Differential effects of metformin on breast cancer proliferation according to markers of insulin resistance and tumor subtype in a randomized presurgical trial

Abstract

Treatment of diabetics with metformin is associated with decreased breast cancer risk in observational studies, but it remains unclear if this drug has clinical antineoplastic activity. In a recent presurgical trial, we found a heterogeneous effect of metformin on breast cancer proliferation (ki-67) depending upon insulin resistance (HOMA index). Here, we determined the associations of additional serum biomarkers of insulin resistance, tumor subtype, and drug concentration with ki-67 response to metformin. Two-hundred non-diabetic women were randomly allocated to metformin (850 mg/bid) or placebo for 4 weeks prior to breast cancer surgery. The ki-67 response to metformin was assessed comparing data obtained from baseline biopsy (ki-67 and tumor subtype) and serum markers (HOMA index, C-peptide, IGF-I, IGFBP-1, IGFBP-3, free IGF-I, hs-CRP, adiponectin) with the same measurements at definitive surgery. For patients with a blood sample taken within 24 h from last drug intake, metformin level was measured. Compared with placebo, metformin significantly decreased ki-67 in women with HOMA > 2.8, those in the lowest IGFBP-1 quintile, those in the highest IGFBP-3 quartile, those with low free IGF-I, those in the top hs-CRP tertile, and those with HER2-positive tumors. In women with HOMA index > 2.8, drug levels were positively correlated with the ki-67 decrease, whereas no trend was noted in women with HOMA < 2.8 (p-interaction = 0.07). At conventional antidiabetic doses, the effect of metformin on tumor ki-67 of non-diabetic breast cancer patients varies with host and tumor characteristics. These findings are relevant to design breast cancer prevention and treatment trials with metformin.Electronic supplementary materialThe online version of this article (doi:10.1007/s10549-014-3141-1) contains supplementary material, which is available to authorized users.

Effect of Metformin on Breast Ductal Carcinoma In Situ Proliferation in a Randomized Presurgical Trial

“…2.8 under metformin, in line with our prior observation in invasive cancer (10), although this finding was based on eight cases only. These results extend and further complement our prior findings in HER2þve invasive disease, where metformin significantly reduced the Ki-67 increase observed in the placebo arm after 4 week between biopsy and surgery (15,34). In addition, the number of adjacent HER2þve DCIS was larger than that of HER2þve invasive cancer, in line with prior data (35), indicating that our findings do not simply replicate results in HER2þve invasive disease (15).…”

“…Moreover, metformin selectively decreased Ki-67 LI in HER2þve cancers and in women with additional markers of insulin resistance (15). In the present study, we show the high prevalence of the field cancerization effect, with a 70% prevalence of intraepithelial neoplastic lesions in tissue surrounding invasive cancers, supporting the notion that the presurgical model may be a cost effective model to screen agents with preventive potential.…”

“…Our presurgical trial showed a null effect overall but a heterogeneous effect with a trend to a decreased proliferation (Ki-67 LI) and apoptosis (by TUNEL) in women with insulin resistance (HOMA> 2.8) and an opposite trend in women with normal insulin sensitivity (10,14). Moreover, metformin selectively decreased Ki-67 in HER2-positive (HER2þve) cancers and in women with additional markers of insulin resistance (15). Preclinical and epidemiologic studies have suggested an effect of metformin specifically on HER2þve tumors (16).…”

Metformin and Breast Cancer Stage at Diagnosis: A Population-Based Study

“…However, our study failed to support that possibility: results were similar when insulin users were excluded. Furthermore, there is evidence that metformin is associated with a greater reduction in tumour growth in individuals who attain the largest reduction in insulin level 29 . Thus, metformin's effect might be lost when not accounting for varying levels of insulin resistance.…”

Metformin Versus Sulfonylurea in Breast Cancer Risk of Diabetic Patients: A Systematic Review and Meta-Analysis

“…Also the increased risk of cancer-related death in diabetic patients who have used sulfonylureas and exogenous insulin was much more significant in comparison with metformin users (15). Clinical evidences have suggested that metformin could prevent proliferation and growth of certain types of cancers, such as breast cancer, even in absence of diabetes (16). According to the above results about the efficacy of metformin in treatment and prevention of breast cancer death; in comparison with other medicines such as sulfonylureas, it would be necessary to perform a metaanalysis in related research of metformin effects on prevention and treatment of breast cancer The results of this study could be the basis for making beneficial therapeutic purposes in prevention, treatment and reducing the effects of breast cancer, such as breast cancer mortality.…”