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A pilot 'window of opportunity' neoadjuvant study of metformin in localised prostate cancer
A M Joshua1, V E Zannella1, M R Downes2
1Princess Margaret Cancer Centre, Toronto, ON, Canada.
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.
Insights
Neoadjuvant metformin is safe and well-tolerated in prostate cancer patients before surgery. The drug significantly reduced tumor cell proliferation (Ki67) and affected key signaling pathways.
Area of Science:
- Oncology
- Pharmacology
- Metabolic disease
Background:
- Metformin, a respiratory chain complex 1 inhibitor, is used for insulin resistance and has shown pleiotropic effects, including mTOR inhibition via AMPK.
- Pre-clinical and epidemiological studies suggest metformin may influence prostate cancer progression.
- This study investigated the safety and biological effects of neoadjuvant metformin in prostate cancer patients.
Purpose of the Study:
- To assess the safety and tolerability of metformin administered before radical prostatectomy.
- To evaluate the impact of metformin on tumor proliferative (Ki67) and signaling (AMPK-related) markers.
Main Methods:
- A single-arm, 'window of opportunity' study enrolled 24 patients undergoing radical prostatectomy.
- Metformin was administered at doses up to 500 mg three times daily.
- Ki67 index and immunohistochemical markers (P-AMPK, P-ACC, P-4EBP1) were analyzed in paired tumor biopsies and prostatectomy specimens.
Main Results:
- Metformin treatment was well-tolerated, with only three patients experiencing Grade 3/4 toxicities.
- A significant reduction in the Ki67 proliferation index was observed (28-30%, P < 0.005).
- A decrease in P-4EBP1 staining was noted, but no significant changes in P-AMPK or P-ACC levels were found. A trend towards PSA reduction was observed (P=0.08).
Conclusions:
- Neoadjuvant metformin is safe and well-tolerated in men undergoing radical prostatectomy for prostate cancer.
- Metformin demonstrated promising effects on reducing tumor cell proliferation and modulating key signaling pathways.
- Further investigation in larger cohorts is warranted to confirm these findings and explore therapeutic potential.
