Dr. Victoria Costanzo. Alexander Fleming Institute, Buenos Aires, Argentina

Introduction

Annually, more than one million cases of breast cancer are diagnosed worldwide¹. In industrialized countries, the percentage of metastatic disease, at the moment of presentation, is 6-10% and this percentage is a little higher in non-industrialized countries². Approximately one third of patients with early disease will have metastasis during the course of the disease despite having received an appropriate treatment³.
The traditional treatment administered to patients with metastatic breast cancer has been based on the use of chemotherapy. Under this circumstance, the appearance of a therapy directed against molecular targets has significantly changed survival in certain sub-groups of patients with metastatic disease.

Function of the human epidermal growth factor receptor type 2

The human epidermal growth factor receptor type 2 (HER2) gene was discovered in 1984⁴. HER2 is localized in the chromosome 17q and it encodes a protein receptor of transmembrane tyrosine kinase⁵, member of the family of epidermal growth factor receptors. This family is involved in cell-cell and cell-stroma communication through the signal-transduction process⁵. HER2 signal promotes cell proliferation through the mitogen-activated ras-protein kinase pathway and it inhibits cell death through the target of rapamycin pathway (mTOR, phosphatidylinositol triphosphate kinase)⁶.
The amplification of the HER2 gene and/or the overexpression of the protein have been identified in 10-34% of invasive-breast-cancer cases.4 In this disease, gene amplification and HER2 protein overexpression are uniform; the incidence of the overexpression of a single copy is very rare⁵.
HER2 amplification/overexpression is associated with higher cell proliferation, higher cell motility, higher invasion, growth and metastasis capacity, higher angiogenesis power and lower apoptosis⁷. From the pathology aspect, when compared with HER2-negative tumors, HER2-positive tumors are commonly high-grade, with negative hormone receptors and positive axillary nodes at the moment of manifestation⁴.

Trastuzumab: Development and action mechanism

Trastuzumab is a humanized immunoglobin (Ig)-G1 murine monoclonal antibody, designed using recombinant technology to specifically bind to the transmembrane portion of HER2⁵.
It has two specific antigen sites which bind to the juxtamembrane portion of the extracellular domain of HER2 receptor and it prevents the activation of its intracellular tyrosine kinase⁶. The rest is a human IgG antibody with its Fc portion.
The exact mechanism of its antitumor action is not fully known. There are several hypotheses to explain the interference in the HER2 signal pathway: preventing dimerization of the receptor, increasing destruction by receptor endocytosis, inhibiting secretion of the extracellular domain and through immune activation⁸. Preclinical models suggest that trastuzumab recruits immune effector cells which cause antibody-dependent cytotoxicity⁹. These models also suggest that trastuzumab has an anti-angiogenic effect and induces vasculature regression and normalization through the pro- and anti-angiogenic factors modulation¹⁰.
Below we will review the clinical evidence which supports the use of trastuzumab for the treatment of HER2-positive metastatic breast cancer.