Abstract
We previously identified matrix metalloproteinase 2 (MMP2) and MMP9 plasma levels as candidate biomarkers of bevacizumab activity in patients with recurrent glioblastoma. The aim of this study was to assess the predictive value of MMP2 and MMP9 in a randomized phase III trial in patients with newly diagnosed glioblastoma and to explore their tumor source. In this post hoc analysis of the AVAglio trial (AVAGlio/NCT00943826), plasma samples from 577 patients (bevacizumab, n = 283; placebo, n = 294) were analyzed for plasma MMP9 and MMP2 levels by enzyme-linked immunosorbent assay. A prospective local cohort of 38 patients with newly diagnosed glioblastoma was developed for analysis of tumor characteristics by magnetic resonance imaging and measurement of plasma and tumor levels of MMP9 and MMP2. In this AVAglio study, MMP9, but not MMP2, was correlated with bevacizumab efficacy. Patients with low MMP9 derived a significant 5.2-month overall survival (OS) benefit with bevacizumab (HR 0.51, 95% CI 0.34–0.76, p = 0.0009; median 13.6 vs. 18.8 months). In multivariate analysis, a significant interaction was seen between treatment and MMP9 (p = 0.03) for OS. In the local cohort, we showed that preoperative MMP9 plasma levels decreased after tumor resection and were correlated with tumor levels of MMP9 mRNA (p = 0.03). However, plasma MMP9 was not correlated with tumor size, invasive pattern, or angiogenesis. Using immunohistochemistry, we showed that MMP9 was expressed by inflammatory cells but not by tumor cells. After cell sorting, we showed that MMP9 was expressed by CD45+ immune cells. Finally, using flow cytometry, we showed that MMP9 was expressed by tumor-infiltrating neutrophils. In conclusion, circulating MMP9 is predictive of bevacizumab efficacy and is released by tumor-infiltrating neutrophils.
Highlights
Glioblastoma is the most aggressive and frequent primary brain tumor in adults
Plasma MMP9 predicts bevacizumab efficacy in patients with newly diagnosed glioblastoma: AVAglio ancillary study To assess the predictive value of plasma matrix metalloproteinase 2 (MMP2) and MMP9 levels, we analyzed 577 of 921 patients included in the AVAglio trial for whom plasma samples were available at inclusion: 283 patients treated by radiochemotherapy and bevacizumab and 294 patients treated by radiochemotherapy and placebo
Patients with low MMP9 plasma levels (< quartile 1) presented with a significant overall survival (OS) benefit from bevacizumab (HR 0.51, 95% CI 0.34–0.76, p = 0.0009), which translated into a median increase in OS of 5.2 months (Fig. 1B); a consistent benefit in progressionfree survival (PFS) was seen (HR 0.36, 95% CI 0.24–0.54, p < 0.0001)
Summary
Glioblastoma is the most aggressive and frequent primary brain tumor in adults. Despite standard first-line treatment based on surgical resection, radiotherapy, and chemotherapy, recurrence remains systematic, with a median delay of 7 to 10 months [1]. The use of bevacizumab (Avastin), an antiangiogenic therapy against vascular endothelial growth factor type A (VEGFA), was associated with a response rate of 25% to 35% in patients with recurrent glioblastoma and was evaluated in phase III trials in the initial and recurrent setting [3,4,5]. In these trials, bevacizumab significantly improved progressionfree survival (PFS) of patients at initial diagnosis and at relapse. The heterogeneity of bevacizumab efficacy, its cost, and its potential side effects, as well as the multiplication of other new therapies under investigation, highlight the need to identify predictive biomarkers of antiangiogenic activity
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