Metformin may reduce the incidence of
breast cancer and enhance response to
neoadjuvant chemotherapy in diabetic women. This trial examined the effects of
metformin on Ki67 and gene expression in primary
breast cancer. Non-diabetic women with operable invasive
breast cancer received pre-operative
metformin. A pilot cohort of eight patients had core biopsy of the
cancer at presentation, a week later (without treatment; internal control), then following
metformin 500-mg o.d. for 1 week increased to 1-g b.d. for a further week continued to surgery. A further 47 patients had core biopsy at diagnosis were randomized to
metformin (the same dose regimen) or no drug, and 2 weeks later had core biopsy at surgery. Ki67 immunohistochemistry, transcriptome analysis on
formalin-fixed
paraffin-embedded cores and serum
insulin determination were performed blinded to treatment. Seven patients (7/32, 21.9%) receiving
metformin withdrew because of gastrointestinal upset. The mean percentage of cells staining for Ki67 fell significantly following
metformin treatment in both the pilot cohort (P = 0.041, paired t-test) and in the
metformin arm (P = 0.027, Wilcoxon rank test) but was unchanged in the internal control or
metformin control arms.
Messenger RNA expression was significantly downregulated by
metformin for PDE3B (
phosphodiesterase 3B, cGMP-inhibited; a critical regulator of cAMP levels that affect activation of
AMP-activated protein kinase, AMPK), confirmed by immunohistochemistry, SSR3, TP53 and CCDC14. By ingenuity pathway analysis, the tumour
necrosis factor receptor 1 (
TNFR1) signaling pathway was most affected by
metformin: TGFB and
MEKK were upregulated and cdc42 downregulated; mTOR and AMPK pathways were also affected. Gene set analysis additionally revealed that p53, BRCA1 and cell cycle pathways also had reduced expression following
metformin. Mean serum
insulin remained stable in patients receiving
metformin but rose in control patients. This trial presents
biomarker evidence for anti-proliferative effects of
metformin in women with
breast cancer and provides support for therapeutic trials of
metformin.