Prospective study of colorectal cancer risk in men and plasma levels of insulin-like growth factor (IGF)-I and IGF-binding protein-3

BACKGROUND: Insulin-like growth factor-I (IGF-I) is a potent mitogen for normal and neoplastic cells, whereas IGF-binding protein-3 (IGFBP-3) inhibits cell growth in many experimental systems. Acromegalics, who have abnormally high levels of growth hormone and IGF-I, have higher rates of colorectal cancer. We therefore examined associations of plasma levels of IGF-I and IGFBP-3 with the risk of colorectal cancer in a prospective case-control study nested in the Physicians' Health Study. METHODS: Plasma samples were collected at baseline from 14916 men without diagnosed cancer. IGF-I, IGF-II, and IGFBP-3 were assayed among 193 men later diagnosed with colorectal cancer during 14 years of follow-up and among 318 age- and smoking-matched control subjects. All P values are two-sided. RESULTS: IGFBP-3 levels correlated with IGF-I levels (r=.64) and with IGF-II levels (r=.90). After controlling for IGFBP-3, age, smoking, body mass index (weight in kg/[height in m]2), and alcohol intake, men in the highest quintile for IGF-I had an increased risk of colorectal cancer compared with men in the lowest quintile (relative risk [RR]=2.51; 95% confidence interval [CI]=1.15-5.46; P for trend = .02). After controlling for IGF-I and other covariates, men with higher IGFBP-3 had a lower risk (RR=0.28; 95% CI=0.12-0.66; P for trend = .005, comparing extreme quintiles). The associations were consistent during the first and the second 7-year follow-up intervals and among younger and older men. IGF-II was not associated with risk. CONCLUSIONS: Our findings suggest that circulating IGF-I and IGFBP-3 are related to future risk of colorectal cancer.