Insulin in the Adjuvant Breast Cancer Setting: A Novel Therapeutic Target for Lifestyle and Pharmacologic Interventions?
Authors: Pamela J. Goodwin
Journal: Journal of Clinical Oncology (2008)

The use of targeted treatments in breast cancer has led to major important improvements in breast cancer outcomes. Key examples of such therapies include tamoxifen and aromatase inhibitors in estrogen receptor (ER) –positive breast cancer and trastuzumab in human epidermal growth factor receptor 2–positive breast cancer. In general, the introduction of these targeted therapies has paralleled advances in understanding the biology of breast cancer. However, our knowledge is incomplete, and major research efforts continue to focus on identifying additional factors responsible for breast cancer. Over the last 10 to 15 years, a substantial body of knowledge has developed regarding the role of insulin and other members of the insulin-like growth factor (IGF) family in breast cancer. This family includes three ligands (insulin, IGF-1, and IGF-2), at least four receptors, and six binding proteins. Until recently, much of the research involving this family has focused on IGFs, notably IGF-1. This research has led to the development of antibodies targeting the IGF-1 receptor, which are in the early stages of clinical testing. In parallel, there has been increasing evidence that insulin, at physiologic concentrations, may play a clinically important role in breast cancer. A modest increased risk of breast cancer has been identified in women with high insulin levels and, to a lesser extent, among women with diabetes. Of greater relevance is the growing evidence that insulin increases risk of breast cancer recurrence and death. We identified a significant adverse prognostic effect of fasting insulin levels in locoregional breast cancer. Women with insulin levels in the highest quartile had a doubled risk of recurrence and a tripled risk of death. Similar findings have subsequently been reported by Pasanisi et al, who reported that either high insulin levels or the presence of the insulin resistance syndrome (IRS) was significantly associated with breast cancer mortality. Pollak et al, in a correlative study associated with the National Cancer Institute of Canada MA.14 study (an adjuvant study of octreotide in ER-positive postmenopausal breast cancer), reported that women with high levels of C-peptide (a breakdown product formed when insulin is cleaved from proinsulin) had significantly worse breast cancer outcomes. These studies have also shown that hyperinsulinemia occurring in newly diagnosed breast cancer patients is strongly associated with obesity (an adverse prognostic factor). Furthermore, it seems to reflect the presence of IRS, a condition associated with obesity and physical inactivity that increases risk of diabetes and cardiovascular disease. Thus, insulin may prove to be the elusive link between obesity, other aspects of Western lifestyle, and breast cancer (and possibly colon cancer). Although the mechanism by which insulin influences breast cancer growth is the subject of intense research, it seems that insulin may signal, at least in part, through its own receptor to activate a cascade of proliferative and antiapoptotic events. Recent research has demonstrated that insulin receptors are almost ubiquitously present in human breast cancer and that the presence of these receptors is prognostically important. Furthermore, a fetal form of the insulin receptor (IR), is commonly expressed in breast cancer cells; this receptor seems to play a key role in stimulating growth. Targeting of insulin as a therapeutic modality in breast cancer is of particular interest because insulin can be modified by lifestyle and pharmacologic interventions. Ligibel et al, in their article in this issue, demonstrate that a lifestyle intervention can lower insulin levels in women with breast cancer. They instituted a mixed strength and endurance exercise intervention to sedentary, obese breast cancer survivors who had completed primary surgery, chemotherapy, and radiation. The intervention resulted in significant reductions in circulating insulin levels (reduced by 28%, P .03), with an associated nonsignificant improvement in insulin sensitivity (calculated empirically using the Homeostasis Model Assessment). The relative reduction in insulin in the intervention arm compared with the control arm attained borderline significance (P .07). These results differ from earlier exercise studies in breast cancer that did not focus on obese, sedentary women and that failed to identify insulin-lowering effects of exercise. The demonstration by Ligibel et al that a physical activity program significantly lowers insulin levels raises the intriguing possibility that a lifestyle intervention may act as a targeted therapy in breast cancer. It is likely that other lifestyle interventions (including weight loss interventions) will also lower insulin levels in breast cancer patients. The only lifestyle intervention study in the breast cancer adjuvant setting that has demonstrated a beneficial effect on disease-free survival (the Women’s Intervention and Nutrition Study) used an intervention that lowered dietary fat intake and also resulted in significant weight loss (a 2.3-kg relative difference between the two study arms). The beneficial effects of the intervention were greatest in women with the highest baseline body mass index, suggesting that weight loss may have been an important mediator. Although the effect of the intervention on insulin levels has not been reported, it is conceivable that reduction in insulin as a result of weight loss was an important mediating factor. The observation that the beneficial effect of the lifestyle intervention was greatest in ER-negative breast cancer is consistent JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 26 NUMBER 6 FEBRUARY 2