Trastuzumab-Resistance and Breast Cancer

Evolution of therapeutic monoclonal antibodies significantly benefited from the recombinant DNA technologies that are used to generate chimeric, humanized, and human versions of monoclonal antibody to reduce the problem of immunogenicity and neutralization, as well as from understanding mechanisms of action mediated by monoclonal antibodies (Nelson et al., 2010; Reichert, 2009; Ranson & Sliwkowski , 2002). One of the significant advances in the application of monoclonal antibodies in oncology was the introduction and approval of trastuzumab, a humanized anti-HER2 antibody, for the treatment of HER2-positive breast cancer. Despite initial successes and encouraging results, development of monoclonal antibody-based therapies faces several challenges (Yan et al., 2009). Among them are the selection of patients most likely to benefit from clinical trials and lack of understanding of mechanisms of resistance to monoclonal antibody-based therapies (Yan et al., 2009). Selection of patients most likely to benefit from clinical trials of monoclonal antibody-based therapies was initially based on the expression of the antigen targeted by the monoclonal antibody. The anti-HER-2 antibody trastuzumab was tested in patients whose breast tumors overexpress HER2 (Pegram et al., 1998) and the anti-epidermal growth factor receptor (EGFR) antibody cetuximab was used in patients with colorectal cancer and head and neck cancers that overexpress EGFR (Shin et al., 2001). Even with careful characterization of the antigen expression level in the patient population eligible for the clinical trials, primary resistance to monoclonal antibodybased therapies is a common problem. Up to 50% of EGFR-positive colorectal cancer patients are resistant to cetuximab (Saltz et al., 2004), and 74% of HER2-positive breast cancer patients are resistant to anti-HER2 antibody trastuzumab (Vogel et al., 2002). It has emerged that the levels of antigen expression are not the only determinant of the patient response to monoclonal antibody therapies and that better understanding of the mechanisms of resistance to monoclonal antibodies in different patient subgroups has a potential to improve the effectiveness of the monoclonal antibody treatment. A retrospective analysis of the colorectal tumor samples from the patients that received cetuximab therapy indicated that EGFR-positive colorectal cancer patients with wild-type KRAS gene had increased overall