Anti-erbB-2 antibody trastuzumab in the treatment of HER2-amplified breast cancer

Abstract

Human epidermal growth factor receptor-2 (HER2/erbB-2) is a member of a family of four transmembrane receptor tyrosine kinases that regulate cell growth, survival and differentiation via multiple signal transduction pathways. Amplification of the HER2 gene occurs in 20-25% of human breast cancers. This amplification event is an independent adverse prognostic factor as well as a predictive factor for increased response to doxorubicin-based combination chemotherapy, response to trastuzumab and decreased response to hormonal therapy. Methods for detecting protein overexpression or gene amplification in clinical tumor specimens include immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) techniques, with the latter considered by some to be more accurate. Trastuzumab (Herceptin) is a recombinant humanized monoclonal antibody which targets an epitope in the extracellular domain of the HER2 protein. Preclinical models demonstrated that this antibody has significant anti-tumor activity as a single agent and has synergy with certain chemotherapeutic drugs. Phase II and III clinical trials performed in women with metastatic breast cancer that overexpress HER2 have shown that trastuzumab has clinical activity when used as first-, second- or third-line monotherapy, and improves survival when used as first-line therapy in combination with chemotherapy. Newer combinations with numerous chemotherapeutic drugs have also shown significant clinical activity in phase II studies. In all of these trials, trastuzumab was generally well-tolerated, but cardiac toxicity (particularly when the antibody was combined with anthracyclines) was an unexpected adverse effect. Although trastuzumab is currently usually administered on a weekly intravenous schedule, evidence suggests that a triple dose of the drug given once every three weeks has a pharmacokinetic profile expected to be equally efficacious. Neither the optimal schedule nor the optimal duration of trastuzumab therapy has yet been clearly defined in controlled clinical trials. Current clinical investigations of trastuzumab include its use in both the adjuvant and neoadjuvant settings as well as in combination with other chemotherapy drugs or new biologic targeted agents.

Pre-clinical evaluation of [111In]-benzyl-DOTA-ZHER2:342, a potential agent for imaging of HER2 expression in malignant tumors

“…Such strategies include the use of monoclonal antibodies, for example trastuzumab (5) and pertuzumab (6) or degradation of HER2 expression (7). The humanized monoclonal antibody trastuzumab has confirmed clinical efficacy for treatment of breast cancer and has been accepted for routine clinical use (8). Apparently, such therapy can be efficiently used only for patients with tumors expressing HER2.…”

Combination treatment with Grb7 peptide and Doxorubicin or Trastuzumab (Herceptin) results in cooperative cell growth inhibition in breast cancer cells

“…Herceptin in combination with cisplatin, paclitaxel, docetaxel, gemcitabine and vinorelbine have shown promising clinical results (Yeon and Pegram, 2005;Nahta and Esteva, 2006). The theory is that combining Herceptin with other biological targeting agents may increase the extent of the patient response.…”

“…The theory is that combining Herceptin with other biological targeting agents may increase the extent of the patient response. Some of the newer novel combinations include Herceptin plus anti-EGFR tyrosine kinase inhibitor gefitinib (Iressa), lapatinib (Tarceva), a combined EGFR/ErbB2 inhibitor lapatinib (GW572016), cyclin-dependent kinase inhibitor flavopiridol, VEGF inhibitor becacizumab (Avastin) and Interleukin inhibitors (Yeon and Pegram, 2005;Nahta and Esteva, 2006).…”

uPAR and HER-2 gene status in individual breast cancer cells from blood and tissues

“…The methods used for selecting patients for trastuzumab therapy are immunohistochemical (IHC) and gene-based FISH analysis of primary tumor. Retrospective studies have shown that measurement of gene amplification is the best predictive marker of response to trastuzumab-based therapy (4)(5)(6).…”