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
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Emeline Tabouret1,2,3,20, François Bertucci1,4,19,20, Jean-Yves Pierga5, Thierry Petit6, Christelle Levy7, Jean-Marc Ferrero8, Mario Campone9, Joseph Gligorov10,11, Florence Lerebours12, Henri Roché13, Thomas Bachelot14, Steven van Laere15,16,17, Naoto T. Ueno18, Yves Toiron4,19, Pascal Finetti4, Daniel Birnbaum4, Jean-Paul Borg4,19, Patrice Viens1,4,19,20, Olivier Chinot2,3,20,*, Anthony Gonçalves1,4,19,20,*
1Institut Paoli-Calmettes, Medical Oncology Department, Marseille, France
2CRO2, Neuro-Oncology Department, UMRS_911, Marseille, France
3APHM, Marseille, France
4Centre de Recherche en Cancérologie de Marseille, Inserm, Marseille, France
5Institut Curie & Université Paris Descartes, Medical Oncology Department, Paris, France
6Centre Paul Strauss, Medical Oncology Department, Strasbourg, France
7Centre François Baclesse, Medical Oncology Department, Caen, France
8Centre Antoine Lacassagne, Medical Oncology Department, Nice, France
9Centre René Gauducheau, Medical Oncology Department, Saint-Herblin, France
10APHP-Tenon, APREC, Paris, France
11IUC-UPMC, Sorbonne University, Paris, France
12Hopital Rene Huguenin-Institut Curie, Medical Oncology Department, Saint-Cloud, France
13Institut Claudius Regaud, Medical Oncology Department, Toulouse, France
14Institut Leon Berard, Medical Oncology Department, Lyon, France
15Translational Cancer Research Unit, GZA Hospitals Sint-Augustinus, Wilrijk, Belgium
16Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
17Department of Oncology, KU Leuven, Leuven, Belgium
18The University of Texas MD Anderson Cancer Center, Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, Houston, TX, USA
19Centre de Recherche en Cancérologie de Marseille, CNRS, Marseille, France
20Aix-Marseille University, Marseille, France
*These authors have contributed equally to this work
Anthony Gonçalves, e-mail: Gonçalvesa@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
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.
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