Background: Metformin reduces the overall risk of cancer incidence by 31%, improves cancer-related mortality and enhances response to neoadjuvant chemotherapy in type 2-diabetics receiving metformin. There is evidence that metformin works through activation of Adenosine Monophosphate Protein Kinase (AMPK), an energy-sensing kinase that maintains cellular energy homeostasis. In a pre-operative window-of-opportunity randomized trial we have demonstrated that metformin significantly reduces proliferation and blunts the insulin response in primary operable breast cancer. This study further analysed cancer tissue from the trial to dissect the molecular mechanisms involved.

Methodology: Non-diabetic women with operable invasive breast cancer were randomised to receive pre-operative metformin or no drug. Forty seven patients had core biopsy at diagnosis then were randomized to metformin (metformin 500mg o.d. for 1 week increased to 1g b.d for a further week continued to surgery) or no drug, and 2 weeks later had core biopsy at surgery. Insulin receptor, phospho-AMPK (pAMPK), phospho-Akt (pAkt) and Ki67 immunohistochemistry was performed on formalin-fixed paraffin-embedded cores and scored blinded to treatment. Paired t-test was used for analysis.

Results: Significant up-regulation of pAMPK (p = 0.04) and down-regulation of pAkt (p = 0.04) in metformin treated patients was demonstrated compared to the control group. No change in insulin receptor expression was identified but, as previously reported, there was a fall in ki67. Changes were independent of Body Mass Index. Seven patients (7/24) receiving metformin withdrew because of gastro-intestinal upset and were excluded from the immunohistochemical analyses.

Conclusion: These findings suggest that metformin works in vivo in breast cancer patients via up-regulation of tumor pAMPK and down-regulation of pAkt and proliferation. Since down-regulation of pAMPK is a feature of breast cancer, this suggests mechanistic evidence for the therapeutic effect of metformin.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD03-02.