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      Association between Metformin Therapy and Breast Cancer Incidence and Mortality: Evidence from a Meta-Analysis

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          Abstract

          Purpose

          Metformin may be associated with a decreased risk of breast cancer. We performed a meta-analysis to assess the effect of metformin intake on breast cancer risk and mortality.

          Methods

          We performed a PubMed and EMbase search for all available studies that described the risk of breast cancer and all-cause mortality in relation to the use of metformin among patients with type 2 diabetes mellitus. Pooled relative risks (RRs) were determined using a random effects model to assess the strength of association between metformin and the risk of breast cancer.

          Results

          Fifteen articles from PubMed satisfied the inclusion criteria, including a total of 838,333 participants. Compared with the control group, metformin use was not related to a reduced incidence of breast cancer (RR, 0.964; 95% confidence interval [CI], 0.761-1.221; p=0.761). However, metformin therapy was associated with decreased all-cause mortality (RR, 0.652; 95% CI, 0.488-0.873; p=0.004). No obvious publication bias was detected (incidence: p Begg=0.755, p Egger=0.008; mortality: p Begg=0.072, p Egger=0.185).

          Conclusion

          The present study suggested that metformin therapy may decrease the all-cause mortality of patients affected by breast cancer. However, this finding should be considered carefully and confirmed with further studies.

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          The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level.

          I Ben Sahra, K. Laurent, A Loubat … (2008)
          Metformin is a widely used antidiabetic agent, which regulates glucose homeostasis through inhibition of liver glucose production and an increase in muscle glucose uptake. Recent studies suggest that metformin may reduce the risk of cancer, but its mode of action in cancer remains not elucidated. We investigated the effect of metformin on human prostate cancer cell proliferation in vitro and in vivo. Metformin inhibited the proliferation of DU145, PC-3 and LNCaP cancer cells with a 50% decrease of cell viability and had a modest effect on normal prostate epithelial cell line P69. Metformin did not induce apoptosis but blocked cell cycle in G(0)/G(1). This blockade was accompanied by a strong decrease of cyclin D1 protein level, pRb phosphorylation and an increase in p27(kip) protein expression. Metformin activated the AMP kinase pathway, a fuel sensor signaling pathway. However, inhibition of the AMPK pathway using siRNA against the two catalytic subunits of AMPK did not prevent the antiproliferative effect of metformin in prostate cancer cells. Importantly, oral and intraperitoneal treatment with metformin led to a 50 and 35% reduction of tumor growth, respectively, in mice bearing xenografts of LNCaP. Similar, to the in vitro study, metformin led to a strong reduction of cyclin D1 protein level in tumors providing evidence for a mechanism that may contribute to the antineoplastic effects of metformin suggested by recent epidemiological studies.
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            Mortality After Incident Cancer in People With and Without Type 2 Diabetes

            Craig J. Currie, Chris Poole, Sara Jenkins-Jones … (2012)
            OBJECTIVE Type 2 diabetes is associated with an increased risk of several types of cancer and with reduced survival after cancer diagnosis. We examined the hypotheses that survival after a diagnosis of solid-tumor cancer is reduced in those with diabetes when compared with those without diabetes, and that treatment with metformin influences survival after cancer diagnosis. RESEARCH DESIGN AND METHODS Data were obtained from >350 U.K. primary care practices in a retrospective cohort study. All individuals with or without diabetes who developed a first tumor after January 1990 were identified and records were followed to December 2009. Diabetes was further stratified by treatment regimen. Cox proportional hazards models were used to compare all-cause mortality from all cancers and from specific cancers. RESULTS Of 112,408 eligible individuals, 8,392 (7.5%) had type 2 diabetes. Cancer mortality was increased in those with diabetes, compared with those without (hazard ratio 1.09 [95% CI 1.06–1.13]). Mortality was increased in those with breast (1.32 [1.17–1.49]) and prostate cancer (1.19 [1.08–1.31]) but decreased in lung cancer (0.84 [0.77–0.92]). When analyzed by diabetes therapy, mortality was increased relative to nondiabetes in those on monotherapy with sulfonylureas (1.13 [1.05–1.21]) or insulin (1.13 [1.01–1.27]) but reduced in those on metformin monotherapy (0.85 [0.78–0.93]). CONCLUSIONS This study confirmed that type 2 diabetes was associated with poorer prognosis after incident cancer, but that the association varied according to diabetes therapy and cancer site. Metformin was associated with survival benefit both in comparison with other treatments for diabetes and in comparison with a nondiabetic population.
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              Diabetes and cancer: two diseases with obesity as a common risk factor

              S. Garg, H Maurer, K A Reed … (2013)
              There is a growing body of evidence to support a connection between diabetes (predominantly type 2), obesity and cancer. Multiple meta-analyses of epidemiological data show that people with diabetes are at increased risk of developing many different types of cancers, along with an increased risk of cancer mortality. Several pathophysiological mechanisms for this relationship have been postulated, including insulin resistance and hyperinsulinaemia, enhanced inflammatory processes, dysregulation of sex hormone production and hyperglycaemia. In addition to these potential mechanisms, a number of common risk factors, including obesity, may be behind the association between diabetes and cancer. Indeed, obesity is associated with an increased risk of cancer and diabetes. Abdominal adiposity has been shown to play a role in creating a systemic pro-inflammatory environment, which could result in the development of both diabetes and cancer. Here, we examine the relationship between diabetes, obesity and cancer, and investigate the potential underlying causes of increased cancer risk in individuals with diabetes. Current treatment recommendations for reducing the overall disease burden are also explored and possible areas for future research are considered.
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                Author and article information

                Journal
                Journal ID (nlm-ta): J Breast Cancer
                Journal ID (iso-abbrev): J Breast Cancer
                Journal ID (publisher-id): JBC
                Title: Journal of Breast Cancer
                Publisher: Korean Breast Cancer Society
                ISSN (Print): 1738-6756
                ISSN (Electronic): 2092-9900
                Publication date (Print): September 2015
                Publication date (Electronic): 24 September 2015
                Volume: 18
                Issue: 3
                Pages: 264-270
                Affiliations
                Department of Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
                [1 ]Department of Cardiovascular Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
                Author notes
                Correspondence to: Shengchun Liu. Department of Surgery, The First Affiliated Hospital of Chongqing Medical University, 1 Youyi Road, Yuanjiagang, Yuzhong District, Chongqing 400016, China. Tel: +86-2389018463, Fax: +86-2389011122, liushengchun1968@ 123456126.com
                Article
                DOI: 10.4048/jbc.2015.18.3.264
                PMC ID: 4600691
                PubMed ID: 26472977
                SO-VID: 8279bfa2-835c-4bac-8447-cf3c5cd46eca
                Copyright © © 2015 Korean Breast Cancer Society. All rights reserved.
                License:

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 16 December 2014
                Date accepted : 15 May 2015
                Funding
                Funded by: National Natural Science Foundation of China
                Award ID: 81272265
                Award ID: 81472658
                Categories
                Subject: Original Article

                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: breast neoplasms,meta-analysis,metformin,risk assessment
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: breast neoplasms, meta-analysis, metformin, risk assessment

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