Insulin resistance in breast cancer: relevance and clinical implications

Breast cancer risk is increased in women who have attributes of the insulin resistance syndrome, such as obesity (postmenopausal), central obesity (premenopausal and postmenopausal), high endogenous insulin levels, clinical diabetes and physical inactivity. There is a large body of evidence that obesity is associated with a 25 to 50% relative increase in risk of breast cancer recurrence or death, with adverse effects that appear to be independent of hormone receptor status. Obesity, particularly when it is central, is strongly associated with insulin resistance in healthy individuals and breast cancer patients. Several studies have shown that higher insulin and/or C-peptide levels (a marker of insulin secretion), both of which are linked to insulin resistance, are associated with an increased risk of recurrence and death in women with early stage breast cancer, even in the absence of diabetes. Risk is increased twofold to threefold in those with insulin levels in the highest (versus lowest) quartile. Data from our group suggest that these prognostic associations of insulin are most marked in the first 5 years post diagnosis. A role of insulin in breast cancer outcomes is biologically plausible given overexpression of insulin receptors (IR), most frequently the fetal form of the receptor (IR-A), by the majority of human breast cancers. IR-A often hybridizes with insulin-like growth factor 1 receptors to stimulate mitogenic signaling pathways; hybrid receptor activation has been associated with poor clinical outcomes. The current observational and preclinical evidence linking insulin to breast cancer is sufficiently compelling that neoadjuvant and adjuvant intervention studies have been initiated to evaluate clinical anti-cancer effects of metformin, an agent that lowers insulin levels and has other potential non-insulin-mediated anti-cancer effects (mainly through activation of adenosine monophosphate-activated protein kinase). Early results from window of opportunity neoadjuvant studies suggest short-term, single-agent metformin (2 to 3 weeks) lowers insulin levels, reduces proliferation and increases apoptosis. NCIC MA32, an ongoing randomized, multicenter, placebo-controlled, adjuvant trial involving 3,582 women with early stage breast cancer, will provide more definitive evidence regarding potential anti-cancer effects. Additional studies of metformin in the metastatic setting are underway and/or planned. Because other factors (such as inflammation, adipocytokines (leptin, adiponectin), higher estrogen levels) may also mediate prognostic effects of obesity and/or insulin resistance in breast cancer, additional research targeting these mediators as well as obesity per se is also needed.