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1.  Evaluation of the clinical benefits of nanoparticle albumin-bound paclitaxel in women with metastatic breast cancer in British Columbia 
Current Oncology  2013;20(2):97-103.
Background
Altered formulations of taxanes may lack cross-resistance with standardly used solvent-based taxanes. The primary objective of the present study was to assess the clinical benefit of nanoparticle albumin-bound (nab)–paclitaxel in women with metastatic breast cancer previously treated with and without adjuvant taxane in British Columbia.
Methods
The BC Cancer Agency Pharmacy data repository and Breast Cancer Outcomes Unit database were linked to identify all patients who received nab-paclitaxel in British Columbia since its introduction in 2007. Hormone receptor status, demographic characteristics, number of cycles prescribed, and time to treatment failure were extracted and analyzed.
Results
From 2007 to 2011, 138 patients in British Columbia received nab-paclitaxel, with 122 patients available for analysis. Most (70.5%) received adjuvant chemotherapy; about a quarter (24.6%) received an adjuvant taxane. Patients who received adjuvant taxane were more likely to have node-positive (86.7% vs. 48.9%, p = 0.007), estrogen receptor–negative (46.7% vs. 13.0% p < 0.001) disease and to receive initial adjuvant radiotherapy (76.7% vs. 51.1%, p < 0.001). For the entire cohort, the median number of nab-paclitaxel cycles prescribed was 4.4 (range: 0.3–13). The median number of nab-paclitaxel cycles was greater when that agent was given as first- or second-line therapy than as third-line or greater therapy (5.0 cycles vs. 3.7 cycles respectively). The median time to treatment failure was 96 days in the prior adjuvant taxane group (range: 0–361) and 73.5 days in the no prior adjuvant taxane group (range: 0–1176).
Conclusions
This retrospective study demonstrates potential clinical activity of nab-paclitaxel in metastatic breast cancer regardless of whether patients had prior exposure to adjuvant taxanes.
doi:10.3747/co.20.1256
PMCID: PMC3615860  PMID: 23559872
Nanoparticle; albumin-bound; nab-paclitaxel; metastatic breast cancer; adjuvant taxane
2.  Ixabepilone as Monotherapy or in Combination with Capecitabine for the Treatment of Advanced Breast Cancer 
Breast Cancer is the most prevalent cancer in the world with 4.4 million survivors up to 5 years following the diagnosis.1 In the US alone approximately forty thousand women die annually of metastatic breast cancer (MBC). Despite many effective systemic treatment options approximately 50% of women with MBC succumb to the disease within 24 months of the diagnosis.2 Ixabepilone is a novel, first in class member of the epothilone class of antineoplastic agents. Ixabepilone is indicated as monotherapy for the treatment of metastatic or locally advanced breast cancer in patients whose tumors are resistant or refractory to anthracyclines, taxanes, and Capecitabine. Ixabepilone is also indicated in combination with Capecitabine for the treatment of patients with metastatic or locally advanced breast cancer resistant to treatment with an anthracycline and a taxane, or whose cancer is taxane resistant and for whom further anthracycline therapy is contraindicated. Ixabepilone was extensively studied as a single agent in patients with MBC and was found to be effective and well tolerated with a predictable and manageable safety profile. Not surprisingly prior exposure to anthracyclines and taxanes affects significantly the potential for response to therapy with single agent Ixabepilone in metastatic setting. MBC patients with taxane resistant MBC have objective response rate (RR) of 12%, patients with prior low exposure to taxanes and/or resistance RR = 22%, Ixabepilone treatment after adjuvant anthracycline therapy exposure renders RR = 42% and in Taxane naïve patients RR = 57%. In two large phase III studies of Ixabepilone + Capecitabine versus Capecitabine alone, progression free survival (PFS) and overall response rates (RR) were higher in the combination treatment arms, but no survival advantage was seen overall. Treatment with Ixabepilone + Capecitabine in a phase II study resulted in an overall response rate (ORR) of 23% in ER/PR/HER2 negative, triple-negative breast cancer patients (TNBC) while ORR of 31% was seen in a preplanned pooled analysis of TNBC in the phase III trials of Ixabepilone + Capecitabine. Significantly prolonged median PFS was seen for TNBC treated with the combination of Ixabepilone + Capecitabine compared to Capecitabine alone 4.2 vs. 1.7 months respectively. Ixabepilone as single agent appears to show excellent antitumor activity in patients with TNBC MBC. Addition of Ixabepilone to Capecitabine results in approximately doubling in median PFS for TNBC versus Capecitabine alone. Single agent Ixabepilone is generally well tolerated, and its toxicity profile does not overlap with that of Capecitabine and therefore depending on prior exposure to chemotherapy both single agent Ixabepilone or in combination with Capecitabine can be used safely and effectively for treatment of advanced breast cancer.
doi:10.4137/BCBCR.S5331
PMCID: PMC3076013  PMID: 21494397
Ixabepilone; metastatic breast cancer; monotherapy; in combination with capecitabine; triple negative breast cancer
3.  Weekly nab-Paclitaxel in Metastatic Breast Cancer – Summary and Results of an Expert Panel Discussion 
Breast Care  2012;7(2):137-143.
Taxanes are regarded as the most effective single agents in the treatment of metastatic breast cancer (MBC). For conventional taxanes, crucial toxicities and impairments in clinical efficacy are related to solvents necessary because of the agents’ hydrophobicity. The mandatory premedication with corticosteroids causes additional side effects. Nab-paclitaxel is a solvent-free colloidal suspension of paclitaxel and human serum albumin that exploits the physiological transport properties of albumin. It is registered as monotherapy with a recommended dose of 260 mg/m2 every 3 weeks for the treatment of patients with MBC, who have failed a first-line treatment of metastatic disease and for whom a standard anthracycline treatment is not indicated. Clinical evidence is available for the registered 3-weekly administration and for alternative weekly schedules in first and further lines of therapy of patients with MBC. During an advisory board meeting, a group of 8 German breast cancer experts reviewed the clinical data of nab-paclitaxel in MBC and discussed how nab-paclitaxel could be used in clinical practice on the basis of the current data.
doi:10.1159/000338273
PMCID: PMC3376367  PMID: 22740801
First-line therapy; Metastatic breast cancer; Chemotherapy; Weekly; nab-Paclitaxel; Paclitaxel; Docetaxel
4.  The role of taxanes in the management of gastroesphageal cancer 
Upper gastrointestinal cancers commonly referred to as gastroesophageal carcinomas encompass cancers of the esophagus, stomach and gastroesophageal junction. Although the number of newly diagnosed cases of gastric cancer has decreased in the United States, the whole burden of upper gastrointestinal carcinomas on society remains significantly high, with only a small improvement in overall survival achieved over the past two decades. Traditionally, therapeutic agents used to treat gastroesophageal cancers have been platinums and fluoropyrimidines. Taxanes are di-terpenes produced by the plants of the genus Taxus (yews). As their name suggests, taxanes were first derived from natural sources, but now they are all synthesized artificially. Interfering with cellular microtubular function during cell division is the main mechanism of action for currently available taxanes. Since their introduction into therapeutic oncology, many different other taxane-derivatives have been manufactured and are being developed. Changing the formulation of the drug to improve delivery such as liposomal encapsulation, and target deliver with antibody-drug conjugation, as well as introducing new class of cytotoxic agents that can overcome taxane-resistance. The two most commonly used taxanes are paclitaxel and docetaxel. Taxane is a class of cytotoxic agents more commonly administered in patients with breast and lung cancers. However, the regulatory approval of docetaxel to treat patients with metastatic or advanced gastroesophageal cancers in 2006 established the role of taxanes in the management of upper gastroesophageal cancers. This paper will review the current data of taxanes in the management of patients with upper gastrointestinal cancers.
doi:10.3978/j.issn.2078-6891.2011.027
PMCID: PMC3397631  PMID: 22811858
Taxanes; gastric; esophageal; gastroesophageal junction; chemotherapy
5.  Specific kinesin expression profiles associated with taxane resistance in breast cancer 
Introduction
Breast cancer is a genetically heterogenous disease with subtypes differing in prognosis and chemosensitivity. The basal-like breast cancer (BLBC) molecular subtype is associated with poorer outcomes, but is more responsive to taxane-based chemotherapy, which is used in multiple settings of breast cancer. Kinesins are intracellular transport proteins that interact with microtubules, which are also the mechanistic target for taxanes. We investigated the relationship between taxane resistance in BLBC and kinesins using both expression and functional studies.
Methods
Kinesin (KIF) expression was evaluated in three settings in relation to taxane resistance: (i) the NCI-60 cancer cell lines, (ii) pre-treatment samples from four BLBC patient cohorts receiving neoadjuvant chemotherapy regimens with and without taxanes, and (iii) post-treatment samples from residual breast cancer following neoadjuvant taxane-containing chemotherapy. We used a novel functional approach to gene modification, validation-based insertional mutagenesis, to select kinesin-overexpressing clones of BLBC cells for evaluation of related mechanisms of taxane resistance.
Results
In the NCI-60 cell line dataset, overexpression of the kinesin KIFC3 is significantly correlated with resistance to both docetaxel (p<0.001) and paclitaxel (p<0.001), but not to platinum-based chemotherapy, including carboplatin (p=0.49) and cisplatin (p=0.10). Overexpression of KIFC3 and KIF5A in pre-chemotherapy samples similarly predicted resistance to paclitaxel in the MDACC cohorts (p=0.01); no KIF predicted resistance to fluorouracil-epirubicin-cyclophosphamide or cisplatin in BLBC patient cohorts treated without taxanes. KIF12 is the most overexpressed KIF gene in post-chemotherapy taxane-resistant residual breast cancers (2.8 fold-change). Functional studies established that overexpression of KIFC3, KIF5A and KIF12 were specific in mediating resistance to docetaxel and not vincristine or doxorubicin. We demonstrated that mutation of the ATP-binding domain of a kinesin abolishes its ability to mediate docetaxel resistance.
Conclusions
We show that kinesin overexpression correlates with specific taxane resistance in BLBC cell lines and tissue. Our results suggest a novel approach to overcoming taxane resistance in breast cancer through concurrent or sequential use of kinesin inhibitors, highlighting the ATP-binding domain as a drug development target.
doi:10.1007/s10549-011-1500-8
PMCID: PMC4038085  PMID: 21479552
6.  Meta-analysis of phase III trials of docetaxel alone or in combination with chemotherapy in metastatic breast cancer 
Purpose
Whether combination chemotherapy offers an advantage over sequential therapy in metastatic breast cancer (MBC) is still an unsettled issue. Polychemotherapy regimens containing taxanes has been shown to increase overall survival (OS), time to tumor progression (TTP), and overall response rate (ORR) when compared with regimens that did not contain a taxanes, while taxane-based doublets have a statistically significant benefit over single-agent taxane only for progression-free survival. However, the term “taxanes” generally includes both paclitaxel and docetaxel, drugs with different clinical activity. Aim of this work is to compare OS, TTP, and ORR in patients with MBC receiving docetaxel alone or in combination with chemotherapy using a formal meta-analysis.
Methods
We performed a systematic review of all published trials comparing docetaxel alone or in combination with other chemotherapeutic agents in MBC.
Results
Three randomized clinical trials including 1,313 patients were retrieved. A significant reduction of risk ratio was found in TTP (P ≤ 0.0001) but not in OS (P = 0.48) or ORR (P = 0.10) for patients treated with a chemotherapy agent plus docetaxel compared with docetaxel alone. Treatment with docetaxel alone is associated with a lower incidence of grade 3 diarrhea and stomatitis (diarrhea, P = 0.011; stomatitis, P = 0.0004).
Conclusion
Combination chemotherapy regimens with docetaxel show a statistically significant advantage for TTP, but not for OS and ORR in MBC. This review confirms that it is unlikely that any single agent or combination chemotherapy regimen will emerge as superior in MBC, due to its heterogeneous nature.
doi:10.1007/s00432-011-1091-0
PMCID: PMC3258394  PMID: 22095437
Metastatic breast cancer; Meta-analysis; Docetaxel; Taxanes
7.  Paclitaxel-resistant advanced recurrent breast cancer: a case of partial response due to addition of bevacizumab to paclitaxel therapy: a case report 
BMC Research Notes  2013;6:254.
Background
Paclitaxel plus bevacizumab have shown a high response rate and prolonged progression-free survival in metastatic breast cancer patients. However, overall survival was not prolonged. Thus, no conclusion has been made on the effectiveness of bevacizumab. In our report, taxane plus bevacizumab were used to treat a metastatic breast cancer patient with taxane resistance, and a good therapeutic result was obtained.
Case presentation
The patient was a 68-year-old woman with a non-contributory history. In September 2004, she underwent a pectoral muscle-conserving mastectomy with axillary dissection for right-sided breast cancer (pT3N0M0-stage IIB, estrogen receptor positive, progesterone receptor negative, and human epidermal growth factor receptor type 2 negative). Adjuvant therapy consisted of 6 cycles of cyclophosphamide, epirubicin and fluorouracil, and subsequent oral anastrozole. In August 2007, the patient developed a recurrence in the left axillary lymph node. The chemotherapy was changed to high-dose toremifene, and radiation therapy was also performed. The patient achieved a complete response. In April 2009, CT showed left axillary lymph node enlargement once again and multiple lung metastases. Hormone therapy was changed to exemestane and long-term stable disease was achieved. In March 2011, the lung and left axillary lymph node metastases were enlarged and progressive disease was noted. Thus, the tumors were determined to be resistant to hormone therapy, and weekly paclitaxel was begun in May. Since partial response was achieved, this therapy was continued. In December, CT showed that lung and axillary lymph node metastases were enlarged and progressive disease was observed. Therefore, the tumors were determined to be resistant to paclitaxel. In January 2012, bevacizumab and weekly paclitaxel were begun. In April, lung and axillary lymph node metastases were reduced in size, and partial response was achieved. Thereafter the same treatment has been continued, and the patient has been followed up without clinical exacerbation as of January 2013.
Conclusion
Taxane plus bevacizumab were used to treat a metastatic breast cancer patient with taxane resistance, and a good therapeutic result was obtained. This result is considered important in increasing treatment options for patients with taxane resistance or patients using adjuvant taxane-based therapy and in examining the effectiveness of bevacizumab in metastatic breast cancer patients.
doi:10.1186/1756-0500-6-254
PMCID: PMC3707777  PMID: 23830415
Breast cancer; Bevacizumab; Paclitaxel
8.  Chemotherapy in Patients with Anthracycline- and Taxane-Pretreated Metastatic Breast Cancer: An Overview 
Current breast cancer reports  2013;5(1):42-50.
Anthracyclines and taxanes are cytotoxic agents that are commonly used for the treatment of breast cancer, including in the adjuvant, neoadjuvant, and metastatic setting. Each drug class of is associated with cumulative and potentially irreversible toxicity, including cardiomyopathy (anthracyclines) and neuropathy (taxanes). This may either limit the duration of therapy for advanced disease, or prevent retreatment for recurrence if previously used as component of adjuvant or neoadjuvant therapy. Several classes of cytotoxic agents have been evaluated in patients with anthracycline and taxane-pretreated metastatic breast cancer (MBC), including other antitubulins (vinorelbine, ixabepilone, eribulin), antimetabolites (capecitabine, gemcitabine), topoisomerase I inhibitors (irinotecan), platinum analogues (cisplatin, carboplatin), and liposomal doxorubicin preparations. No trials have shown an overall survival advantage for combination chemotherapy in this setting, indicating that single cytotoxic agents should usually be used, expect perhaps in patients with rapidly progressive disease and/or high tumor burden.
doi:10.1007/s12609-012-0097-1
PMCID: PMC3579672  PMID: 23440080
Metastatic breast cancer; MBC; Chemotherapy; Cytotoxic agents; Anthracycline; Taxane; Pretreated; Systemic cytotoxic therapy; Drug resistance
9.  Beyond taxanes: the next generation of microtubule-targeting agents 
Taxanes are a standard first-line option for metastatic breast cancer (MBC), but their utility may be limited by primary or acquired resistance. New microtubule-targeting agents have been developed to overcome taxane resistance and provide additional options for improving patient outcomes. This article reviews these alternative microtubule-targeting agents and their potential clinical benefits for MBC patients. Relevant clinical data were compiled through searches within PubMed and congress abstract databases. Ixabepilone, a novel microtubule-stabilizing drug approved by the US Food and Drug Administration (FDA), has proven efficacy across multiple lines of therapy, including patients with taxane-resistant/refractory disease. In phase III trials, ixabepilone plus capecitabine significantly improved progression-free survival compared with capecitabine alone in anthracycline/taxane-pretreated patients. Eribulin has recently been approved by the FDA and by the European Medicines Agency for the treatment of patients with MBC who have received at least two prior chemotherapy regimens for late-stage disease. In a phase III trial, eribulin extended overall survival compared with the physician’s treatment choice in heavily pretreated MBC patients. In addition, several investigational microtubule-targeting agents may have therapeutic potential in MBC. The development of new microtubule-targeting agents helps to address the need for additional effective regimens for patients progressing after standard treatment with anthracycline- and taxane-containing regimens.
doi:10.1007/s10549-011-1875-6
PMCID: PMC3387492  PMID: 22113255
Taxanes; Microtubule-targeting agents; Epothilones; Ixabepilone; Eribulin
10.  Safety and Efficacy of nab-Paclitaxel in the Treatment of Patients with Breast Cancer 
Taxanes are highly active chemotherapeutic agents in the treatment of early-stage and metastatic breast cancer. Novel formulations have been developed to improve efficacy and decrease toxicity associated with these cytotoxic agents. nab-paclitaxel is a solvent free, albumin-bound 130-nanometer particle formulation of paclitaxel (Abraxane®, Abraxis Bioscience), which was developed to avoid toxicities of the Cremophor vehicle used in solvent-based paclitaxel. In a phase III clinical trial, nab-paclitaxel demonstrated higher response rates, better safety and side-effect profile compared to conventional paclitaxel, and improved survival in patients receiving it as second line therapy. Higher doses can be administered over a shorter infusion time without the need for special infusion sets or pre-medications. It is now approved in the US for treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant therapy, where prior therapy included an anthracycline. Recently, several phase II studies have suggested a role for nab-paclitaxel as a single agent and in combination with other agents for first-line treatment of metastatic breast cancer.
doi:10.4137/BCBCR.S5857
PMCID: PMC3091407  PMID: 21603258
nab-paclitaxel; nab-technology; paclitaxel; metastatic breast cancer; taxanes
11.  Impact of a Scientific Presentation on Community Treatment Patterns for Primary Breast Cancer 
Background
The publication of results from randomized clinical trials can have a dramatic effect on treatment patterns, but the impact of oral presentations at national scientific meetings is unknown. We investigated the temporal association between the oral presentation of the results from the Cancer and Leukemia Group B (CALGB) Study 9344 at the May 1998 meeting of the American Society of Clinical Oncology, which showed that paclitaxel improves survival of women with lymph node – positive breast cancer, and use of taxane chemotherapy for breast cancer.
Methods
We studied chemotherapy use in 3341 women identified through the Surveillance, Epidemiology, and End Results–Medicare database who were diagnosed with stage I–III breast cancer in 1994–1999 at age 65 years or older and received adjuvant chemotherapy, as identified through claims data, within 1 year of diagnosis. We assessed the temporal association between the CALBG presentation and taxane use with piecewise regression analysis. Multivariable logistic regression analysis was used to determine which patient characteristics were associated with taxane use.
Results
The use of taxanes increased substantially after the CALGB presentation, with absolute rates of taxane use of 5.2% before May 1998 and 23.6% in May 1998 and later. Initially, this increase was confined to patients with lymph node–positive disease (40% of whom were receiving taxanes by the end of 1999), but over time it extended to patients with lymph node–negative disease (15% of whom were receiving taxanes by the end of 1999). In multivariable analysis, patients who were treated in May 1998 or later were statistically significantly more likely to have received a taxane than patients treated before this date (estimated relative risk = 6.84, 95% confidence interval = 5.71 to 8.07). Younger patient age, larger number of lymph nodes involved, higher tumor grade, and larger tumor size were also independently associated with adjuvant taxane use.
Conclusions
The oral presentation of a single study at a national conference was temporally associated with an increase in the use of taxanes for primary breast cancer, even before study publication or Food and Drug Administration approval.
doi:10.1093/jnci/djj090
PMCID: PMC1853252  PMID: 16537830
12.  Ixabepilone: a new chemotherapeutic option for refractory metastatic breast cancer 
Biologics : Targets & Therapy  2008;2(3):505-515.
Taxane therapy is commonly used in the treatment of metastatic breast cancer. However, most patients will eventually become refractory to these agents. Ixabepilone is a newly approved chemotherapeutic agent for the treatment of metastatic breast cancer. Although it targets microtubules similarly to docetaxel and paclitaxel, ixabepilone has activity in patients that are refractory to taxanes. This review summarizes the pharmacology of ixapebilone and clinical trials with the drug both as a single agent and in combination. Data were obtained using searches of PubMed and abstracts of the annual meetings of the American Society of Clinical Oncology and the San Antonio Breast Cancer Symposium from 1995 to 2008. Ixapebilone is a semi-synthetic analog of epothilone B that acts to induce apoptosis of cancer cells via the stabilization of microtubules. Phase I clinical trials have employed various dosing schedules ranging from daily to weekly to 3-weekly. Dose-limiting toxicites included neuropathy and neutropenia. Responses were seen in a variety of tumor types. Phase II studies verified activity in taxane-refractory metastatic breast cancer. The FDA has approved ixabepilone for use as monotherapy and in combination with capecitabine for the treatment of metastatic breast cancer. Ixabepilone is an efficacious option for patients with refractory metastatic breast cancer. The safety profile is similar to that of taxanes, with neuropathy and neutropenia being dose-limiting. Studies are ongoing with the use of both iv and oral formulations and in combination with other chemotherapeutic and biologic agents.
PMCID: PMC2721395  PMID: 19707381
ixabepilone; epothilone; metastatic breast cancer; taxane-refractory
13.  Management of advanced breast cancer with the epothilone B analog, ixabepilone 
Despite the activity of standard chemotherapies in advanced breast cancer, disease progression remains inevitable. Most patients exposed to anthracyclines and taxanes develop resistance and a significant subset shows primary resistance. The increasing use of these agents as adjuvant therapy may result in more anthracycline- and taxane-resistant patients in the metastatic setting; few treatment options are available for patients with metastatic breast cancer (MBC) resistant to multiple chemotherapies. The heterogeneity of breast cancer represents another therapeutic challenge. Breast cancers may be classified as luminal, human epidermal growth factor 2 (HER2)-positive, or estrogen receptor-, progesterone receptor-, and human epidermal growth factor 2-negative (ER/PR/HER2-negative, triple negative). HER2-positive and ER/PR/HER2-negative tumors are associated with poor prognosis owing to aggressive disease and poor long-term response to therapy. The epothilone B analog ixabepilone has low susceptibility to multiple mechanisms of resistance and has demonstrated activity in patients with MBC resistant to anthracyclines, taxanes, and/or capecitabine. Ixabepilone is the first epothilone to be approved, as monotherapy or in combination with capecitabine, for treatment of resistant/refractory MBC or locally advanced breast cancer. Treatment with ixabepilone is an option for patients with ER/PR/HER2-negative or HER2-positive disease and/or primary resistance to taxanes.
PMCID: PMC2769224  PMID: 19920932
breast cancer; drug resistance; epothilone; HER2-positive; ixabepilone; ER/PR/HER2-negative (triple negative)
14.  Optimal use of taxanes in metastatic breast cancer 
Current Oncology  2009;16(3):8-20.
The role of taxanes in the treatment of breast cancer is becoming increasingly important. In clinical practice, the taxanes are now standard therapy in both early-stage and metastatic breast cancer. Since the 1990s, multiple randomized clinical trials have been evaluating the efficacy of taxanes in the treatment of metastatic breast cancer. These trials have included treatment with taxanes alone or in combination with other chemotherapeutic agents. Pre-existing published guidelines for the use of taxanes in the management of metastatic breast cancer are available. The mandate of the Alberta Cancer Board Provincial Breast Tumour Group Guideline Panel was to consider and adapt the recommendations of the existing guidelines and to develop de novo guidelines to account for current evidence. For this task, the panel used the adapte process, which is a systematic process of guideline adaptation developed by the adapte Collaboration.
The recommendations formulated by the panel included the identification of taxane regimens that could be offered in anthracycline-naïve patients, anthracycline-pretreated or -resistant patients, and patients overexpressing the human epidermal growth factor receptor 2. Potential toxicities and benefits in terms of time to progression, progression-free survival, overall survival, and quality of life were also considered.
PMCID: PMC2695713  PMID: 19526080
Metastatic breast cancer; docetaxel; paclitaxel; nab-paclitaxel; chemotherapy
15.  Bevacizumab in the treatment of HER2-negative breast cancer 
Biologics : Targets & Therapy  2008;2(4):813-821.
Angiogenesis has a clear and definite role in the breast cancer progression process, making antivascular endothelial growth factor (VEGF) therapies an attractive option for the treatment of metastatic breast cancer (MBC). Bevacizumab is a potent humanized monoclonal antibody to VEGF, which has shown regression of breast cancer in preclinical and clinical setting, either alone or in combination with cytotoxic treatment. Additionally, bevacizumab potentially increases the effectiveness of other anticancer therapies through the normalization of tumor vasculature, reduction of intratumoral pressure and improved tumor oxygenation. Phase 1/2 trials showed significant antitumor effects of bevacizumab in MBC, in particular in tumors not expressing HER2 receptor. A first phase 3 trial in pre-treated MBC patients showed better response rates but no survival benefit from the addition of bevacizumab to capecitabine. However, in two phase 2 trial in first-line setting in patients with MBC, bevacizumab improved progression-free survival in combination with weekly paclitaxel in comparison to paclitaxel alone or in combination with 3-weekly docetaxel in comparison with docetaxel alone, respectively. Bevacizumab in combination with taxanes seems to be a highly effective first-line treatment for MBC patients. Future research will investigate bevacizumab in the neoadjuvant or adjuvant setting, where even more potential may exist for these patients.
PMCID: PMC2727886  PMID: 19707460
bevacizumab; breast cancer; HER2; HER2-negative breast cancer
16.  Albumin-bound formulation of paclitaxel (Abraxane® ABI-007) in the treatment of breast cancer 
Breast cancer is the most common type of malignancy diagnosed in women. In the metastatic setting this disease is still uncurable. Taxanes represent an important class of antitumor agents which have proven to be fundamental in the treatment of advanced and early-stage breast cancer, but the clinical advances of taxanes have been limited by their highly hydrophobic molecular status. To overcome this poor water solubility, lipid-based solvents have been used as a vehicle, and new systemic formulations have been developed, mostly for paclitaxel, which are Cremophor-free and increase the circulation time of the drug. ABI-007 is a novel, albumin-bound, 130-nm particle formulation of paclitaxel, free from any kind of solvent. It has been demonstrated to be superior to an equitoxic dose of standard paclitaxel with a significantly lower incidence of toxicities in a large, international, randomized phase III trial. The availability of new drugs, such as Abraxane®, in association with other traditional and non-traditional drugs (new antineoplastic agents and targeted molecules), will give the oncologist many different effective treatment options for patients in this setting.
PMCID: PMC2720743  PMID: 19516888
paclitaxel; Abraxane; breast cancer; nanotechnology
17.  Targeted delivery of albumin bound paclitaxel in the treatment of advanced breast cancer 
OncoTargets and therapy  2009;2:179-188.
Taxanes are chemotherapeutic agents with a large spectrum of antitumor activity when used as monotherapy or in combination regimens. Paclitaxel and docetaxel have poor solubility and require a complex solvent system for their commercial formulation, Cremophor EL® (CrEL) and Tween 80® respectively. Both these biological surfactants have recently been implicated as contributing not only to the hypersensitivity reactions, but also to the degree of peripheral neurotoxicity and myelosuppression, and may antagonize the cytotoxicity. Nab-paclitaxel, or nanoparticle albumin-bound paclitaxel (ABI-007; Abraxane®), is a novel formulation of paclitaxel that does not employ the CrEL solvent system. Nab-paclitaxel demonstrates greater efficacy and a favorable safety profile compared with standard paclitaxel in patients with advanced disease (breast cancer, non-small cell lung cancer, melanoma, ovarian cancer). Clinical studies in breast cancer have shown that nab-paclitaxel is significantly more effective than standard paclitaxel in terms of overall objective response rate (ORR) and time to progression. Nab-paclitaxel in combination with gemcitabine, capecitabine or bevacizumab has been shown to be very active in patients with advanced breast cancer. An economic analysis showed that nab-paclitaxel would be an economically reasonable alternative to docetaxel or standard paclitaxel in metastatic breast cancer. Favorable tumor ORR and manageable toxicities have been reported for nab-paclitaxel as monotherapy or in combination treatment in advanced breast cancer.
PMCID: PMC2886338  PMID: 20616905
breast cancer; nab-paclitaxel; chemotherapy
18.  Delayed Emotional Recovery After Taxane-based Chemotherapy 
Cancer  2008;113(3):638-647.
Background
There are few patient-reported data regarding quality of life after taxane-based adjuvant chemotherapy and none regarding mental health outcomes.
Methods
This was a naturalistic, longitudinal study that used a case–control design. Data were derived from a randomized clinical trial in patients who had stage II/III breast cancer (N = 227). Paclitaxel (Taxol) was approved for use midway during the accrual period (1994–1999). Patients who received taxanes as part of their adjuvant chemotherapy (the taxane group; n = 55) were matched with patients receiving regimens without taxanes (the no-taxane group; n = 83) on trial arm, lymph node status, surgery type, menopausal status, and partner status. Mixed-effects models tested for group differences in nurse evaluations of patients' symptoms and Karnofsky performance status and in patient-reported quality of life (the 36-item Medical Outcomes Study Short Form) and emotional distress (Profile of Mood States; Center for Epidemiological Studies Depression scale).
Results
As expected, patients in the taxane group experienced significantly higher rates of selected toxicities, including arthralgia/myalgia (45% vs 26%) and ataxia (20% vs 5%). Patients in the taxane group also had significantly worse emotional distress and mental quality of life throughout adjuvant treatment. Rates of probable clinical depression also were high. In contrast, these outcomes were improving for patients in the no-taxane group (all P <.023). Emotional recovery for patients in the taxane group required 2 years on average versus 6 to 12 months for patients in the no-taxane group. During Years 3 through 5, the groups had similar outcomes.
Conclusions
These data suggested that taxane-based chemotherapies confer risk for significant psychological symptoms. Depression, in particular, should be monitored.
doi:10.1002/cncr.23589
PMCID: PMC2746480  PMID: 18521922
breast neoplasms; depression; adverse effects; paclitaxel; quality of life
19.  Comparisons between different polychemotherapy regimens for early breast cancer: meta-analyses of long-term outcome among 100 000 women in 123 randomised trials 
Lancet  2012;379(9814):432-444.
Summary
Background
Moderate differences in efficacy between adjuvant chemotherapy regimens for breast cancer are plausible, and could affect treatment choices. We sought any such differences.
Methods
We undertook individual-patient-data meta-analyses of the randomised trials comparing: any taxane-plus-anthracycline-based regimen versus the same, or more, non-taxane chemotherapy (n=44 000); one anthracycline-based regimen versus another (n=7000) or versus cyclophosphamide, methotrexate, and fluorouracil (CMF; n=18 000); and polychemotherapy versus no chemotherapy (n=32 000). The scheduled dosages of these three drugs and of the anthracyclines doxorubicin (A) and epirubicin (E) were used to define standard CMF, standard 4AC, and CAF and CEF. Log-rank breast cancer mortality rate ratios (RRs) are reported.
Findings
In trials adding four separate cycles of a taxane to a fixed anthracycline-based control regimen, extending treatment duration, breast cancer mortality was reduced (RR 0·86, SE 0·04, two-sided significance [2p]=0·0005). In trials with four such extra cycles of a taxane counterbalanced in controls by extra cycles of other cytotoxic drugs, roughly doubling non-taxane dosage, there was no significant difference (RR 0·94, SE 0·06, 2p=0·33). Trials with CMF-treated controls showed that standard 4AC and standard CMF were equivalent (RR 0·98, SE 0·05, 2p=0·67), but that anthracycline-based regimens with substantially higher cumulative dosage than standard 4AC (eg, CAF or CEF) were superior to standard CMF (RR 0·78, SE 0·06, 2p=0·0004). Trials versus no chemotherapy also suggested greater mortality reductions with CAF (RR 0·64, SE 0·09, 2p<0·0001) than with standard 4AC (RR 0·78, SE 0·09, 2p=0·01) or standard CMF (RR 0·76, SE 0·05, 2p<0·0001). In all meta-analyses involving taxane-based or anthracycline-based regimens, proportional risk reductions were little affected by age, nodal status, tumour diameter or differentiation (moderate or poor; few were well differentiated), oestrogen receptor status, or tamoxifen use. Hence, largely independently of age (up to at least 70 years) or the tumour characteristics currently available to us for the patients selected to be in these trials, some taxane-plus-anthracycline-based or higher-cumulative-dosage anthracycline-based regimens (not requiring stem cells) reduced breast cancer mortality by, on average, about one-third. 10-year overall mortality differences paralleled breast cancer mortality differences, despite taxane, anthracycline, and other toxicities.
Interpretation
10-year gains from a one-third breast cancer mortality reduction depend on absolute risks without chemotherapy (which, for oestrogen-receptor-positive disease, are the risks remaining with appropriate endocrine therapy). Low absolute risk implies low absolute benefit, but information was lacking about tumour gene expression markers or quantitative immunohistochemistry that might help to predict risk, chemosensitivity, or both.
Funding
Cancer Research UK; British Heart Foundation; UK Medical Research Council.
doi:10.1016/S0140-6736(11)61625-5
PMCID: PMC3273723  PMID: 22152853
20.  Clinical outcomes of women with metastatic breast cancer treated with nab-paclitaxel: experience from a single academic cancer centre 
Current Oncology  2013;20(1):24-29.
Background
Nab-paclitaxel is a solvent-free, taxane-based chemotherapy approved for the treatment of metastatic breast cancer (mbc). This study reports clinical benefit and toxicities experienced by women with mbc treated with nab-paclitaxel at the Ottawa Hospital Cancer Centre.
Methods
Women with mbc treated with single-agent nab-paclitaxel between June 2006 and December 2010 were included in this analysis. Retrospective data obtained included demographics, disease characteristics, prior chemotherapy, nab-paclitaxel treatment, toxicity, and survival. Clinical benefit was defined as partial or complete response or stable disease (by clinical or radiologic evaluation, or both) at 6 months or more.
Results
Of 43 women (mean age: 57.0 years; range: 34–74 years), most had disease positive for estrogen or progesterone receptor (72.1%, 58.1%), or both. Nab-paclitaxel was administered weekly (qw: 44.2%), every 3 weeks (q3w: 46.5%), q3w switched to qw (7.0%), or qw switched to q3w (2.3%). Median duration of therapy was 5.1 months (qw) and 3.0 months (q3w). Sensory neuropathy was the primary toxicity (45.4% qw, 38.1% q3w; p = 0.62). Clinical benefit was observed in most women (76.2% qw, 57.1% q3w; p = 0.20). Women receiving nab-paclitaxel had a median overall survival of 13.6 months qw (range: 8.1–28.3 months) and 10.8 months q3w (range: 5.9–17.9 months; p = 0.03). Regardless of dosing schedule, women experiencing clinical benefit lived significantly longer than those not experiencing a benefit (17.3 months vs. 7.7 months; hazard ratio: 0.14; 95% confidence interval: 0.06 to 0.33).
Conclusions
Our clinical experience demonstrates that most women treated with nab-paclitaxel experienced some clinical benefit. Patients achieving clinical benefit lived significantly longer than those who did not. Nab-paclitaxel was well tolerated, with the primary toxicity being mild sensory neuropathy. Nab-paclitaxel represents another treatment option, with a favourable toxicity profile, for women with mbc.
doi:10.3747/co.20.1202
PMCID: PMC3557328  PMID: 23443761
Nab-paclitaxel; taxane; mbc; Abraxane
21.  Identification and cost of adverse events in metastatic breast cancer in taxane and capecitabine based regimens 
SpringerPlus  2014;3:259.
Purpose
We sought to compare the economic impact of treatment-related adverse events (AEs) in patients with metastatic breast cancer (mBC) using taxane- or capecitabine-based treatment regimens as either first- or second-line (FL or SL) therapy in the US.
Methods
We used healthcare claims data from the Truven Health Analytics MarketScan® Commercial Databases to conduct a retrospective cohort study comparing the economic impact of AEs amongst taxane- and capecitabine-treated mBC patients in the US. We selected women diagnosed with mBC between 2008–2010 who received a taxane or capecitabine as first- or second-line (FL or SL) chemotherapy. Costs related to hospitalization, outpatient services, emergency department visits, chemotherapy and other medications were tabulated and combined to determine total healthcare costs. The incremental monthly costs associated with the presence of AEs compared to no AEs were estimated using generalized linear models, controlling for age and Charlson Comorbidity Index.
Results
We identified 15,443 mBC patients meeting inclusion criteria. Adjusted total monthly costs were significantly higher in those who experienced AEs than in those without AEs in both lines of treatment (FL incremental cost: taxanes $1,142, capecitabine $1,817; SL incremental cost: taxanes $1,448, capecitabine $4,437). Total costs increased with the number of AEs and were primarily driven by increased hospitalization amongst those with AEs.
Conclusions
Adverse events in taxane- or capecitabine-treated mBC patients are associated with significant increases in costs. Selecting treatment options associated with fewer AEs may reduce costs and improve outcomes in these patients.
doi:10.1186/2193-1801-3-259
PMCID: PMC4047276  PMID: 24926422
Breast neoplasms; Adverse effects; Antineoplastic agents; Costs and cost analysis
22.  Incidence of taxane-induced pain and distress in patients receiving chemotherapy for early-stage breast cancer: a retrospective, outcomes-based survey 
Current Oncology  2010;17(4):42-47.
Introduction
With the widespread use of sequential anthracycline/taxane–based chemotherapy for early-stage breast cancer, clinicians are becoming rapidly aware of toxicities associated with those regimens. Despite the low incidence reported in the literature of significant arthralgia and myalgia with those regimens, it is clinically evident that a substantial proportion of patients develop such toxicities. We performed a pilot study to investigate the extent of this problem.
Patients and Methods
Patients who had received prior adjuvant or neoadjuvant chemotherapy [doxorubicin–cyclophosphamide followed by paclitaxel (ac-t), doxorubicin–cyclophosphamide followed by docetaxel (ac-d), or 5-fluourouracil–epirubicin–cyclophosphamide followed by docetaxel (fec-d)] completed a retrospective outcomes-based survey. The survey utilized the Functional Assessment of Cancer Therapy–Taxane Scale, the Memorial Symptom Assessment Scale, and a modified Brief Pain Inventory.
Results
Interviews were conducted with 82 patients. Interviewees had received ac-t (43%), fec-d (43%), and ac-d (14%). Pain as a side effect of either the anthracycline or the taxane chemotherapy was reported by 87% of patients. Most of the patients (79%) indicated that their worst pain occurred during the taxane component of treatment. Compared with paclitaxel, docetaxel was reported to cause more pain. Narcotics for pain management were required by 35 of 82 patients (43%).
Conclusions
A significant number of patients receiving sequential anthracycline/taxane–based chemotherapy for early-stage breast cancer experience pain, particularly during the taxane component. Prospective patient-reported outcome assessments are needed to help individualize treatment interventions and to improve symptom management in this population.
PMCID: PMC2913828  PMID: 20697513
Breast cancer; taxanes; anthracyclines; toxicities
23.  Differential effect of adjuvant taxane-based and taxane-free chemotherapy regimens on the CK-19 mRNA-positive circulating tumour cells in patients with early breast cancer 
British Journal of Cancer  2013;108(3):549-556.
Background:
To determine the effect of adjuvant taxane-free and taxane-based chemotherapy regimens on the elimination of circulating tumour cells (CTCs) in patients with early breast cancer.
Methods:
The presence of CK-19 mRNA-positive CTCs in the peripheral blood was evaluated before and after chemotherapy, using a real-time RT–PCR assay, in a historical comparison of two cohorts of women with stage I–III breast cancer treated with adjuvant taxane-free (N=211; FE75C or E75C) and taxane-based (N=334; T/E75C or T/E75) chemotherapy.
Results:
Taxane-based chemotherapy resulted in a higher incidence of CTCs' elimination than taxane-free regimens since 49.7% (74 of 149) and 33.0% (29 of 88) of patients with detectable CTCs before chemotherapy, respectively, turned negative post-chemotherapy (P=0.015). Patients treated with taxane-free regimens had a significantly lower disease-free survival (DFS) (P=0.035) than patients treated with taxane-based regimens; this difference was observed in patients with but not without detectable CTCs before chemotherapy (P=0.018 and P=0.481, respectively). The incidence of deaths was significantly higher in the taxane-free cohort of patients with but not without detectable CTCs before chemotherapy compared with that of the taxane-based cohort (P=0.002). Multivariate analysis revealed that the chemotherapy regimen was significantly associated with prolonged DFS (HR: 2.00; 95% CI=1.20–3.34).
Conclusion:
Elimination of CK-19 mRNA-positive CTCs during adjuvant chemotherapy seems to be an efficacy indicator of treatment and is associated with a favourable clinical outcome of patients with detectable CTCs before chemotherapy.
doi:10.1038/bjc.2012.597
PMCID: PMC3593552  PMID: 23329233
breast cancer; circulating tumour cells; CK-19; metastasis
24.  Phase II Trial of Sorafenib in Patients With Metastatic Breast Cancer Previously Exposed to Anthracyclines or Taxanes: North Central Cancer Treatment Group and Mayo Clinic Trial N0336 
Journal of Clinical Oncology  2008;27(1):11-15.
Purpose
We conducted a cooperative group phase II study to assess antitumor activity and toxicity of sorafenib in patients with metastatic breast cancer (MBC) who had received prior treatment for their disease.
Patient and Methods
Patients were eligible if they had measurable disease and had previously received an anthracycline and/or a taxane in the neoadjuvant, adjuvant, or metastatic setting. The primary end point of the study was tumor response per Response Evaluation Criteria in Solid Tumors (RECIST). The study was designed in two stages. Sorafenib was administered as 400 mg twice daily on days 1 through 28 of each 4-week cycle.
Results
Twenty-three patients were enrolled with a median age of 54 years (range, 37 to 70 years). Twenty-two (96%) had prior anthracycline treatment and 16 (70%) had prior taxane treatment. Patients received sorafenib for a median of two cycles (range, one to 15 cycles) with a median follow-up of 2.4 years (range, 2.2 to 2.6 years). There were no grade 4 toxicities and few grade 3 toxicities. Among the 20 patients eligible for efficacy analysis, no patients experienced a partial response or complete response per RECIST criteria. Thus, the trial stopped at the end of the first stage per study design. Two patients (10%; 90% CI, 1.8% to 28.3%) achieved stable disease lasting longer than 6 months.
Conclusion
Sorafenib as a single agent, although well tolerated, did not exhibit activity when measured by tumor shrinkage in patients with MBC who had received prior treatment. Further research should focus on combinations with standard therapy and end points more sensitive to effects of targeted agents, such as disease stabilization.
doi:10.1200/JCO.2007.15.5242
PMCID: PMC2645094  PMID: 19047293
25.  Nanoparticle albumin-bound paclitaxel in a patient with locally advanced breast cancer and taxane-induced skin toxicity: a case report 
Introduction
Taxanes have demonstrated effectiveness in the treatment of breast cancer, the most common type of cancer in women. The toxicity profile of taxanes (including skin toxicities) induces dose adjustment, delay, or discontinuation, which prevents a sufficient dose intensity to achieve a response. Nanoparticle albumin-bound paclitaxel, a solvent-free form of paclitaxel, prevents toxicities and reduces the pharmacokinetic interferences between paclitaxel and other drugs.
Case presentation
We describe the case of a 55-year-old Caucasian woman with locally advanced breast cancer treated with neoadjuvant therapy who developed secondary skin toxicity due to delayed hypersensitivity to taxanes. She received Adriamycin® (doxorubicin), cyclophosphamide and docetaxel and developed toxicity that promoted treatment delay and a switch to weekly paclitaxel. After the third and fourth weeks of treatment, paclitaxel toxicities also induced treatment delay and paclitaxel was switched to nanoparticle albumin-bound paclitaxel. She completed the five planned nanoparticle albumin-bound paclitaxel cycles with acceptable tolerability (including persistent grade 2 neuropathy) and without dose delay or adjustments. Clinical response was achieved although pathological response was not good.
Conclusions
Nanoparticle albumin-bound paclitaxel treatment is a good option for patients with breast cancer with taxanes-related skin toxicity. This drug allows the treatment to be completed with acceptable tolerance in our case.
doi:10.1186/1752-1947-8-6
PMCID: PMC3917539  PMID: 24386978
Breast cancer; Nab-paclitaxel; Taxane-induced toxicity

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