MMP2 and MMP9 as candidate biomarkers to monitor bevacizumab therapy in high-grade glioma
Authors: Emeline Tabouret, Françoise Boudouresque, Patrizia Farina, Maryline Barrié, Céline Bequet, Marc Sanson, Olivier Chinot
Journal: Neuro-Oncology (2015)

Glioblastoma remains the most frequent and aggressive primary brain tumor in adults and is characterized by extensive angiogenesis.1 Recently, bevacizumab, a monoclonal antibody against vascular endothelial growth factor A (VEGFA), was associated with valuable, but heterogeneous, activity in patients with recurrent high-grade gliomas.2,3 In addition to the standard of care for newly diagnosed glioblastoma, the use of bevacizumab as a first-line treatment has been associated with prolonged progression-free survival (PFS) and maintenance of functional independence, but no difference has been observed in overall survival (OS).4,5 Given this heterogeneous activity and the uncertain impact on OS, a predictive biomarker of bevacizumab activity remains an unmet medical need. In this context, we recently reported that before bevacizumab administration, a baseline of high and low plasma levels of MMP2 and MMP9, respectively, were associated with a high response rate and prolonged PFS and OS in recurrent high-grade gliomas treated with bevacizumab.6 Moreover, we did not observe any correlation between these 2 biomarkers and the survival of patients when the plasma levels were measured before administration of cytotoxic agents without antiangiogenic therapy, suggesting a predictive—rather than a prognostic—value of the biomarkers.6 Considering the potential role of biomarkers in treatment monitoring, it is of interest to analyze the successive change in the plasma levels of these markers during bevacizumab treatment.

We retrospectively included all patients with recurrent high-grade gliomas who had been referred to both of our institutions (APHM, Marseille, and APHP, Paris). They were treated with a combination of bevacizumab (10 mg/kg on days 1 and 15) and irinotecan until progression, and their plasma samples at each cycle and at progression were available as part of the ongoing studies (APHM Tumor Bank, authorization number 2013–1786). Plasma samples were collected before bevacizumab administration and then every 14 days, on day 1 and day 15 (before bevacizumab administration) of each cycle until progression. All patients provided written informed consent in accordance with our institutional and national guidelines and the Declaration of Helsinki. The plasma levels of MMP2 and MMP9 were assessed using ELISA kits (R&D Systems). Changes were analyzed using the paired-samples t test, and correlations were analyzed using the Spearman test.

Forty-one patients were included. Patient and treatment characteristics are reported in Table 1. The plasma level of MMP2 significantly increased during bevacizumab treatment from baseline (B) to the last point prior to progression (PTP) (P = .001) and decreased at the time of progression (P) (P = .033); B, PTP, and P mean plasma levels of MMP2 were 210.4 ng/mL, 245.9 ng/mL, and 220.4 ng/mL, respectively (Fig. 1). In contrast, the plasma level of MMP9 decreased during bevacizumab treatment (P = .034) and tended to increase at P (not significant); B, PTP, and P mean plasma levels of MMP9 were 194.6 ng/mL, 113.0 ng/mL, and 151.0 ng/mL, respectively. Finally, the plasma levels of MMP2 and MMP9 were inversely correlated at B and at P (P < .001 and P = .011, respectively). A trend was observed at the last cycle before progression (P = .065). 



Table 1.

Patient characteristics at the time of bevacizumab + irinotecan administration





Fig. 1.

Variations of MMP2 (A) and MMP9 (B) mean plasma levels during bevacizumab treatment from baseline until progression.



In this retrospective bicentric study, we showed that the plasma level of MMP2, and to a lesser extent that of MMP9, varied during treatment and at the time of progression. We previously reported that these markers could potentially allow initial patient selection for treatment.6 In the present study, the change in the levels of these biomarkers provided additional information on tumor response events during bevacizumab treatment. In particular, considering the challenge of assessing progression during the bevacizumab treatment, the decrease in the plasma levels of MMP2 observed at P suggests that this biomarker can help in monitoring bevacizumab treatment. This predictive value, observed at B in our previous work and at P in the present study demonstrating the changes observed during bevacizumab treatment, reinforces the potential value of these markers and the need of their assessment in a prospective trial. Variations in the plasma levels of MMP2 were previously reported for the multitargeted antiangiogenic tyrosine kinase inhibitor cediranib.7 In a phase 2 trial conducted in patients with recurrent glioblastoma, the use of cediranib induced a transient decrease in the plasma level of MMP2 between 8 and 24 hours after the first administration. While the baseline level of MMP2 had no impact on patient outcome, the increase in the plasma level of MMP2 8 hours after the administration of cediranib was associated with a reduced PFS and OS. The plasma level of MMP9 at B and changes during treatment were not correlated to patient outcome. It is not known if these differences in variations and impact are related to the differences in the activity or the mechanism of action between cediranib and bevacizumab.

Finally, MMP2 and MMP9 appeared to be inversely correlated at both B and P. This inverse correlation suggests a biological interaction of these 2 proteases in the tumor vascularization process and is in line with their inverse predictive values that were also observed at B.6 MMP2 was reported to be particularly implicated in angiogenesis through the promotion of VEGFA expression and its coexpression with VEGFR2.8,9 Indeed, in the absence of MMP2 expression, tumor vessel density as well as VEGFA and VEGFR2 expressions decreased dramatically, suggesting an important role of MMP2 in the angiogenic process. In contrast, MMP9 is required for tumor vasculogenesis but not for angiogenesis.10 Indeed, MMP9 appeared to be particularly implicated in the recruitment of circulating endothelial and myeloid precursors, an alternative vascularization process that was in part independent of the VEGF pathway.10

This study on MMP2 and MMP9 changes during bevacizumab treatment provides additional support for considering the potential value of these biomarkers in predicting bevacizumab activity in patients with high-grade glioma. Adequate prospective studies in this regard are warranted.