The New Generation of Targeted Therapies for Breast Cancer
The New Generation of Targeted Therapies for Breast Cancer
Syed and Rowinsky present a
comprehensive review of new
targeted therapies for breast cancer.
This is an important review that
summarizes new biologic targets and
current drugs in development for the
treatment of breast cancer-a rapidly
evolving field. Among the targets addressed
in the article are epidermal
growth factor receptor (EGFR-), Ras/
Raf/mitogen-activated protein (MAP)
kinase, phosphatidylinositol 3-kinase
(PI3K)/protein kinase B (AkT)/molecular
target of rapamycin (mTOR), tumor
angiogenesis, apoptosis, and
histone deacetylases. The list should
also be expanded to include differentiating
agents and inhibitors of invasion
and metastasis. It is critical to
emphasize the future of customized
therapy and the use of biologic agents
alone, together, or in combination with
chemotherapy for the treatment of
The use of genomic and proteomic technologies will be important in identifying new targets and their level of expression in tumor samples. Ideally, a combination of biologic agents that can be used to treat patient-specific phenotypes has the advantage of increasing the efficacy rate in a specific population, while avoiding undue toxicities. This is the case particularly for HER2 expression in breast cancer patients and the benefits seen in this population with the use of trastuzumab (Herceptin). One strategy that is currently being evaluated is the combination of EGFR inhibitors with angiogenesis inhibitors. A phase II trial being conducted at the University of California, Los Angeles, is evaluating the combination of trastuzumab with bevacizumab (Avastin) in breast cancer patients expressing HER2, as vascular endothelial growth factor (VEGF) appears to be overexpressed in many breast cancer tumors and may play a critical role in its pathogenesis. The combination of bevacizumab plus capecitabine (Xeloda) was evaluated against capecitabine alone in a phase III trial in patients with refractory metastatic breast cancer, and the response rate doubled in the two-drug arm (19% vs 9%). However, these responses were short-lived, and no survival benefit was noted. Two possible explanations for this are as follows: First, the disease was advanced, and the tumors may have been expressing multiple angiogenic factors. The therapy may have selected for tumor cells that were not dependent or not expressing VEGF thus allowing for the return of rapid tumor growth and subsequent short-lived responses. Second, the chemotherapy agent itself was not antiangiogenic, and thus, a potential synergistic effect would not have occurred. Paclitaxel and docetaxel (Taxotere) would be better choices in this regard. The administration of these agents using weekly or metronomic dosing to optimize endothelial-cell killing would also be ideal. A randomized, phase III trial by the Eastern Cooperative Oncology Group is currently evaluating weekly paclitaxel vs paclitaxel plus bevacizumab in metastatic breast cancer patients. Similarly, two phase II trials are evaluating docetaxel in combination with bevacizumab in patients with inflammatory and locally advanced breast cancer. Combination Therapy
As breast tumors develop after the switch to an angiogenic phenotype, they secrete multiple angiogenic growth factors that allow for continued growth and expansion of tumor cells. Smaller tumors secrete fewer of these factors and may thus be amenable to treatment with one or fewer agents targeting angiogenesis. It is likely, then, that successful treatment of larger tumors would entail the use of multiple antiangiogenic agents in combination. For optimal synergistic effects on tumor kill, it may be advantageous to target intracellular signaling pathways that are distinct but critical to growth, differentiation, and apoptosis of tumor cells. Examples might include the combination of an antiangiogenic agent, an EGFR inhibitor, an agent that targets the PI3K/AkT pathway, and an agent that targets the tumor necrosis factor (TNF)/TNF-related apoptosis ligand (TRAIL)-receptor pathway. Such combinations might work best in the setting of a small tumor burden, when limited growth factors and escape mechanisms are driving the tumor. How to Incorporate Targeted Therapies in Clinical Trials
Targeted therapies may be incorporated into breast cancer trials in many ways. For patients with locally advanced disease (stage IIIA/B) and chest wall or skin involvement, surgical resection may be difficult without initial cytoreduction. Targeted therapies might be used in combination with chemotherapy for optimal reduction of tumor bulk. Antiangiogenic agents might be useful in this regard in "pruning" tumor blood vessels to allow for better penetration of chemotherapy.[ 4] Similarly, in the setting of recurrent or metastatic disease, the use of combinations of biologic agents with or without chemotherapy might be useful in palliation, especially when response may be critical for better quality of life, as, for example, in the treatment of bony metastases. Combinations of biologic agents may also be used after cytoreductive therapy with standard chemotherapy agents such as doxorubicin, cyclophosphamide (Cytoxan, Neosar), paclitaxel, and docetaxel. In this scenario, such combinations may be considered in maintenance programs that could stabilize disease and prevent tumor progression or allow tumor progression at a slow pace. Targeted therapies might also function as radiosensitizers and could be incorporated into the treatment of local disease. The safety of these agents must be considered especially when they are combined with chemotherapy agents or with each other. Overall, targeted therapies hold promise in the rational design of cancer therapies that may effectively control cancer with less toxicity.
2. Klement G, Baruchel S, Rak J, et al: Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity. J Clin Invest 105:R15-R24, 2000.
3. Relf M, LeJeune S, Scott PA, et al: Expression of the angiogenic factors vascular endothelial cell growth factor, acidic and basic fibroblast growth factor, tumor growth factor beta-1, platelet-derived endothelial cell growth factor, placenta growth factor, and pleiotrophin in human primary breast cancer and its relation to angiogenesis. Cancer Res 5:963-969, 1997.
4. Jain RK: Normalizing tumor vasculature with anti-angiogenic therapy: A new paradigm for combination therapy. Nat Med 7:987-989, 2001.