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      Treatment with insulin (analogues) and breast cancer risk in diabetics; a systematic review and meta-analysis of in vitro, animal and human evidence

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          Abstract

          Introduction

          Several studies have suggested that anti-diabetic insulin analogue treatment might increase cancer risk. The aim of this study was to review the postulated association between insulin and insulin analogue treatment and breast cancer development, and plausible mechanisms.

          Method

          A systematic literature search was performed on breast cell-line, animal and human studies using the key words ‘insulin analogue’ and ‘breast neoplasia’ in MEDLINE at PubMed, EMBASE, and ISI Web of Science databases. A quantitative and qualitative review was performed on the epidemiological data; due to a limited number of reported estimates, a meta-analysis was performed for glargine only. A comprehensive overview was composed for in vitro and animal studies. Protein and gene expression was analysed for the cell lines most frequently used in the included in vitro studies.

          Results

          In total 16 in vitro, 5 animal, 2 in vivo human and 29 epidemiological papers were included. Insulin AspB10 showed mitogenic properties in vitro and in animal studies. Glargine was the only clinically available insulin analogue for which an increased proliferative potential was found in breast cancer cell lines. However, the pooled analysis of 13 epidemiological studies did not show evidence for an association between insulin glargine treatment and an increased breast cancer risk (HR 1.04; 95 % CI 0.91-1.17; p=0.49) versus no glargine in patients with diabetes mellitus. It has to be taken into account that the number of animal studies was limited, and epidemiological studies were underpowered and suffered from methodological limitations.

          Conclusion

          There is no compelling evidence that any clinically available insulin analogue (Aspart, Determir, Glargine, Glulisine or Lispro), nor human insulin increases breast cancer risk. Overall, the data suggests that insulin treatment is not involved in breast tumour initiation, but might induce breast tumour progression by up regulating mitogenic signalling pathways.

          Electronic supplementary material

          The online version of this article (doi:10.1186/s13058-015-0611-2) contains supplementary material, which is available to authorized users.

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          Most cited references67

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          Diabetes mellitus and risk of breast cancer: a meta-analysis.

          Susanna C Larsson, Christos S. Mantzoros, Alicja Wolk (2007)
          Diabetes mellitus has been associated with an increased risk of several types of cancers, but its relationship with breast cancer remains unclear. We conducted a meta-analysis of case-control and cohort studies to assess the evidence regarding the association between diabetes and risk of breast cancer. Studies were identified by searching MEDLINE (1966-February 2007) and the references of retrieved articles. We identified 20 studies (5 case-control and 15 cohort studies) that reported relative risk (RR) estimates (odds ratio, rate ratio/hazard ratio, or standardized incidence ratio) with 95% confidence intervals (CIs) for the relation between diabetes (largely Type II diabetes) and breast cancer incidence. Summary RRs were calculated using a random-effects model. Analysis of all 20 studies showed that women with (versus without) diabetes had a statistically significant 20% increased risk of breast cancer (RR, 1.20; 95% CI, 1.12-1.28). The summary estimates were similar for case-control studies (RR, 1.18; 95% CI, 1.05-1.32) and cohort studies (RR, 1.20; 95% CI, 1.11-1.30). Meta-analysis of 5 cohort studies on diabetes and mortality from breast cancer yielded a summary RR of 1.24 (95% CI, 0.95-1.62) for women with (versus without) diabetes. Findings from this meta-analysis indicate that diabetes is associated with an increased risk of breast cancer.
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            Insulin glargine use and short-term incidence of malignancies-a population-based follow-up study in Sweden.

            R Ljung, B Haglund, Klara J. Jonasson … (2009)
            In the light of a report suggesting that insulin glargine may increase cancer occurrence, the EASD asked us to perform this study. We followed 114,841 individuals who had a prescription dispensed for insulin between 1 July and 31 December 2005. From 1 January 2006 to 31 December 2007, we noted the occurrence of malignancies. Seven different nationwide registers were used to obtain information on insulin exposure, outcome and possible confounders; these were linked using the unique personal identity number assigned to every Swedish resident. After adjustment for age and, when appropriate, sex, users of insulin glargine alone (no other types of insulin), compared with users of types of insulin other than insulin glargine, had an RR of 1.99 (95% CI 1.31-3.03) for breast cancer, 0.93 (95% CI 0.61-1.40) for gastrointestinal cancer, 1.27 (95% CI 0.89-1.82) for prostate cancer and 1.07 (95% CI 0.91-1.27) for any type of malignancy. Adjustment for age, smoking, BMI, age at onset of diabetes, age at birth of first child, cardiovascular disease and oestrogen use gave an RR for breast cancer of 1.97 (95% CI 1.29-3.00). The 95% CIs crossed 1.0 for the RR calculated in all analyses of users of insulin glargine in combination with other types of insulin. In Sweden, during 2006 and 2007, women using insulin glargine alone (no other types of insulin) had an increased incidence rate of breast cancer as compared with women using types of insulin other than insulin glargine. This result may be due to a random fluctuation; the possibilities for examining validity are limited, and no statistically significant results were obtained for any other individual cancer site or for the outcome 'all malignancies'. No definitive conclusions regarding a possible causal relationship between insulin glargine use and the occurrence of malignancies can be drawn from the results of this study.
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              Use of insulin glargine and cancer incidence in Scotland: a study from the Scottish Diabetes Research Network Epidemiology Group

              H M Colhoun (2009)
              Aims/hypothesis The aim of the present study was to examine whether patients with diabetes in Scotland using insulin glargine have a greater cancer risk than patients using other types of insulin. Methods We used a nationwide diabetes clinical database that covers the majority of the Scottish population with diagnosed diabetes, and examined patients with diabetes who were exposed to any insulin therapy between 1 January 2002 and 31 December 2005. Among these we defined a fixed cohort based on exposure during a 4 month period in 2003 (n = 36,254, in whom 715 cases of cancer occurred) and a cohort of new insulin users across the period (n = 12,852 in whom 381 cancers occurred). Records from these cohorts were linked to cancer registry data up to the end of 2005. We used Cox proportional hazards models for survival analyses. Results Those receiving any insulin glargine (n = 3,959) had the same incidence rate for all cancers as those not receiving insulin glargine (HR 1.02, 95% CI 0.77–1.36, p = 0.9 in the fixed cohort) The subset of patients using insulin glargine alone (n = 447) had a significantly higher incidence of all cancers than those using other insulins only (n = 32,295) (HR 1.55, 95% CI 1.01–2.37, p = 0.045), and those using insulin glargine with other insulins (n = 3,512) had a slightly lower incidence (HR 0.81, 95% CI 0.55–1.18, p = 0.26). There were important differences in baseline characteristics between these three groups, although the risk ratios were broadly unaltered on adjustment for these. Overall, there was no increase in breast cancer rates associated with insulin glargine use (HR 1.49, 95% CI 0.79–2.83, though insulin glargine only users had a higher rate than those using non-glargine insulin only (HR 3.39, 95% CI 1.46–7.85, p = 0.004). Among type 2 diabetic incident insulin users, no significant difference between the three groups was observed with respect to all cancer or breast cancer. All the above HRs are adjusted for age, calendar time prior cancer and type of diabetes, as appropriate, and are stratified according to sex. Conclusions/interpretation Overall, insulin glargine use was not associated with an increased risk of all cancers or site-specific cancers in Scotland over a 4 year time frame. Given the overall data, we consider the excess of cases of all cancers and breast cancer in the subgroup of insulin glargine only users to more likely reflect allocation bias rather than an effect of insulin glargine itself. Electronic supplementary material The online version of this article (doi:10.1007/s00125-009-1453-1) contains supplementary material, which is available to authorised users.
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                Author and article information

                Contributors
                Heleen K Bronsveld: h.bronsveld@nki.nl
                Bas ter Braak: basterbraak@gmail.com
                Øystein Karlstad: Oystein.Karlstad@fhi.no
                Peter Vestergaard: p-vest@post4.tele.dk
                Jakob Starup-Linde: Jakob.Linde@auh.rm.dk
                Marloes T Bazelier: M.T.Bazelier@uu.nl
                Marie L De Bruin: M.L.deBruin@uu.nl
                Anthonius de Boer: a.deboer@uu.nl
                Christine L E Siezen: cl.siezen@cbg-meb.nl
                Bob van de Water: water_b@lacdr.leidenuniv.nl
                Jan Willem van der Laan: jw.vd.laan@cbg-meb.nl
                Marjanka K Schmidt: mk.schmidt@nki.nl
                Journal
                Journal ID (nlm-ta): Breast Cancer Res
                Journal ID (iso-abbrev): Breast Cancer Res
                Title: Breast Cancer Research : BCR
                Publisher: BioMed Central (London )
                ISSN (Print): 1465-5411
                ISSN (Electronic): 1465-542X
                Publication date (Electronic): 5 August 2015
                Publication date PMC-release: 5 August 2015
                Publication date (Print): 2015
                Volume: 17
                Issue: 1
                Electronic Location Identifier: 100
                Affiliations
                [ ]Division of Molecular Pathology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands
                [ ]Division of Toxicology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands
                [ ]Department of Pharmacoepidemiology, Norwegian Institute of Public Health, Oslo, Norway
                [ ]Departments of Clinical Medicine and Endocrinology, Aalborg University, Aalborg, Denmark
                [ ]Department of Endocrinology and Internal Medicine (MEA), Aarhus University Hospital THG, Aarhus, Denmark
                [ ]Division of Pharmacoepidemiology & Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, Netherlands
                [ ]Medicines Evaluation Board (MEB), Utrecht, The Netherlands
                [ ]Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands
                Article
                Publisher ID: 611
                DOI: 10.1186/s13058-015-0611-2
                PMC ID: 4531810
                PubMed ID: 26242987
                SO-VID: ac5a69e3-40bd-4275-b30b-af1adc7320db
                Copyright © © Bronsveld et al. 2015
                License:

                Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                Date received : 27 February 2015
                Date accepted : 7 July 2015
                Categories
                Subject: Research Article
                Custom metadata
                issue-copyright-statement © The Author(s) 2015

                ScienceOpen disciplines: Oncology & Radiotherapy
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                ScienceOpen disciplines: Oncology & Radiotherapy

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