Abstract PD03-02: Evidence for the anti-cancer action of metformin mediated via tumor AMPK, Akt and Ki67, in a preoperative window of opportunity trial
Bibliographic record
Abstract
Abstract 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.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.002 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.006 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".