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Clinical Research

A pilot ‘window of opportunity’ neoadjuvant study of metformin in localised prostate cancer

Prostate Cancer and Prostatic Diseases volume 17, pages 252–258 (2014)Cite this article

Subjects

Abstract

Background:

Metformin is an inhibitor of complex 1 in the respiratory chain, and is widely used to reduce insulin resistance. It has also been described to have pleotropic effects including via AMPK on inhibiting the mTOR kinase. Pre-clinical and epidemiological studies suggest an ability to modulate disease evolution in prostate cancer. In this study, we aimed to (i) demonstrate safety and tolerability of neoadjuvant metformin administration and (ii) document changes in proliferative (Ki67) and AMPK-related signalling indices between matching biopsies and prostatectomies

Methods:

Men were treated in a single-arm ‘window of opportunity’ study between their decision to undergo radical prostatectomy and the operation itself. Forty patients were planned but only 24 patients were enrolled owing to slow accrual. Twenty-one patients were evaluable for pathological outcomes and 22 for serum metabolic indices. Metformin was given at doses to 500 mg t.i.d. Ki67 index was calculated using the Aperio-positive pixel count algorithm, whereas immunohistochemical measurements were by consensus H-Score. Comparative statistics were analysed by students t-tests and/or Wilcoxon matched pairs signed rank test.

Results:

Baseline characteristics included median PSA 6 ng ml−1 (3.22–36.11 ng ml−1). Median duration of drug treatment was 41 days (18–81). Treatment was well tolerated with only three patients developing G3/4 toxicities. In a per patient and per tumour analyses, metformin reduced the Ki67 index by relative amounts of 29.5 and 28.6 % (P=0.0064 and P=0.0042) respectively. There was also a significant decrease in P-4EBP1 staining (P<0.001) but no change in P-AMPK or P-ACC. There were no correlations between any metabolic, morphometric or cancer-related serum indices. There was a trend towards PSA reduction (P=0.08). The study is limited by small patient numbers and tumour heterogeneity.

Conclusions:

Neoadjuvant metformin is well tolerated prior to radical prostatectomy. Data to date indicate promising effects on metabolic and tissue proliferation and signalling parameters.

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Acknowledgements

This research was funded in part by the Terry Fox Foundation, Princess Margaret Hospital Foundation and the Jewish General Hospital Foundation. MS was in part supported by the Robert-Bosch Foundation, Stuttgart, Germany, and the IZEPHA Grant, University of Tübingen, Tübingen, Germany

Author information

Author notes

  1. V E Zannella and M R Downes: These authors contributed equally to this paper

Authors and Affiliations

  1. Princess Margaret Cancer Centre, Toronto, ON, Canada

    A M Joshua, V E Zannella, M R Downes, B Bowes, K Hersey, M Koritzinsky, A Evans, T van der Kwast, J Trachtenberg, A Finelli, N Fleshner & J Sweet

  2. Department of Pathology, University Health Network, Toronto, ON, Canada

    M R Downes, A Evans, T van der Kwast & J Sweet

  3. Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany

    M Schwab, U Hofmann, J Trachtenberg & A Finelli

  4. University of Tübingen, Stuttgart, Germany

    M Schwab, U Hofmann, J Trachtenberg & A Finelli

  5. Division of Urology, Department of Surgery, University Health Network, Toronto, ON, Canada

    N Fleshner

  6. Jewish General Hospital, Montreal, QC, Canada

    M Pollak

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  1. A M Joshua
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Correspondence to A M Joshua.

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Joshua, A., Zannella, V., Downes, M. et al. A pilot ‘window of opportunity’ neoadjuvant study of metformin in localised prostate cancer. Prostate Cancer Prostatic Dis 17, 252–258 (2014). https://doi.org/10.1038/pcan.2014.20

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