VEGF-A levels in bevacizumab-treated breast cancer patients: a systematic review and meta-analysis

Abstract

Bevacizumab may improve outcomes of patients with breast cancer, but the absence of an established biomarker hampers patient selection and researchers´ ability to demonstrate a clear survival benefit. Its putative target, circulating VEGF-A, emerged as the main candidate and we sought to identify the relationship between VEGF-A levels and outcomes through systematic review. We searched electronic databases and meeting proceedings for randomized controlled trials (RCTs) comparing the addition of bevacizumab to standard chemotherapy for breast cancer. RCTs were included if outcomes were presented separately according to VEGF-A plasma levels. Random-effects model were applied to calculate the pooled hazard ratios for progression-free survival, event-free survival (EFS), comprising disease recurrence, progression or any-cause death, and overall survival (OS), with respective confidence intervals (95 % CI). High and low VEGF-A levels subgroups followed each trial definition, and results were compared using the interaction test. Heterogeneity was calculated using χ (2) test (I (2)). Three trials enrolled a total of 3748 patients. 1713 patients had baseline VEGF-A levels in plasma available for assessment and were included. One trial added bevacizumab in the adjuvant setting (N = 2591) and two on first-line metastatic disease with taxane-based therapy (N = 1160) There was no interaction between VEGF-A levels and study setting (adjuvant vs. first line therapy). Bevacizumab improved PFS of patients with above median VEGF-A plasma levels (HR 0.56; 95 % CI 0.43-0.73; P < 0.001; I (2) = 0 %), but not of those with below median VEGF-A levels (HR 0.89; 95 % CI 0.68-1.15; P = 0.37; I (2) = 0 %), with relevant differences between these two groups, P-for interaction = 0.02. The same happened with EFS (VEGF-A above median HR 0.62; 95 % CI 0.39-0.79; P < 0.001; I (2) = 11 %; below median HR 0.89; 95 % CI 0.71-1.14; P = 0.98; I (2) = 17 %; P-for interaction = 0.03). OS data were not available. VEGF-A level is a reasonable candidate biomarker for bevacizumab in the treatment of breast cancer. Further studies have to confirm its surrogacy in overall survival and in other scenarios including other anti-angiogenic therapies.

Loss of the endothelial glycocalyx is associated with increased E-selectin mediated adhesion of lung tumour cells to the brain microvascular endothelium

“…It is interesting to note that the measured secreted levels of VEGF were relatively low compared to some of the other proteins detected. However, comparable, picogram levels of VEGF-A have been reported in the plasma of cancer patients [ 25 ] and to have significant effects on endothelial function [ 26 ]. The pathogenic role of VEGF in tumour growth is well documented (reviewed in [ 17 ]) and not only has enhanced VEGF expression been observed in all forms of NSCLC, but also high serum levels have been correlated with poor prognosis in patients [ 27 , 28 ].…”

MicroRNA-16-5p overexpression suppresses proliferation and invasion as well as triggers apoptosis by targeting VEGFA expression in breast carcinoma

“…Stepwise investigation demonstrated miR-29c directly bound to the 3′-UTR region of VEGFA, and reduced VEGFA protein expression in breast carcinoma cells, coupled with the downregulation of HIF-α. To deeply understand the molecular mechanisms of miR-16-5p in vivo , we found that miR-16-5p overexpression evidently downregulated HIF-α and VEGF protein expression in nude mice tumor tissues, which were an accepted fact that these two proteins play an essential role in the development and progression of many tumors by multiple different mechanisms [ 36 – 46 ]. These findings highlight the potential therapeutic value of miR-16-5p in breast carcinoma, and combination of miR-16-5p with the related signaling pathway of HIF-α and VEGFA may be an effective molecular target for the patients with breast carcinoma in future.…”

Bevacizumab Induces Acute Hypoxia and Cancer Progression in Patients with Refractory Breast Cancer: Multimodal Functional Imaging and Multiplex Cytokine Analysis

“…Despite comprehensive research, the mechanism of bevacizumab resistance remains poorly understood. One possible reason is the difficulty of identifying molecular biomarkers associated with the synergistic effect of bevacizumab and cytotoxic chemotherapy in humans (20,21). We believe that intrinsic resistance to bevacizumab is more dependent on physiologic changes during treatment than genomic alterations (22,23).…”