New therapies in HER2-positive breast cancer: A major step towards a cure of the disease? Ahmad Awada a,⇑ , Ivana Bozovic-Spasojevic a , Louis Chow b,1 a Jules Bordet Institute, Université Libre de Bruxelles, Brussels, Belgium b UNIMED Medical Institute, Comprehensive Centre for Breast Diseases, Organization for Oncology and Translational Research, Hong Kong, China article info Article history: Received 5 August 2011 Received in revised form 2 January 2012 Accepted 3 January 2012 Available online xxxx Keywords: Anti-HER2 antibodies HER2 Metastatic breast cancer Trastuzumab Tyrosine-kinase inhibitors summary Overexpression of the human epidermal growth factor receptor 2 (HER2) predicts a poor prognosis in metastatic breast cancer. While the introduction of HER2-targeted therapies, such as the monoclonal antibody trastuzumab and the small-molecule tyrosine kinase inhibitor lapatinib, has significantly improved outcomes in HER2+ breast cancer compared with previously available therapies, use of these targeted therapies is often limited by the development of drug resistance and tolerability issues. These limitations create the need for further development and investigation of new targeted therapies that show potent and selective inhibition of these targets or closely connected molecular pathways. Recently, several agents have demonstrated promising activity in HER2+ metastatic breast cancer, either as mono- therapy or in combination therapy, including the tyrosine-kinase inhibitors neratinib (HKI-272) and afatinib (BIBW-2992) and the anti-HER2 monoclonal antibodies pertuzumab and trastuzumab-DM1 (T-DM1). Agents that target other molecular pathways, such as the vascular endothelial growth factor receptor, mammalian target of rapamycin, PI3-kinases, insulin-like growth factor (IGFR), HSP-90, and other kinases also have potential, in combination with anti-HER2 and/or other systemic therapies, to be active in this subtype of breast cancer. Innovative clinical studies are required in well-characterized patient populations to define the true clinical value of these emerging new approaches. Ó 2012 Elsevier Ltd. All rights reserved. Introduction Breast cancer patients diagnosed with distant metastatic dis- ease still face a dismal 5-year survival rate of only 27%, while those initially diagnosed with localized and regional breast cancer have shown 5-year survival rates of 99% and 84%, respectively. 1 Cur- rently, the treatment of patients with metastatic breast cancer (MBC) involves the use of multiple agents, including endocrine therapies for hormone receptor-positive (HR+) disease, cytotoxic chemotherapy (e.g., anthracycline-, taxane-, or antimetabolite- based regimens), therapies targeting HER2 and vascular endothe- lial growth factor (VEGF) pathways, and more recently, though not yet an approved treatment, the poly-ADP-ribose polymerase (PARP) inhibitors in breast cancer gene 1 or 2 (BRCA1/2)-mutated tumors as well as triple negative subtypes. 2 In particular, human epidermal growth factor (EGF) receptor 2 (HER2; ErbB2) has been identified as an important target for breast cancer. 3 HER2 is amplified or overexpressed in approximately 20% of breast cancers, and increased HER2 expression correlates with more aggressive breast tumors and, prior to the introduction of trastuzumab, a poorer prognosis than tumors with normal HER2 expression. This review examines the current state of HER2- targeted therapies for MBC, identifies unmet needs for these pa- tients, particularly for those who have already received treatment with trastuzumab, and examines emerging data with investiga- tional agents and combination therapies that might help improve outcomes for patients with MBC. Ultimately, these new agents or approaches that exhibit significant efficacy in the metastatic set- ting will be moved quickly to the adjuvant setting, where cure is the main objective. Approved HER2-targeted therapies for MBC Trastuzumab Trastuzumab, a humanized anti-HER2 monoclonal antibody (MAb), is currently recommended as first-line treatment for patients with metastatic HER2+ tumors, either as a single agent (limited group of patients) or in combination with endocrine ther- apy or chemotherapy, as well as in the adjuvant setting. 2 Although the mechanisms of action of trastuzumab are not yet completely understood, trastuzumab is likely to exerts its antitumor activity 0305-7372/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. doi:10.1016/j.ctrv.2012.01.001 ⇑ Corresponding author. Address: Jules Bordet Institute, Boulevard de Waterloo 121, B-1000 Brussels, Belgium. Tel.: +32 2 541 31 89; fax: +32 2 541 33 39. E-mail addresses: ahmad.awada@bordet.be (A. Awada), ivana.bozovic@ bordet.be (I. Bozovic-Spasojevic), lwcchow@ootr.org (L. Chow). 1 Tel.: +852 2861 0286. Cancer Treatment Reviews xxx (2012) xxx–xxx Contents lists available at SciVerse ScienceDirect Cancer Treatment Reviews journal homepage: www.elsevierhealth.com/journals/ctrv Please cite this article in press as: Awada A et al. New therapies in HER2-positive breast cancer: A major step towards a cure of the disease? Cancer Treat Rev (2012), doi:10.1016/j.ctrv.2012.01.001