Abstract
It has now been 15 years since the HER2-targeted monoclonal antibody trastuzumab was introduced in clinical and revolutionized the treatment of HER2-positive breast cancer patients. Despite this achievement, most patients with HER2-positive metastatic breast cancer still show progression of their disease, highlighting the need for new therapies. The continuous interest in novel targeted agents led to the development of pertuzumab, the first in a new class of agents, the HER dimerization inhibitors. Pertuzumab is a novel recombinant humanized antibody directed against extracellular domain II of HER2 protein that is required for the heterodimerization of HER2 with other HER receptors, leading to the activation of downstream signalling pathways. Pertuzumab combined with trastuzumab plus docetaxel was approved for the first-line treatment of patients with HER2-positive metastatic breast cancer and is currently used as a standard of care in this indication. In the neoadjuvant setting, the drug was granted FDA-accelerated approval in 2013. Pertuzumab is also being evaluated in the adjuvant setting. The potential of pertuzumab relies in the dual complete blockade of the HER2/3 axis when administered with trastuzumab. This paper synthetises preclinical and clinical data on pertuzumab and highlights the mechanisms underlying the synergistic activity of the combination pertuzumab-trastuzumab which are essentially due to their complementary mode of action.
Highlights
The essential role of HER3 in tumor progression and drug resistance in HER2-dependent cells has previously been suggested. When both BT474MI and MCF-7 breast cancer cell lines were treated with heregulin and either pertuzumab or trastuzumab, pertuzumab was more efficient in disrupting ligand-mediated HER2/ HER3 complex formation and in blocking the appearance of a HRG-dependent phosphorylation signal of HER2 (Agus et al 2002)
This study suggested a role of pertuzumab in treating trastuzumab-resistant HER2 breast cancer (Baselga et al 2010)
The introduction of trastuzumab in the treatment of HER2-positive metastatic breast cancer patients favorably changed the natural history of this disease
Summary
The human epidermal growth factor receptor 2 (HER2, ErbB-2 or HER-2/neu) gene, which encodes the HER2 receptor tyrosine kinase, is amplified in about 20% of breast cancers (Ross and Fletcher 1998) and is associated with a poor prognosis and an aggressive phenotype (Slamon et al 1987). Several of the proposed mechanisms of resistance to trastuzumab involve persistence or reactivation of the PI3K signalling through amplification of alternative tyrosine kinase receptor and/or mutations in the PI3K components (Rexer and Arteaga 2013). The mechanism of HER2 signalling has been the focus of extensive research in order to identify additional targets therapies for patients with trastuzumab-resistant breast cancer. A number of agents targeting various downstream components of the pathways associated with HER2 signalling are currently under clinical investigation. These molecules include extracellular targeted therapies (monoclonal antibodies directed against HER family receptors), intracellular targeted therapies (tyrosine kinase inhibitors) and agents that target downstream effectors including members of either the mitogen-activated protein kinase (MAPK) or the phosphatidylinositol 3-kinase (PI3K) pathways. In addition to PI3K/AKT modulators, targeted therapies directed at the Hsp-90 apoptotic pathway as well as factors modulating angiogenesis are currently being developed (Rosen et al 2010)
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