Abstract
The coexistence of type 2 diabetes with breast cancer may result in poorer cancer-related survival due to a number of mediating factors including an alteration of tumor tissue hormonal sensitivity. Previous studies have shown that receptor status of breast tumors in diabetics may be changed; however, the mode of therapy for diabetes was usually ignored. This work presents the results of an analysis of the receptor status of breast carcinomas in 90 postmenopausal women suffering with diabetes mellitus type 2 who had been cured, for not less that 1 year prior to surgery, with different modes of antidiabetic therapy, including a dietary treatment only, sulfonylurea preparations, insulin therapy, and metformin as a monotherapy or in combination with sulfonylurea derivatives. No differences in estrogen receptors occurrence in tumor tissue were found in different treatment groups. The frequency of progesterone receptor-positive mammary carcinomas in women who were treated with metformin, irrespective of whether it was combined with sulfonylurea preparations, was significantly higher than in the sulfonylurea only group (P = 0.043) and in the combined group of patients treated with either sulfonylurea or insulin (P = 0.041). The exclusion of the patients who received neoadjuvant chemotherapy (24 persons) did not significantly affect the above results. The data may be used as an explanation of the distinctions in cancer characteristics and course between diabetic patients treated with either metformin or sulfonylurea derivatives and insulin.
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References
Wolf I, et al. Association between diabetes mellitus and adverse characteristics of breast cancer at presentation. Eur J Cancer. 2006;42(8):1077–82.
Hjartåker A, Langseth H, Weiderpass E. Obesity and diabetes epidemics: cancer repercussions. In: Berstein L, Santen R, editors. Innovative endocrinology of cancer. Austin, TX: Landes Bioscience & Springer Science + Business Media; 2008. p. 72–93.
Dowsett M, Cuzick J, Wale C, Howell T, Houghton J, Baum M. Retrospective analysis of time to recurrence in the ATAC trial according to hormone receptor status: a hypothesis-generating study. J Clin Oncol. 2005;23(30):7512–7.
Santen RJ. Endocrine-responsive cancer. In: Larsen PR, Kronenberg HM, Melmed S, et al., editors. Williams textbook of endocrinology. Philadelphia: WB Saunders Comp; 2007. p. 1763–801.
Guastamacchia E, et al. Breast cancer: biological characteristics in postmenopausal type 2 diabetic women. Identification of therapeutic targets. Curr Drug Targets Immune Endocr Metabol Disord. 2003;3(3):205–9.
Michels KB, et al. Type 2 diabetes and subsequent incidence of breast cancer in the Nurses’ Health Study. Diabetes Care. 2003;26(6):1752–8.
Bershtein LM, Tsyrlina EV, Kovalenko IG, Vasil’ev DA, Semiglazov VF. Breast cancer receptor status in smoking and diabetic patients [in Russian]. Vopr Onkol. 2005;51(2):187–91.
Berstein LM, et al. Genotoxic factors associated with the development of receptor-negative breast cancer: potential role of the phenomenon of switching of estrogen effects. Exp Oncol. 2006;28(1):64–9.
Larsson SC, Bergkvist L, Wolk A. Glycemic load, glycemic index and breast cancer risk in a prospective cohort of Swedish women. Int J Cancer. 2009;125(1):153–7.
Evans JM, et al. Metformin and reduced risk of cancer in diabetic patients. Br Med J. 2005;330:1304–5.
Oliveria SA, Koro CE, Ulcickas Yood M, Sowell M. Cancer incidence among patients treated with antidiabetic pharmacotherapy. Diabetes and Metabolic Syndrome: Clinical Research and Reviews. 2008;2(1):47–57.
Goodwin PJ, Pritchard KI, Ennis M, Clemons M, Graham M, Fantus IG. Insulin-lowering effects of metformin in women with early breast cancer. Clin Breast Cancer. 2008;8(6):501–5.
Currie CJ, Poole CD, Gale EA. The influence of glucose-lowering therapies on cancer risk in type 2 diabetes. Diabetologia. 2009;52(9):1766–77.
Bowker SL, Majumdar SR, Veugelers P, Johnson JA. Increased cancer-related mortality for patients with type 2 diabetes who use sulfonylureas or insulin. Diabetes Care. 2006;29(2):254–8.
Landman GW, et al. Metformin associated with lower cancer mortality in type 2 diabetes: ZODIAC-16. Diabetes Care. 2010;33(2):322–6.
Jiralerspong S, et al. Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer. J Clin Oncol. 2009;27(20):3297–302.
Berstein LM. Clinical usage of hypolipidemic and antidiabetic drugs in the prevention and treatment of cancer. Cancer Lett. 2005;224(2):203–12.
Hadad SM, Fleming S, Thompson AM. Targeting AMPK: a new therapeutic opportunity in breast cancer. Crit Rev Oncol Hematol. 2008;67(1):1–7.
Rice S, Pellatt L, Ramanathan K, Whitehead SA, Mason HD. Metformin inhibits aromatase via an ERK (extracellular signal-regulated kinase)–mediated pathway. Endocrinology. 2009;150(10):4794–801.
Berstein LM. Metformin, insulin, breast cancer and more. Future Oncol. 2009;5(3):309–12.
Brown KA, Hunger NI, Docanto M, Simpson ER. Metformin inhibits aromatase expression in human breast adipose stromal cells via stimulation of AMP-activated protein kinase. Breast Cancer Res Treat. 2010. [Epub ahead of print].
Rendell M. Dietary treatment of diabetes mellitus. New Engl J Med. 2000;342:1440–1.
Saez S, Martin PM, Chouvet CD. Oestradiol and progesterone receptor levels in human breast adenocarcinoma in relation to plasma estrogen and progesterone levels. Cancer Res. 1978;38:3468–73.
Allred DC, Harvey JM, Berardo MD, Clark GM. Prognostic and predictive factors in breast cancer by immunohistochemical analysis. Mod Pathol. 1998;11:155–68.
Kurosumi M. Immunohistochemical assessment of hormone receptor status using a new scoring system (J-score) in breast cancer. Breast Cancer. 2007;14(2):189–93.
Richardson LC, Pollack LA. Therapy insight: Influence of type 2 diabetes on the development, treatment and outcomes of cancer. Nat Clin Pract Oncol. 2005;2(1):48–53.
Allred DC. Problems and solutions in the evaluation of hormone receptors in breast cancer. J Clin Oncol. 2008;26:2433–5.
Krentz AJ, Bailey CJ. Oral antidiabetic agents: current role in type 2 diabetes mellitus. Drugs. 2005;65(3):385–411.
Lee SH, Chung MA, Quddus MR, Steinhoff MM, Cady B. The effect of neoadjuvant chemotherapy on estrogen and progesterone receptor expression and hormone receptor status in breast cancer. Am J Surg. 2003;186(4):348–50.
Monami M, Lamanna C, Balzi D, Marchionni N, Mannucci E. Sulphonylureas and cancer: a case-control study. Acta Diabetol. 2008;46(4):279–84.
Goodwin PJ, Ligibel JA, Stambolic V. Metformin in breast cancer: time for action. J Clin Oncol. 2009;27(20):3271–3.
Cazzaniga M, Bonanni B, Guerrieri-Gonzaga A, Decensi A. Is it time to test metformin in breast cancer clinical trials? Cancer Epidemiol Biomarkers Prev. 2009;18(3):701–5.
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This study was supported by Grant 09-04-00139 from RFBR (Russian Foundation of Basic Research).
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Berstein, L.M., Boyarkina, M.P., Tsyrlina, E.V. et al. More favorable progesterone receptor phenotype of breast cancer in diabetics treated with metformin. Med Oncol 28, 1260–1263 (2011). https://doi.org/10.1007/s12032-010-9572-6
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DOI: https://doi.org/10.1007/s12032-010-9572-6