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Trastuzumab in the treatment of HER2 positive breast cancer

The Pharmacy Department, Guy’s Hospital, London, UK

Objective. To provide a comprehensive review of the preclinical and clinical pharmacology and toxicology of the monoclonal antibody trastuzumab, with particular reference to its use in its approved indication, HER2/neu-overexpressing breast cancer.

Data sources. A MEDLINE search was conducted using the terms ‘trastuzumab’ and ‘Herceptin’ for the period 1995-2001. The reference lists from retrieved articles were reviewed and other relevant papers identified. The abstract books from the annual meetings of the American Society of Clinical and Oncology and the European Society of Medical Oncology were also reviewed.

Data extraction. The aim of the review was to be comprehensive and descriptive. All studies containing information deemed to be of interest were reviewed by the author; none were excluded on grounds of quality.

Data summary. Trastuzumab is a chimeric monoclonal antibody with a hypervariable region of murine origin inserted into a human IgG1 skeleton. Trastuzumab recognizes p185^HER2/neu, the 185-kDa product of the HER2/neu protooncogene. This gene is overexpressed in around 20% of breast cancers and encodes for a trans-membrane protein that has extensive structural homology with the EGFR. HER2/neu overexpression is prognostic of short relapse-free and overall survival and, possibly, of poor response to certain hormonal and cytotoxic treatments. Trastuzumab inhibits the growth of HER2/neu-overexpressing tumour cells grown in tissue culture or as xeno-grafts in mice. It also potentiates the action of certain cytotoxic drugs against such cells. These properties stimulated clinical trials of trastuzumab in women with HER2/neu-positive breast cancer. Used alone, in women with heavily pretreated HER2/neu-positive breast cancer, trastuzumab stabilized disease in 35% of cases and induced regression in a further 22%. Its use was associated with prolonged stabilization of quality of life. When used in combination with paclitaxel, or anthracycline-based chemotherapy, as a first-line treatment for metastatic breast cancer, it increased response rates, time to disease progression and survival. Unfortunately, when used in conjunction with anthracyclines, trastuzumab has been associated with an unacceptable incidence of cardiotoxicity. For this reason, it is currently approved for use alone or in combination with paclitaxel. When added to paclitaxel as a first-line treatment, it increased the median time to disease progression from 3.0 to 6.9 months (P= 0.0001) and the 1-year survival rate from 62% to 73%, with little toxicity except occasional and, generally, mild infusion reactions.

Key Words: Trastuzumab • breast cancer • monoclonal antibodies • chemotherapy

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