Metformin and Pathologic Complete Responses to Neoadjuvant Chemotherapy in Diabetic Patients With Breast Cancer

Jiralerspong, Sao; Palla, Shana L.; Giordano, Sharon H.; Meric‐Bernstam, Funda; Liedtke, Cornelia; Barnett, Chad M.; Hsu, Limin; Hung, Mien‐Chie; Hortobágyi, Gabriel N.; González-Angulo, Ana M.

doi:10.1200/jco.2009.19.6410

Cited by 799 publications

(608 citation statements)

References 40 publications

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“…Whereas certain insulin analogues do lead to tumour development in rats, their effect in human patients remains controversial ( Refs 150,151,152). In line with the amelioration of obesity and hyperinsulinemia by metformin, observational data showed that its use was associated with a reduced risk of cancer (Refs 143,153,154). Additionally, it might also inhibit tumor progression by AMPK-mediated inhibition of mTORC1, and possibly also by a Rac GTPase-dependent and AMPK-independent mechanism (Ref.…”

Section: Metformin and Ampk In Clinical Usementioning

confidence: 99%

PI3K/AKT, MAPK and AMPK signalling: protein kinases in glucose homeostasis

Schultze

Hemmings

Nießen

et al. 2012

Expert Rev. Mol. Med.

408

300

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New therapeutic approaches to counter the increasing prevalence of obesity and type 2 diabetes mellitus are in high demand. Deregulation of the phosphoinositide-3-kinase (PI3K)/v-akt murine thymoma viral oncogene homologue (AKT), mitogen-activated protein kinase (MAPK) and AMP-activated protein kinase (AMPK) pathways, which are essential for glucose homeostasis, often results in obesity and diabetes. Thus, these pathways should be attractive therapeutic targets. However, with the exception of metformin, which is considered to function mainly by activating AMPK, no treatment for the metabolic syndrome based on targeting protein kinases has yet been developed. By contrast, therapies based on the inhibition of the PI3K/AKT and MAPK pathways are already successful in the treatment of diverse cancer types and inflammatory diseases. This contradiction prompted us to review the signal transduction mechanisms of PI3K/AKT, MAPK and AMPK and their roles in glucose homeostasis, and we also discuss current clinical implications.

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Section: Metformin and Ampk In Clinical Usementioning

confidence: 99%

PI3K/AKT, MAPK and AMPK signalling: protein kinases in glucose homeostasis

Schultze

Hemmings

Nießen

et al. 2012

Expert Rev. Mol. Med.

408

300

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“…Data collected between 1991 and 1996 demonstrated that patients with type 2 diabetes mellitus exposed to sulfonylureas and exogenous insulin had significantly greater cancer-related mortality rates than did patients treated with metformin [23]. Recently, Jiralerspong and colleagues [24] compared the rates of pathological complete response (pCR) in diabetic patients with breast cancer who were receiving neoadjuvant chemotherapy and being treated with metformin or not. The rate of pCR (better outcomes) was 24% in the metformin group and 8% in the non-metformin group (p=0.007).…”

Section: Merriam-webster Dictionary 11th Edition (1977)mentioning

confidence: 99%

Mitogenic action of insulin: friend, foe or ‘frenemy’?

Draznin

2009

Diabetologia

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Either endogenous or exogenous hyperinsulinaemia in the setting of insulin resistance promotes phosphorylation and activation of farnesyltransferase, a ubiquitous enzyme that farnesylates Ras proteins. Increased availability of farnesylated Ras at the plasma membrane enhances mitogenic responsiveness of cells to various growth factors, thus contributing to progression of cancer and atherosclerosis. This effect is specific to insulin, but is not related to the type of insulin used. The stimulatory effect of hyperinsulinaemia on farnesyltransferase in the presence of insulin resistance represents one potential mechanism responsible for mitogenicity and atherogenicity of insulin.

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“…Diabetics treated with metformin have a 23% reduced risk of cancer, including breast cancer, compared to those on sulfonylureas [1] and a lower cancer-related mortality at 36 months [2]. Coincidental use of metformin in diabetics undergoing neoadjuvant chemotherapy for breast cancer resulted in a higher pathological complete response (24%), compared to diabetics not on metformin (8%) or non-diabetic patients (16%) [3].…”

Section: Introductionmentioning

confidence: 99%

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

Hadad

Inomata

Jordan

et al. 2011

Breast Cancer Res Treat

264

199

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, 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.

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Metformin and Pathologic Complete Responses to Neoadjuvant Chemotherapy in Diabetic Patients With Breast Cancer

Abstract: Diabetic patients with breast cancer receiving metformin and neoadjuvant chemotherapy have a higher pCR rate than do diabetics not receiving metformin. Additional studies to evaluate the potential of metformin as an antitumor agent are warranted.

Cited by 799 publications

References 40 publications

PI3K/AKT, MAPK and AMPK signalling: protein kinases in glucose homeostasis

PI3K/AKT, MAPK and AMPK signalling: protein kinases in glucose homeostasis

Mitogenic action of insulin: friend, foe or ‘frenemy’?

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

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