MMP2 and MMP9 serum levels are associated with favorable outcome in patients with inflammatory breast cancer treated with bevacizumab-based neoadjuvant chemotherapy in the BEVERLY-2 study

// Emeline Tabouret 1, 2, 3, 20 , Francois Bertucci 1, 4, 19, 20 , Jean-Yves Pierga 5 , Thierry Petit 6 , Christelle Levy 7 , Jean-Marc Ferrero 8 , Mario Campone 9 , Joseph Gligorov 10, 11 , Florence Lerebours 12 , Henri Roche 13 , Thomas Bachelot 14 , Steven van Laere 15, 16, 17 , Naoto T. Ueno 18 , Yves Toiron 4, 19 , Pascal Finetti 4 , Daniel Birnbaum 4 , Jean-Paul Borg 4, 19 , Patrice Viens 1, 4, 19, 20 , Olivier Chinot 2, 3, 20, * , Anthony Goncalves 1, 4, 19, 20, * 1 Institut Paoli-Calmettes, Medical Oncology Department, Marseille, France 2 CRO2, Neuro-Oncology Department, UMRS_911, Marseille, France 3 APHM, Marseille, France 4 Centre de Recherche en Cancerologie de Marseille, Inserm, Marseille, France 5 Institut Curie & Universite Paris Descartes, Medical Oncology Department, Paris, France 6 Centre Paul Strauss, Medical Oncology Department, Strasbourg, France 7 Centre Francois Baclesse, Medical Oncology Department, Caen, France 8 Centre Antoine Lacassagne, Medical Oncology Department, Nice, France 9 Centre Rene Gauducheau, Medical Oncology Department, Saint-Herblin, France 10 APHP-Tenon, APREC, Paris, France 11 IUC-UPMC, Sorbonne University, Paris, France 12 Hopital Rene Huguenin-Institut Curie, Medical Oncology Department, Saint-Cloud, France 13 Institut Claudius Regaud, Medical Oncology Department, Toulouse, France 14 Institut Leon Berard, Medical Oncology Department, Lyon, France 15 Translational Cancer Research Unit, GZA Hospitals Sint-Augustinus, Wilrijk, Belgium 16 Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium 17 Department of Oncology, KU Leuven, Leuven, Belgium 18 The University of Texas MD Anderson Cancer Center, Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, Houston, TX, USA 19 Centre de Recherche en Cancerologie de Marseille, CNRS, Marseille, France 20 Aix-Marseille University, Marseille, France * These authors have contributed equally to this work Correspondence to: Anthony Goncalves, e-mail: Goncalvesa@ipc.unicancer.fr Keywords: inflammatory breast cancer, bevacizumab, matrix metalloproteinase 2, matrix metalloproteinase 9, biomarker Received: August 29, 2015      Accepted: January 19, 2016      Published: February 23, 2016 ABSTRACT Purpose: Addition of bevacizumab to trastuzumab-based neoadjuvant chemotherapy in HER2-positive inflammatory breast cancer (IBC) was associated with favorable outcome in the BEVERLY-2 phase II trial. Circulating levels of matrix metalloproteinases (MMP) 2 and 9 were correlated to high response rate and prolonged survival in high-grade glioma treated with bevacizumab. We examined the prognostic impact of MMP2 and MMP9 serum levels in BEVERLY-2 patients. Experimental design: MMP2 and MMP9 serum levels were assessed using ELISA at baseline and before surgery in 45/52 available samples. Correlations were tested with pathological complete response (pCR), disease-free survival (DFS) and overall survival (OS). Results: Baseline (b) MMP2 and MMP9 serum levels were independent from patient characteristics and circulating tumor or endothelial cells, and were not correlated to pCR. High bMMP2 was correlated to better DFS (p=0.001) and OS (p=0.032), while low bMMP9 was correlated to better OS (p=0.022) and tended to be associated with longer DFS (p=0.071). In multivariate analyses, bMMP2 (p=0.003, Hazard Ratio [HR]: 0.115) and bMMP9 (p=0.041, HR: 3.511) remained correlated to DFS. As continuous variables, bMMP2 was associated with relapse (p=0.002) and death (p=0.049), while bMMP9 was associated with death (p=0.035). During treatment, significant increase in MMP2 and decrease in MMP9 levels (p<0.001 for both) were observed in 100% and 87% of patients respectively. Conclusions: High bMMP2 and low bMMP9 serum levels were associated with better survival in HER2-positive IBC patients treated with bevacizumab- and trastuzumab-based neoadjuvant chemotherapy. Their predictive value of bevacizumab benefit should be evaluated in a randomized trial.