Trastuzumab: triumphs and tribulations

Abstract

The human epidermal growth factor receptor 2 (HER2) tyrosine kinase receptor is overexpressed in approximately 20–30% of human breast cancers, and is associated with reduced survival. Hence, numerous therapeutic strategies have been tested for their ability to target the HER2 protein. The humanized monoclonal antibody trastuzumab (Herceptin) was the first HER2-targeted agent approved for clinical use in breast cancer patients. Response rates to single-agent trastuzumab range from 12 to 34% for metastatic breast cancer (MBC), and significant improvements in survival rates are achieved in patients with early-stage HER2-overexpressing breast cancer in the adjuvant setting. Despite its initial efficacy, acquired resistance to trastuzumab develops in a majority of patients with MBC, and a large subset never responds, demonstrating primary resistance. Molecular mechanisms of trastuzumab antineoplastic activity and potential mechanisms contributing to its resistance will be discussed in this review. Novel agents that may enhance trastuzumab efficacy will also be discussed.

Introduction

Human epidermal growth factor receptor 2 (HER2) is a member of the epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases, which also includes HER4 and the catalytically inactive HER3 protein. HER2, the only member for which a specific ligand has not been identified, mediates lateral signaling to other HER receptors as the preferred heterodimerization partner of this family (Graus-Porta et al., 1997). Signaling by the HER family is performed primarily through the phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) cascades (Sliwkowski et al., 1999; Baselga et al., 2001). In addition, HER2 signaling reduces expression of the proteins cyclin D and c-myc, which sequester the cyclin-dependent kinase (cdk) inhibitor p27kip1, such that it is not available to inhibit cdk2 activity and ultimately results in increased cellular proliferation (Lane et al., 2000; Neve et al., 2000).

Overexpression of HER2, with subsequent constitutive kinase activation, is found in approximately 20–30% of human breast cancers, primarily owing to gene amplification, and is associated with reduced disease-free and overall survival (Slamon et al., 1987, 1989; Press et al., 1997). Trastuzumab (Herceptin; Genentech; South San Francisco, CA, USA) is a recombinant humanized monoclonal antibody (rhumAb 4D5) directed against an extracellular region of the HER2 protein (Carter et al., 1992). Trastuzumab was the first HER2-targeted therapy approved by the United States Food and Drug Administration (FDA) for the treatment of HER2-overexpressing metastatic breast cancer (MBC). Recent clinical trials established that addition of trastuzumab to adjuvant chemotherapy (either in sequence or in combination) resulted in significant improvements in disease-free and overall survival rates in patients with early-stage HER2-overexpressing breast cancer (Buzdar et al., 2005; Piccart-Gebhart et al., 2005; Romond et al., 2005). Although trastuzumab represents an early success story in the field of targeted antineoplastic agents, there are many questions that remain regarding the mechanisms of activity of this agent and how to improve on its efficacy in breast cancer patients.

Clinical trials

The initial clinical trials of trastuzumab tested it as a single agent in HER2-overexpressing MBC, and demonstrated response rates ranging from 12 to 34% for a median duration of 9 months (Baselga et al., 1996; Cobleigh et al., 1999; Vogel et al., 2002). Phase III trials combining trastuzumab with paclitaxel (Seidman et al., 2001; Slamon et al., 2001) or docetaxel (Esteva et al., 2002; Marty et al., 2005) demonstrated increased response rates, time to disease progression and overall survival compared with trastuzumab monotherapy. In patients with MBC showing her2 amplification and no history of previous chemotherapy for metastatic disease, the median time to progression (TTP) in response to single-agent trastuzumab treatment was 4.9 months and 7.4 months in patients who received trastuzumab plus chemotherapy (Slamon et al., 2001). Hence, although there was an improvement, the median duration of response remained less than 1 year. The use of trastuzumab in the adjuvant setting, either in combination with or following chemotherapy, improves the disease-free and overall survival rates for patients with early-stage breast cancer (Buzdar et al., 2005; Piccart-Gebhart et al., 2005; Romond et al., 2005). However, approximately 15% of patients receiving trastuzumab-based adjuvant chemotherapy will progress to develop metastatic disease. Therefore, resistance to trastuzumab, both primary or de novo resistance and acquired or treatment-induced resistance, is a major clinical concern facing breast oncologists today. Understanding the molecular mechanisms contributing to trastuzumab resistance and identifying more effective combinations or novel agents is critical to improving the survival of patients whose tumors overexpress HER2 (Nahta et al., 2006).

Mechanisms of action

Part of the success of trastuzumab appears to arise from its effects on multiple biological processes and signaling pathways. Experimental models have suggested several molecular mechanisms of antineoplastic activity for trastuzumab (Nahta and Esteva, 2006). Initial studies supported trastuzumab-mediated endocytosis and degradation of the HER2 receptor, with subsequent inhibition of the downstream PI3K and MAPK signaling cascades. Reduced downstream signaling through these pathways induces p27kip1, which reduces cdk2 activity and promotes cell-cycle arrest and apoptosis (Sliwkowski et al., 1999; Lane et al., 2000; Neve et al., 2000; Baselga et al., 2001). Although further studies have consistently verified diminished downstream signaling in response to trastuzumab, downregulation of cell surface HER2 receptor levels has not been observed in all cases (Lane et al., 2000; Nahta et al., 2004a). Furthermore, one of the problems with trastuzumab is that it is unable to block dimerization of HER2 with other HER family members, such as EGFR and HER3. Thus, signaling from these heterodimers appears to proceed in the presence of trastuzumab-based treatment, which may contribute to reduced response.

An advantageous property of trastuzumab that may set it apart from the newer generation of small molecule kinase inhibitors is the fact that antibodies possess the ability to modulate the immune system. HER2-targeted antibodies, including trastuzumab, promoted apoptosis in MBC cell lines via antibody-dependent cellular cytotoxicity (ADCC) (Cooley et al., 1999; Clynes et al., 2000; Gennari et al., 2004; Arnould et al., 2006). Mice with suppressed natural killer (NK) cell function, which is important for ADCC, demonstrated only 29% tumor growth inhibition in response to trastuzumab versus 96% tumor growth inhibition in control mice with intact NK cell function (Clynes et al., 2000). Thus, an active immune response may contribute significantly to trastuzumab efficacy. Clinical data showed a higher in situ infiltration of leukocytes and ADCC activity in patients, who achieved complete or partial remission with preoperative trastuzumab relative to those who did not respond (Gennari et al., 2004). However, it is important to remember that patients with advanced cancer are immunosuppressed, making it difficult to determine the ability of the immune system to facilitate response to antineoplastic agents such as trastuzumab. Thus, additional studies are required to obtain a greater understanding of the importance of ADCC in mediating the response to trastuzumab. In addition, understanding the relative importance of the immune response in the efficacy of trastuzumab in the metastatic versus adjuvant setting may be of interest, as patients with early-stage breast cancers may be able to elicit a stronger immune reaction.

Another mechanism that appears to be employed by trastuzumab is inhibition of angiogenesis. Reduced microvessel density in vivo (Izumi et al., 2002; Klos et al., 2003; Wen et al., 2006) and reduced endothelial cell migration in vitro (Klos et al., 2003) have been observed in response to trastuzumab. Trastuzumab-treated mouse mammary tumors showed reduced expression of VEGF, transforming growth factor-α, Ang-1 and PAI-1, which normally act to promote angiogenesis (Izumi et al., 2002; Klos et al., 2003; Wen et al., 2006). In addition to trastuzumab inhibiting angiogenesis on its own, the combination of trastuzumab with paclitaxel inhibited angiogenesis to an even greater degree (Klos et al., 2003). Thus, inhibition of angiogenesis by trastuzumab may result in improved tumor vasculature, such that drugs like paclitaxel can circulate and reach tumor cells more efficiently (Izumi et al., 2002).

Another potentially important antitumor mechanism employed by trastuzumab is its ability to block cleavage of the HER2 extracellular domain (ECD). In addition to the full-length 185 kDa HER2 receptor, a 95-kDa N-terminally truncated membrane-associated HER2 fragment (p95) with increased kinase activity (Christianson et al., 1998) can sometimes be found on the cell surface. Along with the presence of p95, a 110-kDa ECD is released and detected in cell culture media of HER2-overexpressing cells (Lin and Clinton, 1991; Zabrecky et al., 1991; Pupa et al., 1993). This HER2 ECD can be detected in the serum of approximately 40–50% of MBC patients (Leitzel et al., 1995; Yamauchi et al., 1997; Colomer et al., 2000; Hayes et al., 2001), and HER2 p95 has been found in some breast tumors (Christianson et al., 1998), indicating that HER2 ECD is present in vivo, and thus may have clinical relevance with respect to disease progression or treatment response. High serum levels of HER2 ECD correlated with poor prognosis, increased metastasis (Molina et al., 2002) and decreased responsiveness to endocrine therapy and chemotherapy in patients with advanced breast cancer (Leitzel et al., 1995; Yamauchi et al., 1997; Colomer et al., 2000; Hayes et al., 2001). HER2 ECD release or ectodomain shedding may be due to proteolytic cleavage mediated by metalloproteases. Trastuzumab was shown to block this HER2 ECD proteolytic cleavage and shedding in vitro (Molina et al., 2001). Recent evidence, however, suggests that truncated forms of HER2 may also result from alternative initiation of translation using different start codons in the her2 gene (Anido et al., 2006). Importantly, response to trastuzumab may be predictable in part by the presence of elevated serum ECD levels before treatment initiation (Esteva et al., 2002, 2005). The value of measuring circulating HER2 ECD levels for predicting response to trastuzumab is debatable, however, as some believe an increased ECD level is a reflection of tumor burden, rather than representing a tumor marker. Thus, further clinical studies examining ECD and trastuzumab response are warranted to clarify its predictive value.

Potential mechanisms of resistance

The majority of MBC patients who initially respond to trastuzumab begin to demonstrate disease progression again within 1 year (Seidman et al., 2001; Slamon et al., 2001; Esteva et al., 2002). Even in the adjuvant setting, where trastuzumab improves survival rates in patients with early-stage breast cancer (Buzdar et al., 2005; Piccart-Gebhart et al., 2005; Romond et al., 2005), approximately 15% of patients eventually develop metastatic disease. Preclinical studies that examine the molecular mechanisms contributing to trastuzumab resistance (Figure 1a) are important to achieve a greater response rate in this population, and to identify novel agents that will benefit patients whose cancers are trastuzumab refractory (Figure 1b).

Figure 1
figure1

Trastuzumab resistance: mechanisms and novel agents. (a) Trastuzumab (Tras) binds to the extracellular domain of HER2, but is incapable of disrupting the interaction of HER2 with other receptors such as EGFR. Hence, downstream signaling is partially reduced owing to HER2 inhibition, but compensatory signaling from EGFR is still possible. Increased levels of erbB ligands such as EGF may increase this signaling and promote resistance to trastuzumab-based therapy. In addition, signaling from another growth factor receptor, IGF-IR, may contribute to trastuzumab resistance. A unique interaction occurs between IGF-IR and HER2 in resistant cells and facilitates crosstalk from IGF-IR to HER2. Hence, in the presence of circulating IGF-I, this interaction may result in increased phosphorylation of HER2 and downstream signaling. A reduced p27kip1 level was correlated with resistance and occurs subsequent to IGF-I signaling. Finally, another potential mechanism of resistance is elevated levels of circulating HER2 ECD, which is being studied as a predictive marker for response to trastuzumab. (b) Pertuzumab (Ptz) is another HER2-targeted monoclonal antibody that sterically hinders interaction of HER2 with EGFR, HER3 or IGF-IR. Clinical efficacy of pertuzumab in trastuzumab-refractory MBC is unknown. Testing of IGF-IR-targeted agents including monoclonal antibodies (mAb) and tyrosine kinase inhibitors (TKI) is warranted giving preclinical data supporting increased IGF-I signaling as a mechanism of trastuzumab resistance. However, no such clinical trials are underway to date to the authors' knowledge. Finally, the agent showing the most promise in the HER2 overexpressing, trastuzumab-refractory setting is lapatinib (Lap). Lapatinib blocks signaling from EGFR and HER2, and may have some inhibitory effect on IGF-I signaling. Interestingly, lapatinib blocked growth of in vivo tumors that overexpressed truncated HER2 receptors. Also, lapatinib induces p27kip1, which may partially contribute to growth arrest and apoptosis. Lapatinib will likely hold an important place in the treatment of HER2-overexpressing, trastuzumab-refractory metastatic breast cancers.

The first preclinical study to examine trastuzumab resistance demonstrated that stable overexpression of the insulin-like growth factor-I receptor (IGF-IR) reduced trastuzumab-mediated growth arrest of SKBR3 HER2-overexpressing breast cancer cells (Lu et al., 2001). In this study, expression of IGF-binding protein 3 (IGFBP3), which blocks IGF-I-mediated activation of IGF-IR, restored trastuzumab sensitivity. In addition, IGFBP3 increased the trastuzumab sensitivity of HER2-stably transfected MCF7 cells, which have high endogenous IGF-IR levels.

By developing an in vitro model of resistance by chronic exposure of SKBR3 cells to trastuzumab (Nahta et al., 2004b), we further demonstrated that IGF-IR plays a role in resistance. Although total IGF-I receptor levels were unchanged between trastuzumab-sensitive parental cells and resistant cells, a unique interaction between IGF-IR and HER2 was identified exclusively in resistant cells (Nahta et al., 2005). This interaction appeared to facilitate crosstalk from IGF-IR to HER2, such that IGF-I stimulation induced phosphorylation of HER2, and inhibition of IGF-IR, either by the neutralizing antibody alpha IR3 or the IGF-IR tyrosine kinase inhibitor I-OMe-AG538, blocked phosphorylation of HER2. This crosstalk occurred uniquely in the trastuzumab-resistant cells, and not in the trastuzumab-sensitive parental cells. Furthermore, our results showed that resistant cells exhibit more rapid IGF-I stimulation of downstream PI3K/Akt and MAPK pathways relative to parental cells. Inhibition of IGF-IR signaling either by antibody blockade or IGF-IR tyrosine kinase inhibition restored trastuzumab sensitivity in our in vitro resistant model, demonstrating the potential importance of the IGF-I pathway as a therapeutic target in trastuzumab-resistant breast cancer. Furthermore, IGF-I stimulation resulted in the downregulation of p27kip1 in breast cancer cells (Lu et al., 2004; Nahta et al., 2005). Reduced expression of p27kip1 was associated previously with trastuzumab resistance (Yakes et al., 2002; Le et al., 2003; Nahta et al., 2004b), and increased expression of p27kip1 restored trastuzumab sensitivity in our resistant model (Nahta et al., 2004b). Hence, p27kip1 downregulation may occur subsequent to increased IGF-IR signaling, and reduced p27kip1 levels may serve as a predictive marker for trastuzumab resistance.

Another potential mechanism of resistance that has been receiving more attention recently is the presence of multiple truncated forms of HER2 and the effects of these forms on trastuzumab response. HER2-targeted monoclonal antibodies have been shown to bind to circulating HER2 ECD, decreasing the level of antibodies available to bind to membrane-bound HER2 (Zabrecky et al., 1991). Hence, signaling from the receptor form of HER2 continued in the presence of HER2 antibodies, suggesting that the presence of HER2 ECD may reduce efficacy of HER2-targeted antibodies. However, the predictive value of ECD before treatment is not clear. In one study, elevated HER2 ECD levels predicted favorably for response to trastuzumab and docetaxel (Esteva et al., 2002), with declining levels of circulating HER2 ECD during treatment correlating with improved disease-free survival (Esteva et al., 2002; Kostler et al., 2004). In fact, a meta-analysis of eight clinical trials showed improved disease-free and overall survival in patients with at least a 20% decline in HER2 ECD levels within the first few weeks of trastuzumab-based therapy versus those whose ECD levels did not drop (Ali et al., 2006). Thus, monitoring circulating ECD levels during treatment may be an informative serum marker for predicting response to trastuzumab.

A recent preclinical study suggested that C-terminal fragments of HER2 result from alternative translation start sites rather than from proteolytic cleavage (Anido et al., 2006). The authors demonstrated that trastuzumab was ineffective against in vivo tumor growth of T47D breast cancer cells stably transfected with a truncated form of HER2. Of potential translational importance, the authors went on to show that growth of these same xenografts was inhibited by the EGFR/HER2 tyrosine kinase inhibitor lapatinib (Tykerb, GSK572016, formerly GW572016, GlaxoSmithKline; RTP, NC, USA). Hence, trastuzumab-resistant tumors that express truncated forms of HER2 may be responsive to HER2 kinase inhibition by lapatinib.

Novel strategies

A major focus in the field of HER2-targeted therapies has been the clinical development of the dual EGFR/HER2 tyrosine kinase inhibitor lapatinib. Lapatinib has shown remarkable in vitro and in vivo activity, leading to the growth arrest and apoptosis in HER2-overexpressing tumor cell lines. Lapatinib reduced tyrosine phosphorylation of EGFR and HER2 and also inhibited downstream MAPK and Akt activation (Xia et al., 2002). Although lapatinib inhibits EGFR kinase activity, the HER2 status of the tumor appears to be the critical determinant of its efficacy.

With respect to trastuzumab, increased apoptosis was achieved when lapatinib was combined with anti-HER2 antibodies (Xia et al., 2005). In addition, lapatinib plus trastuzumab mediated synergistic growth inhibition in HER2-overexpressing breast cancer cell lines. Importantly, lapatinib retained significant activity against cell lines that were maintained long-term on trastuzumab (Konecny et al., 2006). We have observed that lapatinib induces significant apoptosis in trastuzumab-resistant cells to the same degree as in parental trastuzumab-sensitive cells. Furthermore, lapatinib appears to have inhibitory effects on IGF-I signaling in the resistant cells, suggesting that its growth inhibitory activity may be due not only to anti-EGFR/HER2 activities, but also to IGF-IR inhibition, although not to the same degree as inhibition of HER2 (Nahta R, Yuan LX, Yu D, Esteva FJ, submitted). Identification of other potential molecular targets of lapatinib will be important for assessing which patient sub-populations will benefit the most from its clinical use.

A recent phase III trial of HER2-overexpressing MBC patients, who were heavily pretreated and trastuzumab refractory demonstrated that lapatinib plus capecitabine doubled the median TTP and median progression-free survival (PFS) (both 36.9 weeks) compared with capecitabine alone (median TTP 19.7 weeks and PFS 17.9 weeks) (Geyer et al., 2006). These exciting results support lapatinib as a promising new agent for patients whose disease has progressed on trastuzumab-based therapy.

It will also be important to determine if development of brain metastases is reduced in patients with lapatinib-treated HER2-overexpressing breast cancers versus trastuzumab-treated tumors, as small molecule kinase inhibitors like lapatinib are more likely to cross the blood–brain barrier in contrast to large molecule antibodies such as trastuzumab. This may prove to be an important difference between lapatinib and trastuzumab, as patients with HER2-overexpressing breast cancers are at increased risk of developing isolated central nervous system metastases (Burstein et al., 2005).

Another HER2-targeted agent currently being tested in clinical trials is the recombinant humanized HER2 monoclonal antibody called pertuzumab (Omnitarg, 2C4, Genentech, South San Francisco, CA, USA). One downfall of trastuzumab is its inability to prevent heterodimerization and subsequent downstream signaling. In contrast, pertuzumab was designed to bind HER2 at a site different from trastuzumab, such that it sterically inhibits receptor heterodimerization (Franklin et al., 2004; Adams et al., 2006). The result is disruption of HER2/EGFR and HER2/HER3 with decreased downstream signaling (Agus et al., 2002; Nahta et al., 2004a). We showed that disruption of HER2/IGF-IR heterodimers is also achieved by pertuzumab in trastuzumab-resistant cells (Nahta et al., 2005). However, whereas combining trastuzumab with pertuzumab produced synergistic apoptosis in HER2-overexpressing trastuzumab-naive breast cancer cells (Nahta et al., 2004a), pertuzumab failed to demonstrate statistically significant differences on the viability of trastuzumab-resistant breast cancer cells (Tanner et al., 2004; Nahta et al., 2005). Although pertuzumab offers the added benefit of blocking dimerization, its efficacy in trastuzumab refractory breast cancers remains uncertain, as little clinical data have become available regarding this agent in MBC.

Preclinical studies also support clinical testing of IGF-IR-inhibiting agents in the trastuzumab refractory setting. Research indicating that overexpression of IGF-IR is associated with resistance to trastuzumab in MCF7/HER18 cells, which have high endogenous levels of IGF-IR and are stably transfected with HER2 (Lu et al., 2001), also showed that co-targeting of HER2 using trastuzumab and IGF-IR using a dominant-negative construct resulted in synergistic growth inhibition (Camirand et al., 2002). In this same cell culture model, as well as in SKBR3/IGF-IR, which have her2 amplification and stable transfection of IGF-IR, treatment with recombinant human IGFBP3 restored or potentiated the response to trastuzumab both in vitro and in vivo in xenograft mouse models (Jerome et al., 2006). In addition, treatment of BT474 ER-positive HER2-overexpressing breast cancer cells or MCF7 ER-positive IGF-IR-elevated breast cancer cells with the triple combination of ER, HER2 and IGF-IR antagonists augmented apoptotic effects of single agents or dual combinations (DiGiovanna and Chakraborty, 2006). Our work demonstrated that targeting IGF-IR with the antibody α-IR3 restored sensitivity of resistant cells to trastuzumab and disrupted interaction between IGF-IR and HER2. Inhibition of the IGF-IR kinase using I-OMe-AG538 also resulted in cytotoxicity of the resistant cells (Nahta et al., 2005). More recently, we have data demonstrating that viability of trastuzumab-resistant cells is reduced to a greater extent when α-IR3 is combined with lapatinib versus when either agent is given alone (Nahta R, Yuan LX, Yu D, Esteva FJ, submitted). Collectively, these data support further testing of strategies that co-target IGF-IR and HER2 in HER2-overexpressing breast cancer patients, in particular in the trastuzumab refractory population.

Conclusion

Trastuzumab has been without a doubt a major success story in the field of molecular targeted antineoplastic agents. However, the time has come to improve upon the success of trastuzumab by recognizing its limitations. As the use of trastuzumab expands into the adjuvant setting, resistance to this targeted agent becomes an even greater issue. Preclinical studies performed in the past few years have improved our understanding of mechanisms contributing to the antineoplastic activity of this agent and development of resistance. However, much work remains to be carried out. Validation of potential predictive markers such as ECD levels, p27kip1 and phosphorylated or total IGF-IR in clinical samples must be carried out. In addition, appropriate animal studies testing novel combinations such as lapatinib and IGF-IR-targeting agents in trastuzumab-resistant tumors are needed to move therapies into the clinic. The next several years promise to be an exciting and productive time in the field of HER2-targeted therapeutics, offering the hope of improved outcomes for patients with HER2-overexpressing cancers including those that have become trastuzumab refractory.

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Acknowledgements

We thank funding from the National Cancer Institute (K01CA118174, R Nahta), the Breast Cancer Research Foundation (FJ Esteva), the University Cancer Foundation at the University of Texas MD Anderson Cancer Center (FJ Esteva, R Nahta), the Nellie B Connally Breast Cancer Research Fund, and NIH Cancer Center Support Grant CA-16672 (Media Preparation Facility and Flow Cytometry facilities).

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Correspondence to R Nahta or F J Esteva.

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Nahta, R., Esteva, F. Trastuzumab: triumphs and tribulations. Oncogene 26, 3637–3643 (2007). https://doi.org/10.1038/sj.onc.1210379

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Keywords

  • breast neoplasms
  • erbB-2 receptor
  • monoclonal antibodies
  • antineoplastic agents

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