Abstract 2268: Serum insulin and glucose, indices of insulin resistance, and risk of lung cancer

Background: Although insulin is crucial in human growth and development, it also harbors antiapoptotic properties and acts as a growth factor by stimulating mitosis through the Akt pathway, which could lead to tumor growth and promotion. Insulin has been positively associated with several cancer sites, but no studies to date have examined fasting serum insulin concentrations and risk of lung cancer. Methods: The Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study was a randomized, double-blind intervention trial conducted among 29,133 male smokers in southwest Finland. Participants were randomly assigned to one of four groups in a 2x2 factorial design (α-tocopherol alone, β-carotene alone, both supplements, or placebo). 196 lung cancer cases and 395 subcohort members were sampled from the larger cohort. Fasting serum collected at enrollment (5-12 years prior to diagnosis) was analyzed for insulin using a double-antibody immunochemiluminometric assay, and for glucose using a hexokinase assay. Cox proportional hazards models were used to estimate the hazard ratio (HR) and 95% confidence intervals (CI) of lung cancer risk by quartiles of insulin, glucose, and surrogate indices of insulin resistance (insulin:glucose molar ratio and homeostasis model assessment of insulin resistance [HOMA-IR]). Multivariable models adjusted for age, BMI, family history of lung cancer, and pack-years of smoking. Results: Insulin was positively associated with risk of lung cancer (Q4 vs. Q1 HR: 2.10, 95% CI: 1.12, 3.94). A similar association was seen with HOMA-IR (Q4 vs. Q1 HR: 1.83, 95% CI: 0.99, 3.38). We observed no statistically significant associations with glucose or the insulin:glucose molar ratio (P-trend=0.55 and P-trend = 0.27, respectively). Insulin and HOMA-IR were associated with lung cancer risk regardless of stage, although the findings were stronger for the lower stage cancers (Q4 vs. Q1 insulin, stage I-II HR=2.85, 95% CI: 1.14, 7.15, P-trend=0.01; stage III-IV HR=0.94, 95% CI: 0.93 - 4.06, P-trend=0.23; HOMA-IR stage I-II HR=2.25, 95% CI 0.89-5.69, P-trend=0.02, stage III-IV HR=1.78, 95% CI=0.87 - 3.61, P-trend=0.34). Findings were similar across histologic subtypes of lung cancer. Conclusion: Higher fasting serum insulin and insulin resistance appear to be associated with an increased risk of lung cancer. In addition, elevated insulin concentrations may be more strongly associated with lower stage lung malignancies, suggesting a role for insulin in