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Impact of taxanes on androgen receptor signaling.
Bai, S, Zhang, BY, Dong, Y
Asian journal of andrology. 2019;(3):249-252
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Abstract
The development and progression of metastatic castration-resistant prostate cancer is the major challenge in the treatment of advanced prostate cancer. The androgen receptor signaling pathway remains active in metastatic castration-resistant prostate cancer. Docetaxel and cabazitaxel are the first- and second-line chemotherapy, respectively, for patients with metastatic castration-resistant prostate cancer. These two taxanes, in general, function by (i) inhibiting mitosis and inducing apoptosis and (ii) preventing microtubule-dependent cargo trafficking. In prostate cancer, taxanes have been reported to inhibit the nuclear translocation and activity of the androgen receptor. However, whether this is attainable or not clinically remains controversial. In this review, we will provide a comprehensive view of the effects of taxanes on androgen receptor signaling in prostate cancer.
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Taxane-containing regimens for metastatic breast cancer.
Ghersi, D, Willson, ML, Chan, MM, Simes, J, Donoghue, E, Wilcken, N
The Cochrane database of systematic reviews. 2015;(6):CD003366
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BACKGROUND It is generally accepted that taxanes are among the most active chemotherapy agents in the management of metastatic breast cancer. This is an update of a Cochrane review first published in 2003. OBJECTIVES The objective of this review was to compare taxane-containing chemotherapy regimens with regimens not containing a taxane in the management of women with metastatic breast cancer. SEARCH METHODS In this review update, we searched the Cochrane Breast Cancer Group Specialised Register, MEDLINE, EMBASE, the World Health Organization's International Clinical Trials Registry Platform (WHO ICTRP), and ClinicalTrials.gov on 14 February 2013 using keywords such as 'advanced breast cancer' and 'chemotherapy'. We searched reference lists of articles, contacted study authors, and did not apply any language restrictions. SELECTION CRITERIA Randomised controlled trials comparing taxane-containing chemotherapy regimens to regimens without taxanes in women with metastatic breast cancer. We included published and unpublished studies. DATA COLLECTION AND ANALYSIS Two review authors independently assessed trial quality and extracted data. We derived hazard ratios (HRs) for overall survival, time to progression, and time to treatment failure where possible, and used a fixed-effect model for meta-analysis. We represented objective tumour response rates and toxicity as risk ratios (RRs). We extracted quality of life data where present. MAIN RESULTS This review included 28 studies. The updated analysis included 6871 randomised women, while the original review had 3643 women. Of the 28 included studies, we considered 19 studies to be at low risk of bias overall; however, some studies failed to report details on allocation concealment and methods of outcome assessment for those outcomes that are more likely to be influenced by a lack of blinding (for example tumour response rate). Studies varied in the taxane-containing chemotherapy backbone, and the comparator arms and were categorised into three groups: Regimen A plus taxane versus Regimen A (2 studies); Regimen A plus taxane versus Regimen B (14 studies); and single-agent taxane versus Regimen C (13 studies). Thirteen studies used paclitaxel, 14 studies used docetaxel, and 1 study allowed the investigator to decide on the type of taxane; the majority of studies delivered a taxane every 3 weeks. Twenty studies administered taxanes as first-line treatment, and 21 studies involved anthracycline naïve women in the metastatic setting. The combined HR for overall survival and time to progression favoured the taxane-containing regimens (HR 0.93, 95% confidence interval (CI) 0.88 to 0.99, P = 0.002, deaths = 4477; and HR 0.92, 95% CI 0.87 to 0.97, P = 0.002, estimated 5122 events, respectively) with moderate to substantial heterogeneity across trials. If the analyses were restricted to studies of first-line chemotherapy, this effect persisted for overall survival (HR 0.93, 95% CI 0.87 to 0.99, P = 0.03) but not for time to progression (HR 0.96, 95% CI 0.90 to 1.02, P = 0.22). Tumour response rates appeared to be better with taxane-containing chemotherapy in assessable women (RR 1.20, 95% CI 1.14 to 1.27, P < 0.00001) with substantial heterogeneity across studies. Taxanes were associated with an increased risk of neurotoxicity (RR 4.84, 95% CI 3.18 to 7.35, P < 0.00001, 24 studies) and hair loss (RR 2.37, 95% CI 1.45 to 3.87, P = 0.0006, 11 studies) but less nausea/vomiting compared to non-taxane-containing regimens (RR 0.62, 95% CI 0.46 to 0.83, P = 0.001, 26 studies). Leukopaenia and treatment-related death did not differ between the two groups (RR 1.07, 95% CI 0.97 to 1.17, P = 0.16, 28 studies; and RR 1.00, 95% CI 0.63 to 1.57, P = 0.99, 23 studies, respectively). For quality of life measures, none of the individual studies reported a difference in overall or any of quality of life subscales between taxane-containing and non-taxane chemotherapy regimens. AUTHORS' CONCLUSIONS Taxane-containing regimens appear to improve overall survival, time to progression, and tumour response rate in women with metastatic breast cancer. Taxanes are also associated with an increased risk of neurotoxicity but less nausea and vomiting compared to non-taxane-containing regimens. The considerable heterogeneity encountered across studies probably reflects the varying efficacy of the comparator regimens used in these studies and indicates that taxane-containing regimens are more effective than some, but not all, non-taxane-containing regimens.
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Taxanes: their impact on gynecologic malignancy.
Schwab, CL, English, DP, Roque, DM, Santin, AD
Anti-cancer drugs. 2014;(5):522-35
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The use of taxanes in the treatment of gynecologic malignancies has expanded tremendously over the past 30 years. Both paclitaxel and docetaxel have unique microtubule stabilizing, antiangiogenic and radiation sensitizing properties that endow them with remarkable activity as chemotherapeutic agents. As research into the appropriate dose, timing, treatment interval, and response rates have been studied, they have emerged as one of the most active agents available in the treatment of gynecologic cancer. The body of research on taxanes continues to expand especially with regard to the use of taxanes in alternative formulations and in combination with newer treatments or routes of treatment. This review focuses on the development of taxanes as an effective therapy in the treatment of gynecologic cancers and data currently available in the literature regarding their efficacy. Future directions of taxane-based chemotherapy with regards to ovarian, uterine, and cervical cancers are also addressed. There is little doubt that taxane-based chemotherapy will remain an integral part of the treatment of gynecologic cancer for the foreseeable future.
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Evolving approaches to metastatic breast cancer patients pre-treated with anthracycline and taxane.
Saji, S
BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy. 2013;(5):469-78
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Metastatic breast cancer is currently incurable and the goals of therapy focus on prolonging survival and maintaining quality of life by controlling symptoms and minimizing toxicity. Treatments for metastatic breast cancer include chemotherapeutic agents from various classes, such as taxanes, vinca alkaloids, anthracyclines and antimetabolites. This review provides an overview of chemotherapeutic agents for the treatment of metastatic breast cancer patients previously treated with anthracyclines and taxanes, focusing on a clinical evaluation of eribulin, the most recently approved agent for the treatment of metastatic breast cancer. Eribulin is a synthetic derivative of halichondrin B, a tumour growth inhibitor found in marine sponges, which prevents microtubule growth and sequesters the tubulin molecules into unusual aggregates, initiating apoptosis. Studies of eribulin have shown that the drug is effective in the treatment of previously treated metastatic breast cancer, and has an acceptable toxicity profile. Importantly, in the phase III EMBRACE study, eribulin treatment resulted in a survival advantage, a difficult endpoint to achieve with a single chemotherapeutic agent. An additional phase III study showed that eribulin has similar efficacy to capecitabine in women treated with no more than three prior therapies. Furthermore, pre-specified exploratory analyses suggest that particular patient subgroups may have greater therapeutic benefit with eribulin and may warrant further study to explore the potential mechanisms.
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Tumor-targeting drug delivery of new-generation taxoids.
Ojima, I, Zuniga, ES, Berger, WT, Seitz, JD
Future medicinal chemistry. 2012;(1):33-50
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A long-standing problem of conventional cancer chemotherapy is the lack of tumor specificity. Tumor-targeting drug-delivery systems have been explored to overcome this problem. These systems combine a powerful cytotoxic anticancer agent with a tumor-targeting molecule via a 'smart' linker to form highly efficacious drug conjugates. These drug conjugates can deliver potent cytotoxic drugs specifically to tumors and tumor cells with minimal systemic toxicity. This review describes our groups' research on the molecular approaches to the design and development of a novel drug-delivery system bearing highly potent new-generation taxoids for tumor-targeting chemotherapy in our laboratory.
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[Treatment possibilities in breast cancer progressing after anthracyclines and/or taxanes].
Tamás, N, László, L, Edina, M
Magyar onkologia. 2010;(1):9-16
Abstract
The treatment of recurrent, progressing, metastatic breast cancer, which has previously been exposed to anthracyclines and/or taxanes is not only a major clinical challenge, but has a significant social impact too. In the absence of formal guidelines, this review has aimed to summarize the published evidence that is needed to guide clinical decision-making. Four new agents are approved for use in this setting: capecitabine, gemcitabine, ixabepilone, and nanoparticle albumin-bound paclitaxel. Nevertheless this review summarizes the results of studies with other active agents, as liposomal doxorubicin, rotation of taxanes, larotaxel, vinorelbine, and other biological agents.
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Predictive factors for response to docetaxel in human breast cancers.
Noguchi, S
Cancer science. 2006;(9):813-20
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Docetaxel has come into wide use recently for the treatment of breast cancer in neoadjuvant, adjuvant and metastatic settings. Docetaxel binds to beta-tubulin and causes kinetic abnormalities in the dynamics of microtubules by increasing their polymerization and inhibiting their depolymerization, resulting in elevated levels of microtubule formation. During metaphase, defective spindle formation induced by docetaxel activates the mitotic checkpoint and leads to cell cycle arrest, culminating in apoptosis. However, docetaxel is not effective for all breast cancers. For example, in metastatic settings, the response rate to docetaxel reportedly ranges from 30 to 50%. It is therefore very important to develop a diagnostic method with high accuracy for the prediction of sensitivity to docetaxel in order to avoid unnecessary treatment. Currently it is impossible to identify, before the initiation of therapy, the patients for whom docetaxel will be effective. Various biological parameters have been studied clinically for their ability to predict response to docetaxel, such as parameters related to: (1) efflux (p-glycoprotein) and metabolism (CYP3A4); (2) beta-tubulin (somatic mutation of beta-tubulin and changes in beta-tubulin isotypes levels); (3) cell cycle (HER2, BRCA1 and Aurora-A); and (4) apoptosis (p53, BCL2 and thioredoxin). More recently, gene expression profiling techniques have been used for the development of a prediction model for response to docetaxel. In the present paper, clinical studies that have been conducted recently to identify predictive factors for response to docetaxel are reviewed together with a presentation of our recent work in this field.
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Advances in prostate cancer chemotherapy: a new era begins.
Pienta, KJ, Smith, DC
CA: a cancer journal for clinicians. 2005;(5):300-18; quiz 323-5
Abstract
Prostate cancer continues to be the most common lethal malignancy diagnosed in American men and the second leading cause of male cancer mortality. Over 60 years ago, Huggins and Hodges discovered androgen deprivation as a first-line therapy for metastatic prostate cancer, which leads to remissions typically lasting 2 to 3 years, but in most men prostate cancer ultimately progresses to an androgen-independent state resulting in death due to widespread metastases. Multiple mechanisms of androgen independence have now been documented, including amplification of the androgen receptor as well as signal transduction pathways that bypass the androgen receptor completely. In 2004, two landmark studies demonstrated a survival advantage in androgen-independent prostate cancer patients utilizing docetaxel chemotherapy, setting a new standard of care for this disease. In addition, treatments with the bisphosphonate zoledronic acid and systemic radioisotopes have also been shown to have palliative benefits in this population. Building on these advances, several new traditional chemotherapeutic agents as well as new targeted therapies are under development.
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[Update on docetaxel and breast cancer].
Diéras, V, Girre, V, Pierga, JY, Laurence, V, Piperno-Neumann, S, Pouillart, P
Bulletin du cancer. 2004;(5):409-17
Abstract
Docetaxel (Taxotère) has been developed in breast cancer during the last decade. First its activity in monotherapy was proven in metastatic setting after failure of anthracycline therapy. Then the association with anthracycline demonstrated substantial activity leading to its development in early stages of breast cancer and its incorporation in adjuvant and neoadjuvant settings. Recently the first adjuvant trial comparing the association TAC versus FAC was presented. In the TAC arm, the disease free survival was better comparing with FAC (p = 0.0011) and survival was better in the subgroup with less than four positive lymph nodes. In the neoadjuvant setting, the incorporation of docetaxel after an anthracycline-based regimen (protocols Aberdeen and NSABP-B27) led to better clinical response, subsequently to better breast conservation and more important the increase of the pathological response rate. Improvement of survival has been reported in the Aderbeen study but a longer follow-up of the NSABP B27 study is required to confirm the impact of Taxotère in the outcome of breast cancer. The next step will be the development of the combination of the most active chemotherapeutic regimen with targeted therapies according to molecular characteristics of the tumor. The integration of trastuzumab with taxane-based chemotherapy has already demonstrated high activity in metastatic breast cancer with overexpression of HER2 and adjuvant trials are ongoing.