Molecularly Targeted Therapies for Breast Cancer
Authors: Timothy J. Hobday, MD; Edith A. Perez, MD
Abstract
Background: The management of patients with localized and advanced breast cancer continues to evolve. Chemotherapy, endocrine therapy, and trastuzumab are effective therapies but leave considerable room for improvement. As the cellular aberrations inherent to cancer cells in general and breast cancer cells specifically are better understood, therapies to target specific cellular pathways continue to be developed with the goal of expanding available effective therapy through better patient selection.
Methods: We conducted a computerized search of the medical literature as well as a manual search of selected meeting abstracts.
Results: Several targeted therapies are in phase III clinical trials testing their promise in the treatment of breast cancer. Many other agents are completing phase I and II testing. An overview of the most promising agents in clinical development is discussed herein.
Conclusions: Targeted therapy for breast cancer is a reality at this time, and several new agents hold promise for expanding and refining the pool of patients likely to further benefit from this approach in the near future.
Introduction
Despite advances in early detection of breast cancer, adjuvant therapy of localized disease, and palliative therapy of metastatic disease, breast cancer remains a significant public health problem, with an estimated 212,930 new cases and 40,840 deaths in the United States alone in 2005.[1] Cytotoxic chemotherapy remains an important part of optimal therapy for patients in all stages of disease, but it is limited by toxicity, nonspecificity, and inevitable development of resistance. Cytotoxic therapy has not been considered a "targeted" therapy since many of its specific targets have not been identified; it is evident that to be effective against cancer, it has to target cellular pathways involved in growth regulation.The term targeted therapy ideally connotes the ability to identify a known therapeutic target that is important in the biology of the cancer cell and use a specific agent that can treat the disease by modifying the expression or activity of the target in the growth and progression of the cancer. With this approach, only patients with a likelihood of benefit are treated, so the therapeutic index will hopefully be improved.
The story of selective and targeted therapy for breast cancer is an old one that involves the use of oophorectomy, hypophysectomy, and adrenalectomy as palliative and adjuvant endocrine therapy throughout the past century. With the discovery of the estrogen receptor (ER) and with our evolving understanding of the biology of this receptor pathway, the development of targeted agents to modulate the activity of this pathway (selective estrogen receptor modulators [SERMS]), to inhibit the production of the ligand (aromatase inhibitors), and to downregulate the receptor expression and activity (fulvestrant) has markedly improved outcomes of localized and advanced breast cancer expressing the ER.[2] Only patients who express the estrogen and/or progesterone receptor (PgR) benefit from endocrine therapy, although identification of other predictors of benefit to endocrine therapies is still needed as only approximately 30% of patients receiving first-line endocrine therapy for metastatic disease will achieve partial or complete regression of disease with such therapies.
The humanized monoclonal antibody trastuzumab was developed as a therapy targeted against the human epidermal growth factor receptor 2 (HER2), which is over-expressed in roughly one fourth of patients with invasive breast cancer. Readily available markers of overexpression and/or gene amplification of HER2 in tumor tissue predict for the activity of this agent and exclude those who will not benefit from this therapy. Randomized trials have demonstrated a survival benefit associated with the introduction of this agent in addition to chemotherapy in women who have metastatic breast cancer that overexpresses the HER2 protein or have amplification of the HER2 gene.[3,4] It is hopeful that ongoing trials of this agent in the adjuvant setting will also demonstrate an improvement in survival with the addition of this agent to chemotherapy. Other than concerns of cardiac toxicity, the tolerability of this agent is excellent.
Although these examples of targeted therapy for breast cancer using antiestrogen or anti-HER2 therapies have been successful, there is more to be done. Many patients have tumors that do not express either steroid hormone receptors or HER2. Resistance to trastuzumab and endocrine therapy develops in essentially all patients with advanced disease. As the understanding of the biology of breast cancer evolves, several other important intracellular pathways have been discovered as targets for novel therapeutic agents, including other members of the HER family, proangiogenic pathways, proliferative pathways, pathways of cell-cycle regulation, apoptosis pathways, and many others. It is also becoming clearer that the complex interplay of these pathways will likely require multiple targets to be inhibited to optimize cytotoxicity and overcome resistance mechanisms. This review highlights agents that are furthest along in their clinical development as breast cancer therapeutics.
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