Blood baseline neutrophil count predicts bevacizumab efficacy in glioblastoma

Abstract

Bevacizumab is used to treat glioblastoma; however, no current biomarker predicts its efficacy. We used an exploratory cohort of patients treated with the radiochemotherapy then bevacizumab or chemotherapy at recurrence (N = 265). Bevacizumab use increased median overall survival (OS) 18.7 vs 11.3 months, p = 0.0014). In multivariate analysis, age, initial surgery, neutrophil count, Karnofsky status >70% and bevacizumab administration were independent prognostic factors of survival. We found an interaction between bevacizumab use and baseline neutrophil count. The cut-off value for the neutrophil count was set at 6000/mm3. Only patients with a high neutrophil count benefited from the bevacizumab treatment (17.3 vs 8.8 months p < 0.0001). We validated this result using data from the TEMAVIR trial, which tested the efficacy of neoadjuvant bevacizumab plus irinotecan versus radiochemotherapy in the first-line treatment of glioblastoma. Transcriptomic data from TCGA underlined that CSF3 expression, the gene encoding G-CSF, the growth factor for neutrophils, correlated with VEGF-A-dependent angiogenesis. In another independent cohort (BELOB trial), which compared lomustine versus lomustine plus bevacizumab at recurrence, bevacizumab only benefited patients with high CSF3 expression in the tumor. These data suggest that only patients with a high peripheral neutrophil count before bevacizumab treatment benefited from this therapy.

Role of Neutrophils and Myeloid-Derived Suppressor Cells in Glioma Progression and Treatment Resistance

“…In addition, Schernberg et al reported that pretreatment neutrophilia is negatively associated with overall survival in GBM patients who undergo concurrent treatment with TMZ and RT [43]. Baseline circulatory neutrophil count predicts bevacizumab efficacy in GBM patients, although the role of neutrophils in the antitumor response of anti-VEGF therapy is unclear [44]. A recent study also showed that the absolute baseline number of neutrophils is negatively associated with overall survival, and has a prognostic value for bevacizumab response in patients with recurrent GBM who have not received corticosteroids [45].…”

The Microenvironmental Landscape of Brain Tumors

“…Most studies to date on neutrophils and brain tumors have focused on the impact of these cells on the response to anti-angiogenic therapy and vascularity – a hallmark feature of high-grade glioma. Clinically, while it has been shown that high peripheral neutrophil count prior to treatment correlates with positive initial response to the anti-VEGF-A antibody bevacizumab (Bertaut et al, 2016), enhanced neutrophil infiltration into tumor tissue is associated with acquired resistance and higher glioma grade at later stages (Fossati et al, 1999; Liang et al, 2014) (Figure 1C). These studies and others suggest that neutrophils may have prognostic value in glioblastoma (Bertaut et al, 2016; Fossati et al, 1999; Gabrusiewicz et al, 2016; Liang et al, 2014).…”

“…Clinically, while it has been shown that high peripheral neutrophil count prior to treatment correlates with positive initial response to the anti-VEGF-A antibody bevacizumab (Bertaut et al, 2016), enhanced neutrophil infiltration into tumor tissue is associated with acquired resistance and higher glioma grade at later stages (Fossati et al, 1999; Liang et al, 2014) (Figure 1C). These studies and others suggest that neutrophils may have prognostic value in glioblastoma (Bertaut et al, 2016; Fossati et al, 1999; Gabrusiewicz et al, 2016; Liang et al, 2014). Indeed, preclinical studies have shown that neutrophils contribute to glioblastoma progression by supporting the expansion of the glioma stem cell pool in a manner that is dependent on S100 proteins (specifically, S100A4) (Liang et al, 2014).…”

“…DC vaccinations such as DCVax-L have shown promising results, and as a consequence are in advanced clinical trials (newly-diagnosed glioblastoma, NCT00045968, Phase III) (Prins et al, 2011). Neutrophils also hold potential for their prognostic value in patients with primary brain tumors (Bertaut et al, 2016; Fossati et al, 1999), and metastatic disease (Koh et al, 2016; Mitsuya et al, 2016; Serdarevic et al, 2016). Targeting the vasculature through anti-angiogenic strategies is also relevant in glioblastoma patients given that this tumor type is highly vascularized; however, the current evidence seems to suggest that these strategies may be optimally used in the recurrent setting in combination with additional therapies (Friedman et al, 2009; Kreisl et al, 2009), rather than as frontline monotherapy on newly diagnosed, untreated disease (Gilbert et al, 2014).…”

Molecular biomarker‐guided anti‐angiogenic targeted therapy for malignant glioma

“…35 To address this possibility, researchers investigated the predictive role of the peripheral blood neutrophil count before BEV treatment on the efficacy of BEV. 36 A total of 256 GBM patients have been included in the analysis since 2006 and the best cut-off for the baseline neutrophil count was found to be 6000/mm 3…”