Chemotherapy of breast cancer: are the taxanes going to change the natural history of breast cancer?

Among the novel chemotherapeutic drugs introduced in the last decade, taxanes have emerged as the most powerful compounds and results available to date suggest that they will be remembered in the future as the breast cancer chemotherapy of the 1990s. The two taxanes (paclitaxel, Taxol, Bristol-Myers Squibb and docetaxel, Taxotere, Rh?ne-Poulenc Rorer) share some characteristics, but are also significantly different both in preclinical profile and, most importantly, in clinical characteristics. The main clinical differences are related to their different efficacy-toxicity ratio in relation to dose and schedule; the differing integrability of paclitaxel and docetaxel in anthracycline-taxane containing regimens, secondary to major differences in pharmacokinetic interactions between each taxane and the anthracyclines, and; the potential differences in level of synergism between each taxane and herceptin (HeR2Neu antibody/trastuzumab, Genentech/Roche). In clinical practice, the taxanes are now standard therapy in metastatic breast cancer after prior chemotherapy, in particular anthracyclines, has failed. Their role in combination with anthracyclines in first-line therapy of advanced breast cancer is emerging and sheds new light on the potential role of taxanes in the adjuvant setting. However, the impact of taxanes on the natural history of breast cancer is yet to be defined, despite the trend of results suggesting that these agents have the potential for significant improvements in advanced and, most importantly, adjuvant therapy of breast cancer. The results of all completed or ongoing Phase III trials in first-line metastatic and the adjuvant setting will help determine if taxanes will further improve the outcome of breast cancer or not.     

Chemotherapy of breast cancer: are the taxanes going to change the natural history of breast cancer?

Among the novel chemotherapeutic drugs introduced in the last decade, taxanes have emerged as the most powerful compounds and results available to date suggest that they will be remembered in the future as the breast cancer chemotherapy of the 1990s. The two taxanes (paclitaxel, Taxol?, Bristol-Myers Squibb and docetaxel, Taxotere?, Rhône-Poulenc Rorer) share some characteristics, but are also significantly different both in preclinical profile and, most importantly, in clinical characteristics. The main clinical differences are related to their different efficacy-toxicity ratio in relation to dose and schedule; the differing integrability of paclitaxel and docetaxel in anthracycline-taxane containing regimens, secondary to major differences in pharmacokinetic interactions between each taxane and the anthracyclines, and; the potential differences in level of synergism between each taxane and herceptin (HeR2Neu antibody/trastuzumab, Genentech/Roche). In clinical practice, the taxanes are now standard therapy in metastatic breast cancer after prior chemotherapy, in particular anthracyclines, has failed. Their role in combination with anthracyclines in first-line therapy of advanced breast cancer is emerging and sheds new light on the potential role of taxanes in the adjuvant setting. However, the impact of taxanes on the natural history of breast cancer is yet to be defined, despite the trend of results suggesting that these agents have the potential for significant improvements in advanced and, most importantly, adjuvant therapy of breast cancer. The results of all completed or ongoing Phase III trials in first-line metastatic and the adjuvant setting will help determine if taxanes will further improve the outcome of breast cancer or not.     

Flaxseed oil–trastuzumab interaction in breast cancer

Flaxseed oil (FO), which is rich in n?3 fatty acid, is commonly consumed by breast cancer patients because of its potential anti-cancer effects. Trastuzumab (TRAS) is the primary drug for epidermal growth factor receptor 2 (HER2) positive breast cancer. We investigated in athymic mice whether combining dietary FO (8%) with TRAS treatment (2.5 or 5 mg/kg body weight) can cause better or adverse effect on established human breast tumors overexpressing HER2 (BT-474). Control tumors significantly grew 187%, TRAS2.5 treated tumors did not change, while TRAS5, FO + TRAS2.5 and FO + TRAS5 treated tumors significantly regressed 75%, 89% and 84%, respectively, after 4 weeks treatment. Two weeks after stopping TRAS treatment while continuing on same diet, tumor size in FO + TRAS2.5 group was 87% lower than in TRAS2.5 group and was not different from TRAS5 group with or without FO. Combined TRAS2.5 treatment with FO caused a significantly lower tumor cell proliferation and higher apoptosis compared to TRAS2.5 treatment alone and showed similar effect to TRAS5 treatment with or without FO. Hence, FO did not interfere with TRAS but rather enhanced its tumor-reducing effects and combined FO and low dose TRAS was as effective as high dose TRAS treatment.     

Chemokines and breast cancer: a gateway to revolutionary targeted cancer treatments?

Breast cancer is an example of a solid tumour which is well treated in the early stages of disease by surgical excision, but once metastatic spread has occurred, medical therapies (chemotherapy and radiotherapy) are highly toxic, expensive and palliative. It is known that certain tumours exhibit specific patterns of metastasis, chemokines may provide a molecular answer to this mystery. Chemokines and their receptors play important roles in the various stages of tumour development and metastasis. Chemokines interact with their specific receptors as well as interacting with the glycosaminoglycan (GAG) component of proteoglycan. We discuss the basic metastatic process and the involvement of chemokines in breast cancer biology. Finally, we summarize potential therapeutic applications of chemokines and chemokine/glycosaminoglycan interactions including chemokine agonists, antagonists, anti-sense therapy, immunotherapy and soluble GAGs, as well as future perspectives in this field.     

miRNAs in breast cancer: ready for real time?

Over the past decade, major advances in our comprehension of breast cancer biology have led to improved diagnostic and prognostic techniques and the development of novel targeted therapies. However, the efficacy of new treatments remains limited by a combination of drug toxicity, resistance and persisting insufficiencies in our understanding of tumor-signaling pathways; furthermore, the reliability of identified biomarkers is contentious. Following their recent discovery, miRNAs have been established as critical regulators of gene expression, and their putative roles as oncogenes and tumor-suppressor genes has provided a potential new dimension to our clinical approach to breast cancer diagnosis and treatment. Their role as biomarkers and therapeutic targets is appealing; however, several barriers have limited our ability to translate this potential into a clinical reality. This review focuses on the currently accepted roles of miRNAs in breast cancer pathogenesis, and highlights the clinical challenges and breakthroughs in this field to date.     

Integrin α3β1 as a breast cancer target

Introduction: Integrin receptors for cell adhesion to the extracellular matrix have important roles in all stages of cancer progression and metastasis. Since the integrin family was discovered in the early 1980's, many studies have identified critical adhesion and signaling functions for integrins expressed on tumor cells, endothelial cells and other cell types of the tumor microenvironment, in controlling proliferation, survival, migration and angiogenesis. In recent years, the laminin-binding integrin α3β1 has emerged as a potentially promising anti-cancer target on breast cancer cells.

Areas covered: Studies from the past decade that implicate integrins as promising anti-cancer targets and the development of integrin antagonists as anti-cancer therapeutics. Recent preclinical studies that have identified the laminin-binding integrin α3β1 as an appealing anti-cancer target and the knowledge gaps that must be closed to fully exploit this integrin as a therapeutic target for breast cancer.

Expert opinion: Although the tumor-promoting functions of α3β1 implicate this integrin as a promising therapeutic target on breast cancer cells, successful exploitation of this integrin as an anti-cancer target will require a better understanding of the molecular mechanisms whereby it regulates specific tumor cell behaviors and the identification of the most appropriate α3β1 functions to antagonize on breast cancer cells.     

Integrin α3β1 as a breast cancer target

INTRODUCTION: Integrin receptors for cell adhesion to the extracellular matrix have important roles in all stages of cancer progression and metastasis. Since the integrin family was discovered in the early 1980's, many studies have identified critical adhesion and signaling functions for integrins expressed on tumor cells, endothelial cells and other cell types of the tumor microenvironment, in controlling proliferation, survival, migration and angiogenesis. In recent years, the laminin-binding integrin α3β1 has emerged as a potentially promising anti-cancer target on breast cancer cells. AREAS COVERED: Studies from the past decade that implicate integrins as promising anti-cancer targets and the development of integrin antagonists as anti-cancer therapeutics. Recent preclinical studies that have identified the laminin-binding integrin α3β1 as an appealing anti-cancer target and the knowledge gaps that must be closed to fully exploit this integrin as a therapeutic target for breast cancer. EXPERT OPINION: Although the tumor-promoting functions of α3β1 implicate this integrin as a promising therapeutic target on breast cancer cells, successful exploitation of this integrin as an anti-cancer target will require a better understanding of the molecular mechanisms whereby it regulates specific tumor cell behaviors and the identification of the most appropriate α3β1 functions to antagonize on breast cancer cells.     

Cryptotanshinone switches target from estrogen receptor α to breast cancer resistance protein(BCRP/ABCG2) to reverse multidrug resistance in breast cancer

OBJECTIVE Targeting individual molecule is not only difficult to cure multigenic cancers, but also prone to inducing resistance. The so-cal ed multidrug resistance(MDR) in breast cancer is highly associated with estrogen receptor α induction and the overexpression of breast cancer resistance protein(BCRP) transporter.Thus, one of the strategies to overcome MDR is to inhibit the expression of the transporter by small molecule inhibitors. METHODS Western blotting and RT-PCR were used respectively for quantification of protein expression and m RNA, non-reducing gradientgel electrophoresis and fluorescence resonance energy transfer(FRET) microscopy imaging for determination of BCRP dimer. RESULTS Cryptotanshinone(CPT) a natural anti-cancer compound,was found to bind BCRP and inhibit its membrane dimerization to attenuate its transport function. And this process is dependent on estrogen receptor α(ERα) in breast cancer. Furthermore, the resistant breast cancer cells with high BCRP expression are also sensitive to CPT followed with the inhibition of membrane dimer of BCRP although they are ERα-negative, suggesting that BCRP expression is essential to CPT reversing the resistance.Meanwhile, the combination of CPT and chemotherapy drugs could obviously enhance the chemotherapeutic effect in vitro. CONCLUSION Totally, we thought that CPT is a novel natural BCRP inhibitor via blocking the formation of BCRP membrane dimer. At the presence of ERα, it functions via ERα regulation, but directly propels BCRP at the absence of ER in resistant cells. CPT can target multi molecules and switch the target from ERα to BCRP in ERα-negative breast cancer, contributing to decrease the occurrence of resistance and reverse multidrug resistance in breast cancer.     

Pharmacotherapy of bone metastases in breast cancer patients – an update

Introduction: Bone metastases in breast cancer patients are a common clinical problem and pose a threat to the quality of life of such patients. Multiple randomized trials have demonstrated the benefit of both bisphosphonates and denosumab in reducing the incidence and delaying the onset of skeletal related events (SREs) in breast cancer patients with bone metastases.

Areas covered: We review the current literature on the use of bisphosphonates and denosumab along with strategies to maximize benefit and minimize risk of these agents. We also review potential future targets.

Expert opinion: Despite the potent osteoclast inhibiting effects of the bone-targeted agents in current clinical use, we have likely maximized their ability to inhibit SREs and must in turn focus on minimizing their potential toxicity. The future will likely involve more novel treatment strategies as well as the development of new agents. The current ‘one size fits all’ approach for the management of breast cancer bone metastases will be replaced by ‘tailored’ treatment for each individual patient as we usher in the era of ‘personalized medicine.’ In addition, new bone-targeted agents (e.g., sclerostin inhibitors) and combinations will continue to be explored, as will the evaluation of the bone-targeting properties of more conventional non-osteoclast targeting therapies.     

Is long-term adjuvant treatment of breast cancer with anastrozole indicated?

Background: Tamoxifen is the established adjuvant treatment for postmenopausal women with hormone-sensitive breast cancer. Objective: To determine whether the aromatase inhibitor anastrozole should replace tamoxifen as the adjuvant treatment in this cancer. Methods: Two recent trials of anastrozole and tamoxifen as adjuvant treatment were evaluated. Results/conclusion: The Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial showed that 5 years of adjuvant therapy with anastrozole reduced recurrence of breast cancer to a greater extent than did tamoxifen. The Austrian Breast and Colorectal Cancer Study Group (ABCSG) Trial 6a showed that after 5 years of adjuvant treatment with tamoxifen more benefit was achieved by continuing with adjuvant anastrozole for 3 years than no further treatment. Although the long-term adjuvant treatment of hormone receptor positive breast cancer with anastrozole is indicated, questions remain as to how long the adjuvant treatment with anastrozole should continue.     

Palbociclib for the treatment of postmenopausal breast cancer – an update

Introduction

Breast cancer is a heterogeneous disease comprising different biological subtypes. In two thirds of tumours, expression of steroid-receptors is present, allowing for targeted treatment with endocrine therapy. In metastatic breast cancer, sequential administration of different non-cross resistant drugs offers a chance to delay cytotoxic chemotherapy. Activity of endocrine therapy, however, decreases with time as indicated by a shorter progression-free survival interval with every further treatment line, suggesting onset of resistance. Current research therefore focuses on prevention or delay of resistance by combining endocrine therapy with other targeted treatment approaches such as small-molecule pathway-inhibitors. Indeed, combining the steroidal aromatase-inhibitor exemestane with the mTor-inhibitor everolimus doubles activity of endocrine therapy in a pretreated population albeit at the price of increased toxicity.

Data from several clinical trials suggest that inhibitors of the cycline-dependent kinases (CDK) 4 and 6 are able to delay or reverse resistance to endocrine therapy as well, while tolerability may be superior.

Areas Covered

This review provides a summary of clinical data on CDK 4/6 inhibitors, summarizes the biological rational for their use and provides an outlook to future developments in this field. A systematic literature search was performed in order to identify publications concerning the use of CDK 4/6 inhibitors in breast cancer. The search included original research articles, abstracts from major conferences and reviews published from 2005 to 2015 and was limited to English-language publications.

Expert opinion

Based upon available data regarding activity and tolerability, it is believed that CDK 4/6 inhibitors will evolve to become a valuable addition to the therapeutic options in metastatic breast cancer.     

The UKCCCR adjuvant breast cancer(ABC) trial-strengthened by worldwide collaboration

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Sentinel node biopsy for breast cancer: showtime or dress rehearsal?

INTRODUCTION: Sentinel lymph node biopsy (SLNB) may prove superior to axillary node dissection (AND) for breast cancer staging. At issue is whether existing clinical data support performance of SLNB without AND at this time. DISCUSSION: The various methods of SLNB are discussed in detail. SLNB using radiocolloids and surgical probes (with or without blue dye) yields superior SLN localization rates as compared to blue dye alone. However, the incidence of false-negative SLNB is variable with all methods and frequently 10% or higher (11.4% in the only published multicenter study). CONCLUSIONS: Outside of a clinical trial, SLNB should be performed in addition to, not instead of, AND. The sensitivity of pathological staging is enhanced and nonaxillary SLNs are identified, while concomitant AND apprehends all false-negative SLNBs. Two prospective randomized cooperative trials provide excellent educational, training and research opportunities for North American breast surgeons as they gain experience with this new, promising staging procedure.     

HER-2 positive breast cancer: what else beyond trastuzumab-based therapy?

HER-2 is a tyrosine kinase receptor which is overexpressed in 20-25% of breast cancer patients and is associated with poor prognosis. Trastuzumab, a humanized monoclonal antibody directed against the HER-2 receptor, used alone or in combination with chemotherapy, has shown significant clinical benefit in improving survival in metastatic patients, as well as halving the recurrence rate and improving survival in early breast cancer. Even with these impressive results, the reality is that not all patients will benefit form this therapy, and in those who do, resistance to trastuzumab can often develop within 1 year of treatment initiation. Beyond trastuzumab therapy, a "second wave" of monoclonal antibodies and tyrosine kinase inhibitors has emerged. These drugs have variable properties including: 1) dual inhibition against EGFR and HER-2, such as lapatinib, HKI-272 and pertuzumab; 2) anti-angiogenesis such as bevacizumab and pazopanib; 3) anti-mTOR action such as Temsirolimus; and 4) anti-Hsp90 such as 17-AAG. When used in combination with trastuzumab, or with cytotoxic chemotherapy, or as single agents, these new anti-HER-2 strategies bear the potential of arresting the tumorigenesis process. In this article, we present the current strategies in the treatment of breast cancer patients who overexpress HER-2, with particular focus on new tyrosine kinase inhibitors that can be used in combination with or after trastuzumab therapy.     

ERα signaling imparts chemotherapeutic selectivity to selenium nanoparticles in breast cancer

The present study focuses on the synthesis of stable selenium nanoparticles (SeNPs) and the elucidation of their mechanism of action in preventing the growth of mammary tumors. Selenious acid and reduced glutathione in the presence of sodium alginate were used as precursors for synthesis of SeNPs. Cell viability and expression of apoptotic markers (pp38, Bax, and cytochrome c) were assessed in MCF-7 and MDA-MB-231 breast cancer cells treated with SeNPs. Reduction in tumor volume was measured in rats with dimethylbenz[a]anthracene-induced mammary tumors. Synthesized SeNPs ranged in size from 40 to 90 nm and were stable up to 3 months of storage. We report that SeNP-induced cell death and expression of pp38, Bax, and cytochrome c were significantly higher in estrogen receptor-α (ERα)-positive cells (MCF-7) but not in ERα-negative cells (MDA-MB-231). Interestingly, animals showing significant decrease in tumor volume (small tumors) had lower levels of ERα as compared with animals showing a nonsignificant decrease in tumor volume (large tumor). This is the first report in our knowledge suggesting that the anticancer activity of SeNPs correlates with the level of ERα in breast cancer cells both in vivo and in vitro. FROM THE CLINICAL EDITOR: This study focuses on the synthesis of selenium nanoparticles (SeNPs) with the goal of preventing the growth of breast cancer cells, suggesting that the anticancer activity of SeNPs correlates with the level of ERα in breast cancer cells both in vivo and in vitro.