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  • br Interpretation We demonstrate that


    Interpretation: We demonstrate that BCF, as a single agent or in combination with radiation, is a novel treatment approach to the treatment of 36913-39-0 metastases. This paradigm shifting modality warrants further clinical trials for this unmet medical need.
    © 2019 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://
    Corresponding author at: Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, Unites States of America
    E-mail address: [email protected] (K. Watabe). 
    1. Introduction
    Brain metastasis is an emerging problem in oncology and there are N170,000 new cases in the US every year [1,2]. Breast cancer is the sec-ond leading cause of brain metastasis, and approximately 5–15% of pa-tients with metastatic breast cancer will develop symptomatic brain metastasis [3–5]. Radiation therapy with stereotactic radiosurgery
    Research in context
    Evidence before this story
    Our group has previously identified amplitude modulated radiofre-quency electromagnetic fields (AM RF EMF) in patients diagnosed with multiple cancers. In a pilot study, we administered these fre-quencies to cancer patients in compassionate clinical trials, and observed both complete and partial responses in some patients with breast and hepatocellular cancer metastatic to multiple or-gans, thus demonstrating systemic antitumour effects of AM RF EMF. However, the underlying mechanism behind the response was unknown.
    Added value of this study
    We tested the hypothesis that this approach is effective in the treatment of brain metastasis of breast cancer patients. We exam-ined the antitumour effect of breast cancer-specific AM RF EMF (BCF) in brain metastatic disease at the same Specific Absorption Rate (SAR) levels as those delivered to the patients. BCF sup-pressed the growth of two brain-metastatic breast cancer cell lines and two brain-metastatic PDXs. Additionally, BCF had long-lasting antitumour activity in a patient with breast cancer brain me-tastasis. We also discovered that combining radiation treatment with BCF resulted in increased treatment efficacy, suggesting that this novel treatment approach could enhance the effect of ra-diation therapy. We then studied the mechanism of action and found that BCF triggered calcium influx from the extracellular to the intracellular compartments through CaV3.2 voltage-gated cal-cium channels (CACNA1H), increasing calcium mediated Calmodulin-activated kinase II (CAMKII) dependent activation of p38 MAPK pathway leading to cell growth inhibition. Importantly, BCF suppressed the cancer stem cell properties of brain metastatic cells by decreasing HMGA2 gene expression. Activation of CAMKII by BCF phosphorylated and primed β-catenin for degrada-tion thereby decreasing HMGA2 expression and cancer stem cell (CSC) population. Additionally, BCF reduced the level of miR-1246 in exosomes secreted by brain metastatic cells, which re-sulted in decreased angiogenesis in brain microenvironment.
    Implications of all the available evidence
    Our results demonstrate that BCF is a novel targeted treatment ap-proach for breast cancer brain metastasis with minimum toxicity. Considering the efficacy and established safety profile of BCF, our results have strong implication in improving survival and qual-ity of life of patients with brain metastasis.
    and/or whole brain radiation therapy are considered effective treat-ments; however, most patients eventually experience disease recur-rence [6]. Radiation therapy also often causes cognitive side effects which significantly dampen the quality of life [7]. Therefore, there is an unmet need for a novel therapeutic approach that can increase sur-vival outcome of patients with brain metastasis.
    The biological activity of athermal electromagnetic fields in cancer has been extensively studied and there are many controversial and con-tradictory findings [8,9]. Using non-invasive methods assessing changes in pulse pressure, we have previously reported the identification of tumour-specific modulation frequencies in patients with various forms of cancer [10]. We sought to determine if administration of RF EMF sinusoidally amplitude-modulated at tumour-specific frequencies by means of an emitting antenna placed in the patient's mouth could af-fect tumour growth. Such an approach results in a whole body averaged specific absorption rate (SAR) of 1.35 mW/kg, which is more than one 
    hundred fold lower than the SAR generated by cellphones and does not result in heating of any body part and is well below the International Standards for Safety Exposure [11]. In our feasibility study treatment of breast cancer patients with RF EMF, which were amplitude-modulated at breast cancer-specific frequencies, resulted in both complete and par-tial responses in patients with stage IV metastatic disease. Objective tu-mour shrinkage was documented in bone and adrenal gland, thus demonstrating systemic antitumour effects of BCF [10]. Importantly, this treatment has been shown to be minimally invasive, low risk, well tolerated and yields tumour shrinkage in patients with metastatic breast cancer. In July 2018, the TheraBionic P1 medical device emitting hepatocellular carcinoma-specific AM RF EMF received European regu-latory approval as a class IIa, low risk systemic treatment for patients with advanced hepatocellular carcinoma who have failed or are intoler-ant to first- and second-line therapies [12]. Additional dosimetry studies have recently demonstrated that AM RF EMF are delivered from head to toe in patients receiving treatment administered by means of an an-tenna placed in their mouth with similar SAR in the brain and the liver [13]. Therefore, AM RF EMF could be ideal for treating brain metastatic disease which has limited treatment options available. In this study, we examined the effect of BCF and its mechanistic action in treatment of brain metastasis of breast cancer.