Di Leo; Andrew R Green; Ian O Ellis; Emad A Rakha; Denis Larsimont; Elia Biganzoli; Christos Sotiriou Journal: J Natl Cancer Inst Date: 2018-07-01 Impact factor: 13.506