Phosphorylated HER-2 tyrosine kinase and Her-2/neu gene amplification as predictive factors of response to trastuzumab in patients with HER-2 overexpressing metastatic breast cancer (MBC) 5 Rosa Giuliani a , Virginie Durbecq a , Angelo Di Leo a , Marianne Paesmans a , Denis Larsimont a , Jean-Yves Leroy a , Marleen Borms b , Anita Vindevoghel c , Guy Jerusalem d , Veronique D’Hondt e , Luc Dirix f , Jean-Luc Canon g , Vincent Richard h , Veronique Cocquyt i , Franc ¸oise Majois j , Michel Reginster k , Jan Demol l , Jean-Pierre Kains m , Paul Delree n , Carine Keppens o , Christos Sotiriou a , Martine J. Piccart a , Fatima Cardoso a, * a Translational Research Unit, Jules Bordet Institute, 125, Boulevard de Waterloo, 1000 Brussels, Belgium b Medical Oncology, AZ Groeninge, Kortrijk, Belgium c Medical Oncology, St Elisabeth Hospital, Namur, Belgium d Medical Oncology, CHU Sart Tilman, Liege, Belgium e Medical Oncology, Cliniques Universitaires St Luc, Universite Catholique de Louvain, Brussels, Belgium f Medical Oncology, AZ St Augustinus, Wilrijk, Belgium g Medical Oncology, Clinique Notre Dame, Charleroi, Belgium h Medical Oncology, RHMS, Baudour, Belgium i Medical Oncology, University Hospital, Ghent, Belgium j Medical Oncology, Jolimont Hospital, Haine St-Paule, Belgium k Medical Oncology, CH Huy, Belgium l Medical Oncology, Heilig Hart, Roeselare, Belgium m Medical Oncology, Ho ˆpitaux Iris Sud, Ixelles, Brussels, Belgium n Pathology, Loverval, Belgium o F. Hoffman-La Roche Ltd., Brussels, Belgium ARTICLE INFO Article history: Received 13 July 2006 Received in revised form 27 October 2006 Accepted 27 November 2006 Available online 23 January 2007 Keywords: Metastatic breast cancer Trastuzumab Predictive factors Phosphorylated HER-2 ABSTRACT Aim: Trastuzumab (T), a humanised monoclonal antibody against HER-2, is active in HER- 2-positive MBC patients. However, nearly 60% of the patients do not benefit from T, stress- ing the need for additional predictive markers. The following markers could be implicated in response to T: (1) the magnitude of Her-2 gene amplification; (2) the co-expression of the other HER family receptors, possibly responsible for HER-2 trans-activation; (3) the acti- vated status of HER-2; (4) the activated status of downstream effectors as mitogen-acti- vated protein kinases (MAPKs), p38 and p27. Methods: Medical files of patients with MBC treated with T either as a single agent or in combination with chemotherapy (CT) were reviewed. HER family members (EGFR, HER-2, HER-3, HER-4), the phosphorylated forms of EGFR (p-EGFR), HER-2 (p-HER-2) and of the downstream effectors were evaluated in the archival tumours. The correlation between clinical outcome and the expression of these markers was investigated. 0959-8049/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.ejca.2006.11.019 5 This work partially funded by ‘Les Amis de L’Institut Bordet’ and by F. Hoffman-La Roche Ltd. * Corresponding author: Tel.: +32 2 541 3082; fax: +32 2 538 0858. E-mail address: fatima.cardoso@bordet.be (F. Cardoso). EUROPEAN JOURNAL OF CANCER 43 (2007) 725 – 735 available at www.sciencedirect.com journal homepage: www.ejconline.com