Associate Professor, Breast Medical Oncology/Co-Director, Clinical Cancer Genetics
*Department of Breast Medical Oncology
University of Texas MD Anderson Cancer Center
**Department of Medical Oncology
Hacettepe University Faculty of Medicine
Targeted therapies offer a new approach to breast cancer treatment. These therapies are targeted to second messenger proteins, ligands and receptors that are known to be upregulated in neoplastic cells or are implicated in cancer metastasis. For example, hormonal therapy targets hormone receptors, and this class of drugs still has the greatest overall effect on outcome. The major challenges for the clinical application of targeted therapy include: selection of patients; identification of optimal dosage and schedule of administration; optimal combinations with conventional treatments; and the most appropriate therapeutic strategy. Several targeted therapies for breast cancer are in phase III clinical trials, and many other agents are completing phase I and II testing. This review highlights the most promising agents that are in their preclinical and clinical development as breast cancer therapeutics.
Monoclonal antibody-targeted therapy
The rapid growth in the number of biomolecular markers and development of targeted therapeutic drugs for breast cancer began more than three decades ago after the discovery of steroid-hormone receptors.(1) The family of human epidermal growth factor receptors (HER) has been well characterised, and its role in normal cell growth and carcinogenesis extensively researched. The overexpression of HER2 (usually as a result of HER2 gene amplification) is clinically important in 15–30% of breast cancers. This overexpression results in ligand-independent HER2 homodimer formation. HER2 heterodimers and homodimers are extremely active and therefore able to initiate downstream signalling pathways.(2–5) Trastuzumab, a humanised recombinant monoclonal antibody that recognises the extracellular domain of the HER2 transmembrane protein, was among the first target-specific drugs licensed for clinical use, and its development represents a model integrating new agents with standard treatment strategies (see Figure 1 and Table 1). Monotherapy trials indicate that trastuzumab is active as a single agent in patients with HER2-positive breast cancer, with a response rate ranging from 12% to 34%, is well tolerated and is associated with preservation of quality of life. Furthermore, as a first-line therapy for metastatic breast cancer overexpressing the HER2 receptor, the addition of trastuzumab to taxane- or anthracycline-based chemotherapy significantly increases the rate of objective response, time to disease progression and survival duration when compared with chemotherapy alone.(6) Trastuzumab has shown important activity when used with many chemotherapeutic agents such as platinum salts, gemcitabine, vinorelbine, capecitabine and liposomal anthracyclines. Currently, various trials showed the efficacy of trastuzumab in the adjuvant and neo‑adjuvant therapy settings.(7–9) Although trastuzumab is very well tolerated, it has cardiotoxic effects that are clinically more relevant if the drug is used with anthracyclines. The best schedule of administration, duration of treatment and sequence when combined with other agents, combinations, as well as relevant tests to identify patients who might benefit the most from the drug remain to be determined. Trastuzumab is still the only registered biologically engineered compound for routine use in patients with breast cancer.
Pertuzumab (2C4, Omnitarg; Genentech) is a new recombinant humanised monoclonal antibody that also binds to the extracellular portion of HER2, causing steric hindrance and impairing receptor dimerisation.(10) Ongoing phase I testing has shown that pertuzumab has activity in patients with breast cancers that are HER2-negative or trastuzumab-refractory HER2-positive.(11)
Other tyrosine kinase inhibitors
Because most tyrosine kinase inhibitors have been studied only in preclinical investigations, only a few have been tested in patients with advanced breast cancer. One of these, gefitinib, an inhibitor of the tyrosine kinase of HER1, has shown antitumour activity in preclinical studies and in a phase II trial of patients heavily pretreated for metastatic breast cancer.(12)
Lapatinib (GW572016), another HER1- and HER2-reversible inhibitor, has been shown in a phase I trial to control disease in patients with trastuzumab- unresponsive advanced breast cancer.(13)
CI-1033 is a 4-anilinoquinazoline that is a pan-HER tyrosine kinase inhibitor (rather than an irreversible inhibitor specific for epidermal growth factor receptor) and shows efficacy against breast cancer cell lines. Some responses have been shown in early clinical investigations.(14,15)
Farnesyl transferase inhibitors
Ras proteins are a key intermediary in signal transduction pathways that are involved in several cellular processes, including proliferation, differentiation and apoptosis. The ras gene is mutated in about 30% of human cancers; however, only 2% of breast tumours have ras mutations.(16) The Ras-mediated pathway is crosslinked with several other key signalling pathways, including the oestrogen receptor- activated pathway, and is also an element of the downstream HER signalling cascade. Progress in understanding the specific role of Ras proteins in cell signalling has led to the development of agents that have a direct effect on Ras. Currently, the most promising and advanced Ras-targeted agents are farnesyl transferase inhibitors (FTI), which were developed after farnesyl transferase was found to play a key role in the activation of Ras. These compounds inhibit the proliferation of Ras-transformed cells but are nontoxic to normal cells.(17)
Combinations of FTIs with a variety of commonly used anticancer agents have been tested on human tumours.(18) The FTI R115,777 represents one of the first-in-class inhibitors to enter the clinic. One study showed that combinations of R115,777 with either selective ER ligands or a selective anti‑oestrogen binding site ligand are able to induce large increases in their antiproliferative activities on MCF-7 cells.(19)
The targeting of angiogenesis shows promise for cancer treatment because new blood vessels are needed for primary tumour growth, invasion and metastasis.(20)
Bevacizumab, a recombinant, humanised monoclonal antibody to vascular endothelial growth factor (VEGF) that has shown some efficacy when used alone in phase II clinical trials,(21) has been shown to have biological activity against breast cancer, when used alone and in combination with agents such as capecitabine,(22) docetaxel(23) and vinorelbine.(24)
The Eastern Cooperative Oncology Group (E2100) phase III randomised trial compared weekly paclitaxel plus bevacizumab with weekly paclitaxel alone as a first-line treatment for women with locally recurrent or metastatic breast cancer. The addition of bevacizumab to paclitaxel increased the response rates from 14.2% to 28.2%. Bevacizumab significantly improved progression-free survival from 6.1 months to nearly 11 months.(25)
Several other antiangiogenic drugs have been tested for efficacy, including thalidomide, endostatin, angiostatin, SU6668, SU11248 and cyclooxygenase 2 (COX-2) inhibitors. COX-2 inhibitors also improve the efficacy of aromatase inhibitors by increasing the overexpression of tumour aromatase.
An interesting and promising specialty relates to the antiangiogenic efficacy of low-dose, metronomic cytotoxic agents, such as vinorelbine and cyclophosphamide,(26) and receptors as targets for radio‑nuclides.(27)
Different types of molecules are being developed as targeted therapies for metastatic and adjuvant breast cancer. Thus far, trastuzumab is the only approved monoclonal antibody that has clinical benefit for operable or metastatic breast cancer patients with HER2-overexpression. Phase II and III studies of antibodies directed against vascular endothelial growth factor and endothelial growth factor receptor are ongoing. Optimum combination therapy regimens that incorporate these newer agents need to be developed, and the patients most likely to benefit from targeted therapies need to be identified.
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- 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;344:783-92.
- Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 2005;353:1673-84.
- Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 2005;353:1659-72.
- Buzdar AU, Ibrahim NK, Francis D, et al. Significantly higher pathologic complete remission rate after neoadjuvant therapy with trastuzumab, paclitaxel, and epirubicin chemotherapy: results of a randomized trial in human epidermal growth factor receptor 2-Positive Operable Breast Cancer. J Clin Oncol 2005;23;3676-85.
- Nahta R, Hung MC, Esteva FJ. The HER-2-targeting antibodies trastuzumab and pertuzumab synergistically inhibit the survival of breast cancer cells. Cancer Res 2004;64:2343-6.
- Agus DB, Gordon M, Taylor C, et al. Clinical activity in a phase I trial of HER-2-targeted rhuMab 2C4 (pertuzumab) in patients with advanced solid malignancies. Proc Am Soc Clin Oncol 2003;22:192.
- Albain K, Elledge R, Gradishar WJ, et al. Open-label, phase II, multicenter trial of ZD1839 (‘Iressa’) in patients with advanced breast cancer. Breast Cancer Res Treat 2002;76 Suppl 1:S33.
- Burris HA 3rd. Dual kinase inhibition in the treatment of breast cancer: initial experience with the EGFR/ErbB-2 inhibitor lapatinib. Oncologist 2004;9 Suppl 3:10-5.
- Allen LF, Eiseman IA, Fry DW, Lenehan PF. CI-1033, an irreversible pan-erbB receptor inhibitor and its potential application for the treatment of breast cancer. Semin Oncol 2003;30 Suppl 16:65-78.
- Eder JP, Hidalgo M, Mendelson D, Ryan PD, et al. A phase I clinical and pharmacokinetic (PK) study of oral CI-1033 + docetaxel (DOC) in the treatment of patients with advanced solid tumors [Abstract]. J Clin Oncol 2005;23 Suppl 16:Abstract 3111.
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- Mazieres J, Pradines A, Favre G. Perspectives on farnesyl transferase inhibitors in cancer therapy. Cancer Lett 2004;206:159-67.
- Baum C, Kirschmeier P. Preclinical and clinical evaluation of farnesyltransferase inhibitors. Curr Oncol Rep 2003;5:99-107.
- Dalenc F, Giamarchi C, Petit M, et al. Farnesyl-transferase inhibitor R115,777 enhances tamoxifen inhibition of MCF-7 cell growth through estrogen receptor dependent and independent pathways. Breast Cancer Res 2005;7:R1159-67.
- Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med 1995;1:27-31.
- LG Presta, Chen H, O’Connor SJ, et al. Humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders. Cancer Res 1997;57:4593-9.
- Maung K. Capecitabine/bevacizumab compared to capecitabine alone in pretreated metastatic breast cancer: results of a phase III study. Clin Breast Cancer 2003;3:375-7.
- Ramaswamy B, Rhoades CA, Kendra K. CTEP-sponsored phase II trial of bevacizumab (Avastin) in combination with docetaxel (Taxotere) in metastatic breast cancer. Breast Cancer Res Treat 2003;82:S50.
- Burstein HJ, Parker LM, Savoie J. Phase II trial of the anti-VEGF antibody bevacizumab in combination with vinorelbine for refractory advanced breast cancer [Abstract 446]. Breast Cancer Res Treat 2002;76:S115.
- Miller KD, Wang M, Gralow J, et al. E2100: a randomized phase III trial of paclitaxel versus paclitaxel plus bevacizumab as first-line therapy for locally recurrent or metastatic breast cancer. Proc Am Soc Clin Oncol 2005; 23(16S): LBA.
- Colleoni M, Rocca A, Sandri MT, et al. Low-dose oral methotrexate and cyclophosphamide in metastatic breast cancer: antitumour activity and correlation with vascular endothelial growth factor levels. Ann Oncol 2002;13:73-80.
- Britz-Cunningham SH, Adelstein SJ. Molecular targeting with radionuclides: state of the science. J Nucl Med 2003;44:1945-61.