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Breast Cancer Research and Treatment

, Volume 135, Issue 3, pp 821–830 | Cite as

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

  • Saroj Niraula
  • Ryan J. O. Dowling
  • Marguerite Ennis
  • Martin C. Chang
  • Susan J. Done
  • Nicky Hood
  • Jaime Escallon
  • Wey Liang Leong
  • David R. McCready
  • Michael Reedijk
  • Vuk Stambolic
  • Pamela J. Goodwin
Clinical Trial

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.

Keywords

Breast cancer Metformin Neoadjuvant Ki67 TUNEL Insulin 

Notes

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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Copyright information

© Springer Science+Business Media, LLC. 2012

Authors and Affiliations

  • Saroj Niraula
    • 1
  • Ryan J. O. Dowling
    • 2
  • Marguerite Ennis
    • 3
  • Martin C. Chang
    • 4
    • 5
  • Susan J. Done
    • 5
    • 6
  • Nicky Hood
    • 7
  • Jaime Escallon
    • 8
    • 9
  • Wey Liang Leong
    • 9
    • 10
  • David R. McCready
    • 8
    • 9
  • Michael Reedijk
    • 9
    • 10
  • Vuk Stambolic
    • 2
  • Pamela J. Goodwin
    • 1
    • 7
  1. 1.Division of Medical Oncology and Hematology, Department of MedicineMount Sinai Hospital and Princess Margaret Hospital, University of TorontoTorontoCanada
  2. 2.Ontario Cancer Institute, University Health NetworkTorontoCanada
  3. 3.Applied StatisticianMarkhamCanada
  4. 4.Department of Pathology and Laboratory MedicineMount Sinai HospitalTorontoCanada
  5. 5.Department of Laboratory Medicine and PathobiologyUniversity of TorontoTorontoCanada
  6. 6.Campbell Family Institute for Breast Cancer Research and Laboratory Medicine ProgramUniversity Health NetworkTorontoCanada
  7. 7.Division of Clinical EpidemiologySamuel Lunenfeld Research Institute, Mount Sinai HospitalTorontoCanada
  8. 8.Department of SurgeryMount Sinai Hospital, University of TorontoTorontoCanada
  9. 9.Department of Surgical OncologyUniversity Health Network, University of TorontoTorontoCanada
  10. 10.Campbell Family Institute for Breast Cancer ResearchPrincess Margaret HospitalTorontoCanada

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