Insulin, insulin-like growth factor-I, endogenous estradiol and risk of colorectal cancer in postmenopausal women

B92 Obesity is a risk factor for colorectal cancer, and hyperinsulinemia, a common condition in obese patients, may underlie this relationship. Insulin, in addition to its metabolic effects, has pro-mitotic and anti-apoptotic activity that may be tumorigenic. Insulin-like growth factor (IGF)-I, a related hormone, shares sequence homology with insulin, and has even stronger mitogenic effects. However, few prospective colorectal cancer studies directly measured fasting insulin, and none evaluated free IGF-I, or endogenous estradiol, a potential cofactor in postmenopausal women. Therefore, we conducted a case-cohort investigation of colorectal cancer among non-diabetic subjects enrolled in the Women’s Health Initiative (WHI) Observational Study, a prospective cohort of 93,676 postmenopausal women. Fasting baseline serum from all incident colorectal cancer cases (N=438) and a random subcohort (N=816) of WHI-OS subjects was tested for insulin, glucose, total IGF-I, free IGF-I, IGF binding protein-3, and estradiol. Comparing extreme quartiles, insulin [Hazard Ratio,HR,q4-q1]=1.73, 95% confidence interval[CI], 1.16-2.57; Ptrend=0.005), waist circumference (HRq4-q1=1.82, 95%CI, 1.22-2.70; Ptrend=0.001), and free IGF-I (HRq4-q1=1.35, 95%CI, 0.92-1.98; Ptrend=0.05) were each associated with colorectal cancer incidence in multivariate models. However, these associations each became non-significant when adjusted for one another. Endogenous estradiol levels, in contrast, were positively associated with risk of colorectal cancer (HR comparing high versus low levels =1.53, 95% CI, 1.05-2.22), even after control for insulin, free IGF-I and waist circumference. These data suggest the existence of at least two independent biologic pathways that are related to colorectal cancer: one that involves endogenous estradiol, and a second pathway broadly associated with obesity, hyperinsulinemia, and free IGF-I.