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      Phase II clinical study of eribulin monotherapy in Japanese patients with metastatic breast cancer who had well-defined taxane resistance

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          Abstract

          No clinical evidence on the efficacy and safety of eribulin monotherapy has been obtained by a prospective clinical study in patients with metastatic breast cancer (MBC) who had well-defined taxane resistance. The present Phase II, multicenter, single-arm, open-label study aimed to obtain the evidence. Japanese female patients, aged 33–74 years who had the metastasis of taxane-resistant and histopathologically confirmed breast cancer, received eribulin mesylate 1.4 mg/m 2 (equivalent to eribulin 1.23 mg/m 2 [expressed as free base]) as a 2- to 5-min intravenous infusion on days 1 and 8 of each 21-day cycle. The primary endpoint was the clinical benefit rate (CBR) [complete response (CR), partial response (PR), and long-term stable disease (LSD) ≥24 weeks]. A total of 51 patients underwent chemotherapy cycles (median 4; range 1–42 cycles). The CBR was 39.2 % (CR 2.0 %; PR 23.5 %; and LSD 13.7 %), and the rate of progressive disease was 49.0 %. The median progression-free survival and the median overall survival were 3.6 months [95 % confidence interval (CI) 2.6–4.6 months] and 11.7 months (95 % CI 9.2–14.2 months), respectively. Grade 3 or greater adverse events were leukopenia (23.5 %), neutropenia (35.3 %), anemia (5.9 %), and febrile neutropenia (7.8 %). The incidences of grade 3 and 4 peripheral sensory neuropathy were 2.0 and 0 %, respectively. Eribulin showed a clinically manageable tolerability profile by dose adjustments or symptomatic treatment. Eribulin was effective and well tolerated in heavily pretreated patients with MBC who had well-defined taxane resistance, thus providing a potential therapeutic option in the clinical settings.

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          Eribulin mesilate suppresses experimental metastasis of breast cancer cells by reversing phenotype from epithelial–mesenchymal transition (EMT) to mesenchymal–epithelial transition (MET) states

          Background: Eribulin mesilate (eribulin), a non-taxane microtubule dynamics inhibitor, has shown trends towards greater overall survival (OS) compared with progression-free survival in late-stage metastatic breast cancer patients in the clinic. This finding suggests that eribulin may have additional, previously unrecognised antitumour mechanisms beyond its established antimitotic activity. To investigate this possibility, eribulin's effects on the balance between epithelial–mesenchymal transition (EMT) and mesenchymal–epithelial transition (MET) in human breast cancer cells were investigated. Methods: Triple negative breast cancer (TNBC) cells, which are oestrogen receptor (ER−)/progesterone receptor (PR−)/human epithelial growth receptor 2 (HER2−) and have a mesenchymal phenotype, were treated with eribulin for 7 days, followed by measurement of EMT-related gene and protein expression changes in the surviving cells by quantitative real-time PCR (qPCR) and immunoblot, respectively. In addition, proliferation, migration, and invasion assays were also conducted in eribulin-treated cells. To investigate the effects of eribulin on TGF-β/Smad signalling, the phosphorylation status of Smad proteins was analysed. In vivo, the EMT/MET status of TNBC xenografts in mice treated with eribulin was examined by qPCR, immunoblot, and immunohistochemical analysis. Finally, an experimental lung metastasis model was utilised to gauge the metastatic activity of eribulin-treated TNBC in the in vivo setting. Results: Treatment of TNBC cells with eribulin in vitro led to morphological changes consistent with transition from a mesenchymal to an epithelial phenotype. Expression analyses of EMT markers showed that eribulin treatment led to decreased expression of several mesenchymal marker genes, together with increased expression of several epithelial markers. In the TGF-β induced EMT model, eribulin treatment reversed EMT, coincident with inhibition of Smad2 and Smad3 phosphorylation. Consistent with these changes, TNBC cells treated with eribulin for 7 days showed decreased capacity for in vitro migration and invasiveness. In in vivo xenograft models, eribulin treatment reversed EMT and induced MET as assessed by qPCR, immunoblot, and immunohistochemical analyses of epithelial and mesenchymal marker proteins. Finally, surviving TNBC cells pretreated in vitro with eribulin for 7 days led to decreased numbers of lung metastasis when assessed in an in vivo experimental metastasis model. Conclusions: Eribulin exerted significant effects on EMT/MET-related pathway components in human breast cancer cells in vitro and in vivo, consistent with a phenotypic switch from mesenchymal to epithelial states, and corresponding to observed decreases in migration and invasiveness in vitro as well as experimental metastasis in vivo. These preclinical findings may provide a plausible scientific basis for clinical observations of prolonged OS by suppression of further spread of metastasis in breast cancer patients treated with eribulin.
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            Mesenchymal-epithelial transition (MET) as a mechanism for metastatic colonisation in breast cancer.

            As yet, there is no cure for metastatic breast cancer. Historically, considerable research effort has been concentrated on understanding the processes of metastasis, how a primary tumour locally invades and systemically disseminates using the phenotypic switching mechanism of epithelial to mesenchymal transition (EMT); however, much less is understood about how metastases are then formed. Breast cancer metastases often look (and may even function) as 'normal' breast tissue, a bizarre observation against the backdrop of the organ structure of the lung, liver, bone or brain. Mesenchymal to epithelial transition (MET), the opposite of EMT, has been proposed as a mechanism for establishment of the metastatic neoplasm, leading to questions such as: Can MET be clearly demonstrated in vivo? What factors cause this phenotypic switch within the cancer cell? Are these signals/factors derived from the metastatic site (soil) or expressed by the cancer cells themselves (seed)? How do the cancer cells then grow into a detectable secondary tumour and further disseminate? And finally--Can we design and develop therapies that may combat this dissemination switch? This review aims to address these important questions by evaluating long-standing paradigms and novel emerging concepts in the field of epithelial mesencyhmal plasticity.
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              Locally recurrent or metastatic breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.

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                Author and article information

                Contributors
                +81-48-722-1111 , ino.bad.ken@gmail.com
                Journal
                Breast Cancer Res Treat
                Breast Cancer Res. Treat
                Breast Cancer Research and Treatment
                Springer US (New York )
                0167-6806
                1573-7217
                28 April 2016
                28 April 2016
                2016
                : 157
                : 295-305
                Affiliations
                [ ]Division of Breast Oncology, Saitama Cancer Center, 780 Komuro, Ina-machi, Kita-adachi-gun, Saitama, 362-0806 Japan
                [ ]Department of Breast Surgery, Saitama Red Cross Hospital, Saitama, Japan
                [ ]Department of Breast Unit, Toda Central General Hospital, Saitama, Japan
                [ ]Department of Breast Surgery, Kasukabe Municipal Hospital, Saitama, Japan
                [ ]Department of Surgery, Sekishindo Hospital, Saitama, Japan
                [ ]Division of Surgery, JCHO Saitama Medical Center, Saitama, Japan
                [ ]Breast Center, Dokkyo Medical University Koshigaya Hospital, Saitama, Japan
                [ ]Breast Center, Mitsui Hospital, Saitama, Japan
                [ ]Shintoshin Ladies’ Mammo Clinic, Saitama, Japan
                [ ]Department of Pathology, Saitama Cancer Center, Saitama, Japan
                Article
                3808
                10.1007/s10549-016-3808-x
                4875050
                27125669
                d58881cf-0546-4111-85c7-78dbb34f0696
                © The Author(s) 2016

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                History
                : 23 March 2016
                : 19 April 2016
                Funding
                Funded by: National Cancer Center Research and Development Fund
                Award ID: 23-A-16, 23-A-17, 26-A-4
                Award Recipient :
                Funded by: Saitama Breast Cancer Clinical Study Group
                Award ID: SBCCSG24
                Award Recipient :
                Funded by: Research for Innovative Treatment of Cancer from the Ministry of Health, Labour and Welfare
                Award ID: H26-applied-general-043,046
                Award Recipient :
                Funded by: Japan Agency for Medical Research and Development
                Award ID: 15ck0106046h0002, 15ck0106049h0002
                Award Recipient :
                Funded by: Eisai Co., Ltd.
                Categories
                Clinical Trial
                Custom metadata
                © Springer Science+Business Media New York 2016

                Oncology & Radiotherapy
                eribulin mesylate,metastatic breast cancer,taxane resistance,estrogen receptor,human epidermal growth factor receptor 2-negative,triple-negative

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