Obesity, Insulin Resistance and Insulin.

Abstract

Abstract There is growing acceptance that overweight and obesity are associated with poor outcomes in early stage breast cancer. This effect has been reported in pre-and postmenopausal women, regardless of hormone receptor status. Postulated mechanisms have included presentation of cancer at a more advanced stage, underdosing of chemotherapy and higher levels of endogenous estrogens in overweight and obese women. Recent research has provided strong evidence that insulin may play a key role in mediating these prognostic effects. Overweight and obesity are associated with insulin resistance (and resulting hyperinsulinemia) in both the general population and in breast cancer patients; both insulin resistance and high insulin levels have been associated with increased risk of breast cancer recurrence or death, independent of traditional prognostic factors. Breast cancer cells commonly overexpress insulin receptors (frequently a fetal form of the receptor that may hybridize with the IGF-1 receptor), providing a biologic basis for a prognostic effect of insulin. These receptors are not downregulated by circulating insulin; as a result, cancer cell growth may be stimulated by high circulating insulin levels, leading to poor prognosis. Preclinical work provides strong evidence for a mitogenic role of insulin in breast cancer. Taken together, these observations have led to the development of lifestyle interventions targeting insulin and/or insulin resistance in breast cancer patients. Interventions include weight loss (which reduces insulin levels in the general population) and physical activity (which has been shown to reduce insulin in breast cancer patients). Randomized trials of weight loss are ongoing and planned. One completed trial (Women's Intervention Nutrition Study, J Natl Cancer Inst 2006;98:1767-1776) reported improved relapse free survival in breast cancer patients randomized to a reduced fat diet (that was associated with significant weight loss). Effects were greatest in hormone receptor negative breast cancer. Recent interest has focused on the use of metformin, a biguanide commonly used to treat type 2 diabetes. Metformin reduces insulin resistance and lowers insulin levels in many populations, including early stage breast cancer patients. In addition to this indirect (insulin lowering) effect, metformin may also exert direct anti-tumor effects via mTOR inhibition. Studies using metformin in the neoadjuvant setting in breast cancer are ongoing. The effect of metformin on breast cancer outcomes (with embedded correlative studies that will examine direct and indirect effects of the drug) will be examined in NCIC MA.32, a randomized trial of metformin versus placebo involving 3582 women with early breast cancer that will be activated in early 2010. Together, these lifestyle and pharmacologic studies will provide important information on the effect of modification of a key host factor (obesity with associated hyperinsulinemia) on breast cancer outcomes. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr MS2-1.