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BMC Cancer
Published in: BMC Cancer 1/2015

Open Access 01-12-2015 | Research article

Prolonged use of human insulin increases breast cancer risk in Taiwanese women with type 2 diabetes

Author: Chin-Hsiao Tseng

Published in: BMC Cancer | Issue 1/2015

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Abstract

Background

Human insulin is commonly used to treat hyperglycemia in patients with diabetes, but its potential link with female breast cancer is under debate. This study investigated whether human insulin use might be associated with breast cancer risk in Taiwanese women with type 2 diabetes.

Methods

The reimbursement databases of all Taiwanese diabetic patients from 1996 to 2009 were retrieved from the National Health Insurance. An entry date was set at 1 January 2004 and a total of 482,033 women with type 2 diabetes were followed up for breast cancer incidence until the end of 2009. Incidences for ever-users, never-users and subgroups of human insulin exposure (using tertile cutoffs of time since starting insulin, cumulative dose and cumulative duration of insulin) were calculated and the adjusted hazard ratios were estimated by Cox regression. The potential risk modification by concomitant treatment with metformin, statin and angiotensin converting enzyme inhibitor/angiotensin receptor blocker (ACEI/ARB) was also evaluated.

Results

There were 59,798 ever-users and 422,235 never-users of human insulin, with respective numbers of incident breast cancer of 559 (0.93 %) and 4,711 (1.12 %), and respective incidence of 207.9 and 215.1 per 100,000 person-years. The overall adjusted hazard ratio (95 % confidence interval) did not show a significant association with insulin [1.033 (0.936-1.139)]. However, patients in the third tertiles of dose–response parameters might show a significantly higher risk of breast cancer while compared to never-users: 1.185 (1.026-1.368), 1.260 (1.096-1.450) and 1.257 (1.094-1.446) for ≥67 months for time since starting insulin, ≥39,000 units for cumulative dose of insulin, and ≥21.8 months for cumulative duration of insulin, respectively. Additional analyses suggested that the breast cancer risk associated with human insulin use might be beneficially modified by concomitant use of metformin, statin and ACEI/ARB.

Conclusions

This study discloses a significantly higher risk of breast cancer associated with prolonged use of human insulin. The increased risk of breast cancer associated with human insulin use may be modified by medications such as metformin, statin and ACEI/ARB.
Literature
1.
Larsson SC, Mantzoros CS, Wolk A. Diabetes mellitus and risk of breast cancer: a meta-analysis. Int J Cancer. 2007;121:856–62.CrossRefPubMed
2.
Tseng CH, Chong CK, Tai TY. Secular trend for mortality from breast cancer and the association between diabetes and breast cancer in Taiwan between 1995 and 2006. Diabetologia. 2009;52:240–6.CrossRefPubMed
3.
4.
Dool CJ, Mashhedi H, Zakikhani M, David S, Zhao Y, Birman E, et al. IGF1/insulin receptor kinase inhibition by BMS-536924 is better tolerated than alloxan-induced hypoinsulinemia and more effective than metformin in the treatment of experimental insulin-responsive breast cancer. Endocr Relat Cancer. 2011;18:699–709.CrossRefPubMed
5.
Fierz Y, Novosyadlyy R, Vijayakumar A, Yakar S, LeRoith D. Mammalian target of rapamycin inhibition abrogates insulin-mediated mammary tumor progression in type 2 diabetes. Endocr Relat Cancer. 2010;17:941–51.CrossRefPubMedPubMedCentral
6.
Kabat GC, Kim M, Caan BJ, Chlebowski RT, Gunter MJ, Ho GY, et al. Repeated measures of serum glucose and insulin in relation to postmenopausal breast cancer. Int J Cancer. 2009;125:2704–10.CrossRefPubMed
7.
Kurtzhals P, Schäffer L, Sørensen A, Kristensen C, Jonassen I, Schmid C, et al. Correlations of receptor binding and metabolic and mitogenic potencies of insulin analogs designed for clinical use. Diabetes. 2000;49:999–1005.CrossRefPubMed
8.
Call R, Grimsley M, Cadwallader L, Cialone L, Hill M, Hreish V, et al. Insulin--carcinogen or mitogen? Preclinical and clinical evidence from prostate, breast, pancreatic, and colorectal cancer research. Postgrad Med. 2010;122:158–65.CrossRefPubMed
9.
Teng JA, Hou RL, Li DL, Yang RP, Qin J. Glargine promotes proliferation of breast adenocarcinoma cell line MCF-7 via AKT activation. Horm Metab Res. 2011;43:519–23.CrossRefPubMed
10.
Mannucci E, Monami M, Balzi D, Cresci B, Pala L, Melani C, et al. Doses of insulin and its analogues and cancer occurrence in insulin-treated type 2 diabetic patients. Diabetes Care. 2010;33:1997–2003.CrossRefPubMedPubMedCentral
11.
Suissa S, Azoulay L, Dell'aniello S, Evans M, Vora J, Pollak M. Long-term effects of insulin glargine on the risk of breast cancer. Diabetologia. 2011;54:2254–62.CrossRefPubMed
12.
Ruiter R, Visser LE, van Herk-Sukel MP, Coebergh JW, Haak HR, Geelhoed-Duijvestijn PH, et al. Risk of cancer in patients on insulin glargine and other insulin analogues in comparison with those on human insulin: results from a large population-based follow-up study. Diabetologia. 2012;55:51–62.CrossRefPubMed
13.
Lind M, Fahlén M, Eliasson B, Odén A. The relationship between the exposure time of insulin glargine and risk of breast and prostate cancer: An observational study of the time-dependent effects of antidiabetic treatments in patients with diabetes. Prim Care Diabetes. 2012;6:53–9.CrossRefPubMed
14.
Wilson C. Diabetes: long-term use of insulin glargine might increase the risk of breast cancer. Nat Rev Endocrinol. 2011;7:499.CrossRefPubMed
15.
16.
Tseng CH. Rosiglitazone is not associated with an increased risk of bladder cancer. Cancer Epidemiol. 2013;37:385–9.CrossRefPubMed
17.
Tseng CH. Diabetes and risk of bladder cancer: A study using the National Health Insurance database in Taiwan. Diabetologia. 2011;54:2009–15.CrossRefPubMed
18.
Bodmer M, Meier C, Krähenbühl S, Jick SS, Meier CR. Long-term metformin use is associated with decreased risk of breast cancer. Diabetes Care. 2010;33:1304–8.CrossRefPubMedPubMedCentral
19.
Tseng CH. Metformin may reduce breast cancer risk in Taiwanese women with type 2 diabetes. Breast Cancer Res Treat. 2014;145:785–90.CrossRefPubMed
20.
Murtola TJ, Visvanathan K, Artama M, Vainio H, Pukkala E. Statin use and breast cancer survival: a nationwide cohort study from Finland. PLoS One. 2014;9:e110231.CrossRefPubMedPubMedCentral
21.
Herr D, Rodewald M, Fraser HM, Hack G, Konrad R, Kreienberg R, et al. Potential role of Renin-Angiotensin-system for tumor angiogenesis in receptor negative breast cancer. Gynecol Oncol. 2008;109:418–25.CrossRefPubMed
22.
Vinson GP, Barker S, Puddefoot JR. The renin-angiotensin system in the breast and breast cancer. Endocr Relat Cancer. 2012;19:R1–R19.CrossRefPubMed
23.
Rostoker R, Abelson S, Bitton-Worms K, Genkin I, Ben-Shmuel S, Dakwar M, et al. Highly specific role of the insulin receptor in breast cancer progression. Endocr Relat Cancer. 2015;22:145–57.CrossRefPubMedPubMedCentral
24.
25.
Tseng CH. Insulin use and smoking jointly increase the risk of bladder cancer mortality in patients with type 2 diabetes. Clin Genitourin Cancer. 2013;11:508–14.CrossRefPubMed
26.
Tseng CH. Type 2 diabetes, smoking, insulin use and mortality from hepatocellular carcinoma: a 12-year follow-up of a national cohort in Taiwan. Hepatol Int. 2013;7:693–702.CrossRefPubMed
27.
Miele L, Bosetti C, Turati F, Rapaccini G, Gasbarrini A, La Vecchia C, et al. Diabetes and insulin therapy, but not metformin, are related to hepatocellular cancer risk. Gastroenterol Res Pract. 2015;2015:570356.CrossRefPubMedPubMedCentral
28.
Carstensen B, Witte DR, Friis S. Cancer occurrence in Danish diabetic patients: duration and insulin effects. Diabetologia. 2012;55:948–58.CrossRefPubMed
29.
Home PD, Lagarenne P. Combined randomised controlled trial experience of malignancies in studies using insulin glargine. Diabetologia. 2009;52:2499–506.CrossRefPubMedPubMedCentral
30.
Pelton K, Coticchia CM, Curatolo AS, Schaffner CP, Zurakowski D, Solomon KR, et al. Hypercholesterolemia induces angiogenesis and accelerates growth of breast tumors in vivo. Am J Pathol. 2014;184:2099–110.CrossRefPubMedPubMedCentral
31.
Nelson ER, Wardell SE, Jasper JS, Park S, Suchindran S, Howe MK, et al. 27-Hydroxycholesterol links hypercholesterolemia and breast cancer pathophysiology. Science. 2013;342:1094–8.CrossRefPubMedPubMedCentral
32.
33.
Ahern TP, Pedersen L, Tarp M, Cronin-Fenton DP, Garne JP, Silliman RA, et al. Statin prescriptions and breast cancer recurrence risk: a Danish nationwide prospective cohort study. J Natl Cancer Inst. 2011;103:1461–8.CrossRefPubMedPubMedCentral
34.
Bonovas S, Lytras T, Sitaras NM. Statin use and breast cancer: do we need more evidence and what should this be? Expert Opin Drug Saf. 2014;13:271–5.CrossRefPubMed
35.
Devore EE, Kim S, Ramin CA, Wegrzyn LR, Massa J, Holmes MD, et al. Antihypertensive medication use and incident breast cancer in women. Breast Cancer Res Treat. 2015;150:219–29.CrossRefPubMedPubMedCentral
36.
Leung HW, Hung LL, Chan AL, Mou CH. Long-term use of antihypertensive agents and risk of breast cancer: a population-based case–control study. Cardiol Ther. 2015;4:65–76.CrossRefPubMedPubMedCentral
37.
Lee HH, Tsan YT, Ho WC, Lin MH, Lee CH, Tseng CD, et al. Health Data Analysis in Taiwan (hDATa) Research Group. Angiotensin-converting enzyme inhibitors enhance the effect of cyclooxygenase inhibitors on breast cancer: a nationwide case–control study. J Hypertens. 2012;30:2432–9.CrossRefPubMed
38.
Babacan T, Balakan O, Kuzan TY, Sarici F, Koca E, Kertmen N, et al. The effect of renin-angiotensin-system inhibition on survival and recurrence of N3+ breast cancer patients. J BUON. 2015;20:50–6.PubMed
39.
Li CI, Daling JR, Tang MT, Haugen KL, Porter PL, Malone KE. Use of antihypertensive medications and breast cancer risk among women aged 55 to 74 years. JAMA Intern Med. 2013;173:1629–37.CrossRefPubMedPubMedCentral
40.
Namiranian N, Moradi-Lakeh M, Razavi-Ratki SK, Doayie M, Nojomi M. Risk factors of breast cancer in the Eastern Mediterranean Region: a systematic review and meta-analysis. Asian Pac J Cancer Prev. 2014;15:9535–41.CrossRefPubMed
41.
Pierobon M, Frankenfeld CL. Obesity as a risk factor for triple-negative breast cancers: a systematic review and meta-analysis. Breast Cancer Res Treat. 2013;137:307–14.CrossRefPubMed
42.
Anderson KN, Schwab RB, Martinez ME. Reproductive risk factors and breast cancer subtypes: a review of the literature. Breast Cancer Res Treat. 2014;144:1–10.CrossRefPubMedPubMedCentral
43.
Tseng CH. Body mass index and blood pressure in adult type 2 diabetic patients in Taiwan. Circ J. 2007;71:1749–54.CrossRefPubMed
44.
van Stralen KJ, Dekker FW, Zoccali C, Jager KJ. Confounding. Nephron Clin Pract. 2010;116:c143–7.CrossRefPubMed
45.
Cheng TM. Taiwan's new national health insurance program: genesis and experience so far. Health Aff (Millwood). 2003;22:61–76.CrossRef
46.
Bureau of Health Promotion. Cancer Registry Annual Report 2007. Taiwan: Department of Health, Executive Yuan; 2010.
Metadata
Title
Prolonged use of human insulin increases breast cancer risk in Taiwanese women with type 2 diabetes
Author
Chin-Hsiao Tseng
Publication date
01-12-2015
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2015
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-015-1876-7

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