The ABC's of Herceptin

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Science  25 Apr 2008:
Vol. 320, Issue 5875, pp. 427
DOI: 10.1126/science.320.5875.427b

The breast cancer drug trastuzumab (Herceptin) has been heralded as a breakthrough in translational oncology because its development was based on the detailed characterization of a signaling pathway that promotes tumor cell growth. Trastuzumab is a humanized monoclonal anti body whose antigen-binding domain Fab recognizes a tyrosine kinase receptor (HER2/erbB2) that is overexpressed in some breast cancers, and its anticancer activity is thought to involve disruption of cell proliferation signaling through this receptor. Although some patients with HER2/erbB2-positive breast tumors improve when treated with trastuzumab, about 70% do not respond, and the reasons for this have been unclear.

Musolino et al. provide clinical evidence that trastuzumab's anticancer activity may be due, at least in part, to a completely distinct mode of action—antibody-dependent cell-mediated cytotoxicity (ADCC), a process by which immune effector cells such as natural killer cells lyse a target cell bound to an antibody. Studying 54 patients with HER2/erbB2-positive metastatic breast cancer, the authors discovered a correlation between the patients' response to trastuzumab and certain germline sequence variants in genes encoding Fcγ receptors, a class of proteins critically involved in ADCC. These results not only suggest how to predict which breast cancer patients would be most likely to respond to trastuzumab, but also raise the possibility that manipulations aimed at enhancing the drug's capacity to induce ADCC might improve or broaden its clinical efficacy. — PAK

J. Clin. Oncol. 26, 1789 (2008).

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