Insulin treatment and breast cancer risk; A systematic review of in vitro, animal and epidemiological evidence

Abstract

Background: In 2009, the concern has been raised that insulin analogues, especially insulin glargine, might increase risk of (breast) cancer. Many in vitro and epidemiological and some animal studies have been performed, but there is still no clarity on this issue. Objectives: The aim of this study was to investigate the association between insulin and insulin analogue treatment and breast cancer development, and plausible mechanisms, based on in vitro, animal and epidemiological evidence. Methods: 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, and a complete 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: Sixteen in vitro, 5 animal, 2 in vivo human and 29 epidemiological papers were included. Insulin AspB10 showed mitogenic properties in in vitro and 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 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 animal data were limited, and epidemiological studies were underpowered and suffered from methodological limitations. Conclusions: There is no compelling evidence that any clinically available insulin analogue increases breast cancer risk. Overall, the data suggest that insulin treatment is not involved in breast tumour initiation but might induce breast tumour progression by upregulating mitogenic signalling pathways.