Trastuzumab (Herceptin), a fully humanized monoclonal antibody targeting the extracellular domain of HER2 protein, exhibits potent growth-inhibitory activity against HER2- overexpressing tumors (7) and improves overall survival in patients with HER2-overexpressing metastatic breast cancer

Background: Although it was previously reported that lapatinib combined with Herceptin improved the progression-free survival rate compared with lapatinib alone for patients with Herceptin-refractory HER2-positive metastatic breast cancer, the mechanism is purported to be an antiproliferative effect relating to the synergism of these two agents. Materials and Methods: We evaluated how lapatinib interacts with Herceptin in HER2-positive breast cancer, with a particular focus on Herceptin-mediated antibody-dependent cellular cytotoxicity (ADCC). Results: In an in vitro assay, lapatinib induced HER2 expression at the cell surface of HER2-positive breast cancer cell lines, leading to the enhancement of Herceptin-mediated ADCC. Furthermore, we present a case report in which a second Herceptin treatment following lapatinib resulted in the marked shrinkage of multiple metastatic tumors in HER2positive breast cancer. Conclusion: Lapatinib may have the potential to convert Herceptin-refractory to Herceptinsensitive tumors in HER2-positive breast cancer by upregulation of the cell surface expression of HER2. Human epidermal growth factor receptor (EGFR) 2 (HER2) is one of four members of the ErbB receptor tyrosine kinase protein family, and this proto-oncogene encodes a 185-kDa transmembrane glycoprotein (1). The overexpression and gene amplification of HER2 is seen in a variety of human tumors, including 25-30% of breast and ovarian, renal cell, esophageal squamous cell, and gastric and colorectal carcinomas (2-5). In particular, the overexpression and gene amplification of HER2 in breast cancer correlates with a poorer prognosis and more aggressive tumor growth (6). Trastuzumab (Herceptin), a fully humanized monoclonal antibody targeting the extracellular domain of HER2 protein, exhibits potent growth-inhibitory activity against HER2overexpressing tumors (7) and improves overall survival in patients with HER2-overexpressing metastatic breast cancer (8). The diverse mechanisms of Herceptin include the downregulation of HER2 receptors (7), blockade of signaling pathways (7), inhibition of angiogenesis (9), activation of apoptotic signals of tumor cells (10), and enhancement of the immune system, such as via antibody-dependent cellular cytotoxicity (ADCC) (7, 11-13). Lapatinib is a dual tyrosine kinase inhibitor (TKI) targeting both EGFR and HER2 tyrosine kinase domains (14), and has recently been approved by the U.S. Food and Drug Administration for the treatment of HER2-expressing advanced breast cancer. Lapatinib competes with the adenosine triphosphate binding site located within the intracellular kinase domain of EGFR and HER2, and has mechanisms of action distinct from those of Herceptin (1517). Furthermore, Scaltriti et al. and our group also showed that lapatinib induces the accumulation of HER2 at the cell surface and enhances the effects of Herceptinmediated ADCC (18, 19). In several clinical trials, lapatinib prolonged progression-free survival in patients with HER2-overexpressing advanced or metastatic breast cancer, including those with Herceptin-refractory disease, and was established as effective treatment for them (15, 20-23). In this study, we evaluate whether lapatinib induces the accumulation of HER2 at the cell surface of HER2-positive breast cancer cell lines, resulting in the enhancement of Herceptin-mediated ADCC. Furthermore, we present a case report in which lapatinib showed the potential to convert Herceptin-refractory to Herceptin-sensitive tumors in HER2positive breast cancer. 2999 Correspondence to: Koji Kono, MD, Ph.D., First Department of Surgery, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi 409-3898, Japan. Tel: +81 552737390, Fax: +81 552739574, e-mail: [email protected]