Available online http://breast-cancer-research.com/content/11/4/207 Review Advances in systemic therapy for HER2-positive metastatic breast cancer Phuong Khanh H Morrow1, Francisco Zambrana1,2 and Francisco J Esteva1 1Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Holcombe Boulevard, Houston, TX 77030, USA 2Current address: Department of Medical Oncology, Hospital Infanta Sofia, Paseo de Europa, 34, Madrid 28702, Spain Corresponding author: Phuong Khanh H Morrow, [email protected] Published: 15 July 2009 Breast Cancer Research 2009, 11:207 (doi:10.1186/bcr2324) This article is online at http://breast-cancer-research.com/content/11/4/207 © 2009 BioMed Central Ltd Abstract differentiation, survival, and migration that are associated with Human epidermal growth factor receptor (HER)2 over-expression HER2-positive breast cancers (Figure 1). Thus, women with is associated with a shortened disease-free interval and poor HER2-positive breast cancers exhibit significantly decreased survival. Although the addition of trastuzumab to chemotherapy in disease-free survival and overall survival (OS) [2-5]. the first-line setting has improved response rates, progression-free survival, and overall survival, response rates declined when trastu- This review discusses progress in the treatment of HER2- zumab was used beyond the first-line setting because of multiple positive metastatic breast cancer since the discovery of the mechanisms of resistance. Studies have demonstrated the clinical utility of continuing trastuzumab beyond progression, and further HER2 oncogene, with particular focus upon the mechanisms trials to explore this concept are ongoing. New tyrosine kinase of resistance to trastuzumab, treatment with trastuzumab inhibitors, monoclonal antibodies, PTEN (phosphatase and tensin beyond progression, use of lapatinib, and new biologic homolog) pathway regulators, HER2 antibody-drug conjugates, agents that may provide further therapeutic options in and inhibitors of heat shock protein-90 are being evaluated to patients with metastatic HER2-positive breast cancer. determine whether they may have a role to play in treating trastuzumab-resistant metastatic breast cancer. Use of trastuzumab in the treatment of metastatic breast cancer Introduction Trastuzumab is a humanized recombinant monoclonal anti- As knowledge about the treatment of breast cancer has grown, body, of the IgG1 type, which binds with high affinity to the attention has increasingly focused on developing a targeted extracellular domain of the HER2 receptor. The mechanism approach to this diverse disease. In particular, treatment of underlying trastuzumab’s efficacy in the treatment of HER2- human epidermal growth factor receptor (HER)2/neu-positive positive breast cancer is multifaceted and incompletely breast cancer has undergone significant advances since the understood. In vivo breast cancer models have demonstrated cloning of the HER2 oncogene in 1984 [1]. that trastuzumab induces antibody-dependent cellular cyto- toxicity through activation of Fc receptor expressing cells (for The HER2 oncogene encodes one of four transmembrane example, macrophages and natural killer cells), leading to receptors within the erbB family. Its over-expression, which lysis of tumor cells [6,7]. Trastuzumab has also been shown to occurs in approximately 25% of all breast cancer tumors, is downregulate p185ErbB2 [8]. In addition, trastuzumab blocks associated with a shortened disease-free interval and poor the release of the extracellular domain of HER2 by inhibiting survival [2]. Following ligand binding, the glycoprotein cleavage of the HER2 protein by ADAM (a disintegrin and receptor is activated through homodimerization or hetero- metalloproteinase domain) metalloproteinases [9]. Significant dimerization, leading to a cascade of events that involves declines in serum HER2 levels are a predictor of outcome activation of the tyrosine kinase domain, Ras/Raf/mitogen- after trastuzumab-based therapy [10-12]. Furthermore, trastu- activated protein kinase (MAPK) pathway, and phosphatidyl- zumab inhibits downstream PI3K-Akt signaling, leading to inositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin apoptosis [13]. It has also been shown that trastuzumab (mTOR). This sequence promotes the rapid cell growth, downregulates proteins that are involved in p27kip1 seques- 17-AAG = 17-(allylamino)-17-demethoxygeldanamycin; CR = complete response; EGFR = epidermal growth factor receptor; HER = human epi- dermal growth factor receptor; HR = hazard ratio; IGF-IR = insulin-like growth factor receptor-I; MAPK = mitogen-activated protein kinase; mTOR = mammalian target of rapamycin; OS = overall survival; PI3K = phosphatidylinositol-3-kinase; PR = partial response; PTEN = phosphatase and tensin homolog; TTP = time to progression; VEGF = vascular endothelial growth factor. Page 1 of 10 (page number not for citation purposes) Breast Cancer Research Vol 11 No 4 Morrow et al. Figure 1 The HER2 family and interrelated signaling and events. The binding of ligands, including epidermal growth factor and transforming growth factor-α, leads to the activation of signaling cascades involving Ras/Raf/MAPK, PI3K/Akt/mTOR, and JAK/STAT. This sequence of events promotes the apoptosis, proliferation, survival, migration, angiogenesis, and metastasis of HER2-over-expressing breast cancers. BTC, betacellulin; EGF, epidermal growth factor; EPG, epigen; EPR, epiregulin; HB-EGF, heparin-binding EGF-like growth factor; HER, human epidermal growth factor receptor; JAK, Janus kinase; JNK, c-Jun N-terminal kinase 1; mTOR, mammalian target of rapamycin; MAPK, mitogen-activated protein kinase; MEK, mitogen-induced extracellular kinase; MEKK, mitogen-activated protein/ERK kinase kinase; NRG, neuregulin; PI3K, phosphatidylinositol 3-kinase; STAT, signal transducer and activator of transcription; TGF, transforming growth factor; TK, tyrosine kinase. tration, causing release of p27kip1 and enabling inhibition of inositol-3,4,5 triphosphate, which is the site that recruits the cyclin E/Cdk2 complexes and subsequent G1 arrest [14]. pleckstrin-homology domain of Akt to the cell membrane Moreover, trastuzumab has been shown to exert antiangio- [24,25]. PTEN inhibits the ability of PI3K to catalyze the genic effects through normalization of microvessel density [15]. production of phosphotidylinositol-3,4,5 triphosphate and thus antagonizes the Akt cascade [26]. Loss of PTEN Although the mechanism that accounts for trastuzumab’s function occurs in approximately 50% of all breast cancers antitumor activity remains incompletely understood and [27]. Restoration of PTEN expression impedes Akt activation requires further elucidation, the results of the inclusion of and increases apoptosis [28]. Nagata and coworkers [24] trastuzumab in the treatment of HER2-positive breast cancer demonstrated that inhibition of PTEN expression by antisense are clear. Slamon and colleagues [16] found that addition of oligonucleotides resulted in trastuzumab resistance in vitro trastuzumab to chemotherapy, in the first-line setting, resulted and in vivo. Specifically, tumors in which PTEN expression in a significantly improved objective response, time to disease was abrogated by antisense oligonucleotides exhibited tumor progression, and OS. Combinations of trastuzumab with growth patterns that were unaffected by trastuzumab taxanes, platinum salts, vinorelbine, and capecitabine have administration. Patients with PTEN-deficient tumors demon- yielded benefits in the treatment of HER2-positive metastatic strated significantly lower complete response (CR) and breast cancer [17-23]. However, other trials demonstrated partial response (PR) rates to trastuzumab plus taxane that response rates declined markedly when trastuzumab was therapy than those who had PTEN-expressing tumors. used beyond the first-line setting, indicating the development of resistance to this agent. Independent of PTEN mutations, constitutive Akt phosphory- lation may also occur in HER2-over-expressing tumors [29]. Mechanisms of resistance to trastuzumab PTEN/PI3K/mTOR/Akt pathways MUC4 overexpression PTEN (phosphatase and tensin homolog) is a tumor sup- MUC4 is a membrane-associated, glycosylated mucin that pressor gene that causes dephosphorylation of phosphotidyl- has been shown to be over-expressed in breast cancer cells Page 2 of 10 (page number not for citation purposes) Available online http://breast-cancer-research.com/content/11/4/207 [30]. In rat models, MUC4 forms a complex with the HER2 implying that the increase in VEGF protein expression was protein and potentiates its phosphorylation, leading to cell mediated by post-transcriptional changes. In addition, when proliferation [30,31]. In addition to its ligand activity, MUC4 bevacizumab was added to a trastuzumab-based regimen for inhibits binding of trastuzumab to the HER2 receptor. mice bearing tumors of the 231-H2N cell line, a HER2-over- Utilizing JIMT-1, a HER2-over-expressing cell line with primary expressing variant of the MDA-MB-231 cell line, tumor resistance to trastuzumab, Nagy and colleagues [32] growth was delayed significantly. Their cumulative findings demonstrated that MUC4 expression was higher in this indicate that upregulation of VEGF may contribute to the trastuzumab-resistant cell line than in trastuzumab-sensitive mechanism of trastuzumab resistance, and dual inhibition of cell lines, and that the level of MUC4 expression inversely these pathways is currently