Abstract PD03-06: Clinical and Biologic Effects of Metformin in Early Stage Breast Cancer

Abstract

Background: Numerous epidemiological and pre-clinical studies have associated potential antineoplastic activity with the antidiabetic drug metformin in various tumor types including breast cancer (BC). We are conducting a neoadjuvant “window of opportunity” study to examine biologic and clinical effects of metformin in early stage BC. Data from a planned interim analysis are presented here. Materials and methods: 15 of planned 40 non-diabetic women < 75 yo with newly diagnosed untreated BC were given metformin 500 mg tid for ≥2 weeks post diagnostic core biopsy until definitive surgery. Fasting blood and tumor tissue were obtained, anthropometric measurements performed and the EORTC QLQ C-30 administered pre-metformin and on the day of surgery. Clinical (weight, symptoms, EORTC QLQ C-30) and biologic characteristics were compared pre-metformin and at the end of metformin treatment as were Ki67 (our primary end-point), terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), cleaved caspase 3, physiologic markers (insulin, HOMA,TNF-alpha) and molecular markers [phosphorylated 4E-BP1, phosphorylated protein kinase B (P-PKB/Akt), phosphorylated AMPK (P-AMPK), insulin receptor(IR), Insulin-like growth factor 1 receptor(IGF-1R)]. Analysis of Ki67, cleaved Caspase 3 and TUNNEL were performed on a blinded fashion. Ki-67 was scored by manual count selected by and expressed as percentage of cells with positive nuclear staining. Results: Mean age was 51.7 years. 73.3% (11/15) and 26.7% (4/15) had T1 and T2 BC respectively; 40% (6/15) were node positive, 86.7% (13/15) were ER and PR positive and 26.6% (4/15) were HER-2 +. Metformin was administered for a median of 21 days (range 14 - 40). Gastrointestinal (GI) side effects were most frequent and usually self-limiting — mild diarrhoea 60% (9/15), anorexia 53% (8/15) and nausea 46% (7/15). EORTC30 QLQ scores were stable. Weight decreased (mean change -0.81 kg; Mann-Whitney U p-value 0.057). HOMA (a marker of insulin sensitivity) and C-reactive protein improved, mean change -0.32 and -0.21mg/L respectively. Ki67 decreased significantly after metformin treatment (from 27.6 to 22.7, Wilcoxon signed-rank test p-value = 0.043); TUNEL staining increased significantly (from 0.43 to 1.48, p=0.03) and cleaved Caspase 3 increased non-significantly (from 1.01 to 3.96, p=0.31). Conclusion: Preoperative metformin was well tolerated with mild GI toxicities, but no significant QOL effects; it was associated with improved insulin resistance. A short term administration of metformin significantly reduced breast cancer cell proliferation (as measured by change in Ki67 index) and induced apoptosis (reflected by TUNEL). Metformin administration elicited potential physiologic and cellular effects in breast cancer that are in keeping with beneficial anti-cancer effects. Updated results and the impact of metformin on IR/IGF1R/PI3K and AMPK/mTOR signaling pathways within the cancers will be reported. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD03-06.

Understanding the benefit of metformin use in cancer treatment

“…In a recent study, low doses of metformin (250 mg/day) reduced the number of rectal aberrant crypt foci (a surrogate marker for colorectal cancer) and decreased the proliferative activity of colonic epithelium in non-diabetic patients [ 31 ]. Furthermore, interim analyses of ongoing studies involving neoadjuvant metformin treatment of newly diagnosed breast cancer patients have demonstrated that metformin is safe and well tolerated, and exhibits favorable effects on insulin metabolism and tumor cell proliferation and apoptosis [ 32 , 33 ].…”

Antidiabetic Drug Metformin Suppresses Endotoxin-Induced Uveitis in Rats

“…42,[45][46][47][48][49] Moreover, interim analyses of ongoing studies in breast cancer patients demonstrated that metformin is safe and well tolerated, and exhibits therapeutic effects on insulin metabolism, tumor cell proliferation, and apoptosis. 50,51 Besides humans, metformin also displays significant growth inhibitory effects in numerous in vitro and in vivo animal models of carcinogenesis. In an in vitro cell culture model, metformin inhibited the proliferation of a variety of cancer cells, such as breast, prostate, colon, endometrial, ovarian, and glioma.…”

Metformin in cancer: translational challenges

“…Metformin (1000 mg twice daily) was well tolerated and caused a significant reduction in Ki-67 staining in tumours and altered the expression of numerous genes including those involved in metabolism, inflammation and AMPK (PRKAA) and mTOR signalling. Interim data from additional ongoing neoadjuvant studies on breast cancer have provided evidence that metformin administration (in standard clinical dose) to newly diagnosed breast cancer patients is safe and has favourable effects on tumour cell proliferation and apoptosis in the absence of other anti-cancer treatment , Niraula et al 2010. Furthermore, Hosono et al (2010) have reported a randomised trial showing that a very low dose of metformin (250 mg daily) reduces proliferation and aberrant crypt foci formation in the rectal epithelium of non-diabetic patients with previous colorectal polyps when compared with placebo.…”