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Metformin in early breast cancer: a prospective window of opportunity neoadjuvant study

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Abstract

Metformin may exert anti-cancer effects through indirect (insulin-mediated) or direct (insulin-independent) mechanisms. We report results of a neoadjuvant “window of opportunity” study of metformin in women with operable breast cancer. Newly diagnosed, untreated, non-diabetic breast cancer patients received metformin 500 mg tid after diagnostic core biopsy until definitive surgery. Clinical (weight, symptoms, and quality of life) and blood [fasting serum insulin, glucose, homeostasis model assessment (HOMA), C-reactive protein (CRP), and leptin] attributes were compared pre- and post-metformin as were terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) and Ki67 scores (our primary endpoint) in tumor tissue. Thirty-nine patients completed the study. Mean age was 51 years, and metformin was administered for a median of 18 days (range 13–40) up to the evening prior to surgery. 51 % had T1 cancers, 38 % had positive nodes, 85 % had ER and/or PgR positive tumors, and 13 % had HER2 overexpressing or amplified tumors. Mild, self-limiting nausea, diarrhea, anorexia, and abdominal bloating were present in 50, 50, 41, and 32 % of patients, respectively, but no significant decreases were seen on the EORTC30-QLQ function scales. Body mass index (BMI) (−0.5 kg/m2, p < 0.0001), weight (−1.2 kg, p < 0.0001), and HOMA (−0.21, p = 0.047) decreased significantly while non-significant decreases were seen in insulin (−4.7 pmol/L, p = 0.07), leptin (−1.3 ng/mL, p = 0.15) and CRP (−0.2 mg/L, p = 0.35). Ki67 staining in invasive tumor tissue decreased (from 36.5 to 33.5 %, p = 0.016) and TUNEL staining increased (from 0.56 to 1.05, p = 0.004). Short-term preoperative metformin was well tolerated and resulted in clinical and cellular changes consistent with beneficial anti-cancer effects; evaluation of the clinical relevance of these findings in adequately powered clinical trials using clinical endpoints such as survival is needed.

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Acknowledgments

This research was supported by a Grant from Susan G. Komen for the Cure. Dr. Dowling is supported by a Banting Postdoctoral Fellowship from the Canadian Institutes of Health Research.

Conflict of interest

Dr. Chang acknowledges funding from Hoffmann-LaRoche. The remaining authors declare that they have no conflicts of interest.

Ethical standards

Conduct of this study at Mount Sinai and Princess Margaret Hospitals was performed in compliance with the standards of the Ontario Cancer Research Ethics Board.

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Authors and Affiliations

  1. Division of Medical Oncology and Hematology, Department of Medicine, Mount Sinai Hospital and Princess Margaret Hospital, University of Toronto, 1284-600 University Avenue, Toronto, ON, M5G 1X5, Canada

    Saroj Niraula & Pamela J. Goodwin

  2. Ontario Cancer Institute, University Health Network, Toronto, ON, Canada

    Ryan J. O. Dowling & Vuk Stambolic

  3. Applied Statistician, Markham, ON, Canada

    Marguerite Ennis

  4. Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, ON, Canada

    Martin C. Chang

  5. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada

    Martin C. Chang & Susan J. Done

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

    Susan J. Done

  7. Division of Clinical Epidemiology, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, Canada

    Nicky Hood & Pamela J. Goodwin

  8. Department of Surgery, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada

    Jaime Escallon & David R. McCready

  9. Department of Surgical Oncology, University Health Network, University of Toronto, Toronto, ON, Canada

    Jaime Escallon, Wey Liang Leong, David R. McCready & Michael Reedijk

  10. Campbell Family Institute for Breast Cancer Research, Princess Margaret Hospital, Toronto, ON, Canada

    Wey Liang Leong & Michael Reedijk

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  1. Saroj Niraula
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  2. Ryan J. O. Dowling
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  4. Martin C. Chang
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  5. Susan J. Done
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  6. Nicky Hood
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  12. Pamela J. Goodwin
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Corresponding author

Correspondence to Pamela J. Goodwin.

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Niraula, S., Dowling, R.J.O., Ennis, M. et al. Metformin in early breast cancer: a prospective window of opportunity neoadjuvant study. Breast Cancer Res Treat 135, 821–830 (2012). https://doi.org/10.1007/s10549-012-2223-1

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  • DOI: https://doi.org/10.1007/s10549-012-2223-1

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