RESUMEN
OBJECTIVE: To investigate whether women with type 2 diabetes (T2D) develop a more advanced stage of breast cancer and whether treatment with insulin (analogs) is associated with specific breast cancer characteristics. RESEARCH DESIGN AND METHODS: For this nested case-control study, women with breast cancer diagnosed in 2002-2014 were selected from the linked Netherlands Cancer Registry-PHARMO Database Network (N = 33,377). T2D was defined as receiving two or more dispensings of noninsulin blood glucose-lowering drugs prior to breast cancer diagnosis. Women with T2D were matched to women without diabetes. Among women with T2D, insulin users and nonusers were compared. Multivariable ordinal logistic regression was used to investigate the association between T2D/insulin and breast cancer characteristics, including TNM classification (tumor size, lymph node status, metastasis), morphology, grade, estrogen receptor and progesterone receptor (PR), human epidermal growth factor receptor 2, and molecular subtype. RESULTS: Women with T2D (n = 1,567) were more often diagnosed with a more advanced tumor stage (odds ratio 1.28 [95% CI 13-1.44]) and a higher grade (1.22 [1.08-1.39]) though less often with a PR-negative breast tumor (0.77 [0.67-0.89]) than women without diabetes (n = 6,267). No associations were found for the other breast cancer characteristics. Women with T2D using insulin (n = 388) were not diagnosed with different breast cancer characteristics compared with women with T2D not using insulin (n = 1,179). CONCLUSIONS: Our study suggests that women with T2D are at increased risk to be diagnosed with a more aggressive type of breast cancer than women without diabetes. No evidence was found that the use of insulin (analogs) is associated with developing more advanced breast cancer tumors.
Asunto(s)
Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/patología , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/epidemiología , Insulina/uso terapéutico , Adulto , Anciano , Neoplasias de la Mama/complicaciones , Estudios de Casos y Controles , Diabetes Mellitus Tipo 2/complicaciones , Progresión de la Enfermedad , Femenino , Humanos , Insulina/análogos & derivados , Registro Médico Coordinado , Persona de Mediana Edad , Estadificación de Neoplasias , Países Bajos/epidemiología , Farmacias/estadística & datos numéricos , Sistema de Registros/estadística & datos numéricos , Estudios RetrospectivosRESUMEN
BACKGROUND: 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). METHODS: Immunohistochemistry 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. RESULTS: We 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. CONCLUSIONS: In 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.
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Neoplasias de la Mama/metabolismo , Complicaciones de la Diabetes , Insulina/farmacología , Receptores de Somatomedina/genética , Transducción de Señal , Serina-Treonina Quinasas TOR/genética , Neoplasias de la Mama/genética , Estudios Transversales , Diabetes Mellitus/tratamiento farmacológico , Receptores ErbB/análisis , Receptores ErbB/genética , Receptores ErbB/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunohistoquímica , Insulina/uso terapéutico , Sistema de Señalización de MAP Quinasas , Persona de Mediana Edad , Proteína Quinasa 1 Activada por Mitógenos/análisis , Proteína Quinasa 1 Activada por Mitógenos/genética , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Receptor IGF Tipo 1 , Receptores de Somatomedina/análisis , Receptores de Somatomedina/metabolismo , Serina-Treonina Quinasas TOR/análisis , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
AIMS: To quantify breast cancer incidence in women with type-2 diabetes and assess age-standardized trends in invasive breast cancer incidence over time and by age groups. METHODS: A population-based cohort study was conducted using the British general practice database (Clinical Practice Research Datalink) using data from 1989 to 2012. All adult women prescribed anti-hyperglycemic medication were selected and matched (1:1) on age and clinical practice to a reference cohort without diabetes. RESULTS: During approximately 1.6 million person years (py), 2371 breast cancer cases were diagnosed in the diabetes cohort (n=147,998) and 2252 in the reference cohort (n=147,998). Incidence of breast cancer, overall or by age groups, among women with diabetes remained stable over time. The (overall) age-standardized breast cancer IR per 100,000 py of the diabetes cohort (150, 95%CI:143-157) resembled that observed in the reference cohort (148, 95%CI:141-156); with an incidence rate ratio (IRR) of 1.01 (95%CI:0.94-1.08, p>0.05). CONCLUSIONS: Currently, around 2880 women with type-2 diabetes are diagnosed with breast cancer per year in the United Kingdom. However, breast cancer incidence remained stable in the last 10 years and seems to be comparable in women with and without diabetes.
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Neoplasias de la Mama/epidemiología , Diabetes Mellitus Tipo 2/epidemiología , Medicina General/tendencias , Adulto , Distribución por Edad , Anciano , Anciano de 80 o más Años , Índice de Masa Corporal , Neoplasias de la Mama/diagnóstico , Estudios de Casos y Controles , Bases de Datos Factuales , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Prescripciones de Medicamentos , Femenino , Humanos , Hipoglucemiantes/uso terapéutico , Incidencia , Menopausia , Persona de Mediana Edad , Factores de Tiempo , Reino Unido/epidemiologíaRESUMEN
BACKGROUND: Women with diabetes have a worse survival after breast cancer diagnosis compared to women without diabetes. This may be due to a different etiological profile, leading to the development of more aggressive breast cancer subtypes. Our aim was to investigate whether insulin and non-insulin treated women with diabetes develop specific clinicopathological breast cancer subtypes compared to women without diabetes. METHODS AND FINDINGS: This cross-sectional study included randomly selected patients with invasive breast cancer diagnosed in 2000-2010. Stratified by age at breast cancer diagnosis (≤50 and >50 years), women with diabetes were 2:1 frequency-matched on year of birth and age at breast cancer diagnosis (both in 10-year categories) to women without diabetes, to select ~300 patients with tumor tissue available. Tumor MicroArrays were stained by immunohistochemistry for estrogen and progesterone receptor (ER, PR), HER2, Ki67, CK5/6, CK14, and p63. A pathologist scored all stains and revised morphology and grade. Associations between diabetes/insulin treatment and clinicopathological subtypes were analyzed using multivariable logistic regression. Morphology and grade were not significantly different between women with diabetes (n = 211) and women without diabetes (n = 101), irrespective of menopausal status. Premenopausal women with diabetes tended to have more often PR-negative (OR = 2.44(95%CI:1.07-5.55)), HER2-negative (OR = 2.84(95%CI:1.11-7.22)), and basal-like (OR = 3.14(95%CI:1.03-9.60) tumors than the women without diabetes, with non-significantly increased frequencies of ER-negative (OR = 2.48(95%CI:0.95-6.45)) and triple negative (OR = 2.60(95%CI:0.88-7.67) tumors. After adjustment for age and BMI, the associations remained similar in size but less significant. We observed no evidence for associations of clinicopathological subtypes with diabetes in postmenopausal women, or with insulin treatment in general. CONCLUSIONS: We found no compelling evidence that women with diabetes, treated with or without insulin, develop different breast cancer subtypes than women without diabetes. However, premenopausal women with diabetes tended to develop breast tumors that do not express hormonal receptors, which are typically associated with poor prognosis.
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Neoplasias de la Mama/clasificación , Neoplasias de la Mama/epidemiología , Diabetes Mellitus/epidemiología , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/patología , Estudios Transversales , Diabetes Mellitus/tratamiento farmacológico , Femenino , Humanos , Insulina/uso terapéutico , Persona de Mediana Edad , Posmenopausia , PremenopausiaRESUMEN
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.
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Neoplasias de la Mama/inducido químicamente , Neoplasias de la Mama/etiología , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Insulina Glargina/efectos adversos , Insulina Glargina/uso terapéutico , Animales , Línea Celular Tumoral , Femenino , Humanos , Hipoglucemiantes/efectos adversos , Hipoglucemiantes/uso terapéutico , Células MCF-7 , RiesgoRESUMEN
BACKGROUND: Patients suffering from diabetes mellitus (DM) may experience an increased risk of cancer; however, it is not certain whether this effect is due to diabetes per se. OBJECTIVE: To examine the association between DM and cancers by a systematic review and meta-analysis according to the PRISMA guidelines. DATA SOURCES: The systematic literature search includes Medline at PubMed, Embase, Cinahl, Bibliotek.dk, Cochrane library, Web of Science and SveMed+ with the search terms: "Diabetes mellitus", "Neoplasms", and "Risk of cancer". STUDY ELIGIBILITY CRITERIA: The included studies compared the risk of cancer in diabetic patients versus non-diabetic patients. All types of observational study designs were included. RESULTS: Diabetes patients were at a substantially increased risk of liver (RR=2.1), and pancreas (RR=2.2) cancer. Modestly elevated significant risks were also found for ovary (RR=1.2), breast (RR=1.1), cervix (RR=1.3), endometrial (RR=1.4), several digestive tract (RR=1.1-1.5), kidney (RR=1.4), and bladder cancer (RR=1.1). The findings were similar for men and women, and unrelated to study design. Meta-regression analyses showed limited effect modification of body mass index, and possible effect modification of age, gender, with some influence of study characteristics (population source, cancer- and diabetes ascertainment). LIMITATIONS: Publication bias seemed to be present. Only published data were used in the analyses. CONCLUSIONS: The systematic review and meta-analysis confirm the previous results of increased cancer risk in diabetes and extend this to additional cancer sites. Physicians in contact with patients with diabetes should be aware that diabetes patients are at an increased risk of cancer.