Abstract
Whether metformin therapy affects breast cancer risk in Asian patients with type 2 diabetes mellitus (T2DM) has not been investigated. The reimbursement databases of Taiwanese female patients with a new diagnosis of T2DM between 1998 and 2002 (n = 476,282) were retrieved from the National Health Insurance for follow-up of breast cancer until the end of 2009. Metformin was treated as a time-dependent variable; and of these patients, 285,087 were never-users and 191,195 were ever-users. A time-dependent approach was used to calculate breast cancer incidence and estimate hazard ratios by Cox regression for ever-users, never-users, and subgroups of metformin exposure (tertiles of cumulative duration and cumulative dose). During follow-up, 2,412 (1.26 %) metformin ever-users and 9,322 (2.10 %) never-users developed breast cancer, representing an incidence of 201.08 and 535.88 per 100,000 person-years, respectively. The overall multivariable-adjusted hazard ratio (95 % confidence intervals) for ever- versus never-users was 0.630 (0.597–0.665). The multivariable-adjusted hazard ratios for the first, second, and third tertiles of cumulative duration of metformin therapy were 1.122 (1.043–1.207), 0.754 (0.692–0.820), and 0.280 (0.253–0.310), respectively, (P-trend <0.0001); and 1.099 (1.021–1.182), 0.664 (0.611–0.723), and 0.311 (0.281–0.344), respectively, (P-trend <0.0001), for cumulative dose of metformin. Metformin use is associated with a decreased risk of breast cancer.
Similar content being viewed by others
References
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61:69–90
Jain R, Strickler HD, Fine E, Sparano JA (2013) Clinical studies examining the impact of obesity on breast cancer risk and prognosis. J Mamm Gland Biol Neoplasia 18:257–266
Chiang CJ, Chen YC, Chen CJ, You SL, Lai MS, Taiwan Cancer Registry Task Force (2010) Cancer trends in Taiwan. Jpn J Clin Oncol 40:897–904
Bureau of Health Promotion (2010) Cancer Registry Annual Report 2008. Department of Health, Executive Yuan, Taiwan. http://www.bhp.doh.gov.tw/Download%5C97Statistics%5C1.%E7%99%8C%E7%97%87%E7%99%BB%E8%A8%98%E5%B9%B4%E5%BA%A6%E5%A0%B1%E5%91%8A%EF%BC%88%E5%85%A8%EF%BC%89/Y97-%E7%99%8C%E7%97%87%E7%99%BB%E8%A8%98%E5%B9%B4%E5%BA%A6%E5%A0%B1%E5%91%8A%EF%BC%88%E5%85%A8).pdf. Accessed 27 June 2012
Fan YP, Liu CL, Chiang IJ, Lin CY (2011) Development of a prognostic nomogram for identifying those factors which influence the 2- and 5-year survival chances of Taiwanese women diagnosed with breast cancer. Eur J Cancer Care (Engl) 20:620–626
Rizos CV, Elisaf MS (2013) Metformin and cancer. Eur J Pharmacol 705:96–108
Franciosi M, Lucisano G, Lapice E, Strippoli GF, Pellegrini F, Nicolucci A (2013) Metformin therapy and risk of cancer in patients with type 2 diabetes: systematic review. PLoS ONE 8:e71583
Ray WA (2003) Evaluating medication effects outside of clinical trials: new-user designs. Am J Epidemiol 158:915–920
Gerhard T (2008) Bias: considerations for research practice. Am J Health Syst Pharm. 65:2159–68. Erratum in: Am J Health Syst Pharm. 2008;65:2192
Yang XL, Ma RC, So WY, Kong AP, Xu G, Chan JC (2012) Addressing different biases in analysing drug use on cancer risk in diabetes in non-clinical trial settings-what, why and how? Diabetes Obes Metab 14:579–585
Lévesque LE, Hanley JA, Kezouh A, Suissa S (2010) Problem of immortal time bias in cohort studies: example using statins for preventing progression of diabetes. BMJ 340:b5087
Stricker BH, Stijnen T (2010) Analysis of individual drug use as a time-varying determinant of exposure in prospective population-based cohort studies. Eur J Epidemiol 25:245–251
Tseng CH (2014) Human insulin does not increase bladder cancer risk. PLoS ONE 9:e86517
Tseng CH (2013) Pioglitazone does not affect the risk of ovarian cancer: analysis of a nationwide reimbursement database in Taiwan. Gynecol Oncol 131:135–139
Tseng CH (2013) New-onset diabetes with a history of dyslipidemia predicts pancreatic cancer. Pancreas 42:42–48
Tseng CH (2013) Rosiglitazone may reduce thyroid cancer risk in patients with type 2 diabetes. Ann Med 45:539–544
Kato K, Gong J, Iwama H, Kitanaka A, Tani J, Miyoshi H, Nomura K, Mimura S, Kobayashi M, Aritomo Y, Kobara H, Mori H, Himoto T, Okano K, Suzuki Y, Murao K, Masaki T (2012) The antidiabetic drug metformin inhibits gastric cancer cell proliferation in vitro and in vivo. Mol Cancer Ther 11:549–560
Anisimov VN, Berstein LM, Egormin PA, Piskunova TS, Popovich IG, Zabezhinski MA, Kovalenko IG, Poroshina TE, Semenchenko AV, Provinciali M, Re F, Franceschi C (2005) Effect of metformin on life span and on the development of spontaneous mammary tumors in HER-2/neu transgenic mice. Exp Gerontol 40:685–693
Brown KA, Hunger NI, Docanto M, Simpson ER (2010) Metformin inhibits aromatase expression in human breast adipose stromal cells via stimulation of AMP-activated protein kinase. Breast Cancer Res Treat 123:591–596
Zhuang Y, Miskimins WK (2008) Cell cycle arrest in Metformin treated breast cancer cells involves activation of AMPK, downregulation of cyclin D1, and requires p27Kip1 or p21Cip1. J Mol Signal 3:18
Gallagher EJ, LeRoith D (2011) Diabetes, cancer, and metformin: connections of metabolism and cell proliferation. Ann N Y Acad Sci 1243:54–68
Thompson AM (2014) Molecular pathways: preclinical models and clinical trials with metformin in breast cancer. Clin Cancer Res
Acknowledgments
The study was supported by the National Science Council (NSC102-2314-B-002-067) of Taiwan.
Conflict of interest
None.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Tseng, CH. Metformin may reduce breast cancer risk in Taiwanese women with type 2 diabetes. Breast Cancer Res Treat 145, 785–790 (2014). https://doi.org/10.1007/s10549-014-2985-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10549-014-2985-8