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The Oncologist, Vol. 9, Suppl 3, 4–9, June 3, 2004
© 2004 AlphaMed Press

Monoclonal Antibodies, Small Molecules, and Vaccines in the Treatment of Breast Cancer

Francisco J. Esteva

The University of Texas, M.D. Anderson Cancer Center, Houston, Texas, USA

Correspondence: Francisco J. Esteva, M.D., Ph.D., Department of Breast Medical Oncology, The University of Texas, M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 424, Houston, Texas 77030-4009, USA. Telephone: 713-792-2817; Fax: 713-745-5768; e-mail: festeva{at}mdanderson.org


   LEARNING OBJECTIVES
Top
 Learning Objectives
Abstract
 Introduction
 Monoclonal Antibodies
 Small Molecules
 Vaccines
 Summary
 References
 
After completing this course, the reader will be able to:

  1. Describe the specificity and benefits of the monoclonal antibody trastuzumab in treating patients with metastatic breast cancer.
  2. Identify the potential advantages of dual HER tyrosine kinase inhibitors over single HER receptor inhibitors for treating metastatic breast cancer.
  3. Explain the design considerations of clinical trials for therapeutic vaccines to assess effect in patients with various stages of breast cancer.

Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com


   ABSTRACT
Top
 Learning Objectives
 Abstract
Introduction
 Monoclonal Antibodies
 Small Molecules
 Vaccines
 Summary
 References
 
The human epidermal growth factor receptor (HER, ErbB) family of receptors is considered an important therapeutic target, and various types of molecularly based small molecules, including monoclonal antibodies, protein tyrosine kinase inhibitors, and therapeutic vaccines, are in development as potential therapies for metastatic breast cancer. Trastuzumab (Herceptin®; Genentech, Inc.; South San Francisco, CA), the first approved monoclonal antibody for HER-2 (ErbB-2)-overexpressing metastatic breast cancer, provided the proof of principle that targeting specific receptors results in clinical benefit. Other monoclonal antibodies and the small molecule dual protein tyrosine kinase inhibitors show great promise as treatments for metastatic breast cancer but require evaluation in clinical trials to assess their benefits. Therapeutic vaccines may have a role, particularly in early-stage disease, but they are associated with greater limitations and study design issues that make their evaluation difficult. Optimum combination therapy regimens with a variety of novel approaches that incorporate small molecule targeted therapies need to be developed, and the population most likely to benefit from targeted therapies needs to be identified.

Key Words. Breast cancer • Monoclonal antibodies • Tyrosine kinase inhibitors • Vaccines


   INTRODUCTION
Top
 Learning Objectives
 Abstract
 Introduction
Monoclonal Antibodies
 Small Molecules
 Vaccines
 Summary
 References
 
Many traditional cancer treatment regimens provide acceptable response rates and improve survival. However, they generally are nonselective, inducing cytotoxicity in normal as well as in malignant cells, and they often are not well tolerated. In developing novel anticancer agents, the goal is to target specific molecular lesions within tumor cells, leading to improved cure rates and reducing cytotoxicity in normal cells [1]. Advances in the understanding of tumor pathobiology and molecular biology have allowed the development of targeted therapies.

The human epidermal growth factor receptor 2 (HER-2, ErbB-2), is overexpressed in 20%-25% of invasive breast cancers, and its overexpression correlates with the pathogenesis and prognosis of breast cancer [1]. It is considered an important therapeutic target, and several types of molecular therapies, including monoclonal antibodies, small molecules, and vaccines, have been developed to target the HER family of receptors (Fig. 1Go) [2]. These targeted therapies are classified as HER dimerization inhibitors, anti-HER blocking antibodies, anti-ligand blocking antibodies, and tyrosine kinase inhibitors. In development are ligand-toxin and antibody-toxin conjugates that use the ligand or antibody as a delivery system for the toxin that actually kills the cancer cell. The molecular weight of these types of therapies ranges from approximately 400 daltons for tyrosine kinase inhibitors to approximately 150,000 daltons for monoclonal antibodies (Table 1Go), which has implications in terms of tumor penetration.



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  		Figure 1. The HER family of receptors is the target of several targeted therapies for breast cancer. Adapted from Noonberg and Benz [2], with permission.

 

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  		Table 1. Size comparison of molecularly targeted therapies
 

   MONOCLONAL ANTIBODIES
Top
 Learning Objectives
 Abstract
 Introduction
 Monoclonal Antibodies
Small Molecules
 Vaccines
 Summary
 References
 
Monoclonal antibodies are highly specific therapies with low toxicities. In addition to directly inducing cancer cell death, monoclonal antibodies also lead to immune activation, resulting in tumor cell toxicity. Limitations of monoclonal antibodies are their size, which may limit tumor penetration, heterogeneous antigen expression, and expression of tumor antigens in normal cells. Several anti-HER monoclonal antibodies are in development for the treatment of various types of cancers (Table 2Go).


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  		Table 2. Humanized anti-ErbB monoclonal antibodies in development for the treatment of various types of cancers
 
Trastuzumab (Herceptin®; Genentech, Inc.; South San Francisco, CA), the only humanized anti-HER-2 antibody approved for use by the U.S. Food and Drug Administration, targets the HER protein with high affinity (Kd = 0.1 nM). Because it is 95% humanized (5% murine), it can be administered multiple times to patients with breast cancer without resistance developing, the potential for immunogenicity is decreased, and the potential for recruiting immune effector mechanisms is increased. Both cytostatic and cytotoxic mechanisms of action of trastuzumab were identified in preclinical studies (Table 3Go) [1]. The interaction between trastuzumab and chemotherapy to promote apoptosis is not well understood, but it is a phenomenon that occurs both in vitro and in vivo. Trastuzumab was also shown to be antiangiogenic and to downregulate proteins involved in angiogenesis [3].


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  		Table 3. Potential mechanisms of action of trastuzumab
 
Trastuzumab, administered as single-agent, first-line therapy in women with HER-2-overexpressing metastatic breast cancer [4] and as single-agent therapy in women with HER-2-overexpressing metastatic breast cancer that has progressed after chemotherapy [5], produces durable objective responses and is well tolerated. In combination with chemotherapy, improvements in response rate, time to progression, and survival occur in women with HER-2-overexpressing metastatic breast cancer [6, 7]. The synergism between trastuzumab and chemotherapy occurs regardless of the chemotherapeutic agent, but only in HER-2+ tumors (i.e., HER-2+ by fluorescence in situ hybridization [FISH] or immunohistochemistry [IHC] analysis) [8]. In one study of trastuzumab plus docetaxel (Taxotere®; Aventis Pharmaceuticals; Collegeville, PA), the response rate in women with HER-2+ metastatic breast cancer as assessed by FISH was 67%, compared with 50% in women with HER-2– tumors as assessed by FISH [7]. Another study found that overall survival was significantly improved in women with HER-2+, but not HER-2– metastatic breast cancer, as assessed by FISH, treated with trastuzumab and chemotherapy [6, 9].

The positive findings with trastuzumab treatment both alone and in combination with various chemotherapeutic agents has led to studies of its use in the adjuvant setting. Novel treatment regimens under investigation for patients with advanced breast cancer include combinations of trastuzumab and other monoclonal antibodies with endocrine therapies (e.g., aromatase inhibitors, fulvestrant), biologic agents (e.g., GM-CSF, vascular endothelial growth factor [VEGF] antibody, EGFR inhibitors, flavopiridol), and chemotherapy. The goal for using trastuzumab with novel strategies to target HER-2 is to increase the magnitude and duration of response, since disease progression generally is observed within 1 year in patients who initially respond to trastuzumab. The optimum duration of trastuzumab therapy and whether benefit can be achieved with continued treatment after tumor progression have not yet been determined [10]. Ongoing research is also trying to identify new markers that will predict which patients are most likely to benefit from trastuzumab treatment. Another avenue of research is the role of trastuzumab and other humanized anti-HER monoclonal antibodies (Table 2Go), in solid epithelial tumors (other than breasts tumors), that overexpress HER-2. However, it is difficult to identify patients with HER-2 gene amplification in other types of tumors.


   SMALL MOLECULES
Top
 Learning Objectives
 Abstract
 Introduction
 Monoclonal Antibodies
 Small Molecules
Vaccines
 Summary
 References
 
The small molecules of interest in cancer are protein tyrosine kinases, which have increased activity in neoplastic cells. Overexpression of protein tyrosine kinase receptors correlates with poorer prognoses and shorter survival times in patients with breast and ovarian cancers [2]. In breast cancer, several HER tyrosine kinase inhibitors are being investigated (Table 4Go). The principal differences among these tyrosine kinase inhibitors are that gefitinib (Iressa®; AstraZeneca Pharmaceuticals; Wilmington, DE), and erlotinib (TarcevaTM; Genentech, Inc.; South San Francisco, CA), are specific for the epidermal growth factor receptor (EGFR, ErbB-1) and are reversible inhibitors, whereas the others are dual inhibitors of EGFR and HER-2 receptors and produce irreversible inhibition—except lapatinib (GlaxoSmithKline; Research Triangle Park, NC), which is a reversible dual inhibitor. Tyrosine kinase inhibitors bind to the ATP-binding site on the receptor, which prevents activation of, and signal transduction from, the receptor.


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  		Table 4. HER tyrosine kinase (TK) inhibitors
 
As with monotherapy, response rates to single-agent EGFR inhibitors (e.g., gefitinib) are low. Albain and coworkers reported on a multicenter phase II study of gefitinib for patients with metastatic breast cancer [11]. Of the 63 women treated in that clinical trial, one (1.6%) achieved a partial response and seven (11%) had stable disease as their best response. Difficulties with assessing trial results include some patients having received numerous previous therapies and that tumors were both estrogen-receptor positive and negative. It may be that EGFR inhibitors have greater activities and benefits in certain patient subpopulations, but these have not yet been identified clinically. Nonetheless, the small benefit from EGFR inhibitors used alone has led to studies evaluating their efficacy in combination with other agents, such as hormone therapy and monoclonal antibodies.

Dual inhibitors downregulate both the EGFR and HER-2 receptors [12, 13]. The dual inhibitor lapatinib has demonstrated potent cytotoxic activity, which was shown against proliferation of breast cancer cells in vitro [12, 14, 15]. Inhibition of both EGFR and HER-2 receptor tyrosine kinase activity with lapatinib leads to tumor growth arrest and/or apoptosis [14]. The potential advantages of dual EGFR/HER-2 receptor tyrosine kinase inhibitors are that they inhibit both ligand-dependent and ligand-independent signaling, they potentially overcome resistance to trastuzumab if tumors develop compensatory mechanisms by other HER receptor family members, and they appear to have synergy with chemotherapeutic agents. The importance of reversible versus irreversible inhibition with dual tyrosine kinase inhibitors has not been determined. The dual EGFR/HER-2 inhibitors are discussed in greater detail in other articles in this supplement.


   VACCINES
Top
 Learning Objectives
 Abstract
 Introduction
 Monoclonal Antibodies
 Small Molecules
 Vaccines
Summary
 References
 
In cancer therapy, potential roles for vaccines include passive or adoptive immunotherapy and active specific immunotherapy. With passive immunotherapy, the goal is to enhance and/or stimulate the immune system using exogenous cytokines, antibodies, immune cells, or growth factors. With active specific immunotherapy, a specific tumor-associated antigen elicits an endogenous immune or antitumor response. The potential advantages of therapeutic vaccines for cancer are that they can augment an established immunogenic response to the tumor (which is generally weak in breast cancer), they target specific tumor antigens (although there are few), they are nontoxic and can be combined with conventional therapies and/or other immunotherapies, and they elicit immunologic memory to prevent re-emergence of the tumor. It is unclear whether therapeutic vaccines for cancer prolong survival.

Several vaccines against the HER family of proteins have been developed and are actively being studied (Table 5Go) [16]. Many of the studies of vaccines have been conducted in patients with metastatic disease, which is characterized by having the most aggressive malignant cells and the failure of standard cytotoxic regimens. Findings from a dosing study of vaccinations with peptide E75 plus adjuvant GM-CSF to 14 patients with metastatic breast or ovarian cancer suggested that vaccination was well tolerated and induced peptide-specific and epitope-specific cytotoxic T lymphocytes (CTLs), which could lyse HER-2-overexpressing tumors [17]. While therapeutic vaccines for breast cancer may hold promise, there are a number of limitations to their usefulness. A principal limitation is that human antigens are not recognized by the immune system as being antigenic; as "self antigens," the immune system does not elicit a response against the tumor. The cytokine environment may not allow amplification of helper T cells, and antigen-presenting cells may not function. Another limitation is that tumors secrete immunosuppressive factors. Therapeutic vaccines, although studied in advanced disease, may have the greatest activity in patients with early-stage disease. In addition to being less effective in patients with advanced disease or a large tumor burden, it is difficult to demonstrate vaccine activity in these patients.


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  		Table 5. Vaccines being investigated in breast cancer
 
Combined with the limitations of therapeutic vaccines are clinical trial design issues that may impede clinical assessment of efficacy. Dosing of vaccines is different in that the optimum dose is the lowest dose required to generate an immunologic response, and not the most toxic dose. Larger sample sizes, even in phase I studies, are necessary for determining immune responses at each dose level. Traditional end points of cancer therapy (e.g., response, tumor regression) do not apply with vaccine therapy administered to patients with early-stage or minimal residual disease, and reliable surrogate end points to show clinical benefit have not been established. The key clinical outcome measures—time to progression and survival—require a long follow-up period, which has not been incorporated into trials of vaccine therapy. To assess time to progression and overall survival, trials of vaccines may need to move directly from phase I dose-determination to phase III clinical trials. Much more research is necessary to determine the role of therapeutic vaccine therapy in patients with breast cancer.


   SUMMARY
Top
 Learning Objectives
 Abstract
 Introduction
 Monoclonal Antibodies
 Small Molecules
 Vaccines
 Summary
References
 
Various types of molecules are being developed as targeted therapies for metastatic breast cancer. Trastuzumab, the only approved monoclonal antibody for HER-2-overexpressing metastatic breast cancer, provided the proof of principle that targeting specific receptors actually results in clinical benefit. Other monoclonal antibodies and the small molecule dual protein tyrosine kinase inhibitors show great promise but require evaluation in clinical trials to assess their benefits. Therapeutic vaccines may have a role in early-stage disease, but also require further study that encompasses nontraditional trial designs and end points. Optimum combination therapy regimens with a variety of novel approaches that incorporate small molecule targeted therapies need to be developed, and the population most likely to benefit from targeted therapies needs to be identified.


   ACKNOWLEDGMENT
Top
 Learning Objectives
 Abstract
 Introduction
 Monoclonal Antibodies
 Small Molecules
 Vaccines
 Summary
 References
 
Francisco J. Esteva is a recipient of a Career Development Award from the National Cancer Institute (K23 CA82119) and is a member of the Speakers Bureau and receives honoraria from GlaxoSmithKline and Genentech.


   REFERENCES
Top
 Learning Objectives
 Abstract
 Introduction
 Monoclonal Antibodies
 Small Molecules
 Vaccines
 Summary
 References
 

  1. Nahta R, Esteva FJ. HER-2-targeted therapy: lessons learned and future directions. Clin Cancer Res 2003;9:5078–5084.[Abstract/Free Full Text]
  2. Noonberg SB, Benz CC. Tyrosine kinase inhibitors targeted to the epidermal growth factor receptor subfamily: role as anticancer agents. Drugs 2000;59:753–767.[CrossRef][Medline]
  3. Izumi Y, Xu L, di Tomaso E et al. Tumour biology: Herceptin acts as an anti-angiogenic cocktail. Nature 2002;416:279–280.[Medline]
  4. 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]
  5. 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]
  6. Slamon DJ, Leyland-Jones B, Shak S et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER-2. N Engl J Med 2001;344:783–792.[Abstract/Free Full Text]
  7. 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]
  8. Seidman AD, Fornier MN, Esteva FJ et al. Weekly trastuzumab and paclitaxel therapy for metastatic breast cancer with analysis of efficacy by HER2 immunophenotype and gene amplification. J Clin Oncol 2001;19:2587–2595.[Abstract/Free Full Text]
  9. Mass RD, Press M, Anderson S et al. Improved survival benefit from herceptin (trastuzumab) in patients selected by fluorescence in situ hybridization (FISH). Proc Am Soc Clin Oncol 2001;20:85.
  10. Nahta R, Esteva FJ. In vitro effects of trastuzumab and vinorelbine in trastuzumab-resistant breast cancer cells. Cancer Chemother Pharmacol 2004;53:186–190.[CrossRef][Medline]
  11. Albain K, Elledge R, Gradishar W et al. Open-label, phase II multicenter trial of ZD1839 (Iressa) in patients with advanced breast cancer. Breast Cancer Res Treat 2002;76:A20.
  12. Rusnak DW, Lackey K, Affleck K et al. The effects of the novel, reversible epidermal growth factor receptor/ErbB-2 tyrosine kinase inhibitor, GW2016, on the growth of human normal and tumor-derived cell lines in vitro and in vivo. Mol Cancer Ther 2001;1:85–94.[Abstract/Free Full Text]
  13. Rusnak DW, Affleck K, Cockerill SG et al. The characterization of novel, dual ErbB-2/EGFR, tyrosine kinase inhibitors: potential therapy for cancer. Cancer Res 2001;61:7196–7203.[Abstract/Free Full Text]
  14. Xia W, Mullin RJ, Keith BR et al. Anti-tumor activity of GW572016: a dual tyrosine kinase inhibitor blocks EGF activation of EGFR/erbB2 and downstream Erk1/2 and AKT pathways. Oncogene 2002;21:6255–6263.[CrossRef][Medline]
  15. Xia W, Liu LH, Ho P et al. Truncated ErbB2 receptor (p95ErbB2) is regulated by heregulin through heterodimer formation with ErbB3 yet remains sensitive to the dual EGFR/ErbB2 kinase inhibitor GW572016. Oncogene 2004;23:646–653.[CrossRef][Medline]
  16. Ko BK, Kawano K, Murray JL et al. Clinical studies of vaccines targeting breast cancer. Clin Cancer Res 2003;9:3222–3234.[Abstract/Free Full Text]
  17. Murray JL, Gillogly ME, Przepiorka D et al. Toxicity, immunogenicity, and induction of E75-specific tumor-lytic CTLs by HER-2 peptide E75 (369–377) combined with granulocyte macrophage colony-stimulating factor in HLA-A2+ patients with metastatic breast and ovarian cancer. Clin Cancer Res 2002;8:3407–3418.[Abstract/Free Full Text]
Received March 26, 2004; accepted for publication April 15, 2004.




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