Targeted Therapy for Metastatic Breast Cancer

Amelia B. Zelnak* and Ruth O’Regan

Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA

 ABSTRACT

Multiple chemotherapeutic agents are currently being used in the treatment of metastatic breast cancer. Microtubule-targeting drugs, such as the taxanes, are the mainstays of treatment since their introduction in the 1990s. Recently, new classes of microtubule inhibitors have been developed which include epothilones and halichondrins. Another important target in breast cancer is angiogenesis, which is the process of new blood vessel formation and is required for tumor growth and metastasis. There is a biologic rationale to inhibiting angio-genesis in the treatment of breast cancer. Several large clinical trials have demonstrated a significant benefit in progression-free survival with the addition of the anti-vascular endothelial growth factor monoclonal antibody bevacizumab to chemotherapy. This article reviews the role of microtubules in cell growth and the role of angio-genesis in breast cancer pathogenesis. Agents targeting microtubules and angiogenesis are also discussed.

Keywords: microtubule-targeting agents, taxanes, epothilones, angiogenesis, VEGF, bevacizumab, receptor tyrosine kinase inhibitors

 MICROTUBULE INHIBITORS

Introduction

Microtubules are essential components of the cytoskeleton and are made up of α- and β-subunits. They play a critical role in a variety of cellular functions including cell shaping, intracellular signaling, cell migration, and cell division. Therefore, micro-tubules are a suitable target for anticancer therapy. Microtubule inhibitors (MTIs), such as the taxanes, vinca alkaloids, and epothilones, stabilize or destabilize microtubules, leading to arrest in metaphase and subsequent apoptosis. These agents are used in treating a variety of solid malignancies, including breast cancer. Some tumors are intrinsically resistant to these agents, and others develop resistance as treatment progresses. Novel MTIs are being developed to overcome drug resistance and improve the efficacy of cancer treatment.

The Target: Microtubules

Microtubules are polymers of α- and β-tubulin heterodimers. The heterodimers polymerize head to tail, forming protofilaments that run lengthwise along the wall of the tube. A microtubule is made up of the parallel arrangement of 13 protofilaments in an imperfect helix (1). When microtubules assemble, one end called the plus end grows more quickly than the other. In the cell, micro-tubules usually grow outwards from the microtubule organizing center toward the cell membrane. Microtubules are in a dynamic state, growing and shortening by the reversible association and dissociation of α/β-tubulin heterodimers (2).

Each α- and β-tubulin subunit has a guanosine triphosphate (GTP)-binding site. The GTP on β-tubulin is hydrolyzed to guanosine diphosphate (GDP) after polymerization. Microtubule growth occurs when GTP-bound subunits associate and shortening occurs when GDP-bound subunits dissociate. Microtubule dynamics are critical for cell division when the rapid assembly and disassembly of microtubules is needed to align and separate chromosomes in metaphase. Microtubule-stabilizing agents such as the taxanes and epothilones promote microtubule assembly, but prevent the disassembly required to complete mitosis (2).

Microtubule-Destabilizing Agents: Vinca Alkaloids

The vinca alkaloids have been widely used as chemotherapeutic agents in several childhood and adult malignancies. They were initially isolated from the dried leaves of the periwinkle plant Catharanthus rosea, formerly called Vinca rosea. Vinca alkaloids all share a similar structure consisting of a catharanine moiety linked to a vindoline ring. The vincas bind directly to β-tubulin near the GTP-binding site, inhibiting polymerization. This results in impaired microtubule dynamics and mitotic spindle formation, leading to cell death (1,3,4). In a phase II trial of patients with meta-static breast cancer who had previously received an anthracycline and taxane, the objective response rate to weekly vinorelbine was 25% (5). Although vinorelbine is not approved by the US Food and Drug Administration (FDA) for the treatment of metastatic breast cancer, it is commonly used in clinical practice.

Microtubule-Stabilizing Agents: Taxanes

Paclitaxel (Taxol, Bristol-Myers Squibb) is derived from the bark of the pacific yew tree and was first identified at the National Cancer Institute in the late 1960s during a large-scale screening program of natural products for anticancer activity (6). Docetaxel (Taxotere, Sanofi-Aventis) is a semisynthetic derivative of a precursor derived from the yew species. Paclitaxel and docetaxel occupy the same binding site on β-tubulin on the interior surface of microtubules (1, 7). Upon binding, the taxanes stabilize microtubules and shift the dynamic equilibrium toward polymerization. This inhibits cell proliferation by inducing a metaphase arrest and subsequent cell death (8, 9). Paclitaxel and docetaxel are among the most commonly used chemotherapy agents used to treat metastatic breast cancer. Albumin-bound paclitaxel (Abraxane, Abraxis Oncology), a cremophor-free formulation of paclitaxel, is indicated for the treatment of metastatic breast cancer after progression on combination therapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. A phase III trial was conducted in 454 patients with metastatic breast cancer who had not received prior paclitaxel or docetaxel. Patients were randomized 1:1 to receive either nab-paclitaxel 260 mg/m² intravenously every 3 weeks (n = 229) or paclitaxel 175 mg/m²intravenously every 3 weeks (n = 225). Nabpaclitaxel showed an improved progression-free survival (PFS) compared with paclitaxel (23.0 vs 16.9 weeks, respectively; hazard ratio [HR] 0.75; P = .006) (10). Nab-paclitaxel has also been compared with docetaxel in a randomized phase II trial in 302 patients with advanced breast cancer. In this multicenter study, patients were assigned to one of four treatment arms as first-line therapy: (1) nab-paclitaxel 300 mg/m² every 3 weeks, (2) nabpaclitaxel 100 mg/m² weekly, (3) nab-paclitaxel 150 mg/m² weekly, or (4) docetaxel 100 mg/m² every 3 weeks. Nab-paclitaxel given weekly at 150 mg/m² resulted in a better PFS compared with docetaxel given at 100 mg/m² every 3 weeks (12.9 vs 7.5 months, respectively; P = .0065) (11). The advantages of nab-paclitaxel are it does not require premedication with steroids and antihistamines, it can be infused over a shorter duration compared with paclitaxel (30 minutes vs 3 hours), and there is a decreased risk of hypersensitivity reactions.

Resistance

Many tumors have intrinsic or acquired resistance which limits the efficacy of many chemotherapeutic agents, including MTIs. One common mechanism of multidrug resistance is the overexpression of drug efflux proteins such as P-glycoprotein (P-gp). This is a member of the ATP-binding cassette superfamily and protects cells and tissues by extruding potential toxins, including anticancer agents, outside of the cell (12, 13). P-gp confers resistance to a wide variety of chemotherapeutic agents, including taxanes, vinca alkaloids, and topoisomerase I inhibitors. Expression patterns of these emu pumps may serve as molecular markers to help predict response to chemotherapy. Although such relationships are not entirely clear in breast cancer, P-gp expression tends to increase after treatment with chemotherapy (14, 15). However, studies have produced conflicting findings regarding whether P-gp expression in patients with breast cancer correlates with response to taxanes (15, 16).

Resistance may also arise from alterations in the binding site on β-tubulin. Ovarian cancer cell lines resistant to paclitaxel were found to have acquired mutations in the M40 isotype of β-tubulin (17). Altered expression of tubulin isotypes, including loss of βII-tubulin and overexpression of βIII-tubulin, may also lead to taxane resistance (15, 16). Overexpression of βIIItubulin has been associated with poorer outcome in patients with metastatic breast cancer treated with taxane-containing regimens (14,18,19).

Epothilones

The epothilones are a novel group of MTIs with a mechanism of action similar to taxanes, inducing mitotic arrest and subsequent apoptosis (20, 21). Epothilones A and B were initially isolated from the myxobacterium Sorangium cellulosum. Epothilones have a unique binding site on β-tubulin that is not shared with paclitaxel (22). In vitro studies have also shown that epothilones are active in cells that overexpress P-gp, a known mechanism of resistance to the taxanes (23).

The epothilones show promising anticancer activity and have the potential to overcome taxane resistance due to differences in binding site and susceptibility to P-gp overexpression. Ixabepilone (Ixempra, Bristol-Myers Squibb), a semisynthetic derivative of epothilone B, is the first agent in this class to be approved for the treatment of metastatic breast cancer. In preclinical studies, ixapebilone demonstrates activity against paclitaxel-resistant cell lines and tumors (20,23,24). Although both paclitaxel and ixabepilone induce mitotic arrest and apoptosis, studies in vitro have shown that ixabepilone induces apoptosis by activating different cellular pathways compared with paclit-axel. Although paclitaxel is thought to activate apoptosis by inducing cytochrome C release from the mitochondria and activation of Apaf-1 and caspase-9 (25, 26), ixabepilone has been shown to activate caspase-3 and caspase-8, leading to subsequent apoptosis (27). These differences in mechanism may contribute to the activity of ixabepilone in taxane-resistant tumors. Several other epothilones are in various stages of clinical development and include patupilone (natural epothilone B; EPO906), sagopilone (ZK-EPO; synthetic third-generation epothilone), and KOS-1584 (epothi-lone D analogue).

Ixabepilone has been studied in the treatment of metastatic breast cancer as first-line therapy and in patients who have received prior therapy. It is administered once every 3 weeks as a 3-hour intravenous infusion at 40 mg/m². It is approved by the FDA as monotherapy for patients whose tumors are refractory to anthracyclines, taxanes, and capecitabine, and in combination with capecitabine for patients whose tumors are resistant to anthracylines and taxanes. A phase III trial compared the combination of ixabepilone and capecitabine with capecitabine alone in patients with metastatic breast cancer who had received prior anthracycline- and taxane-based therapy. The combination prolonged PFS (median, 5.8 vs 4.2 months, HR 0.75; 95% confidence interval, 0.64–0.88; P = .0003) and increased the objective response rate (35% vs 14%; P <.0001) (28). A phase II clinical trial of ixabepilone in 126 patients whose tumors were resistant to anthracycline, taxane, and capecitabine showed a response rate of 11.5% based on an independent radiologic review, and consisted of partial responses. In this heavily pretreated population, 13% of patients had stable disease for ≥6 months (29). Thomas et al. conducted a phase II clinical trial of ixabepilone in 49 patients with metastatic breast cancer who had progressed while receiving or within 4 months of completing taxane-based therapy or within 6 months of adjuvant taxane. The overall response rate was 12% and consisted of all partial responses. A phase II clinical trial of ixabepilone as first-line therapy in 65 patients with metastatic breast cancer treated with an anthracyline in the adjuvant setting showed a response rate of 41.5% and a median duration of response of 8.2 months (31). Single-agent ixabepilone given for four cycles in the neoadjuvant setting yielded a pathologic complete response rate of 18%, which is quite comparable with studies of single-agent taxane given as neoadjuvant therapy (32). Ixabepilone has shown clinical activity in other solid tumors, such as prostate, renal, non-small cell lung cancer, and ovarian. Additional studies of ixabepilone with other agents are ongoing in these tumor types (33).

The toxicities of ixabepilone are similar to those reported with taxanes. Grade 3 or 4 sensory neuropathy should be the most frequent cause of treatment discontinuation. After stopping ixabepilone, the median time to improvement to baseline or grade 1 neuropathy was 6 weeks (34). Typically, peripheral neuropathy can be managed with dose reductions and/or treatment delays. Other toxicities include neutropenia, fatigue, diarrhea, and nausea (28–31). Ixabepilone is also being evaluated in combination with other targeted agents such as bevacizumab, trastuzumab, and sorafenib.

Halichondrins

Halichondrins are nontaxane MT dynamics inhibitors, initially isolated from the marine sponge Halichondria okadai. Eribulin mesylate (E7389), a synthetic analog of halichondrin B, inhibits microtubule dynamics, resulting in mitotic arrest and subsequent apoptosis (35). A phase II clinical trial in 103 patients with heavily pretreated meta-static breast cancer with eribulin showed an overall response rate of 11%, and a median PFS of 2.6 months (36). Results from a large, phase III clinical trial (EMBRACE) comparing eribulin with treatment of physician’s choice in 762 patients with metastatic breast cancer who had received prior therapy with anthracycline and taxane were recently presented. Patients were randomized 2:1 to receive either eribulin 1.4 mg/m² over 2 to 5 minutes intravenously on days 1 and 8 of a 21-day cycle (n = 508) or treatment of choice, which consisted of cytotoxic, endocrine, biologic, or supportive care (n = 254). The median number of prior chemotherapy regimens was four. All patients had received an anthracycline and a taxane and 73% had prior capecitabine. Eribulin mesylate improved overall survival in this population by 2.4 months (13.1 months vs 10.7 months, P = .04). The regimen was well tolerated. The most common adverse events were neutropenia (45%), neuropathy (8.2%), and fatigue (8.8%) (37, 38). The survival difference seen in this study is noteworthy and further evaluation is needed. Eribulin is being studied in combination with targeted therapy, including bevacizumab and trastuzumab.

Extensive laboratory studies have shown that angiogenesis plays a critical role in the neoplastic transformation of normal breast tissue, invasion, and subsequent metastasis (39). Hyperplastic mouse mammary papillomas and normal breast tissue isolated from a cancerous breast are able to induce neovascularization in preclinical models (40, 41). This suggests that angiogenesis is a key step in progression from normal breast tissue to malignancy.

VEGF is one of the most potent proangiogenic signals and plays a pivotal role in tumor angiogenesis. VEGF binds to and activates receptors on the surface of endothelial cells within the blood vessel wall. Binding of VEGF to these receptors initiates a signaling cascade, leading to the activation of endothelial cells and subsequently to the growth of new blood vessels (42

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