Update on the Role of Epothilones in Metastatic Breast Cancer

The role of epothilones in the treatment of locally advanced and metastatic breast cancer remains unclear. While the pivotal studies for ixabepilone were published between 2005 and 2010, and the agent received approval in 2007 from the U.S. Food and Drug Administration, its uptake in routine treatment of breast cancer that is resistant to anthracyclines and taxanes remains inconsistent. The other agents in the class, patupilone and sagopilone, are being studied in a number of cancer types. In this review, the recently published literature on epothilones in various populations and at various dosages is reviewed including the associated adverse event profile and recent biomarker and genomic studies. While the literature has become increasing robust, the precise clinical role for the epothilones in the management of patients with breast cancer remains to be fully defined.     

Epothilones in breast cancer: current status and future directions

Taxanes have become fundamental in the treatment of early and advanced breast cancer. However, tumors vary in their sensitivity to these agents; resistance can be acquired or de novo resistance can occur. Epothilones and associated analogs are novel microtubule-stabilizing agents that induce apoptosis and promote cell death. There is now a growing body of clinical data describing the efficacy of epothilones in breast cancer patients who have progressed on taxanes and anthracyclines. This culminated with US FDA approval in October 2007 of ixabepilone (Ixempra, Brystol Myers Squibb, NJ, USA) either as single agent or in combination with capecitabine for the treatment of breast cancer, which has progressed after prior therapies. The results of ongoing and future randomized clinical trials will further define how epothilones, in particular ixabepilone, will be integrated into the management of early and metastatic breast cancer. In parallel, the search for biomarkers predictive of sensitivity to epothilones continues in an attempt to tailor these therapies to patients with greater accuracy.     

Epothilones in breast cancer: current status and future directions

Taxanes have become fundamental in the treatment of early and advanced breast cancer. However, tumors vary in their sensitivity to these agents; resistance can be acquired or de novo resistance can occur. Epothilones and associated analogs are novel microtubule-stabilizing agents that induce apoptosis and promote cell death. There is now a growing body of clinical data describing the efficacy of epothilones in breast cancer patients who have progressed on taxanes and anthracyclines. This culminated with US FDA approval in October 2007 of ixabepilone (Ixempra?, Brystol Myers Squibb, NJ, USA) either as single agent or in combination with capecitabine for the treatment of breast cancer, which has progressed after prior therapies. The results of ongoing and future randomized clinical trials will further define how epothilones, in particular ixabepilone, will be integrated into the management of early and metastatic breast cancer. In parallel, the search for biomarkers predictive of sensitivity to epothilones continues in an attempt to tailor these therapies to patients with greater accuracy.     

Current perspectives of epothilones in breast cancer

Taxanes have been broadly used in the treatment of breast cancer. However, the majority of initially responsive breast cancer patients eventually develop resistance to taxanes (acquired resistance) and a non-negligible percentage of patients are primarily resistant to these agents (de novo resistance). Additionally, taxanes require pre-medication and may cause important side effects such as febrile neutropenia and neuropathy. Hence, new agents with better efficacy and/or a better toxicity profile and/or are easier to administer need to be developed. Epothilones are a novel class of microtubule-targeting agents sharing a similar mechanism of action to the taxanes and having a more potent antiproliferative activity in various tumour cells lines, particularly in cases of taxane-resistant breast cancer. This review will focus on clinical development of epothilones in breast cancer, particularly ixabepilone which is in the late stages of development, their potential impact in clinical practice, advantages and limitations.     

The epothilones: new therapeutic agents for castration-resistant prostate cancer

The management of castration-resistant prostate cancer (CRPC) presents a clinical challenge because of limitations in efficacy and durability with currently available therapeutics. The epothilones represent a novel class of anticancer therapy that stabilizes microtubules, causing cell death and tumor regression in preclinical models. The structure of the tubulin-binding site for epothilones is distinct from that of the taxanes. Moreover, preclinical studies suggest nonoverlapping mechanisms of resistance between epothilones and taxanes. In early-phase studies in patients with CRPC, treatment with ixabepilone, a semisynthetic analog of epothilone B, induced objective responses and prostate-specific antigen declines in men previously progressing on docetaxel-based regimens. Clinical activity has been observed in nonrandomized trials for patients with CRPC using ixabepilone in the first- and second-line settings as a single agent and in combination with estramustine. Patupilone and sagopilone were also shown to have promising efficacy in phase II clinical trials of patients with CRPC. All three epothilones appear to be well tolerated, with modest rates of neutropenia and peripheral neuropathy. The lack of crossresistance between epothilones and taxanes may allow sequencing of these agents. Evaluating epothilones in phase III comparative trials would provide much-needed insight into their potential place in the management of patients with CRPC.     

Novel Taxane Formulations and Microtubule-Binding Agents in Non–Small-Cell Lung Cancer

Antitubulin agents are among the most active drugs for the treatment of Non—Small-cell lung cancer. The taxanes paclitaxel and docetaxel are highly active and frequently used for adjuvant therapy after resection of localized disease and in combination with radiation for locally advanced disease and treatment of patients with advanced disease. Despite their benefits, these drugs have significant problems, including toxicity and limited efficacy. Recently, new taxane formulations and novel antitubulin agents have been developed. In some cases, these drugs have reduced toxicity with preserved efficacy. In other cases, these agents have potentially unique activity and have now advanced to late-stage trials. This review evaluates 2 novel paclitaxel formulations, albumin-bound paclitaxel and paclitaxel poliglumex. New antimicrotubulin agents, including the epothilones, colchicine-binding antivascular agents, and vinca alkaloids, are also discussed.     

新型抗肿瘤药埃坡霉素的临床研究进展

埃坡霉素（epothilones）是一类非紫杉烷类促微管蛋白聚合剂,其作用机制与紫杉醇相似,但结构完全不同,临床前研究结果显示其细胞毒活性较紫杉醇强,对紫杉类耐药的细胞株和小鼠肿瘤移植模型显示出较强的抗肿瘤活性。近来合成或半合成了很多埃坡霉素类似物,目前已进入临床抗肿瘤治疗研究的埃坡霉素类似物主要有ixabepilone、patupilone、BMS-310705、ZK—EPO、KOS-862及KOS-1584。现有的临床研究结果提示部分接受过紫杉类药物治疗的晚期乳腺癌、卵巢癌、膀胱癌或非小细胞肺癌患者埃坡霉素治疗有效。本文就埃坡霉素的化学结构,作用机制、药理活性及毒副作用等临床研究的进展进行了回顾和综述。     

Ixabepilone: a novel antineoplastic agent with low susceptibility to multiple tumor resistance mechanisms

Tumor resistance to chemotherapeutic agents ultimately leads to treatment failure in the majority of cancer patients. The identification of new agents that are less susceptible to mechanisms of tumor resistance could, therefore, bring significant clinical benefits to patients with advanced cancer. One new drug class of great interest in this respect is the epothilones and their analogues, which are microtubule inhibitors with low susceptibility to several mechanisms of drug resistance. Ixabepilone is an analogue of natural epothilone B with activity against a wide range of tumor types, including drug-resistant tumors. This is consistent with the preclinical activity of ixabepilone against human cancer cell lines resistant to taxanes and other agents. Taxane resistance in these cells may be acquired or primary and results from several mechanisms, such as overexpression of multidrug-resistance proteins and the betaIII-tubulin isoform. Ixabepilone has demonstrated efficacy as monotherapy or in combination with capecitabine in anthracycline- and taxane-pretreated/resistant metastatic breast cancer (MBC), and has recently been approved for use in resistant/refractory MBC. Other epothilones, such as patupilone, KOS-1584, and ZK-EPO, are also being evaluated in drug-resistant cancers. Ixabepilone represents a new treatment option for MBC patients with cancers resistant to available chemotherapeutic agents.     

Treatment beyond taxanes,emerging new cytotoxic agents

Until recently, taxanes were considered the first choice of therapy for patients with metastatic breast cancer (MBC). However, the clinical utility of the taxanes is limited in some patients by the emergence of drug resistance. Moreover, these agents are increasingly used as adjuvant therapy, increasing the population of patients with prior exposure once the disease has metastasised. Current approved treatment options after prior taxane therapy include capecitabine, liposomal doxorubicin and nab-paclitaxel – as single agents and/or in combination. Vinorelbine and gemcitabine may also be used. Most recently, the epothilones, a novel group of microtubule-stabilising agents, have shown promising activity in patients with MBC, including those resistant to taxanes and other cytotoxic drugs. Currently, three epothilone B synthetic derivatives, ixabepilone (BMS-247550), patupilone (EPO906), and sagopilone (ZK-EPO) are in development. This article will examine the latest data for these next-generation cytotoxics in the treatment of MBC.     

Postmenopausal Metastatic Breast Cancer

Endocrine therapy and chemotherapy play important roles in the management of postmenopausal women with metastatic breast cancer. This paper specifically reviews the indications and options for first-line treatment of metastatic breast cancer and recent advances are highlighted, with particular attention to randomized, controlled, phase III clinical trials. Until recently, tamoxifen was standard first-line endocrine treatment for patients with metastatic breast cancer. Now, potent third generation aromatase inhibitors, such as letrozole and anastrozole, have shown superiority to tamoxifen as first-line endocrine treatment and provide an alternative for postmenopausal women. The most active chemotherapy agents for patients with advanced breast cancer have, until recently, been the anthracyclines, doxorubicin and epirubicin. However, their increasing use in the adjuvant setting has resulted in a need for novel active non-cross-resistant cytotoxic drugs for metastatic breast cancer. Real progress has been made with the introduction of the taxanes, paclitaxel and docetaxel. Other developments include the use of single agent cytotoxics such as vinorelbine, the oral fluoropyrimidine capecitabine and gemcitabine, all of which have some activity following either taxanes or anthracyclines, along with a low toxicity profile. Bisphosphonates are bone-specific palliative treatments that have been instituted on the basis of their impact on symptoms and skeletal related morbidity. Finally, the era of biological therapy in the clinic for patients with breast cancer has been heralded with the development and introduction of trastuzumab, a humanized monoclonal antibody which targets the cell surface growth factor receptor HER2/neu. Importantly, each of these new treatment options has provided an incremental improvement in efficacy over previous standard first-line therapies.     

Neoadjuvant gemcitabine therapy for breast cancer

Neoadjuvant chemotherapy has become a standard treatment in the management of locally advanced breast cancer. Patients with earlier-stage disease may also benefit from neoadjuvant treatment in terms of improved rates of breast-conserving surgery and thus better quality of life. Gemcitabine is a pyrimidine analogue that has shown activity in a variety of solid tumors, a good toxicity profile, and nonoverlapping toxicity with other chemotherapeutic agents. Several phase II/III studies are assessing gemcitabine combined with anthracyclines, taxanes, and/or vinorelbine both in the neoadjuvant and metastatic disease settings. This article reviews developments in neoadjuvant use of gemcitabine in combination with anthracyclines and taxanes. Several phase II trials of gemcitabine combined with doxorubicin/epirubicin or with doxorubicin/paclitaxel have been carried out. Preliminary findings demonstrate increased complete response rates and good tolerability of these regimens in patients with breast cancer.     

Clinical Development of Ixabepilone and Other Epothilones in Patients with Advanced Solid Tumors

Chemotherapy efficacy in patients with solid tumors is influenced by primary and acquired multidrug resistance (MDR). Epothilones represent a novel class of microtubule inhibitors with lower susceptibility to drug resistance and efficacy in taxane‐resistant tumors. While other epothilones are currently under investigation, ixabepilone is the first epothilone B analogue approved by the U.S. Food and Drug Administration. Ixabepilone has been shown to have preclinical activity in chemotherapy‐sensitive and chemotherapy‐resistant tumor models, and synergistic antitumor activity with other chemotherapeutic and targeted agents. Single‐agent ixabepilone has demonstrated clinical activity in multiple solid tumors including advanced breast, lung, prostate, pancreatic, renal cell, and ovarian cancers. Most notably, efficacy has been demonstrated in patients with metastatic breast cancer (MBC) progressing after treatment with anthracyclines and taxanes. A phase III trial in anthracycline‐ and taxane‐resistant MBC showed superior disease control with ixabepilone plus capecitabine versus capecitabine monotherapy, resulting in its approval. Ixabepilone is also active in chemotherapy‐naïve and taxane‐resistant hormone‐refractory prostate cancer and platinum‐resistant non‐small cell lung cancer. Neutropenia and peripheral sensory neuropathy are the most common adverse events associated with treatment. This review discusses the challenges of MDR and the data that support the use of epothilones in this setting, focusing on ixabepilone.     

Efficacy and safety of ixabepilone (BMS-247550), a novel epothilone B analogue

The epothilones are a new class of non-taxane tubulin polymerization agents obtained by natural fermentation of the myxobacteria Sorangium cellulosum. The cytotoxic activities of the epothilones, like those of the taxanes, have been linked to stabilization of microtubules, but they also have important differences. Among the epothilone family, ixabepilone (BMS247550) is a semisynthetic derivative of the natural product epothilone B. Ixabepilone was evaluated in vivo in a panel of human and rodent tumour models, the majority of which were chosen because of their known, well-characterized resistance to paclitaxel, and seems able to overcome the over-expression of multidrug resistance and to be unaffected by mutations in the beta tubulin gene. The interest of ixabepilone was clinically confirmed in clinical studies of phase II which demonstrated a strong activity at the patients with metastatic breast cancer resistant to taxanes and in patients suffering of other types of chemoresistant tumors.     

Gemcitabine and platinum combinations in patients with breast cancer previously treated with anthracyclines and/or taxanes

As anthracycline-based regimens have become a standard treatment and are frequently used in the adjuvant therapy of breast cancer, the number of anthracycline-resistant cancers has begun to increase. Taxanes have also become more commonly used in the first-line metastatic and adjuvant setting, producing a need for new treatment options that are not cross-resistant with anthracyclines or taxanes and that have a relative non-overlapping toxicity profile with these agents. The combination of gemcitabine/cisplatin has been shown to have synergistic cytotoxic activity in vitro in breast cancer cell lines. In addition, several phase II trials have suggested that this combination is feasible and active in patients who have received prior anthracycline and/or taxane therapy.     

Taxanes in the treatment of early breast cancer

The taxanes docetaxel and paclitaxel have established roles as two of the most active agents in the treatment of metastatic breast cancer. These two drugs are now being incorporated into the management of early breast cancer. A first generation of trials has explored whether the addition of taxanes either sequentially or in combination with adjuvant anthracycline-based chemotherapy improves outcome for patients with early breast cancer. A second generation of trials are now underway which are based on the assumption that taxanes are beneficial in the adjuvant setting, and are comparing the different taxanes, dosing regimens and the addition of further agents. Trials in the neoadjuvant setting have recently demonstrated improved response rates with the addition of taxanes into existing anthracycline-based regimes. This review critically appraises these trials and provides an overview of ongoing research in the area.     

Options for the treatment of patients with taxane-refractory metastatic breast cancer

The application of taxane chemotherapy to the treatment of early-stage and advanced breast cancer has resulted in significant improvements in disease-free and overall survival. As a consequence of these improvements in disease outcome, oncologists must face the new challenge of developing additional therapies that are effective against taxane-resistant disease and are associated with a favorable toxicity profile. This article discusses some of the chemotherapeutic options available for the treatment of patients with taxane-resistant metastatic breast cancer. Newer formulations of traditional microtubule-stabilizing agents, such as albumin-bound paclitaxel, which uses a more favorable vehicle for administration compared with conventional paclitaxel, have demonstrated efficacy in this setting. Several novel microtubule-targeting agents have been shown to be less susceptible to traditional mechanisms of taxane resistance, such as the multidrug resistance phenotype associated with increased activity of the P-glycoprotein drug efflux system and the development of structural changes in tubulin. Examples of these therapies include the vinca alkaloids, such as vinorelbine and vinflunine; epothilones; and eribulin. Traditional antimetabolites, such as gemcitabine and capecitabine, used as monotherapy or combination chemotherapy have also shown efficacy in the treatment of patients with taxane-resistant breast cancer. A greater understanding of the mechanism of drug resistance, as it pertains to taxanes, will enable further development and the effective application of chemotherapeutic agents that will circumvent drug resistance and result in improvement in breast cancer control.     

Ixabepilone for the treatment of taxane-refractory breast cancer

The ephothilones are a novel class of agents that bind to beta-tubulin, promote microtubule stabilization and cause cell-cycle arrest in G2/M phase. Ixabepilone (Ixempra) is an epothilone B that has demonstrated preclinical activity against a variety of tumor types and has recently been US FDA approved (application for registration ongoing in Europe) as a single agent for the treatment of taxane-refractory metastatic breast cancer, or in combination with capecitabine for patients with advanced breast cancer refractory to anthracyclines and taxanes. This review will provide an overview of the clinical development of ixabepilone, and emphasize the drug's utility for the treatment of advanced breast cancer.     

Ixabepilone, first in a new class of antineoplastic agents: the natural epothilones and their analogues

Although targeted therapies are becoming increasingly important in oncology, cytotoxic agents are likely to remain a valuable element in the treatment paradigm of cancer. However, resistance to chemotherapy is a major obstacle to the successful treatment of cancer. Therefore, there is a need for novel antineoplastic agents that are able to overcome mechanisms of tumor resistance. Drugs that target microtubules, including paclitaxel and docetaxel, are among the most commonly prescribed anticancer therapies. However, the utility of taxane-based therapies is limited by difficulties with formulation, administration, and resistance induced by P-glycoprotein. The epothilones and their analogues are a novel class of antimicrotubule agents that has demonstrated antitumor activity in the setting of resistance. These antimicrotubule agents are structurally unrelated to the taxanes, with a distinct beta-tubulin-binding mode. Ixabepilone is a rationally designed, semisynthetic analogue of natural epothilone B, which displays reduced susceptibility to a range of common tumor resistance mechanisms. Promising phase II activity and a manageable safety profile with ixabepilone have been seen in a wide range of tumor types, including heavily pretreated/resistant and early-stage breast cancer. Moreover, encouraging phase III results with ixabepilone and capecitabine for patients with breast cancer have recently been presented. Clinical trials are also planned for ixabepilone in combination with targeted agents, such as trastuzumab and bevacizumab. Ixabepilone is likely to be the first available drug in its class, with the potential to bring clinical benefit to patients with a wide range of malignancies.     

New combination chemotherapies for breast cancer

Doxorubicin has been a pivotal role in combination chemotherapy for breast cancer (BC) since 1970's. Over the past decade, a number of new and effective cytotoxic agents have become available for the treatment of breast cancer. The most active agents may be the taxanes, paclitaxel and docetaxel, because their clinical efficacy exceeds that of the anthracyclines, previously the most effective agents against breast cancer. To obtain better quality of life and longer survival for our patients, we need to improve our therapeutic strategy and tactics by developing new combination chemotherapies using taxanes, anthracyclines, and other new promising agents such as vinorelbine, capecitabine, S-1, gemcitabine, liposomal doxorubicin, MTA and so on. Recombinant humanized anti-HER 2 monoclonal antibody is also very active for patients with BC, when used together with taxanes, showing survival advantage compared with taxanes alone. Extensive clinical investigations have been performing with such active agents and biotherapeutics.     

Combination of taxanes and anthracyclines in first-line chemotherapy of metastatic breast cancer: an interim report

Anthracyclines and taxanes are among the most effective agents in the treatment of advanced breast cancer, refractory or non-responsive to endocrine manipulation. Several recently published phase III studies have addressed the role of these compounds in combination compared with established chemotherapy regimens. This report considering a total of 4244 patients evaluates the data of those trials with respect to the efficacy and toxicity of the treatment regimens. Currently, evidence is growing that especially patients with symptomatic visceral tumour spread may benefit from the combined application of anthracyclines and taxanes. Adequately dosed polychemotherapy appears to be more successful than monotherapy, and, at present, the combination of anthracyclines (doxorubicin, epirubicin) and taxanes (docetaxel (Doc), paclitaxel (Pac)) might lead to a promising approach to improve the course of the metastatic disease.