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Evidence for biological effects of metformin in operable breast cancer: biomarker analysis in a pre-operative window of opportunity randomized trial

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Abstract

Metformin has therapeutic potential against breast cancer, but the mechanisms of action in vivo remain uncertain. This study examined biomarker effects of metformin in primary breast cancer in a preoperative window of opportunity trial. Non-diabetic women with operable invasive breast cancer were randomized to receive open label pre-operative metformin (500 mg daily for 1 week then 1 g twice daily for a further week) or as controls, not receiving metformin. Patients in both arms had a core biopsy pre-randomisation and again at the time of surgery. Immunohistochemistry for phospho-AMPK (pAMPK), phospho-Akt (pAkt), insulin receptor, cleaved caspase-3, and Ki67 was performed on formalin-fixed paraffin-embedded cores, scored blinded to treatment and analysed by paired t test. In metformin-treated patients, significant up-regulation of pAMPK (paired t test, p = 0.04) and down-regulation of pAkt (paired t test, p = 0.043) were demonstrated compared to the control group. Insulin receptor and serum insulin remained similar following metformin treatment compared with a rise in insulin receptor and insulin in controls. Significant falls in Ki67 and cleaved caspase-3 (paired t test, p = 0.044) were seen in the metformin-treated patients but not in the control group. Changes were independent of body mass index. These biomarker data suggest mechanisms for metformin action in vivo in breast cancer patients via up-regulation of tumor pAMPK, down-regulation of pAkt, and suppression of insulin responses reflecting cytostatic rather than cytotoxic mechanisms.

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Acknowledgments

The authors are particularly grateful to the patients who were willing to give written informed consent in support of this clinical trial and thank the Tayside Multidisciplinary breast team (Dougal Adamson, Douglas Brown, Emad Elseedawy, Andrew Lee, Denis Mclean, Marta Reis, and Valerie Walker) for supporting patient recruitment and facilitating accrual of clinical materials and clinical data to this study. The trial was conducted through funding from Breast Cancer Research (Scotland), Tenovus Tayside, The Anonymous Trust and Cancer Research-UK.

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Authors and Affiliations

  1. Academic Department of Surgical Oncology, University of Sheffield, Sheffield, UK

    Sirwan M. Hadad

  2. Dundee Cancer Centre, Dundee, UK

    Philip Coates, Lee B. Jordan & Colin A. Purdie

  3. Ontario Cancer Institute, University Health Network, Toronto, Canada

    Ryan J. O. Dowling & Vuk Stambolic

  4. Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, New York, USA

    Martin C. Chang

  5. Campbell Family Institute for Breast Cancer Research and Laboratory Medicine Program, University Health Network, Toronto, Canada

    Susan J. Done

  6. Princess Margaret Hospital and Mount Sinai Hospital, Toronto, ON, Canada

    Pamela J. Goodwin

  7. Department of Breast Medical Oncology, Houston, USA

    Stacy Moulder-Thompson

  8. Department of Surgical Oncology, FCT7.6092, M.D. Anderson Cancer Center, 1400 Pressler Street, Houston, TX, 77030, USA

    Alastair M. Thompson

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  1. Sirwan M. Hadad
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Correspondence to Alastair M. Thompson.

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Hadad, S.M., Coates, P., Jordan, L.B. et al. Evidence for biological effects of metformin in operable breast cancer: biomarker analysis in a pre-operative window of opportunity randomized trial. Breast Cancer Res Treat 150, 149–155 (2015). https://doi.org/10.1007/s10549-015-3307-5

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  • DOI: https://doi.org/10.1007/s10549-015-3307-5

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