Bevacizumab treatment for advanced breast cancer

Abstract

Significant advances in the treatment of patients with breast cancer have been made in the past 10 years. The current systemic treatment of breast cancer is characterized by the discovery of multiple cancer targets leading to treatments that are more sophisticated and specific than conventional cytotoxic chemotherapy. Two classes of compounds that have helped improve clinical outcomes are small molecules and monoclonal antibodies targeting specific tyrosine kinase receptors. Many novel targets have been discovered, and parallel multiple approaches to anticancer therapy have recently emerged from the literature. One promising strategy is targeting the proangiogenic vascular endothelial growth factors (VEGFs), either by ligand sequestration (preventing VEGF receptor binding) or inhibiting downstream receptor signaling. Bevacizumab, a monoclonal antibody directed against VEGF, has been shown to improve the efficacy of taxanes in frontline treatment of patients with metastatic breast cancer. This review outlines the most promising breast cancer studies using bevacizumab combined with traditional cytotoxic agents in advanced breast cancer. In addition, we discuss the current indications reviewed by the Oncologic Drug Advisory Committee and define our vision of how the benefit of patient clinical trials should be measured.

Figure 1.

VEGF-related family. VEGF₁₆₅ is the predominant isoform and is commonly overexpressed in a variety of human solid tumors. VEGF-A expression is efficiently induced by hypoxia and regulates not only physiological but also most pathological angiogenesis, such as tumor angiogenesis. Free VEGF members exert their effects by binding a variety of cell-surface receptors including VEGFR-1, a 180-kDa transmembrane protein also called macrophage-colony stimulating factor receptor (fms)-like tyrosine kinase-1, or Flt-1, and VEGFR-2, a 200-kDa transmembrane protein also called kinase insert domain-containing receptor, or KDR [19]. A third structurally related tyrosine kinase receptor is the 180-kDa VEGFR-3, which is expressed broadly on endothelial cells during early embryogenesis but becomes restrictive to endothelial cells of adult lymphatic tissues and is necessary for adult lymphangiogenesis [57]. Two additional VEGFRs, NRP-1 and NRP-2, were also recently implicated in VEGF-mediated vascularization and lymphangiogenesis [58]. These receptors have a short intracellular domain and are not capable of signal transduction but may instead function as coreceptors for VEGFR-1 and VEGFR-2 to enhance their interaction with their respective ligands. An important preclinical trial revealed that blocking anti-NRP-1 antibodies has an additive effect with anti-VEGF therapy in reducing tumor growth [59]. Both VEGFR-1 and VEGFR-2 are members of the receptor tyrosine kinase superfamily, and they belong to the same subclass as receptors for platelet derived growth factors and fibroblast growth factors. VEGFRs have an extracellular domain composed of seven immunoglobulin-like regions that bind to VEGF, a single transmembrane region, and an intracellular tyrosine kinase domain [60]. Activation of these VEGFRs triggers the phosphorylation of a multitude of proteins that are active in signal transduction cascades. Some of the signaling pathways triggered by these mechanisms include the Akt/protein kinase B, endothelial nitric oxide synthase, mitogen-activated protein kinase, focal adhesion kinase, paxillin, Ras-Raf-mitogen-activated protein kinase/extracellular signal–related kinase kinase-extracellular signal–related kinase, and phospholipase C-γ pathways [61]. Abbreviations: HSPG, heparan sulfate proteoglycans; NO, nitric oxide; NRP, neuropilin; PAI-1, plasminogen activator inhibitor-1; PlGF, placental growth factor; TF, tissue factor; UPA, urokinase plasminogen activator; VEGF, vascular endothelial growth factor; VEGFR, VEGF receptor.

Figure 2.

Intercellular signaling among tumor cells, stroma cells, pericytes, and endothelial cells: cellular players in the tumor/microvascular microenvironment. VEGF is antiapoptotic for endothelial cells via several pathways, including induction of expression of the antiapoptotic proteins Bcl-2 and A1, activation of the phosphoinositide 3-kinase/Akt signaling pathway, stimulation of nitrous oxide and prostacyclin, and increasing focal adhesion kinase tyrosine phosphorylation [62]. The activity of VEGF receptors is primarily regulated by the availability of their respective ligands. Ligand expression levels depend on many factors, such as hypoxia, environmental stress, and glucose deficiency. VEGF-A is the most important factor whose expression is upregulated under hypoxic conditions. Hypoxia allows the stabilization of hypoxia-inducible factors that bind to specific promoter elements that are present in the promoter region of VEGF-A [63]. Abbreviations: EGF, endothelial growth factor; HGF, hepatocytic growth factor; PDGF, platelet-derived growth factor; TGF, transforming growth factor; VEGF, vascular endothelial growth factor.