NATURE REVIEWS | CLINICAL ONCOLOGY VOLUME 6 | JULY 2009 | 387 REVIEWS St Luke’s International Hospital, Tokyo, Japan (H. Yamauchi, S. Nakamura). Department of Breast Medical Oncology at The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA (M. Cristofanilli, G. N. Hortobagyi, N. T. Ueno). Correspondence: N. T. Ueno, Department of Breast Medical Oncology, Unit 1354, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA nueno@ mdanderson.org Molecular targets for treatment of inflammatory breast cancer Hideko Yamauchi, Massimo Cristofanilli, Seigo Nakamura, Gabriel N. Hortobagyi and Naoto T. Ueno Abstract | Despite progress in combined-modality treatment with chemotherapy, surgery, and radiation therapy, the long-term outcome for patients with inflammatory breast cancer (IBC) remains poor. Therapies that target vasculolymphatic processes—angiogenesis, lymphangiogenesis, and vasculogenesis—have shown potential in the treatment for IBC, as represented by bevacizumab. Although the therapeutic effect of targeting lymphangiogenesis and vasculogenesis requires further investigation, targeting of angiogenesis has potential, not only through true antiangiogenic effects, but also through antitumor effects in concert with other pathways. Therapies that target cell proliferation pathways are the most promising targeted therapies for IBC. In particular, therapies that target human epidermal growth factor receptor 2 (for example, trastuzumab and lapatinib) have performed well in the clinical setting, leading to improved outcomes for patients with IBC. Metastatic pathways could have a unique, key role in the aggressiveness of the IBC phenotype. Further extensive work on the unique molecular characteristics of IBC is essential to ensure improved outcomes for patients with this disease. In this Review we discuss three pathways—vasculolymphatic, cell proliferation and metastatic—that could represent important targets in the treatment of IBC. Yamauchi, H. et al. Nat. Rev. Clin. Oncol. 6, 387–394 (2009); published online 26 May 2009; doi:10.1038/nrclinonc.2009.73 Introduction Combined-modality treatment with chemotherapy, surgery, and radiation therapy is the currently recom- mended standard therapeutic strategy for inflammatory breast cancer (IBC). Despite progress in each of these modalities, however, overall survival for patients with IBC is approximately 30%. 1 In one report, on the basis of data collected between 1998 and 2000 in the National Cancer Institute’s Surveillance, Epidemiology and End Results program, the median survival for women with IBC was significantly lower than that for women with noninflammatory locally advanced breast cancer (non-IBC) or non-T4-stage breast cancer (2.9 years, 6.4 years and >10 years, respectively; P <0.0001). 2,3 Furthermore, a review of 398 consecutive patients with IBC treated at The University of Texas M. D. Anderson Cancer Center between 1974 and 2005 showed that there has been no significant improvement in prog- nosis for patients with IBC in the past 30 years. 1 High- dose chemotherapy with hematopoietic stem cell support and hyperfractionated accelerated radiation therapy have both been evaluated as alternatives to the current standard therapy for IBC. These modalities, however, cannot yet be considered the standard of care, as data from prospective, randomized trials are not available. We urgently need to identify the molecular signature of IBC and predictors of response to maximize therapeutic benefit. As novel molecular-targeted therapies have been developed for different types of cancer, especially colon, kidney, lung, leukemia, lymphoma, and breast cancer, there has been renewed interest in the molecular charac- teristics of IBC. One of the main goals in the field of IBC at present is to discover novel molecular targets that could be exploited for therapeutic potential. In the past decade, major efforts have been made to elucidate the molecular basis of IBC. In this Review, we summarize the current understanding of the biological features of IBC and discuss findings from some of the latest preclinical and clinical studies of thera- peutic targeting of IBC-related molecules. We have divided this Review into three sections on the basis of the type of signaling pathway in which molecules are involved— vasculolymphatic, cell proliferation, and metastasis. However, we recognize that many molecules that are important in IBC have roles in a variety of other pathways. Targets in vasculolymphatic pathways Vasculolymphatic processes—angiogenesis, lymphangio- genesis, and vasculogenesis—have more-prominent roles in IBC than in non-IBC. Treatment strategies that target angiogenic pathways have shown effective results in IBC (Figure 1). Whether targeting lymphangiogenic and vasculogenic pathways will prove effective requires further investigation. Overall, however, targeting multiple vasculolymphatic pathways concurrently seems to be a strong therapeutic option for IBC, as discussed below. Angiogenesis Angiogenesis is the mechanism by which new vessels are formed from pre-existing vessels, and this process Competing interests The authors declare no competing interests. © 2009 Macmillan Publishers Limited. All rights reserved