Gelardi T, Damiano V, Rosa R et al.
Università di Napoli Federico II, Naples, Italy.
Br J Cancer 2010;102:513–9.
Editor’s note: Overexpression of HER2 (also known as ErbB2) is found in approximately 25% of breast cancers and is associated with a poor prognosis. Patients whose tumors overexpress HER2 are treated with the humanized monoclonal antibody trastuzumab and, indeed, the use of trastuzumab in combination with chemotherapy results in a longer time to disease progression and a 20% reduction in the risk of death. However, many patients with HER2-positive breast cancer do not respond to trastuzumab or become resistant to it after a period of time. Although the mechanisms involved in resistance are unclear, proposed mechanisms include increased signaling via the HER2-related pathways, reduced p27 levels, loss of function of the tumor suppressor gene PTEN, and masking of the epitope on HER2 that is recognized by the antibody trastuzumab. The latter may be related to the expression of other proteins, for example mucin 4, which interact with HER2 thereby masking the epitope. Given these potential mechanisms of resistance, the current authors investigated the efficacy of immunoconjugates consisting of the single-chain variable fragment of another HER2 antibody known as Erbicin fused to RNase (Erb-hRNase) or to human immunoglobulin G (Erb-hcAb). Both agents recognize a different epitope on HER2 than trastuzumab and have been shown to downregulate downstream signaling from HER2 in trastuzumab-resistant cells in previous work by the group.