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

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

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

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.Toxicolog

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

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.Toxicolog

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

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.Toxicolog

Unravelling the link between diabetes, insulin treatment and breast cancer

Objective The aims of this thesis were to assess whether diabetes, and specifically insulin treatment, is associated with breast cancer development and breast cancer subtypes, and to investigate potential mechanisms involved. Methods Using the Clinical Practice Research Datalink (CPRD) we described trends in incidence rates of breast cancer in women with and without type 2 diabetes in the United Kingdom over a period of 24 years. To further understand how women with diabetes might have a higher risk for breast cancer we evaluated whether insulin and insulin analogues might contribute to an increased risk of breast cancer in women with diabetes. A quantitative and qualitative review of published in vitro, in vivo and epidemiological evidence on this postulated association, as well as on plausible mechanisms involved, were carried out. Based on the results of this systematic review, we generated hypotheses that were addressed in studiesof breast tumors of women with or without diabetes. We used data and tumor tissue from primary invasive breast cancer patients that were randomly selected from an existing nationwide hospital-based cohort in Denmark. We determined clinical-pathological characteristics of insulin and non-insulin treated women with diabetes compared to women without diabetes, and we determined whether these women develop specific breast cancer subtypes defined by clinically used immunohistochemical tumor markers (ER/PR/HER2). Furthermore, we studied protein- and gene expression within or related to the insulin signaling pathway (PI3K/MAPK) of tumors of women with diabetes and specifically those who used insulin (analogues). Results We found using the CPRD data that incidence rates of breast cancer among women with type 2 diabetes in the UK remained stable between 1989-2012, the incidence rate was approximately 150 per 100,000 women years. The breast cancer incidence in women with diabetes was comparable to women without diabetes. Based on the literature review, we concluded that there is no compelling evidence that any of the clinically available insulin analogues, nor human insulin, increases breast cancer risk. Overall, the data suggested that insulin treatment is not involved in breast tumor initiation, but might induce breast tumor progression by upregulating mitogenic signaling pathways (e.g. MAPK/PI3K). In the studies of breast tumors of Danish women, we found some indication that IGF1R and p-MTOR are over-expressed in tumors of insulin users and hormonal receptors are under-expressed in tumors of premenopausal women with diabetes, characteristics that are typically associated with a poor prognosis. However, based on genes expression analyses these findings were not confirmed. Conclusions Our studies show that insulin or insulin analogue treatment in patients with diabetes is not associated with an increased risk of breast cancer. There is also no compelling evidence that women with diabetes treated with or without insulin develop different breast cancer subtypes compared to women without diabetes. Altogether, it is unlikely that diabetes itself, insulin or insulin analogues strongly affect different pathways involved in breast tumor development

Unravelling the link between diabetes, insulin treatment and breast cancer

Objective The aims of this thesis were to assess whether diabetes, and specifically insulin treatment, is associated with breast cancer development and breast cancer subtypes, and to investigate potential mechanisms involved. Methods Using the Clinical Practice Research Datalink (CPRD) we described trends in incidence rates of breast cancer in women with and without type 2 diabetes in the United Kingdom over a period of 24 years. To further understand how women with diabetes might have a higher risk for breast cancer we evaluated whether insulin and insulin analogues might contribute to an increased risk of breast cancer in women with diabetes. A quantitative and qualitative review of published in vitro, in vivo and epidemiological evidence on this postulated association, as well as on plausible mechanisms involved, were carried out. Based on the results of this systematic review, we generated hypotheses that were addressed in studiesof breast tumors of women with or without diabetes. We used data and tumor tissue from primary invasive breast cancer patients that were randomly selected from an existing nationwide hospital-based cohort in Denmark. We determined clinical-pathological characteristics of insulin and non-insulin treated women with diabetes compared to women without diabetes, and we determined whether these women develop specific breast cancer subtypes defined by clinically used immunohistochemical tumor markers (ER/PR/HER2). Furthermore, we studied protein- and gene expression within or related to the insulin signaling pathway (PI3K/MAPK) of tumors of women with diabetes and specifically those who used insulin (analogues). Results We found using the CPRD data that incidence rates of breast cancer among women with type 2 diabetes in the UK remained stable between 1989-2012, the incidence rate was approximately 150 per 100,000 women years. The breast cancer incidence in women with diabetes was comparable to women without diabetes. Based on the literature review, we concluded that there is no compelling evidence that any of the clinically available insulin analogues, nor human insulin, increases breast cancer risk. Overall, the data suggested that insulin treatment is not involved in breast tumor initiation, but might induce breast tumor progression by upregulating mitogenic signaling pathways (e.g. MAPK/PI3K). In the studies of breast tumors of Danish women, we found some indication that IGF1R and p-MTOR are over-expressed in tumors of insulin users and hormonal receptors are under-expressed in tumors of premenopausal women with diabetes, characteristics that are typically associated with a poor prognosis. However, based on genes expression analyses these findings were not confirmed. Conclusions Our studies show that insulin or insulin analogue treatment in patients with diabetes is not associated with an increased risk of breast cancer. There is also no compelling evidence that women with diabetes treated with or without insulin develop different breast cancer subtypes compared to women without diabetes. Altogether, it is unlikely that diabetes itself, insulin or insulin analogues strongly affect different pathways involved in breast tumor development

The association of diabetes mellitus and insulin treatment with expression of insulin-related proteins in breast tumors

The insulin receptor (INSR) and the insulin growth factor 1 receptor (IGF1R) play important roles in the etiology of both diabetes mellitus and breast cancer. We aimed to evaluate the expression of hormone and insulin-related proteins within or related to the PI3K and MAPK pathway in breast tumors of women with or without diabetes mellitus, treated with or without insulin (analogues).\nImmunohistochemistry was performed on tumor tissue of 312 women with invasive breast cancer, with or without pre-existing diabetes mellitus, diagnosed in 2000-2010, who were randomly selected from a Danish breast cancer cohort. Women with diabetes were 2:1 frequency matched by year of birth and age at breast cancer diagnosis to those without diabetes. Tumor Microarrays were successfully stained for p-ER, EGFR, p-ERK1/2, p-mTOR, and IGF1R, and scored by a breast pathologist. Associations of expression of these proteins with diabetes, insulin treatment (human insulin and insulin analogues) and other diabetes medication were evaluated by multivariable logistic regression adjusting for menopause and BMI; effect modification by menopausal status, BMI, and ER status was assessed using interactions terms.\nWe found no significant differences in expression of any of the proteins in breast tumors of women with (n = 211) and without diabetes (n = 101). Among women with diabetes, insulin use (n = 53) was significantly associated with higher tumor protein expression of IGF1R (OR = 2.36; 95%CI:1.02-5.52; p = 0.04) and p-mTOR (OR = 2.35; 95%CI:1.13-4.88; p = 0.02), especially among women treated with insulin analogues. Menopause seemed to modified the association between insulin and IGF1R expression (p = 0.07); the difference in IGF1R expression was only observed in tumors of premenopausal women (OR = 5.10; 95%CI:1.36-19.14; p = 0.02). We found no associations between other types of diabetes medication, such as metformin, and protein expression of the five proteins evaluated.\nIn our study, breast tumors of women with pre-existing diabetes did not show an altered expression of selected PI3K/MAPK pathway-related proteins. We observed an association between insulin treatment and increased p-mTOR and IGF1R expression of breast tumors, especially in premenopausal women. This observation, if confirmed, might be clinically relevant since the use of IGF1R and mTOR inhibitors are currently investigated in clinical trials.Toxicolog