Trastuzumab has been shown to inhibit HER2/neu ectodomain cleavage in breast cancer cells.Experiments in laboratory animals indicate that antibodies, including trastuzumab, when bound to a cell, induce immune cells to kill that cell, and that such antibody-dependent cell-mediated cytotoxicity is another important mechanism of action. Predicting response
Trastuzumab inhibits the effects of overexpression of HER2. If the breast cancer does not overexpress HER2, trastuzumab will have no beneficial effect (and may cause harm). Doctors use laboratory tests to discover whether HER2 is overexpressed. In the routine clinical laboratory, the most commonly employed methods for this are immunohistochemistry (IHC) and either silver, chromogenic or fluorescent in situ hybridisation (SISH/CISH/FISH). HER2 amplification can be detected by virtual karyotyping of formalin-fixed paraffin embedded tumor. Virtual karyotyping has the added advantage of assessing copy number changes throughout the genome, in addition to detecting HER-2 amplification (but not overexpression). Numerous PCR-based methodologies have also been described in the literature. It is also possible to estimate HER2 copy number from microarray data.There are two FDA-approved commercial kits available for HER2 IHC; Dako HercepTest and Ventana Pathway. These are highly standardised, semi-quantitative assays which stratify expression levels into; 0 (<20,000 receptors per cell, no visible expression), 1+ (~100,000 receptors per cell, partial membrane staining, < 10% of cells overexpressing HER-2), 2+ (~500,000 receptors per cell, light to moderate complete membrane staining, > 10% of cells overexpressing HER-2), and 3+ (~2,000,000 receptors per cell, strong complete membrane staining, > 10% of cells overexpressing HER-2). The presence of cytoplasmic expression is disregarded.
Birth control
Women having periods (or whose periods stopped due to chemotherapy) may need to use barrier contraception (such as condoms) while taking trastuzumab, and for at least six months afterwards. This is because of the possibility of harming a developing fetus. Mechanism of action
The HER2 gene (also known as HER2/neu and ErbB2 gene) is amplified in 20–30% of early-stage breast cancers. Trastuzumab is a monoclonal antibody targeting HER2, inducing an immune-mediated response that causes internalization and recycling of HER2. It may also upregulate cell cycle inhibitors such as p21Waf1 and p27Kip1.The HER2 pathway promotes cell growth and division when it is functioning normally; however, when it is overexpressed, cell growth accelerates beyond its normal limits. In some types of cancer, the pathway is exploited to promote rapid cell growth and proliferation and hence tumor formation. The EGF pathway includes the receptors HER1 (EGFR), HER2, HER3, and HER4; the binding of ligands (e.g. EGF etc.) to HER receptors is required to activate the pathway. The pathway initiates the MAP kinase pathway as well as the PI3 kinase/AKT pathway, which in turn activates the NF-κB pathway. In cancer cells the HER2 protein can be expressed up to 100 times more than in normal cells (2 million versus 20,000 per cell). This overexpression leads to strong and constant proliferative signaling and hence tumor formation.