Diabetes and Breast Cancer Subtypes

Abstract

BackgroundWomen 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 FindingsThis 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.ConclusionsWe 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.

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

“…Details on patient selection and methods of data collection have been described previously [24]. In short, the selected women included breast cancer patients with pre-existing diabetes (exposed) and without diabetes (non-exposed) sampled as follows: we frequently matched by year of birth and age at diagnosis (both in 10-year categories)a random sample of women with diabetes (in strata of age ≤ 50 and > 50 years at breast cancer diagnosis) to women without diabetes ( Fig.…”

“…In short, the selected women included breast cancer patients with pre-existing diabetes (exposed) and without diabetes (non-exposed) sampled as follows: we frequently matched by year of birth and age at diagnosis (both in 10-year categories)a random sample of women with diabetes (in strata of age ≤ 50 and > 50 years at breast cancer diagnosis) to women without diabetes ( Fig. 1) [24]. To allow analyses of insulin treatment, we included two times as many women with diabetes as women without diabetes.…”

“…We excluded patients with a history of other cancers, noninvasive or metastasized breast cancer, those treated with neo-adjuvant therapy, patients with diabetes diagnosed ≤1 year prior to their breast cancer diagnosis, and patients with no or insufficient tumor tissue. We obtained data from the DBCG database, linkage with the National Patient Register in Denmark, linkage with the Danish Register of Medicinal Products Statistics, and additional information on height, weight and Body Mass Index (BMI) prior to breast cancer diagnosis from electronic medical records [24]. The study protocol was approved by the Science Ethics Committee of the Region Midtjylland in Denmark (M-20110198).…”

“…As described also previously [24], we classified diabetes status based on medical diagnosis from the Danish National Patient Register; and diabetes duration as time from age of diabetes diagnosis till age of breast cancer diagnosis. We assigned women with diabetes to a treatment group if at least 2 prescriptions of an antidiabetic drug were prescribed in the period up to one year prior to breast cancer diagnosis.…”

“…Morphology, grade, tumor size, number of positive lymph nodes and clinical tumor subtype, immunohistochemically defined by ER, PR, and human epidermal growth factor receptor 2 (HER2) status, were available from central pathology review [24]. All formalin-fixed, paraffin embedded tumor blocks of the primary tumor of each patient were collected, sectioned and hematoxylin and eosin (HE) stained.…”