Insulin breast cancer connection: confirmatory data set the stage for better care.

A growing body of evidence indicates a strong association between type 2 diabetes and cancer. These two common diseases, increasing in incidence as a consequence of Western lifestyle, frequently occur in the same patient. The biologic nature of this association, however, is not completely clear. Epidemiologic data suggest that patients with diabetes have a higher risk of developing several types of cancer, including liver, pancreatic, colorectal, gynecologic, and breast cancer. Cancer prognosis has also been suggested to be adversely affected by diabetes. In recent years, extensive research has attempted to evaluate and clarify the possible links between type 2 diabetes and breast cancer. In particular, the role of insulin in breast cancer etiology and prognosis has received growing attention. The association between insulin and cancer is biologically plausible: hyperinsulinemia induces proliferative tissue abnormalities because of the strong anabolic effect of insulin, which results in stimulated DNA synthesis and cell proliferation. This effect may also be explained by the cross-activation of the insulin-like growth factor (IGF) receptor family. IGFs are endocrine mediators of growth hormone and also act in a paracrine and autocrine fashion to regulate cell growth, differentiation, apoptosis, and transformation in different tissues, including breast tissue. The pathways downstream of the insulin/IGF system are well defined: insulin-like growth factor-I (IGF-I) and insulin activate the tyrosine kinase growth receptor pathway, that is, insulin, IGF-I, and hybrid IGF-I/insulin receptors, all of which are frequently overexpressed in breast cancer cells. Activation of these receptors results in upregulation of the insulin receptor substrate 2, which leads to downstream activation of the mitogen-activated protein kinase and phosphatidylinositol 3-kinase-Akt pathways. In this issue of Journal of Clinical Oncology, four articles shed additional light on the prognosis of breast cancer in women with diabetes or insulin resistance. All of the studies provide additional proof of an unfavorable breast cancer prognosis in patients with either overt or undiagnosed type 2 diabetes or patients with different forms of glucose intolerance as defined by high C-peptide, high homeostasis model assessment (HOMA) index (ie, the ratio of fasting blood glucose to insulin), and low adiponectin levels. In the first article, a meta-analysis by Peairs et al, the investigators were able to detect, using standard meta-analytic procedures, a 49% increased risk of death as a result of nonspecific breast cancer in women with breast cancer and diabetes compared with women with breast cancer who did not have diabetes. Adverse prognostic features, such as delayed diagnosis and suboptimal treatments, were more likely to occur in the population with diabetes. Breast cancer-specific mortality analysis yielded inconsistent results, possibly because of the small number of available studies with specific mortality data (two out of six) and the short follow-up (one study had a follow-up of only 1 year). This meta-analysis does not come without some limitations; the most important limitation is that it is based on published data. Although it is unlikely that mortality results would differ in an analysis conducted on individual patient data, quality control and analyses of the original records were not possible, and the only feasible subgroup analyses were those for which information was available in the original reports. Despite these constraints, this pragmatic analysis provides quantitative evidence of a significantly increased risk of death in patients with breast cancer who also have a clinical diagnosis of type 2 diabetes. Moreover,giventheindirectmethodofdiabetesascertainment, it ispossiblethe risk of death was underestimated. Indeed, undiagnosed or delayeddiagnosed diabetes in patients who are asymptomatic has been reported to occur in approximately 30% of patients with breast cancer. The clinical importance and prognostic relevance of undiagnosed and unreported type 2 diabetes in patients with breast cancer is particularly evident in the article by Erikson et al. In this study, archived baseline blood samples from the Women’s Healthy Eating and Living study, a dietary intervention trial, were retrieved to measure baseline hemoglobin A1c to evaluate the prognostic effect of chronic hyperglycemia among 3003 survivors of early breast cancer who were observed for a median of 7.3 years for additional breast cancer events and 10.3 years for all-cause mortality. In this retrospective analysis, 6% of the patients had chronic hyperglycemia as defined by A1c levels of 6.5% or greater. A1c level was significantly associated with an increased risk of all-cause mortality (hazard ratio [HR], 2.35; 95% CI, 1.56 to 3.54, for A1c 7.0% v 6.5%) after adjustment for stage, grade, age, ethnicity, education, and physical activity. When adjusting for the same factors, the breast cancer–specific event rate (disease-free survival) did not differ significantly by A1c levels. However, women with A1c levels of greater than 7.0% had a clinically meaningful, albeit not significant, 26% increased risk of breast cancer recurrence. Given the retrospective nature of the study and the inconsistent association between hyperglycemia and breast cancer recurrence found in some studies, these results should be regarded as JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L S