Evidence for biological effects of metformin in operable breast cancer: a pre-operative, window-of-opportunity, randomized trial

Abstract

, Colin Purdie, Susan Bray, et al.. Evidence for biological effects of metformin in operable breast cancer: a pre-operative, window-of-opportunity, randomized trial. Breast Cancer Research and Treatment, Springer Verlag, 2011, 128 (3) AbstractMetformin 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 8 patients had core biopsy of the cancer at presentation, a week later (without treatment; internal control), then following metformin 500mg o.d. for one week increased to 1g 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.7 patients (7/32, 21.9%) receiving metformin withdrew due to 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 down-regulated by metformin for PDE3B (phosphodiesterase 3B, cGMP-inhibited; a critical regulator of cAMP levels which 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, MEKK were up-regulated and cdc42 down-regulated; mTOR and AMPK pathways were also affected. Gene Set Analysis additionally revealed that p53, BRCA1 and cell cycle pathways also had reduced expressed 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.

Molecular Pathways: Preclinical Models and Clinical Trials with Metformin in Breast Cancer

“…Overall, these prospective, preoperative window studies in breast cancer (62,64,65), despite reservations about trial design and methodology, demonstrate that metformin is safe for women with primary breast cancer and confirm the attraction of metformin as a therapeutic agent.…”

“…The first randomized clinical trial using metformin (1,000 mg bd) in breast cancer was reported in 2011 and used the preoperative window-of-opportunity setting (62). This novel trial randomized patients to receive metformin for 2 weeks or watchful waiting for 2 weeks between diagnostic biopsy and definitive surgery.…”

NDUFA4L2 Fine-tunes Oxidative Stress in Hepatocellular Carcinoma

“…Reports have indicated that metformin reduced cancer incidence (38,39). Metformin also reduced proliferative output of breast cancer cells in nondiabetic cancer patients (40). These interesting findings highlight an interesting dilemma-is energy or REDOX homeostasis more important for cancer survival?…”

Pretreatment Insulin Levels as a Prognostic Factor for Breast Cancer Progression

“…Hyperinsulinemia, insulin resistance (IR) [7,8,10], and enhanced levels of insulin-like growth factor-1 (IGF-1) [11] have all been proposed as the underlying causative mechanisms, mainly on the basis of in vitro and animal studies supporting a role for insulin, insulin receptor, and IGFs in BC initiation [12][13][14] and progression [15]. These experimental findings are strengthened by indirect observations that metformin, a biguanide oral hypoglycemic agent capable of lowering insulin levels and improving IR, also might The Oncologist 2016;21:1041-1049 www.TheOncologist.com ©AlphaMed Press 2016 be effective in reducing BC incidence [8] and may beneficially act on proliferation and apoptosis markers in early BC stages [16][17][18]. Accordingly, metformin is being investigated in an adjuvant trial investigating invasive cancer-free survival in nondiabetic women with early breast cancer (National Cancer Institute of Canada Clinical Trials Group MA.32); the primary outcome measure is expected to be released late in 2017 [19].…”