New treatment modalities and pharmacologic refinements for metatstatic breast cancer

In this thesis the results of clinical studies with new chemotherapeutic agents and pharmacokinetic studies on taxanes in breast cancer patients are reported. In metastatic breast cancer, endocrine and cytotoxic treatment often result in objective tumor responses, associated with relevant relief of symptoms. At present, however, metastatic breast cancer is still considered to be incurable even despite agressive multi-modality treatment options. Chemotherapy for metastatic breast cancer should therefore aim at a maximum of palliation and prolongation of life, at the cost of a minimal of toxicity

Determining the Effects of CD151 and β\u3csub\u3e1\u3c/sub\u3e on Tumor Cell Adhesion and Migration

Previous studies have shown that the upregulation of CD151 and β1 is associated with poor prognosis in many cancers such as breast cancer. Studies have provided evidence that these proteins are associated with the adhesion and migration of tumor cells. In this study, a microfluidic flow chamber was utilized to determine how CD151 and β1 affected the firm and initial adhesion of metastatic breast cancer cells to a planar endothelial monolayer under shear stress. This system mimicked the adhesion of metastatic breast cancer cells to the endothelial cells of the circulatory system. CD151 and β1 increased the firm adhesion of metastatic breast cancer cells onto an endothelial monolayer when subjected to high shear stresses. CD151 and β1 increased the initial adhesion of metastatic breast cancer cells onto an endothelial monolayer. A transwell assay was utilized to determine how CD151 and β1 affected random migration through different matrixes and random transendothelial migration. CD151 and β1 decreased the random migration of metastatic breast cancer cells through matrices. Additionally, background information is provided related to the metastatic cascade, how it can be modeled with microfluidics, and how CD151 and β1 have been known to effect cancer and metastasis

Treating Triple Negative Breast Cancer with Targeted Nano-Therapy

Bone metastasis in breast cancer patients is a prominent problem, with 70% of metastatic breast cancer patients having bone metastasis.[1] The resulting complications are painful and decrease patient survival rate.[1,3] This study is based on the previous lab work of Ross et al., who found that bone metastatic breast cancer cells over-express the integrin αvβ3. Through a series of in vitro experiments, this study sought to investigate the degree to which the single lipid membrane αvβ3-targeted nanoparticles could function as a less toxic and more effective treatment to bone metastatic breast cancer

The Evolving Endocrine Management of Metastatic Breast Cancer

At the conclusion of this presentation the participant should be able to: 1. Recognize the clinical and molecular subtypes of breast cancer. 2. Recognize the standard endocrine therapies for Estrogen-resistant metastatic breast cancer. 3. Recognize and implement novel molecular therapies in Estrogen-resistant metastatic breast cancer. Presentation: 32 minute

Preference-sensitive decisions of patients with metastatic breast cancer: The need for decision support

Because of disease progression and the increasing number of treatment options, patients with metastatic breast cancer face multiple decisions over time. Our aim was to identify the multiple decisions patients with metastatic breast cancer face in order to decide which decision aids will be developed. First, we analyzed the clinical practice guidelines to identify decisions encountered by patients with metastatic breast cancer and healthcare professionals. Furthermore, an online questionnaire for patients, a focus group interview with patients and interviews with healthcare professionals were performed. In addition, we performed a systematic literature research and internet search to identify relevant decision support tools and we assessed their quality. Finally, all results were discussed with a mixed group of eight experts, consisting of researchers, patients and healthcare professionals and a comprehensive advice was given which decision aid to develop. It turned out that patients with metastatic breast cancer and healthcare professionals are confronted with eight major decision points regarding treatment and examinations during the care process. We identified four decision aids. These tools partially overlap with some of the identified decision points. Experts advised to develop a decision aid for patients with metastatic breast cancer that would address all mentioned decision points. We concluded patients with metastatic breast cancer and healthcare professionals will benefit from a personalized decision aid in which all eight major decision points are addressed. This decision aid would help patients and healthcare professionals to explore patients’ personal values and preferences in order to make a well-informed decision

Detection of Tumor Cell-Specific mRNA in the Peripheral Blood of Patients with Breast Cancer-Evaluation of Several Markers with Real-Time Reverse Transcription-PCR

It is widely known that cells from epithelial tumors, e. g., breast cancer, detach from their primary tissue and enter blood circulation. We show that the presence of circulating tumor cells (CTCs) in samples of patients with primary and metastatic breast cancer can be detected with an array of selected tumor-marker-genes by reverse transcription real-time PCR. The focus of the presented work is on detecting differences in gene expression between healthy individuals and adjuvant and metastatic breast cancer patients, not an accurate quantification of these differences. Therefore, total RNA was isolated from blood samples of healthy donors and patients with primary or metastatic breast cancer after enrichment of mononuclear cells by density gradient centrifugation. After reverse transcription real-time PCR was carried out with a set of marker genes (BCSP, CK8, Her2, MGL, CK18, CK19). B2M and GAPDH were used as reference genes. Blood samples from patients with metastatic disease revealed increased cytokine gene levels in comparison to normal blood samples. Detection of a single gene was not sufficient to detect CTCs by reverse transcription real-time PCR. Markers used here were selected based on a recent study detecting cancer cells on different protein levels. The combination of such a marker array leads to higher and more specific discovery rates, predominantly in metastatic patients. Identification of CTCs by PCR methods may lead to better diagnosis and prognosis and could help to choose an adequate therapy

Sequential therapy in metastatic breast cancer: Survival analysis with time dependent covariates

Metastatic breast cancer, a disease with a high mortality rate among women, is a major public health problem in the United States and other developed countries. This study evaluated the effect of certain treatments within the clinical setting during the patients' individual courses of sequential treatments. A database based on clinical data from one practice of the University of Pittsburgh Cancer Institute Breast Cancer Program was used to analyze from data metastatic breast cancer patients receiving sequential therapies. Data from the clinic cohort were available from January 1999 to July 2005.Taxanes, a specific class of chemotherapeutic agents including Taxol® and Taxotere® have been demonstrated to be very effective in tumor control and symptom relief in metastatic breast cancer patients. However, it is unclear whether there is a benefit in survival compared to non-taxane compounds. Therefore, the survival among patients who received taxane-containing regimes versus those who never received taxane-containing regimes as chemotherapeutic agents needs attention.The purpose of this study is to investigate the survival benefit of taxanes, after initiating chemotherapy or hormonal therapy. Hence, survival analyses with time dependent covariates were employed. The results showed that taxane was beneficial for survival in women with metastatic breast cancer. However, the effect strongly depended on the estrogen receptor type. Patients who had metastatic breast cancer with negative estrogen receptors benefited from taxane therapy. In contrary, taxane showed an adverse effect in patients with positive estrogen receptor cancer. The combination of toxic side effects from the drug, patient characteristics, and timeline of taxane intervention might have possibly contributed to this finding.These results will facilitate the development of guidelines for the management of metastatic breast cancer. In the meantime it will be useful to guide clinicians in their decision-making regarding therapeutic regimes for metastatic breast cancer providing physicians and health care professionals with an important tool to improve public health

Trastuzumab and Gemcitabine in Pretreated HER2 Overexpressing Metastatic Breast Cancer Patients: Retrospective Analysis of Our Series

Trastuzumab-based regimes improved clinical outcome in women with overexpressing HER2 metastatic breast cancer, mainly due to the availability of different combination therapies, clinically active and well tolerated. In this study we retrospectively evaluated clinical activity and toxicity of trastuzuamb plus gemcitabine regimen in heavily pretreated HER2 positive metastatic breast cancer patients. Although the observed population was heavily pretreated, the evaluated regimen was notably effective in terms of response rate, time to progression and survival, with very mild toxicity. These data suggest that in over expressing HER2 metastatic breast cancer patients, sequential trastuzumab based chemotherapeutic regimens can achieve good response rate with prolonged TTP in responding patients, even after other target therapy such as lapatinib based combinations

Role of KCNMA1 gene in breast cancer invasion and metastasis to brain

International audienceBACKGROUND: The prognosis for patients with breast tumor metastases to brain is extremely poor. Identification of prognostic molecular markers of the metastatic process is critical for designing therapeutic modalities for reducing the occurrence of metastasis. Although ubiquitously present in most human organs, large-conductance calcium- and voltage-activated potassium channel (BKCa) channels are significantly upregulated in breast cancer cells. In this study we investigated the role of KCNMA1 gene that encodes for the pore-forming alpha-subunit of BKCa channels in breast cancer metastasis and invasion. METHODS: We performed Global exon array to study the expression of KCNMA1 in metastatic breast cancer to brain, compared its expression in primary breast cancer and breast cancers metastatic to other organs, and validated the findings by RT-PCR. Immunohistochemistry was performed to study the expression and localization of BKCa channel protein in primary and metastatic breast cancer tissues and breast cancer cell lines. We performed matrigel invasion, transendothelial migration and membrane potential assays in established lines of normal breast cells (MCF-10A), non-metastatic breast cancer (MCF-7), non-brain metastatic breast cancer cells (MDA-MB-231), and brain-specific metastatic breast cancer cells (MDA-MB-361) to study whether BKCa channel inhibition attenuates breast tumor invasion and metastasis using KCNMA1 knockdown with siRNA and biochemical inhibition with Iberiotoxin (IBTX). RESULTS: The Global exon array and RT-PCR showed higher KCNMA1 expression in metastatic breast cancer in brain compared to metastatic breast cancers in other organs. Our results clearly show that metastatic breast cancer cells exhibit increased BKCa channel activity, leading to greater invasiveness and transendothelial migration, both of which could be attenuated by blocking KCNMA1. CONCLUSION: Determining the relative abundance of BKCa channel expression in breast cancer metastatic to brain and the mechanism of its action in brain metastasis will provide a unique opportunity to identify and differentiate between low grade breast tumors that are at high risk for metastasis from those at low risk for metastasis. This distinction would in turn allow for the appropriate and efficient application of effective treatments while sparing patients with low risk for metastasis from the toxic side effects of chemotherapy

Emerging Insights into Keratin 16 Expression during Metastatic Progression of Breast Cancer.

Keratins are the main identification markers of circulating tumor cells (CTCs); however, whether their deregulation is associated with the metastatic process is largely unknown. Previously we have shown by in silico analysis that keratin 16 (KRT16) mRNA upregulation might be associated with more aggressive cancer. Therefore, in this study, we investigated the biological role and the clinical relevance of K16 in metastatic breast cancer. By performing RT-qPCR, western blot, and immunocytochemistry, we investigated the expression patterns of K16 in metastatic breast cancer cell lines and evaluated the clinical relevance of K16 expression in CTCs of 20 metastatic breast cancer patients. High K16 protein expression was associated with an intermediate mesenchymal phenotype. Functional studies showed that K16 has a regulatory effect on EMT and overexpression of K16 significantly enhanced cell motility (p < 0.001). In metastatic breast cancer patients, 64.7% of the detected CTCs expressed K16, which was associated with shorter relapse-free survival (p = 0.0042). Our findings imply that K16 is a metastasis-associated protein that promotes EMT and acts as a positive regulator of cellular motility. Furthermore, determining K16 status in CTCs provides prognostic information that helps to identify patients whose tumors are more prone to metastasize