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.     

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.     

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.     

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.     

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.     

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.     

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.     

Aromatase inhibitors in early hormone receptor-positive breast cancer : what is the optimal initiation time for the maximum benefit?

Breast cancer is common, affecting one in nine women worldwide. As stipulated by the St Gallen consensus guidelines, hormone therapy is an integral part of treatment for hormone-responsive disease. Previously, this has been with tamoxifen; however, as a result of a number of recent studies, aromatase inhibitors are now competing for use as first-line agents. In addition, there is as yet no firm consensus as to when and how these drugs should be used within the adjuvant setting. This article reviews the use of aromatase inhibitors in early stage hormone-positive breast cancer. It describes the evidence from the studies involving the aromatase inhibitors in an upfront, switch and extended setting. It further discusses the mathematical models proposed to determine the optimum timing of initiation. In light of the ongoing research into predictive biomarkers, this review then concentrates on whether future focus should be on more individualized treatment strategies than the optimum timing of aromatase inhibitors.     

‘Simply stunning’ – trastuzumab in HER2-positive breast cancer

Human epidermal growth factor receptor-2 (HER-2)-positive metastatic breast cancer is a more aggressive disease than HER-2-negative metastatic breast cancer. The initial Phase III trial with the HER-2 antibody, trastuzumab, in this cancer suggested that, although trastuzumab was beneficial, cardiac adverse events would prevent it from being widely used. Recently trials suggest that, with close monitoring of left ventricular ejection fraction, trastuzumab can be used concurrently or sequentially with the standard adjuvant treatment of HER-2-positive metastatic breast cancer with good benefit. Therefore, with appropriate regimens, trastuzumab will be able to be used routinely in the treatment of HER-2-positive metastatic breast cancer.     

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.     

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.     

Therapeutic targets in triple negative breast cancer - where are we now?

Triple negative breast cancers, defined by lack of expression of estrogen receptor (ER), progesterone receptor (PR) and epidermal growth factor receptor 2 (Her2/EGFR2/ERBB2), are increasingly gaining attention for its intricate relationship with basal-like and BRCA1-linked breast carcinomas, and its lack of effective tailored therapies. Triple negative breast tumors usually account for 10-20% of all breast cancers in Asian populations, similarly in Caucasian populations (10-23%), but occur at much higher frequencies in individuals of African descent (20-47%). In addition, triple negative breast cancers are usually of high histological grade and are accompanied by aggressive clinical behavior with shorter time to recurrences and death, and preference for metastasis to the brain and lungs. In this report, we would like to review recent patents and the relationship between triple negative and basal-like breast cancers, as well as BRCA1-linked breast carcinomas. Specifically, potential treatment modalities and current innovations that are designed for the predictive and prognostic values of triple negative breast tumors will be discussed.     

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.     

Can cancer centres in New Zealand help the cancer registry generate survival data? A pilot study in prostate cancer

AIMS: One of the current limitations of reports issued by the New Zealand Cancer Registry (NZCR) is that the only measure of the success of treatment is provided by the mortality ratio. A pilot study was therefore carried out to see if collaboration between cancer centres and the NZCR might allow the generation of more meaningful survival data that could be used for the audit of treatment outcome. METHODS: Clinical details of patients seen at the Wellington Cancer Centre (WCC), in whom a diagnosis of prostate cancer was made in 1997, were provided to the NZCR. These details were matched with registration and mortality data held by the NZCR. RESULTS: WCC records identified 82 patients who were diagnosed with prostate cancer in 1997. Of these, the NZCR registered 60 (73%) in 1997, 3 (4%) prior to 1997, and 14 (17%) after 1997. Five patients (6%) were not registered at all. In the cohort of 82 patients, 17 (21%) had subsequently died. Of these, 11 (65%) had been treated with palliative intent, and six (35%) with radical intent. Of those patients treated radically, three had died of prostate cancer and three of other causes. CONCLUSIONS: Cooperation between Cancer Centres and the NZCR would allow the NZCR to generate useful survival data. This could help evaluate the impact on survival of specific treatments and interventions, such as screening programs. Regional variations in outcome could be detected. The exercise is feasible, without compromising patient confidentiality.