The Oncologist, Vol. 9, Suppl 3, 16–19,
June 3, 2004
© 2004 AlphaMed Press
The Role of ErbB Inhibitors in Trastuzumab Resistance
Kathy D. Miller
Indiana University School of Medicine, Indianapolis, Indiana, USA
Correspondence:
Kathy D. Miller, M.D., Indiana University School of Medicine, Indiana Cancer Pavilion, 535 Barnhill Drive, RT-473, Indianapolis, Indiana 46202, USA. Telephone: 317-274-0920; Fax: 317-274-3646; e-mail: kathmill{at}iupui.edu
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LEARNING OBJECTIVES
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After completing this course, the reader will be able to:
- Discuss mechanisms of resistance to EGFR inhibitor monotherapy.
- Cite potential treatment strategies and ongoing clinical trials to prevent or delay the development of resistance to EGFR inhibitors.
- Describe results of clinical trials using EGFR inhibitors in patients with metastatic breast cancer.
Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com
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ABSTRACT
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The ErbB family of receptors and ligands is a complex, delicately balanced system involved in the growth and differentiation of normal human cells as well as neoplasms. Targeting this system with therapies that inhibit ErbB receptor activity in cancer patients has been somewhat successful, but resistance to ErbB inhibitor monotherapy is substantial. An understanding of the biology of ErbB receptor inhibitors is necessary to determine how best to utilize them in treatment regimens. Experimental evidence has provided valuable insights regarding mechanisms involved in resistance, and indicates that resistance can be reversed in some models. Ongoing studies in patients are evaluating whether agents that target both the epidermal growth factor (EGFR, ErbB-1) and ErbB-2 (HER-2) receptors can prevent or delay resistance in patients with metastatic breast cancer that overexpresses HER-2. With a better understanding of the biology of breast cancer, and with several novel ErbB receptor inhibitors in development, continued progress for improved patient outcomes is expected.
Key Words. Breast cancer • Resistance • Trastuzumab • Tyrosine kinase receptor
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INTRODUCTION
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The monoclonal antibody trastuzumab (Herceptin®; Genentech, Inc.; South San Francisco, CA) has been used successfully as monotherapy [1, 2] and in combination with chemotherapy [3, 4] in women with HER-2 (ErbB-2) overexpressing metastatic breast cancer. However, response rates are generally less than 50%, indicating that patients either do not respond or have disease progress after an initial response. The ErbB family of receptors and ligands is a complex system in cell differentiation and growth (Fig. 1
), with at least 30 different ligands, the four ErbB receptors (i.e., EGFR, ErbB-2 [HER-2], ErbB-3, and ErbB-4) that can form homo- or heterodimers, and at least 50 identified downstream effectors, all of which can act in various ways. Given the complexity of the ErbB signaling pathways, resistance to trastuzumab has only recently been explored. Several compounds that target ErbB pathways are in development for the treatment of breast cancer. They represent a spectrum of activity, with some exquisitely specific for a single receptor tyrosine kinase (EGFR/ErbB-1 or HER-2/ErbB-2) and others equally active against both receptors (Fig. 2). The inhibitory effects of these compounds may be reversible or irreversible, the clinical significance of which has not yet been determined.
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Figure 1. Schematic of the complex ErbB family of receptors and ligands involved in cell differentiation and growth. There are four receptors, >30 ligands, and >50 identified effectors that interact within this system. Reprinted from Yarden [12], with permission.
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Figure 2. Potential targets for therapeutic intervention within the ErbB receptor family are the EGFR (ErbB-1) and ErbB-2 (HER-2) receptors. Compounds in development include those specific for one ErbB receptor tyrosine kinase or dual inhibitors of both EGFR and ErbB-2 receptors (e.g., lapatinib). Such agents may be reversible or irreversible inhibitors.
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TARGETING THE EGFR RECEPTOR CLINICALLY
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Two phase II trials assessing the activity of the EGFR (ErbB-1)-directed tyrosine kinase inhibitor gefitinib (Iressa®; AstraZeneca Pharmaceuticals; Wilmington, DE) as monotherapy yielded similar results [5, 6]. In one trial, 63 patients (median age 52 years) were treated with a fairly high dose of gefitinib, 500 mg/day [5]. Most patients (79%) had visceral disease and approximately 50% had received three or more previous treatments. Grade 3/4 toxicities (diarrhea, rash, nausea) were experienced by 25% of patients; four patients had a dosage reduction to 250 mg/day. The response rate to gefitinib monotherapy was 1.6%, with a clinical benefit result of 4.8% (one partial response, two stable disease) [5]. In another trial, 69 patients were treated with erlotinib (TarcevaTM; Genentech, Inc.; South San Francisco, CA) at a dose of 150 mg/day [7]. There were two cohorts of patients: One had received previous anthracycline, taxane, and capecitabine therapy (n = 47), and the other had received at least previous treatment for metastatic breast cancer (n = 22). Grade 3 toxicities were less frequent than with the gefitinib regimen and included diarrhea (4%), asthenia (3%), rash (2%), and nausea (2%). In the heavily pretreated first cohort, 2.1% of the patients responded, with one partial remission lasting 23 weeks. No responses were seen in the second cohort, but one patient had stable disease lasting more than 28 weeks. These phase II clinical results are in accord with preclinical study findings in which EGFR inhibition as monotherapy had little impact on tumor growth in xenograft models [8].
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LESSONS FROM THE BIOLOGY OF ERBB INHIBITORS
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Despite the poor results when used as monotherapy in patients with advanced breast cancer, EGFR inhibitors may still have a role in breast cancer therapy. Preclinical studies have partially elucidated the biology of ErbB receptor inhibitors; this emerging understanding guides future clinical trials. The BT-474 cell line overexpresses HER-2 and is sensitive to 4D5, the antibody that gave rise to trastuzumab. In contrast, the MKN-7 cell line also overexpresses HER-2 but is resistant to 4D5 [9]. In culture, at 4 and 7 days, MKN-7 cells demonstrate resistance to, while BT-474 cells are very sensitive to, trastuzumab in a colony-forming cell number assay. How might this differential sensitivity be explained?
An assessment of total and phosphorylated protein levels of ErbB receptor family members indicated that the most striking difference between the cell lines was a significant increase in EGFR phosphorylation in the resistant cells. Moulder and colleagues have shown that transforming growth factor alpha (TGF-
)-induced proliferation of BT-474 cells is not blocked by trastuzumab, but is blocked by gefitinib [10]. TGF--stimulated BT-474 cells treated with gefitinib showed a decrease in phosphorylated (phospho)-AKT whereas phospho-AKT levels were not altered by treatment with trastuzumab. These studies suggest that overexpression of EGFR and activation of the AKT pathway may be an important mechanism of trastuzumab resistance.
Inhibition of the EGFR pathway may enhance the efficacy of trastuzumab in sensitive cells. In BT-474 xenografts, control cells grew rapidly, but growth was attenuated with gefitinib or trastuzumab as monotherapy [10]. However, tumor growth was nearly obliterated by the combination of trastuzumab and gefitinib; tumor growth control was sustained throughout the duration of combination treatment. Similar synergy has been demonstrated for the combination of erlotinib and trastuzumab in three breast cancer cell lines (MDA-361, BT-474, SK-BR-3) that naturally overexpress HER-2 [Finn and Slamon, unpublished data]. In addition, significant synergism between the dual EGFR/ErbB-2 receptor inhibitor lapatinib (GlaxoSmithKline; Research Triangle Park, NC) and trastuzumab in several cell lines (SK-BR-3, BT-474, MDA-MB-361, MDA-MB-453) has been demonstrated (Fig. 3) [11].
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Figure 3. The combination of trastuzumab with the dual ErbB receptor tyrosine kinase inhibitor lapatinib demonstrates synergism in several breast cancer cell lines that naturally overexpress HER-2 [11].
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In a series of experiments, Arteaga and colleagues have shown that resistance may be reversed in BT-474 cells selected for trastuzumab resistance [Arteaga et al., unpublished data]. In their experiments, cultured BT-474 cells were implanted into nude mice, which were then treated with trastuzumab for 84 days until the tumors began to grow exponentially despite continued trastuzumab treatment. The tumors were then resected and cultured. Several clones were selected that grew well and continued to form tumors in nude mice. Examination of the cells showed that they maintained a normal morphology and normal expression of HER-2 by fluorescence in situ hybridization (FISH) and protein assays; there were no HER-2 mutations that would result in a constitutively-activated tyrosine kinase domain or would block trastuzumab binding. Other studies by the group determined that the cells retained exquisite sensitivity to EGFR blockade, with complete control of tumor growth. Whether the emergence of resistance can be prevented or delayed in this nude mouse model by combined EGFR and HER-2 blockade has not yet been studied.
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OVERCOMING RESISTANCE: FUTURE DIRECTIONS FOR ERBB RECEPTOR INHIBITORS
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Combination EGFR and ErbB-2 blockade is being studied in patients as a strategy to prevent or delay resistance. Trastuzumab (2 mg/kg/week) and gefitinib (250–500 mg/day) are being evaluated in a phase I/II trial (Eastern Cooperative Oncology Group 1100) of patients with HER-2+ (3+ by immunohistochemistry [IHC] and/or positive by FISH) breast cancer. Enrolled patients must not have been treated previously with trastuzumab. Patients are treated until disease progression or toxicity occurs; EGFR and HER-2 expression and activation will be analyzed retrospectively by IHC. Accrual is currently on hold until efficacy of the combination is determined in the first 30 patients.
A second ongoing phase I/II trial is evaluating the combination of trastuzumab (4 mg/kg loading dose, 2 mg/kg/week) plus erlotinib (50 mg, 100 mg, and 150 mg daily by mouth) in patients with HER-2+ (by FISH) breast cancer. Enrolled patients must not have received previous trastuzumab therapy. Study end points include response rate, safety, and pharmacokinetics, as well as the pharmacodynamic end points of shed EGFR and HER-2 extracellular domains, and overall survival.
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CONCLUSION
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A better understanding of the biology of breast cancer and its treatment is improving treatment options in the clinic. Additional studies focusing on the biology of ErbB inhibitors and resistance to ErbB inhibitor monotherapy are helping to define the role of these therapies for patients with metastatic breast cancer. With ongoing development of novel ErbB receptor inhibitors and with continued research regarding resistance mechanisms, further progress in treatment outcomes is expected.
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ACKNOWLEDGMENT
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Supported in part by the Breast Cancer Research Foundation and a Clinical Research Training Grant for Junior Faculty #CRTG-00-199-01-CCE from the American Cancer Society. KDM receives research support from Genentech, Medarex, Astra Zeneca, Roche, Aventis, and Pfizer.
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REFERENCES
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- Cobleigh MA, Vogel CL, Tripathy D et al. Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol 1999;17:2639–2648.[Abstract/Free Full Text]
- Vogel CL, Cobleigh MA, Tripathy D et al. Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol 2002;20:719–726.[Abstract/Free Full Text]
- Slamon DJ, Leyland-Jones B, Shak S et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001;344:783–792.[Abstract/Free Full Text]
- Esteva FJ, Valero V, Booser D et al. Phase II study of weekly docetaxel and trastuzumab for patients with HER-2-overexpressing metastatic breast cancer. J Clin Oncol 2002;20:1800–1808.[Abstract/Free Full Text]
- Albain K, Elledge R, Gradishar W et al. Open-label, phase II, mulitcenter trial of ZD1839 (Iressa) in patients with advanced breast cancer. Breast Cancer Res Treat 2002;76:S33.
- Robertson J, Guttedridge E, Cheung K et al. A phase II study of ZD1839 (Iressa) in tamoxifen-resistant ER-positive and endocrine-insensitive (ER-negative) breast cancer. Breast Cancer Res Treat 2002;76:S96.
- Winer EP, Cobleigh M, Dickler M et al. Phase II multicenter study to evaluate the efficacy and safety of Tarceva (erlotinib, OSI-774) in women with previously treated locally advanced or metastatic breast cancer. Breast Cancer Res Treat 2002;76:S115.
- Massarweh S, Shou J, DiPietro M et al. Targeting the epidermal growth factor receptor pathway improves the anti-tumor effect of tamoxifen and delays acquired resistance in a xenograft model of breast cancer. Breast Cancer Res Treat 2002;76:S33.
- Lane HA, Beuvink I, Motoyama AB et al. ErbB2 potentiates breast tumor proliferation through modulation of p27(Kip1)-Cdk2 complex formation: receptor overexpression does not determine growth dependency. Mol Cell Biol 2000;20:3210–3223.[Abstract/Free Full Text]
- Moulder SL, Yakes FM, Muthuswamy SK et al. Epidermal growth factor receptor (HER1) tyrosine kinase inhibitor ZD1839 (Iressa) inhibits HER2/neu (erbB2)-overexpressing breast cancer cells in vitro and in vivo. Cancer Res 2001;61:8887–8895.[Abstract/Free Full Text]
- Konecny GE, Venkatesan N, Beryt M et al. Therapeutic advantage of a dual tyrosine kinase inhibitor (GW2016) in combination with chemotherapy drugs or trastuzumab against human breast cancer cells with HER2 overexpression. Proc Am Assoc Cancer Res 2002;43:1003.
- Yarden Y. The EGFR family and its ligands in human cancer. Signaling mechanisms and therapeutic opportunities. Eur J Cancer 2001;37(suppl 4):S3–S8.
Received March 26, 2004;
accepted for publication April 15, 2004.
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Learning Objectives
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