Decreased Response to Paclitaxel Versus Docetaxel in HER-2/neu Transfected Human Breast Cancer Cells Lois M. Witters, B.S., Samuel M. Santala, B.S., Linda Engle, B.S., Vernon Chinchilli, Ph.D., and Allan Lipton, M.D. Taxanes are effective in the treatment of metastatic breast cancer. Docetaxel has been shown to be more potent than paclitaxel in inducing bcl-2 phosphorylation and apoptosis and is clinically active in some paclitaxel-resistant breast tumors. HER-2/neu overexpression has been shown to correlate with resistance to hormonal therapy as well as chemotherapy. Using a HER-2/neu transfected MCF-7 human breast cancer cell line, we investigated the role of HER-2/neu overexpression on resistance to paclitaxel and docetaxel treatment. A control vector transfected MCF-7 human breast cancer cell line (MCF/ neo) and a HER-2/neu transfected MCF-7 line (MCF/18) were treated with various concentrations of docetaxel or paclitaxel. Cell number was assessed using the MTT tetrazolium dye assay. In the control vector transfected MCF/neo cell line, paclitaxel and docetaxel gave similar dose-dependent growth inhibition (p = 0.175). In HER-2/neu transfected MCF/18 cells, docetaxel treatment resulted in a dose-dependent inhibi- tion similar to that seen in MCF/neo cells. Paclitaxel, however, gave significantly less growth inhibition than docetaxel in the HER-2/neu overexpressing MCF/18 cells (p = 0.0003). These data suggest that HER-2/neu overexpression may contribute to paclitaxel resistance. In contrast, the cytotoxic effects of do- cetaxel in these breast carcinoma cells are not affected by HER-2/neu expression. Therefore, docetaxel may be the pre- ferred taxane therapy in HER-2/neu overexpressing breast tumors. Key Words: Paclitaxel—Docetaxel—HER-2/neu—Breast cancer. Activation of the HER-2/neu receptor tyrosine kinase triggers a cascade of events leading to cell prolifera- tion. 1,2 HER-2/neu is overexpressed in 20% to 30% of breast tumors 3,4 and is associated with a more aggressive disease and worse prognosis. 3–6 Docetaxel and paclitaxel are members of the taxane family. They are promoters of tubulin polymerization and microtubule stabilization. 7–9 They also induce Bcl-2 phosphorylation and apoptosis. Docetaxel has been shown to induce Bcl-2 phosphorylation and apoptosis at 100-fold lower concentration than paclitaxel. 10,11 It has also been reported that docetaxel produces greater anti- tumor activity than paclitaxel at equal doses both in vitro 12,13 and in vivo. 14,15 Docetaxel is 2 to 12 times more potent than paclitaxel in causing cell death. 13,16 In addition, the cellular uptake of docetaxel is greater than that of paclitaxel, and the efflux of docetaxel from the tumor cell is slower, meaning longer tumor retention time. 7,17 Both drugs are effective as first-line treatment of metastatic breast cancer (MBC). Docetaxel, however, has proven to be more effective in second-line treatment of MBC. In a phase II clinical study in anthracycline- resistant breast cancer, the response rate (RR) with do- cetaxel was greater than that with paclitaxel (RR = 32–51%, 6 –30%, respectively). 18 –21 Docetaxel has also been active in patients with paclitaxel-resistant breast cancer, suggesting that there is only a partial cross resistance between paclitaxel and docetaxel. 7,22 In a phase III study in MBC, Chan showed that docetaxel was superior to the previously accepted treatment, doxorubi- cin. 23,24 In contrast, paclitaxel was not better than doxorubicin. 25,26 Many reports have suggested a relationship between HER-2/neu expression and resistance to paclitaxel. Yu 27 has shown that HER-2/neu transfected MDA-MB435 human breast cancer cells are more resistant to paclitaxel than the lower HER-2/neu expressing parental line. Perez-Soler 28 has reported that in non–small-cell lung cancer (NSCLC) heterotransplants, lack of HER-2/neu expression was associated with response to paclitaxel (0% of responding tumors expressed HER-2/neu, whereas 48% of the nonresponders expressed HER-2/ neu). Use of trastuzumab, the humanized monoclonal From the Departments of Medicine (L.M.W., S.M.S., A.L.) and Biostatistics & Epidemiology (L.E., V.C.), Penn State College of Medicine, Hershey, Pennsylvania, U.S.A. Presented in poster form at the San Antonio Breast Cancer Confer- ence, San Antonio, Texas, 2000. Supported by a grant from Aventis Pharmaceuticals, Parsippany, NJ. Address correspondence and reprint requests to Dr. Allan Lipton, Department of Medicine, H046, The Milton S. Hershey Medical Center, Penn State College of Medicine, 500 University Drive, Her- shey, PA 17033, U.S.A. E-mail: alipton@psu.edu Am J Clin Oncol (CCT) 26(1): 50–54, 2003. © 2003 Lippincott Williams & Wilkins, Inc., Philadelphia 50