Only 10%–20% of tobacco smokers develop lung cancer. Identifying biomarkers associated with susceptibility to lung cancer in ever-smokers may help to identify high-risk individuals for lung cancer screening. The epidermal growth factor receptor (EGFR) signaling network is involved in lung carcinogenesis. This study examined whether 6 ligands that activate or suppress these signaling pathways were associated with lung cancer in ever-smokers. A nested case-control study within the Women's Health Initiative cohort of postmenopausal women assessed baseline plasma levels of insulin, insulin-like growth factor (IGF)-1, insulin-like growth factor binding protein (IGFBP)-3, interleukin (IL)-6, hepatocyte growth factor (HGF), and nerve growth factor (NGF) in 1143 ever-smoking lung cancer cases and 1143 controls. Baseline level of leptin was also measured as an adiposity biomarker. Similar to BMI, leptin level was inversely associated with lung cancer risk [odds ratio (OR) per Ln (pg/mL) = 0.85, 95% confidence interval (CI) = 0.74 to 0.98]. After adjusting for adiposity and other lung cancer risk factors, high insulin levels were associated with increased lung cancer risk [OR for 4th quartile vs. others (ORq4) = 2.06, 95% CI = 1.30 to 3.26], whereas IGFBP-3 had a linear inverse association (OR per μg/mL = 0.64, 95% CI = 0.41 to 0.98), in current smokers, but not former smokers. The insulin association was consistent across subgroups defined by BMI and histological type, but the IGFBP-3 association was specific for small cell lung cancer. There was a modest, positive association between IGF-1 and lung cancer risk in current smokers (ORq4 = 1.44, 95% CI = 0.90 to 2.29). Null associations were found for IL-6, HGF, and NGF. High insulin levels, but reduced levels of IGFBP-3, were associated with increased lung cancer risk in current smokers. Involvement of insulin in lung cancer was independent of obesity.
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