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Special Issue "Prevention and Treatment of Bone Metastases from Breast Cancer"

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A special issue of Journal of Clinical Medicine (ISSN 2077-0383).

Deadline for manuscript submissions: closed (31 July 2013)

Special Issue Editor

Guest Editor
Prof. Dr. Robert Coleman (Website)

Department of Oncology, Cancer Clinical Trials Centre, Academic Unit of Clinical Oncology, Broomcross Building, Weston Park Hospital, University of Sheffield, Sheffield, S10 2SJ, UK
Fax: +44 114 226 5364
Interests: cancer induced bone disease especially with relevance to breast cancer; the development of bone targeted agents in oncology, evaluation of bone markers in oncology to aid drug development and provide both prognostic and predictive information in the management of metastatic bone disease, and the assessment of adverse effects of cancer treatments on bone health and evaluation of various treatment strategies

Special Issue Information

Dear Colleagues,

Bone metastases are common in advanced breast cancer and cause considerable morbidity. They result from the interactions between cancer cells in the bone marrow microenvironment, haematopoietic stem cells and normal bone cells. Bone-targeted treatments may modify the course of the disease via inhibitory effects on this “vicious cycle” of growth factor and cytokine signalling between tumour and bone cells within the bone marrow micro-environment. Improvements in both disease free and overall survival in women with early breast cancer have been demonstrated with oral clodronate and in several large randomised adjuvant trials of zoledronic acid. The evidence for this is particularly strong in patients with low levels of reproductive hormones including premenopausal women receiving ovarian suppression therapy and those who have passed through menopause at the time of diagnosis. Bone-targeted agents, including bisphosphonates and denosumab, are an important component of management in advanced malignancy. Combined with systemic cancer therapy, effective symptom control and appropriate surgical and radiological interventions, modern multi-disciplinary care has transformed the care of patients with metastatic bone disease.

These reviews will cover the following important topics spanning clinical and translational cancer medicine:

  • Mechanisms of metastasis
  • Adjuvant therapy to prevent bone metastases
  • Bone targeted treatments for the management of bone metastases
  • Radiotherapy and radioisotopes for the treatment of bone metastases
  • Imaging for diagnosis and monitoring of bone metastases

Prof. Dr. Robert Coleman
Guest Editor

Submission

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. Papers will be published continuously (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are refereed through a peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Journal of Clinical Medicine is an international peer-reviewed Open Access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 300 CHF (Swiss Francs). English correction and/or formatting fees of 250 CHF (Swiss Francs) will be charged in certain cases for those articles accepted for publication that require extensive additional formatting and/or English corrections.

Keywords

  • breast cancer
  • bone metastases
  • bisphosphonates
  • RANK ligand
  • denosumab
  • adjuvant therapy
  • treatment induced bone loss
  • vitamin D

Published Papers (9 papers)

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Research

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Open AccessArticle Can Zoledronic Acid be Beneficial for Promoting Tumor Response in Breast Cancer Patients Treated with Neoadjuvant Chemotherapy?
J. Clin. Med. 2013, 2(4), 188-200; doi:10.3390/jcm2040188
Received: 16 August 2013 / Revised: 5 September 2013 / Accepted: 11 September 2013 / Published: 16 October 2013
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Abstract
The antitumor effect of bisphosphonates (BPs) is under increasing scrutiny. Preclinical and clinical evidence has shown that BPs might sensitize breast tumors to chemotherapy. Here, we present a review of current preclinical and clinical evidence for antitumor effects of BPs, and evaluate [...] Read more.
The antitumor effect of bisphosphonates (BPs) is under increasing scrutiny. Preclinical and clinical evidence has shown that BPs might sensitize breast tumors to chemotherapy. Here, we present a review of current preclinical and clinical evidence for antitumor effects of BPs, and evaluate how BPs might play a role in neoadjuvant treatment of women with breast cancer. Full article
(This article belongs to the Special Issue Prevention and Treatment of Bone Metastases from Breast Cancer)
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Review

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Open AccessReview Prevention of Bone Metastases in Breast Cancer Patients. Therapeutic Perspectives
J. Clin. Med. 2014, 3(2), 521-536; doi:10.3390/jcm3020521
Received: 2 February 2014 / Revised: 3 March 2014 / Accepted: 14 March 2014 / Published: 9 May 2014
PDF Full-text (237 KB) | HTML Full-text | XML Full-text
Abstract
One in four breast cancer patients is at risk of developing bone metastases in her life time. The early prevention of bone metastases is a crucial challenge. It has been suggested that the use of zoledronic acid (ZOL) in the adjuvant setting [...] Read more.
One in four breast cancer patients is at risk of developing bone metastases in her life time. The early prevention of bone metastases is a crucial challenge. It has been suggested that the use of zoledronic acid (ZOL) in the adjuvant setting may reduce the persistence of disseminated tumor cells and thereby might improve outcome, specifically in a population of patients with a low estrogen microenvironment. More recently, the results of a large meta-analysis from 41 randomized trials comparing a bisphosphonate (BP) to placebo or to an open control have been presented at the 2013 San Antonio Breast Cancer Meeting. Data on 17,016 patients confirm that adjuvant BPs, irrespective of the type of treatment or the treatment schedule and formulation (oral or intra-venously (IV)), significantly reduced bone recurrences and improved breast cancer survival in postmenopausal women. No advantage was seen in premenopausal women. BPs are soon likely to become integrated into standard practice. Published data on the mechanisms involved in tumor cell seeding from the primary site, in homing to bone tissues and in the reactivation of dormant tumor cells will be reviewed; these might offer new ideas for innovative combination strategies. Full article
(This article belongs to the Special Issue Prevention and Treatment of Bone Metastases from Breast Cancer)
Open AccessReview Treatment and Prevention of Bone Metastases from Breast Cancer: A Comprehensive Review of Evidence for Clinical Practice
J. Clin. Med. 2014, 3(1), 1-24; doi:10.3390/jcm3010001
Received: 9 November 2013 / Revised: 11 December 2013 / Accepted: 16 December 2013 / Published: 9 January 2014
Cited by 2 | PDF Full-text (732 KB) | HTML Full-text | XML Full-text
Abstract
Bone is the most common site of metastasis from breast cancer. Bone metastases from breast cancer are associated with skeletal-related events (SREs) including pathological fractures, spinal cord compression, surgery and radiotherapy to bone, as well as bone pain and hypercalcemia, leading to [...] Read more.
Bone is the most common site of metastasis from breast cancer. Bone metastases from breast cancer are associated with skeletal-related events (SREs) including pathological fractures, spinal cord compression, surgery and radiotherapy to bone, as well as bone pain and hypercalcemia, leading to impaired mobility and reduced quality of life. Greater understanding of the pathophysiology of bone metastases has led to the discovery and clinical utility of bone-targeted agents such as bisphosphonates and the receptor activator of nuclear factor kappa-B ligand (RANK-L) antibody, denosumab. Both are now a routine part of the treatment of breast cancer bone metastases to reduce SREs. With regards to prevention, there is no evidence that oral bisphosphonates can prevent bone metastases in advanced breast cancer without skeletal involvement. Several phase III clinical trials have evaluated bisphosphonates as adjuvant therapy in early breast cancer to prevent bone metastases. The current published data do not support the routine use of bisphosphonates in unselected patients with early breast cancer for metastasis prevention. However, significant benefit of adjuvant bisphosphonates has been consistently observed in the postmenopausal or ovarian suppression subgroup across multiple clinical trials, which raises the hypothesis that its greatest anti-tumor effect is in a low estrogen microenvironment. An individual patient data meta-analysis will be required to confirm survival benefit in this setting. This review summarizes the key evidence for current clinical practice and future directions. Full article
(This article belongs to the Special Issue Prevention and Treatment of Bone Metastases from Breast Cancer)
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Open AccessReview Bone Health in Patients with Breast Cancer: Recommendations from an Evidence-Based Canadian Guideline
J. Clin. Med. 2013, 2(4), 283-301; doi:10.3390/jcm2040283
Received: 9 November 2013 / Revised: 26 November 2013 / Accepted: 28 November 2013 / Published: 17 December 2013
Cited by 1 | PDF Full-text (227 KB) | HTML Full-text | XML Full-text
Abstract
Bone loss is common in patients with breast cancer. Bone modifying agents (BMAs), such as bisphosphonates and denosumab, have been shown to reverse or stabilize bone loss and may be useful in the primary and metastatic settings. The purpose of this review [...] Read more.
Bone loss is common in patients with breast cancer. Bone modifying agents (BMAs), such as bisphosphonates and denosumab, have been shown to reverse or stabilize bone loss and may be useful in the primary and metastatic settings. The purpose of this review is to provide clear evidence-based strategies for the management of bone loss and its symptoms in breast cancer. A systematic review of clinical trials and meta-analyses published between 1996 and 2012 was conducted of MEDLINE and EMBASE. Reference lists were hand-searched for additional publications. Recommendations were developed based on the best available evidence. Zoledronate, pamidronate, clodronate, and denosumab are recommended for metastatic breast cancer patients; however, no one agent can be recommended over another. Zoledronate or any oral bisphosphonate and denosumab should be considered in primary breast cancer patients who are postmenopausal on aromatase inhibitor therapy and have a high risk of fracture and/or a low bone mineral density and in premenopausal primary breast cancer patients who become amenorrheic after therapy. No one agent can be recommended over another. BMAs are not currently recommended as adjuvant therapy in primary breast cancer for the purpose of improving survival, although a major Early Breast Cancer Cooperative Trialists’ Group meta-analysis is underway which may impact future practice. Adverse events can be managed with appropriate supportive care. Full article
(This article belongs to the Special Issue Prevention and Treatment of Bone Metastases from Breast Cancer)
Open AccessReview The Roles of Epithelial-to-Mesenchymal Transition (EMT) and Mesenchymal-to-Epithelial Transition (MET) in Breast Cancer Bone Metastasis: Potential Targets for Prevention and Treatment
J. Clin. Med. 2013, 2(4), 264-282; doi:10.3390/jcm2040264
Received: 20 September 2013 / Revised: 25 October 2013 / Accepted: 8 November 2013 / Published: 22 November 2013
Cited by 4 | PDF Full-text (361 KB) | HTML Full-text | XML Full-text
Abstract
Many studies have revealed molecular connections between breast and bone. Genes, important in the control of bone remodeling, such as receptor activator of nuclear kappa (RANK), receptor activator of nuclear kappa ligand (RANKL), vitamin D, bone sialoprotein (BSP), osteopontin (OPN), and calcitonin, [...] Read more.
Many studies have revealed molecular connections between breast and bone. Genes, important in the control of bone remodeling, such as receptor activator of nuclear kappa (RANK), receptor activator of nuclear kappa ligand (RANKL), vitamin D, bone sialoprotein (BSP), osteopontin (OPN), and calcitonin, are expressed in breast cancer and lactating breast. Epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) effectors play critical roles during embryonic development, postnatal growth, and epithelial homeostasis, but also are involved in a number of pathological conditions, including wound repair, fibrosis, inflammation, as well as cancer progression and bone metastasis. Transforming growth factor β (TGFβ), insulin-like growth factor I & II (IGF I & II), platelet-derived growth factor (PDGF), parathyroid hormone-related protein (PTH(rP)), vascular endothelial growth factor (VEGF), epithelial growth factors II/I (ErbB/EGF), interleukin 6 (IL-6), IL-8, IL-11, IL-1, integrin αvβ3, matrix metalloproteinases (MMPs), catepsin K, hypoxia, notch, Wnt, bone morphogenetic proteins (BMP), and hedgehog signaling pathways are important EMT and MET effectors identified in the bone microenviroment facilitating bone metastasis formation. Recently, Runx2, an essential transcription factor in the regulation of mesenchymal cell differentiation into the osteoblast lineage and proper bone development, is also well-recognized for its expression in breast cancer cells promoting osteolytic bone metastasis. Understanding the precise mechanisms of EMT and MET in the pathogenesis of breast cancer bone metastasis can inform the direction of therapeutic intervention and possibly prevention. Full article
(This article belongs to the Special Issue Prevention and Treatment of Bone Metastases from Breast Cancer)
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Open AccessReview Bone Targeted Therapies for Bone Metastasis in Breast Cancer
J. Clin. Med. 2013, 2(4), 176-187; doi:10.3390/jcm2040176
Received: 18 July 2013 / Revised: 7 August 2013 / Accepted: 10 September 2013 / Published: 14 October 2013
Cited by 1 | PDF Full-text (220 KB) | HTML Full-text | XML Full-text
Abstract
Cancer metastasis to the bone develops commonly in patients with various malignancies, and is a major cause of morbidity and diminished quality of life in many affected patients. Emerging treatments for metastatic bone disease have arisen from advances in our understanding of [...] Read more.
Cancer metastasis to the bone develops commonly in patients with various malignancies, and is a major cause of morbidity and diminished quality of life in many affected patients. Emerging treatments for metastatic bone disease have arisen from advances in our understanding of the unique cellular and molecular mechanisms that contribute to the bone metastasis. The tendency of cancer cells to metastasize to bone is probably the end result of many factors including vascular pathways, the highly vascular nature of the bone marrow (which increases the probability that cancer cells will be deposited in bone marrow capillaries), and molecular characteristics of the cancer cells that allow them to adapt to the bone marrow microenvironment. The goals of treating osseous metastases are manifold. Proper treatment can lead to significant improvements in pain control and function, and maintain skeletal integrity. The treatment plan requires a multidisciplinary approach. Widespread metastatic disease necessitates systemic therapy, while a localized problem is best managed with surgery, external beam radiotherapy, or both. Patients with bone metastasis can have prolonged survival, and proper management can have a significant impact on their quality of life. We will review the factors in this article that are promising molecular bone-targeted therapies or will be likely targets for future therapeutic intervention to restore bone remodeling and suppress tumor growth. Full article
(This article belongs to the Special Issue Prevention and Treatment of Bone Metastases from Breast Cancer)
Open AccessReview Mechanisms of Metastatic Tumor Dormancy
J. Clin. Med. 2013, 2(3), 136-150; doi:10.3390/jcm2030136
Received: 26 July 2013 / Revised: 20 August 2013 / Accepted: 10 September 2013 / Published: 23 September 2013
Cited by 2 | PDF Full-text (322 KB) | HTML Full-text | XML Full-text
Abstract
Tumor metastasis can occur years after an apparent cure due to a phenomenon known as metastatic tumor dormancy; in which tumor masses or individual tumor cells are growth restricted for extended periods of time. This period of dormancy is induced and maintained [...] Read more.
Tumor metastasis can occur years after an apparent cure due to a phenomenon known as metastatic tumor dormancy; in which tumor masses or individual tumor cells are growth restricted for extended periods of time. This period of dormancy is induced and maintained by several mechanisms, including: (1) Tumor microenvironment factors such as cytokine expression, immunosurveillance and angiogenesis; (2) Metastasis suppressor gene activity; and (3) Cancer therapeutics. Disseminated tumor cells (DTC) are the key cells that result in dormant tumors. However, many challenges exist towards isolating DTCs for mechanistic studies. The main DTC that may represent the dormant cell is the cancer stem cells (CSC) as they have a slow proliferation rate. In addition to limited knowledge regarding induction of tumor dormancy, there are large gaps in knowledge regarding how tumors escape from dormancy. Emerging research into cancer stem cells, immunotherapy, and metastasis suppressor genes, may lead to new approaches for targeted anti-metastatic therapy to prevent dormancy escape. Overall, an enhanced understanding of tumor dormancy is critical for better targeting and treatment of patients to prevent cancer recurrence. Full article
(This article belongs to the Special Issue Prevention and Treatment of Bone Metastases from Breast Cancer)
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Open AccessReview Where Do Bone-Targeted Agents RANK in Breast Cancer Treatment?
J. Clin. Med. 2013, 2(3), 89-102; doi:10.3390/jcm2030089
Received: 12 June 2013 / Revised: 22 July 2013 / Accepted: 25 July 2013 / Published: 28 August 2013
PDF Full-text (567 KB) | HTML Full-text | XML Full-text
Abstract
Breast cancer cells preferentially metastasise to the skeleton, owing, in part, to the fertile environment provided by bone. Increased bone turnover releases growth factors that promote tumour cell growth. In turn, tumour cells release factors that stimulate further bone turnover, resulting in [...] Read more.
Breast cancer cells preferentially metastasise to the skeleton, owing, in part, to the fertile environment provided by bone. Increased bone turnover releases growth factors that promote tumour cell growth. In turn, tumour cells release factors that stimulate further bone turnover, resulting in a vicious cycle of metastasis growth and bone destruction. The RANK-RANK ligand (RANKL) pathway plays a key role in this cycle, and inhibition of RANKL using the fully-human monoclonal antibody denosumab, has demonstrated efficacy in delaying skeletal complications associated with bone metastases in three phase 3 trials. Preclinical studies suggest that the RANKL pathway also plays a role in breast cancer tumourigenesis and migration to bone. In a subgroup analysis of the negative Adjuvant Zoledronic Acid to Reduce Recurrence (AZURE) trial, the bisphosphonate zoledronic acid showed potential for improving survival in patients who were postmenopausal; however, a prospective study in this patient population is required to validate this observation. Ongoing trials are examining whether adjuvant blockade of the RANKL pathway using denosumab can prevent disease recurrence in patients with high-risk breast cancer. These are building on analogous studies that have shown that denosumab improves bone metastasis-free survival in prostate cancer and suggested that it confers an overall survival benefit in non-small-cell lung cancer. Full article
(This article belongs to the Special Issue Prevention and Treatment of Bone Metastases from Breast Cancer)
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Open AccessReview Bone-Targeted Agents for the Management of Breast Cancer Patients with Bone Metastases
J. Clin. Med. 2013, 2(3), 67-88; doi:10.3390/jcm2030067
Received: 24 June 2013 / Revised: 25 July 2013 / Accepted: 29 July 2013 / Published: 19 August 2013
Cited by 3 | PDF Full-text (239 KB) | HTML Full-text | XML Full-text
Abstract
Despite advances in adjuvant therapy for breast cancer, bone remains the most common site of recurrence. The goal of therapy for these patients is palliative and focused on maximizing the duration and quality of their life, while concurrently minimizing any disease or [...] Read more.
Despite advances in adjuvant therapy for breast cancer, bone remains the most common site of recurrence. The goal of therapy for these patients is palliative and focused on maximizing the duration and quality of their life, while concurrently minimizing any disease or treatment-related complications. Bone metastases predispose patients to reduced survival, pain, impaired quality of life and the development of skeletal-related events. With an increased understanding of the pathophysiology of bone metastasis, effective treatments for their management have evolved and are now in widespread clinical use. This article will discuss the pathogenesis of bone metastases and review the key clinical evidence for the efficacy and safety of currently available systemic bone-targeted therapies in breast cancer patients with an emphasis on bisphosphonates and the receptor activator of nuclear factor kappa B ligand (RANKL) inhibitors. We will also discuss novel strategies and therapies currently in development. Full article
(This article belongs to the Special Issue Prevention and Treatment of Bone Metastases from Breast Cancer)

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