Breast cancer HER2 overexpression

Herceptin is the trade name given to one such antibody-based cancer therapy product (Table 8). It is a humanized niAb with binding specificity for the human epidermal growth factor receptor 2 (HER2), which is overexpressed on the surface of 25-30% of metastatic breast cancers. HER2 overexpression induces abnormal proliferation of cells (see also Part I, Chapter 5). The niAb binds specifically to the... 

Slamon, D.J. et al.. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2, N. Engl.. Med., 344, 783-792, 2001. 

Trastuzumab is licensed for the treatment of early breast cancer that overexpresses human epidermal growth factor receptor-2 (HER2). It may be administered as monotherapy or in combination with, for example, paclitaxel, docetaxel (taxanes) or anastrozole (aromatase inhibitors). Since trastuzumab can cause cardiotoxicity, concomitant use with anthracyclines such as... 

HER2, a member of the EGF receptor family, drives growth of breast cancers that overexpress the receptor. Trastuzumab, which binds HER2 and prevents receptor activation, has been shown to be effective in reducing tumor growth and metastasis in such cases. 

G. Other applications Herceptin has been combined with cisplatin in the treatment of heavily pretreated metastatic breast cancer. Treatment of patients with ovarian cancer is under investigation. A recent study demonstrated that Herceptin increased the clinical benefits of first-line chemotherapy—doxorubicin (or epiru-bicin) and cyclophosphamide or pacli-taxel—in metastatic breast cancer that overexpressed HER2. 

Slamon, D., Leyland-Jones, B., Shak, S., Fuchs, H., Paton, V., Bajamonde, A., Fleming, T., Eiermann, W., Wolter, J., and Pegram, M. et al. (2001). Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N. Engl. J. Med. 344, 783-792. 

Slamon D, Leyland-Jones B, Shak S, Paton V, Bajamonde A, Flemiong T, Eirmann W, Wolter J, Baselga J, Norton L. Addition of Herceptin (humanized anti-HER2 antibody) to first line chemotherapy for HER2 overexpressing metastatic breast cancer (HER2-I-/MBC) markedly increases anticancer activity a randomised, multinational, controlled phase III trial (Abstract 377). Proc Am Soc Clin Oncol 1998 17 98a. 

D. Monoclonal Antibodies Rituximab is a monoclonal antibody to a surface protein in non-Hodgkin s lymphoma cells. It is presently used with conventional anticancer drugs (eg, cyclophosphamide plus vincristine plus prednisone) in low grade lymphomas. Trastuzumab is a monoclonal antibody to a surface protein in breast cancers that overexpress the HER2 protein. Acute toxicity of these antibodies includes nausea and vomiting, chills, fevers, and headache. Rituximab use is associated with hypersensitivity reactions and myelosuppression. Trastuzumab may cause cardiac dysfunction, including congestive heart failure. 

Figure 6.7-12. Left Panel Results for a direct binding assay for a In-DTPA-trastuzumab (Herceptin) IgG incubated with SK-BR-3 human breast cancer cells overexpressing HER2/ neu. The Ka and Bmax in this example were 1.2 x 10 L/mole and 1.0 x 10 receptors/cell, respectively. Right Panel Results for measurement of the immunoreactive fraction (IRF) of a Tn-DTPA-trastuzumab IgG incubated with SK-BR-3 cells using the Lindmo method [256]. In this example, the intercept on the ordinate (1/IRF) was 1.7 and the IRF was therefore 0.59. (Data generously provided by Kristin McLarty.)...

Pullarkat Y Deo Y, Link J, Spears L, Marty V, Cumow R, Groshen S, Gee C, Weber JS A phase I study of a HER2/neu bispecific antibody with granulocyte-colony-stimulating factor in patients with metastatic breast cancer that overexpresses HER2/neu. Cancer Immunol Immunother 1999 ... 

Bartlett JMS, Going JJ, Mallon EA, et al. Evaluating HER2 amplification and overexpression in breast cancer. J. Pathol. 2001 195 422 128. 

Treatment of metastatic breast cancer if tumour overexpresses HER2 protein... 

Umemura, S., Sekido, Y., Itoh, H., and Osamura, RY. 2002. Pathological evaluation of HER2 overexpression for the treatment of metastatic breast cancers by humanized anti-HER2 monoclonal antibody (trastuzumab). Acta Histochemica et Cytochemica, Kyoto 35(2), 77-81. 

Baselge, ]., et al., "Recombinant Humanized Anti-HER2 Antibody (HERCEPTIN) Enhances the Antitumor Activity of Paclitaxel and Doxorubicin Against HER2/neu Overexpressing Human Breast Cancer Xenografts," Cancer Res., 58, 2825-2831 (1998). 

Trastuzumab Herceptin Humanized IgGltc anti-HER2 HER2 overexpressing metastatic breast cancer 1998 United States... 

---