Molecular target therapy: basics and clinical application

Abstract

Breast cancer is unique in that molecular target therapy has been widely practiced and has been playing a very important role in its treatment, i.e., hormonal therapy with tamoxifen can be considered as one of the oldest molecular target therapies. Tamoxifen selectively binds to estrogen receptor (ER) and antagonizes the estrogen-dependent growth-stimulative effects. Tamoxifen has been widely used for the treatment of breast cancer in the metastatic and adjuvant setting as a golden standard for more than two decades. Hormonal therapy with aromatase inhibitor is also a molecular targeted therapy because the third-generation aromatase inhibitors selectively bind to aromatase and inhibit its action, resulting in deprivation of intra-tumoral estrogens. Another example of molecular target therapy for breast cancer is trastuzumab (humanized anti-HER2 antibody). Identification of HER2 gene amplification in about 20% of breast cancers leads to trastuzumab, which is currently used as a standard treatment not only in the metastatic setting but also in the adjuvant setting. Furthermore, recent studies have revealed that trastuzumab plus chemotherapy (taxane and anthracycline) dramatically increases the complete pathological response in the neoadjuvant setting, prompting the future use of this combination in this setting. Other novel targeted treatments which are under clinical evaluation, including antiangiogenic compounds (bevacizumab, sunitinib, and others) and bi-functional drugs such as lapatinib [anti-HER2 and (epidermal growth factor receptor) EGFR agent] are showing promise. At the 15th Annual Meeting of the Japanese Breast Cancer Society in Yokohama, Symposium 3, held on 30 June 2007, was entitled ‘‘Molecular target therapy: basics and clinical application’’. In that symposium, updated results of recent clinical studies on the development of molecular target therapies in breast cancer as well as challenges to design a drug in silico and to develop a new drug delivery system targeted at hypoxia were presented by seven speakers, including one invited from the United States. Summaries of their remarks follow. The first speaker Dr. Kathy D. Miller from the Breast Care and Research Center, Division of Hematology and Oncology, Indiana University School of Medicine, USA, made a keynote address on molecular target therapy. She talked about the history of molecular target therapies and stressed the important role played by basic research in the development of such therapies. Updated results of pivotal clinical trials on trastuzumab, lapatinib, and sunitinib were also presented with great enthusiasm. Trastuzumab has been shown to be very active not only in the metastatic setting but also in the adjuvant setting, and adjuvant trastuzumab is now well accepted as a standard therapy for HER2-positive breast cancer. Furthermore, recent success in the introduction of trastuzumab in the neoadjuvant setting in combination with paclitaxel and 5-fluorouracil, epirubicin, cyclophosphamide (FEC) results in a surprisingly high pathological complete response rate with no serious cardiotoxicity, making further studies of neoadjuvant trastuzumab justifiable and attractive. Lapatinib, a dual inhibitor of EGFR and HER2, has also been shown to be active in the metastatic setting for HER2-positive breast cancer which becomes resistant to trastuzumab therapy, and the combination of lapatinib with capecitabin has been S. Noguchi (&) Department of Breast and Endocrine Surgery, Osaka University Graduate School of Medicine, Osaka, Japan e-mail: noguchi@onsurg.med.osaka-u.ac.jp