Volume 1, Number 1
Release date: March, 2008 – Expiration date: March 2009
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Targeted Therapies in Breast Cancer: Mechanisms of Action
G. Lita Smith, RN, ACNP
University of Michigan Breast Cancer Center, Ann Arbor

Although chemotherapy plays an important role in the management of most patients with breast cancer, it is not curative in the metastatic setting and is associated with considerable side effects (eg, alopecia, vomiting). Chemotherapy indiscriminately attacks rapidly dividing cells, an approach that not only affects tumor cells but also many different types of host cells, leading to numerous and potentially lethal toxicities. In contrast, targeted therapies are directed against one or a limited number of cellular components, thereby selectively attacking tumor cells containing the component while sparing all other rapidly dividing cells in its path. In so doing, the targeted therapy acts as a smart bomb, only destroying its intended target—the tumor cell. Although chemotherapy will likely remain an integral component of breast cancer treatment for years to come, current research goals are aimed at providing safer and more effective therapies with potentially fewer toxicities.

Signaling processes occur via signal transduction, which is the communication that occurs either between or within cells. Most often an extracellular signal is transmitted into a cell by a soluble ligand, such as a growth factor, hormone, antibody, or external drug. The binding of this ligand causes the activation of a cell surface receptor, producing phosphorylation of its internal portion, which in turn activates downstream signaling intermediates. In this way, a signal is transmitted all the way to the nucleus, eventually resulting in the regulation of various cell processes and, ultimately, in cell survival and proliferation. While signal transduction is a necessary function of normal cells, it becomes dysregulated in tumor cells by the overexpression or mutation of key signaling components. It is these key signaling components that often make the best therapeutic targets.

BREAST CANCER THERAPEUTIC TARGETS
One of the earliest examples of an anticancer therapeutic target is the estrogen receptor (ER). Estrogen, which binds to the intracellular ER, has been associated in the pathogenesis and growth of breast cancer (Geschickter, Lewis, & Hartman, 1934). Tamoxifen, a selective estrogen receptor modulator (SERM), was the first agent approved by the FDA to target the ER. Upon binding to the ER, the tamoxifenreceptor complex can still bind to DNA, but its altered conformation prevents the recruitment of the necessary cofactors, effectively inhibiting ER-dependent gene transcription (Figure 1). Tamoxifen has been widely used as a targeted agent since 1977 when it was approved for the treatment of metastatic breast cancer. The agent was approved in 1985 for adjuvant treatment of postmenopausal, no-depositive breast cancer and was subsequently shown to reduce the mortality of patients with early stage estrogen- sensitive breast cancer (EBCTCG, 1988). Tamoxifen is the first drug to be approved by the FDA for breast cancer prevention (FDA, 2007).

An increased understanding of the molecular biology underlying tumor cell growth and progression has led to the identification of numerous critical signaling pathways and molecules within these pathways that fit the criteria for therapeutic targets. These advances have ushered in the era of rational drug design, in which drugs are developed to attack specific molecular targets. Therapeutic targets that have been discovered to be important to the development and progression of breast cancer are outlined below, as are the therapies designed to target them.

HER2
The HER family of receptors includes HER1 (also known as epidermal growth factor receptor [EGFR]), HER2, HER3, and HER4. HER2, a proto-oncogene located on chromosome 17, is well known as a target for breast cancer treatment. The HER2 receptor is overexpressed in 25% to 30% of breast cancer tumors (Slamon et al., 1989), a result of an elevated number of HER2 gene copies. HER2 overexpression is correlated with several poor prognostic factors, including positive nodal status and high nuclear grade (Paik et al., 1990). Approximately 50% of HER2-overexpressing tumors are ER-negative, another marker of poor prognosis. As expected, given its association with poor prognosis, HER2 is also correlated with aggressive disease, faster relapse, and shorter survival (Slamon et al., 1987; Paik et al., 1990). These poor outcomes may be understood by the fact that activation of the HER2 pathway inhibits apoptosis and promotes both tumor growth and metastasis (Yarden & Sliwkowski, 2001). Trastuzumab, a humanized monoclonal antibody, was the first anticancer agent to specifically target HER2. It is believed to have multiple mechanisms by which it exerts its antitumor effects (Figure 2). By blocking HER2 receptor dimerization, trastuzumab can inhibit signal transduction and ultimately tumor proliferation. It mobilizes the immune system to kill tumor cells via antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity, and promotes antiangiogenesis. In addition, trastuzumab sensitizes tumor cells to chemotherapy, thus increasing effectiveness. Trastuzumab was initially approved by the FDA in 1998 for use in combination with paclitaxel for the first-line treatment of HER2-overexpressing metastatic breast cancer; this indication was based on a study involving 469 women in whom the addition of trastuzumab to chemotherapy improved median overall survival by 5 months (25.1 months vs. 20.3 months; p = .046; Slamon et al., 2001). Most recently, trastuzumab was awarded an additional indication in the adjuvant setting, in which four large international trials involving a total of approximately 10,000 women showed a progression-free survival (PFS) benefit when trastuzumab was added to chemotherapy for early stage HER2-overexpressing disease (Piccart Gebhart et al., 2005; Romond et al., 2005; Slamon et al., 2006; Smith et al., 2007).

EPIDERMAL GROWTH FACTOR RECEPTOR
EGFR is one of the best-studied anticancer targets and is known to regulate a number of tumor signaling processes. It has a primary role in the stimulation of tumor growth and metastasis, and a more indirect role in angiogenesis and survival (Grunwald & Hidalgo, 2003). EGFR can stimulate the production of matrix metalloproteinases, promoting blood vessel disruption, an important characteristic of tumor angiogenesis (Mendelsohn & Baselga, 2003). The role of EGFR in survival may be observed through EGFR inhibition; this produces the downregulation of proangiogenic factors, which directs the cells to apoptosis (Grunwald & Hidalgo, 2003). EGFR is overexpressed in most tumor types, including breast cancer, making it an attractive anticancer target (Arteaga, 2001). Several targeted agents directed against EGFR (cetuximab, erlotinib, gefitinib) have been approved by the FDA for the treatment of other cancer types, but only lapatinib has been approved for use in breast cancer.

Lapatinib is an orally active small molecule tyrosine kinase inhibitor (TKI) of both EGFR and HER2. As a TKI, lapatinib binds intracellularly to the kinase domains of its targets, inhibiting signal transduction through those pathways (Figure 3). Because of its dual inhibition, lapatinib can block signals arising from EGFR homodimers, HER2 homodimers, and EGFR/HER2 heterodimers. This expanded inhibition relative to trastuzumab may provide lapatinib with the ability to overcome trastuzumab resistance, a problem many patients receiving trastuzumab therapy for metastatic disease will develop. Lapatinib was approved on the basis of a 4-month improvement in PFS observed in patients who had progressed despite previous treatment with a trastuzumab-containing regimen (Geyer et al., 2006).

In 2004, the humanized anti-VEGF monoclonal antibody bevacizumab became the first antiangiogenic agent to be approved by the FDA as an anticancer drug. Bevacizumab appears to have a dual mechanism of action, both inhibiting the growth of new blood vessels and inducing the regression of existing vessels (Ellis, 2006; Figure 4). It also lowers interstitial pressure, improves oxygenation of the tumor, and normalizes tumor vasculature, which may explain why the agent improves the effectiveness of chemotherapy in clinical studies (Hurwitz et al., 2004; Sandler et al., 2006). Bevacizumab is currently approved for the treatment of both colorectal cancer and non-small cell lung cancer. In combination with chemotherapy, the agent has been associated with a significant improvement in disease-free survival in patients with metastatic breast cancer (Miller, Chap et al., 2005).

CONCLUSION
Cancer research is fueled by the goal of someday providing truly individualized patient care. As we gain greater understanding of the molecular pathways involved in tumor development and progression, we come closer to this goal. Several targeted agents have already demonstrated great success against breast cancer, including trastuzumab, lapatinib, and bevacizumab. Current investigative efforts are aimed at optimizing their administration with other agents, and determining which patients are most likely to derive benefit from them. As new agents that target key tumor pathways emerge, the hope is that patients with breast cancer will be allowed to live longer without the burden of disease.

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