265PD - Ten-year safety and efficacy analyses of the BIG 02-98 phase III trial with an exploratory analysis on the role of Ki67 in predicting benefit of ad...

Date 27 September 2014
Event ESMO 2014
Session Breast cancer, early stage
Topics Anti-Cancer Agents & Biologic Therapy
Breast Cancer, Early Stage
Pathology/Molecular Biology
Presenter Amir Sonnenblick
Citation Annals of Oncology (2014) 25 (suppl_4): iv85-iv109. 10.1093/annonc/mdu327
Authors A. Sonnenblick1, H.A. Azim Jr.1, E. De Azambuja1, P. Francis2, B. Nordenskjöld3, J.P. Crown4, J. Gutiérez5, E. Quinaux6, M.G. Mastropasqua7, L. Ameye8, M. Anderson9, A. Lluch10, A. Goldhirsch11, A. Di Leo12, A. Barnadas13, H. Cortes-Funes14, M. Piccart15
  • 1Br.e.a.s.t. Data Centre, Institut Jules Bordet, 1000 - Brussel/BE
  • 2Oncology, Peter MacCallum Cancer Institute, 3002 - East Melbourne/AU
  • 3Swedish Breast Cancer Group, Faculty of Health Science, 58224 - Linkoping/SE
  • 4Medical Oncology, St Vincents University Hospital, IE-4 - Dublin/IE
  • 5Clinica Las Condes, 14Grupo Oncologico Cooperativo Chileno De Investigacion, Santiago/CL
  • 66. international Drug Development Institute, 6. International Drug Development Institute, Louvain/BE
  • 7European Institute Of Oncology, Department of pathology, Milan/IT
  • 8Data Centre, Institute Jules Bordet, BE-1000 - Brussels/BE
  • 9Danish Breast Cancer Cooperative Group, Danish Breast Cancer Cooperative Group, Copenhagen/DK
  • 10Incliva Biomedical Research Institute-university, Hospital Clínico de Valencia, Valencia/ES
  • 11Department Of Medicine, European Institute of Oncology, 20141 - Milan/IT
  • 12Oncology- Istituto Toscano Tumori, Ospedale di Prato Sandro Pitigliani Med. Oncology Unit, 59100 - Prato/IT
  • 13Medical Oncology, Hospital de la Santa Creu i Sant Pau, 08025 - Barcelona/ES
  • 14Servicio De Oncologia Medica, University Hosptial 12 De Octubre Medical oncology, 28041 - Madrid/ES
  • 15Medicine, Institute Jules Bordet, 1000 - Brussels/BE



The BIG 2-98 is a randomized phase III trial that tested the effect of adding docetaxel with anthracycline-based adjuvant chemotherapy (CT) in women with node-positive breast cancer (BC). here we present the 10 year safety and efficacy analyses and report an exploratory analysis of the predictive value of Ki67 for docetaxel efficacy.


In total, 2,887 patients with node positive BC were randomly assigned to one of four treatments: (I) sequential control: doxorubicin (A, 75 mg/m2) × 4 → CMF; (II) concurrent control: AC × 4 → CMF; (III) A × 3 → docetaxel (T, 100 mg/m2) × 3 → CMF and (IV) : AT (50/75 mg/m2) × 4 → CMF. The primary objective was to evaluate the efficacy of docetaxel regardless of the schedule on disease free survival (DFS). Secondary objectives were toxicity, DFS between sequential arms and concurrent arms, and overall survival (OS). Ki67 expression was centrally evaluated by immunohistochemistry. Tumours with Ki67 ≥14% were considered to have a high proliferation index.


After a median follow-up 10.1 years (max 12.9 years) and 1,072 DFS events, docetaxel treatment did not improve DFS or OS compared to control arms (DFS: HR = 0.91, 95% CI = 0.81-1.04; P = 0.16; OS: HR = 0.88, 95% CI = 0.76-1.03; P = 0.11). Similar results were obtained in secondary comparisons where sequential docetaxel was compared with sequential control (DFS: HR = 0.86, 95% CI = 0.72-1.03, P = 0.1; OS: HR = 0.85, 95% CI = 0.68-1.06; P = 0.15) or with concurrent doxorubicin–docetaxel (DFS: HR = 0.88, 95% CI = 0.7-1.01; P = 0.09; OS: HR = 0.84, 95% CI = 0.7-1.01; P = 0.06). Worsening or development of treatment-related neurotoxicity following completion of adjuvant chemotherapy occurred in 1.6% and 1% of patients in the docetaxel and non-docetaxel-based regimens, respectively. Out of 1,492 patients with ER positive BC, central Ki67 evaluation was performed in 1,198 (80.2%), of whom 892 (74.4%) had Ki67 ≥ 14%. In a multivariate model, there was a trend for improved DFS and OS in 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).


At a median follow-up of 10 years, the DFS benefit previously demonstrated with docetaxel is no longer present in node-positive BC patients. However, an exploratory analysis suggested a benefit of docetaxel in patients with highly proliferative ER-positive BC.


P. Francis: Travel support from Sanofi; J.P. Crown: Received research funding and speaking honoraria from Sanofi Aventis; M. Piccart: Board member: PharmaMar Consultant (honoraria) : Amgen, Astellas, AstraZeneca, Bayer, Eli Lilly, Invivis, MSD, Novartis, Pfizer, Roche-Genentech, sanofi Aventis, Symphogen, Synthon, Verastem Research grants to my Institute : most companies. All other authors have declared no conflicts of interest.