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.     

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.     

Is there a growing role for endocrine therapy in the treatment of breast cancer?

Novel biochemical findings on the molecular mechanisms of estrogen actions may help us to understand some of the unexplained observations seen in breast cancer treatment and suggest new therapeutic opportunities. Thus, apart from the challenge of improving the clinical treatment of patients with advanced disease, results from trials in this setting may reveal new therapeutic principles that may be evaluated in the adjuvant setting. The role of endocrine therapy in metastatic as well as early breast cancer is increasing, and the possibility of improving cure rates for breast cancer by implementing therapy with novel aromatase inhibitors in the adjuvant setting is exciting. While the results from prevention trials are most interesting, suggesting the possibility of reducing breast cancer incidence in high-risk groups, more data are needed before we can decide whether such interventions are warranted in women at high risk of developing breast cancer.     

cMET in triple-negative breast cancer: is it a therapeutic target for this subset of breast cancer patients?

Introduction: The identification and validation of a targeted therapy for triple-negative breast cancer (TNBC) is currently one of the most urgent needs in breast cancer therapeutics. The cMET oncogene encodes a membrane-bound tyrosine kinase implicated in the formation and/or progression of several cancer types, including TNBC. Currently, inhibitors targeting cMET are undergoing clinical trials for a variety of cancers, including TNBC. These include anti-cMET and anti-hepatocyte growth factor (HGF) monoclonal antibodies and tyrosine kinase inhibitors.

Areas covered: This article reviews the structure and mode of action of cMET, the role of cMET in cancer formation/development, with particular emphasis on its role in basal/TNBC and its potential as a therapeutic target for this subtype of breast cancer.

Expert opinion: Due to cancer heterogeneity, it is unlikely that all TNBC patients will be responsive to anti-cMET drugs. Therefore, if cMET is to be used as a target for treatment, it will be important to identify predictive biomarkers to select, upfront, those patients likely to benefit. Potential predictive biomarkers for anti-cMET treatments in basal/TNBC include cMET, phospho-cMET, downstream signaling proteins or HGF. These putative predictive biomarkers should be evaluated in a large panel of basal/TNBC cell lines before incorporation into clinical trials involving anti-cMET drugs.     

Lipid–polymer nanoparticles encapsulating curcumin for modulating the vascular deposition of breast cancer cells

Vascular adhesion and endothelial transmigration are critical steps in the establishment of distant metastasis by circulating tumor cells (CTCs). Also, vascular inflammation plays a pivotal role in steering CTCs out of the blood stream. Here, long circulating lipid–polymer nanoparticles encapsulating curcumin (NANOCurc) are proposed for modulating the vascular deposition of CTCs. Upon treatment with NANOCurc, the adhesion propensity of highly metastatic breast cancer cells (MDA-MB-231) onto TNF-α stimulated endothelial cells (HUVECs) reduces by ~ 70%, in a capillary flow. Remarkably, the CTCs vascular deposition already reduces up to ~ 50% by treating solely the inflamed HUVECs. The CTCs arrest is mediated by the interaction between ICAM-1 on HUVECs and MUC-1 on cancer cells, and moderate doses of curcumin down-regulate the expression of both molecules. This suggests that NANOCurc could prevent metastasis and limit the progression of the disease by modulating vascular inflammation and impairing the CTCs arrest.From the Clinical EditorIn this novel study, lipid nanoparticles encapsulating curcumin were able to prevent metastasis formation and limited the progression of the disease by modulating vascular inflammation and impairing the circulating tumor cells' arrest as a result of down-regulation of ICAM1 and MUC1 in a highly metastatic breast cancer cell line model.     

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.     

Comparative bioavailability study of capecitabine tablets of 500 mg in metastatic breast cancer and colorectal cancer patients under fed condition

Capecitabine (oral prodrug of 5-fluorouracil) is the first-line treatment for the metastatic breast and colorectal cancer. The objective of the study was to determine the bioequivalence between the test product (capecitabine tablets 500?mg) of Dr. Reddy’s Laboratories Limited relative to that of reference product XELODA^® (capecitabine) 500?mg tablets of Roche Registration Inc. in patients of metastatic breast or colorectal cancer stabilized with twice daily dosing of capecitabine monotherapy. This was an open-label, randomized, single dose, two-way cross-over bioequivalence study under fed conditions. The subjects received either of the treatments (test or reference) 30?min after consumption of a high fat, high calorie breakfast as a single morning dose of 2000?mg on two separate days (days 1 and 2) based on their body surface area. Blood samples were collected up to 10?h post-dose and analyzed for capecitabine using the validated liquid chromatographic mass spectrometric (LC-MS/MS) method. The least square mean ratio and 90% confidence intervals of C_max, AUC_0–t and AUC_0–∞ were within the regulatory acceptance criteria of 80.00–125.00% and considered as bioequivalent.     

Triptolide inhibits human breast cancer MCF-7 cell growth via downregulation of the ERα-mediated signaling pathway

Aim:

To investigate the anticancer mechanisms of triptolide, a diterpenoid isolated from the plant Tripterygium wilfordii Hook F, against human breast cancer cells and the involvement of the estrogen receptor-α (ERα)-mediated signaling pathway in particular.

Methods:

Human breast cancer ERα-positive MCF-7 cells and ERα-negative MDA-MB-231 cells were tested. PrestoBlue assay was used to evaluate the cell viability. The levels of ERα mRNA and protein were detected with real-time PCR and immunoblotting, respectively. Mouse models of MCF-7 or MDA-MB-231 xenograft tumors were treated with triptolide (0.4 mg·kg⁻¹·d⁻¹, po) or a selective estrogen receptor modulator tamoxifen (mg·kg⁻¹·d⁻¹, po) for 3 weeks, and the tumor weight and volume were measured.

Results:

Triptolide (5–200 nmol/L) dose-dependently inhibited the viability of both MCF-7 and MDA-MB-231 cells, with a more potent inhibition on MCF-7 cells. Knockdown of ERα in MCF-7 cells by siRNA significantly attenuated the cytotoxicity of triptolide, whereas overexpression of ERα in MDA-MB-231 cells markedly enhanced the cytotoxicity. Triptolide dose-dependently decreased the expression of ERα in MCF-7 cells and MCF-7 xenograft tumors. Furthermore, treatment of MCF-7 cells with triptolide inhibited the phosphorylation of ERK1/2 in dose- and time-dependent manners. In the mice xenografted with MCF-7 cells, treatment with triptolide or tamoxifen resulted in significant reduction in the tumor weight and volume. Similar effects were not obtained in the mice xenografted with MDA-MB-231 cells.

Conclusion:

The anticancer activity of triptolide against ERα-positive human breast cancer is partially mediated by downregulation of the ERα-mediated signaling pathway.     

Can sequential administration minimise the cost of high dose chemotherapy? An economic assessment in inflammatory breast cancer

OBJECTIVE: To evaluate the potential cost savings of using sequential high dose chemotherapy (HDC), with granulocyte colony-stimulating factor (filgrastim) and stem cell support, rather than single course administration of HDC with bone marrow transplantation (BMT) or peripheral blood stem cell transplantation (PBSCT). PERSPECTIVE: French public hospital perspective. METHODS: Direct medical costs of sequential treatment, estimated on the basis of physical quantities of resources consumed by 95 patients with inflammatory breast cancer (IBC) included in a French pilot multicentric trial (PEGASE 02), were compared with those of historical control groups of patients treated with single course HDC, either with BMT (n = 27) or PBSCT (n = 14). Costs were evaluated in 1998 French francs (1 Euro = 6.55957 French francs). RESULTS: The total cost of sequential HDC was significantly lower than that for single course HDC both with BMT (-29%; 22,755 Euros vs 32,284 Euros; p < 0.001) or PBSCT (-16%; 22,755 Euros vs 27,209 Euros; p = 0.026). This was mainly due to a reduction in the length of hospitalisation in transplantation units. CONCLUSION: According to our results, economic arguments cannot be used against the widespread use of sequential HDC for patients with IBC. However, further economic evaluations based on overall and disease-free survivals alongside a randomised clinical trial are still needed to definitively establish the cost effectiveness of sequential administration of HDC.     

Can we replace the microscope with microarrays for diagnosis, prognosis and treatment of early breast cancer?

In recent years, molecular research has translated into remarkable changes for breast cancer diagnostics and therapeutics. Molecular tests such as Oncotype DX? and MammaPrint? have revolutionized the predictive and prognostic tools in the clinic. By stratifying the risk of recurrence for patients, the tests are able to provide clinicians with more information on the treatment outcomes of using chemotherapy, endocrine therapy or combination therapies for patients with genetic expression patterns. However, it is still questionable for clinical applications as some areas remain unclear; the true benefit still needs prospective evaluation. In this paper, the limitation and the possibility to replace traditional histopathologic features of molecular tests are discussed. At the moment, it seems there are still limitations that prevent microarrays from replacing the microscope for diagnosis, prognosis and treatment of early breast cancer. However, additional important clinical information is added to traditional histology and IHC determination of ER, PR and HER2 in terms of prognostic and predictive power.     

Anticancer activity of thymoquinone in breast cancer cells: possible involvement of PPAR-γ pathway

Thymoquinone (TQ), an active ingredient of Nigella sativa, has been reported to exhibit anti-oxidant, anti-inflammatory and anti-tumor activities through mechanism(s) that is not fully understood. In this study, we report the anticancer effects of TQ on breast cancer cells, and its potential effect on the PPAR-γ activation pathway. We found that TQ exerted strong anti-proliferative effect in breast cancer cells and, when combined with doxorubicin and 5-fluorouracil, increased cytotoxicity. TQ was found to increase sub-G1 accumulation and annexin-V positive staining, indicating apoptotic induction. In addition, TQ activated caspases 8, 9 and 7 in a dose-dependent manner. Migration and invasive properties of MDA-MB-231 cells were also reduced in the presence of TQ. Interestingly, we report for the first time that TQ was able to increase PPAR-γ activity and down-regulate the expression of the genes for Bcl-2, Bcl-xL and survivin in breast cancer cells. More importantly, the increase in PPAR-γ activity was prevented in the presence of PPAR-γ specific inhibitor and PPAR-γ dominant negative plasmid, suggesting that TQ may act as a ligand of PPAR-γ. Also, we observed using molecular docking analysis that TQ indeed formed interactions with 7 polar residues and 6 non-polar residues within the ligand-binding pocket of PPAR-γ that are reported to be critical for its activity. Taken together, our novel observations suggest that TQ may have potential implication in breast cancer prevention and treatment, and show for the first time that the anti-tumor effect of TQ may also be mediated through modulation of the PPAR-γ activation pathway.     

PC-SPES for the treatment of prostate cancer?

A 73-year-old man recently attended his local USToo International prostate cancer support group and during the meeting several members were discussing using PC-SPES for treatment of their prostate cancer. The patient's history is significant for prostate cancer and as a result he had a radical prostatectomy. Two years ago, he relapsed with bone metastases and he was subsequently treated with combined anti-androgen therapy. Over the last 6 months his symptoms and prostate-specific antigen have increased, despite anti-androgen withdrawal and a regimen of cancer chemotherapy. The patient is aware that his prostate cancer is incurable, but he wants to know if PC-SPES can help.     

The role of α-blockers in the management of prostate cancer

Prostate cancer is the second most common cause of cancer death in men in the US. Patients with prostate cancer are initially treated with surgical resection, radiation or antiandrogen therapy. After an initial remission, however, the majority of prostate tumours evolve into a highly aggressive, metastatic androgen-independent state, for which successful therapy has not yet been established. During the past few years, new perspectives have emerged towards the development of preventive and therapeutic approaches for prostate cancer. Quinazoline-based α₁-blockers have been shown to have antitumour efficacy against prostate cancer cells in inducing apoptosis and anoikis via an α₁-adrenoceptor-independent mechanism. Specifically, doxazosin and terazosin can induce apoptosis, inhibit invasion and migration of prostate cancer and endothelial cells, and reduce their adhesion potential to extracellular matrix components, thus enhancing their susceptibility to anoikis. This review discusses recent evidence suggesting the apoptotic efficacy of quinazoline-based α₁-adrenoceptor antagonists, doxazosin and terazosin and speculates on the therapeutic promise of these drugs as novel antitumour agents against prostate cancer. From a drug discovery perspective, separation of the effect of doxazosin on apoptosis in prostate cancer cells from its original pharmacological activity in normal prostate cells, will provide a molecular basis in developing a novel class of apoptosis-inducing agents through lead optimisation.     

A role for L-��-lysophosphatidylinositol and GPR55 in the modulation of migration, orientation and polarization of human breast cancer cells

Background and purpose:

Increased circulating levels of L-α-lysophosphatidylinositol (LPI) are associated with cancer and LPI is a potent, ligand for the G-protein-coupled receptor GPR55. Here we have assessed the modulation of breast cancer cell migration, orientation and polarization by LPI and GPR55.

Experimental approach:

Quantitative RT-PCR was used to measure GPR55 expression in breast cancer cell lines. Cell migration and invasion were measured using a Boyden chamber chemotaxis assay and Cultrex® invasion assay, respectively. Cell polarization and orientation in response to the microenvironment were measured using slides containing nanometric grooves.

Key results:

GPR55 expression was detected in the highly metastatic MDA-MB-231 breast cancer cell line. In these cells, LPI stimulated binding of [³⁵S]GTPγS to cell membranes (pEC₅₀ 6.47 ± 0.45) and significantly enhanced cell chemotaxis towards serum. MCF-7 cells expressed low levels of GPR55 and did not migrate or invade towards serum factors. When GPR55 was over-expressed in MCF-7 cells, serum induced a robust migratory and invasive response, which was further enhanced by LPI and prevented by siRNA to GPR55. The physical microenvironment has been identified as a key factor in determining breast tumour cell metastatic fate. LPI endowed MDA-MB-231 cells with the capacity to detect shallow (40 nm deep) grooved slides and induced marked cancer cell polarization on both flat and grooved surfaces.

Conclusions and implications:

LPI and GPR55 play a role in the modulation of migration, orientation and polarization of breast cancer cells in response to the tumour microenvironment.This article is part of a themed issue on Cannabinoids. To view the editorial for this themed issue visit http://dx.doi.org/10.1111/j.1476-5381.2010.00831.x