Serum insulin-like growth factor (IGF) and IGF-binding protein levels and risk of lung cancer: A case-control study nested in the β-carotene and retinol efficacy trial cohort

Recent prospective studies have suggested that insulin-like growth factor (IGF)-I levels are related to risk of some epithelial cancers. We previously reported in a case-control study a significant association between IGF-I level and lung cancer risk, with a 2-fold increased risk in the highest quartile. We now report the results of a lung cancer case-control study nested in the placebo arm of the β-Carotene and Retinol Efficacy Trial in heavy smokers. We identified 159 cases for whom sera had been collected at least 3 years before diagnosis and for whom 2 suitable controls/case (final number, 297) could be matched from the same study arm on age (within 5-year intervals), sex, ethnicity, year of enrollment into the β-Carotene and Retinol Efficacy Trial, year of blood draw, and exposure category (smoking or asbestos). The cases were significantly heavier smokers than the controls (mean pack-years, 58.7 and 45.9, respectively; P < 0.001). An inverse relationship between IGF-I level and age was evident only for former smokers, and not for those who were current smokers at the time of blood draw. Both IGF-I and IGF-binding protein (IGFBP)-3 levels were higher in cases than in controls, but none of the differences achieved statistical significance. The odds ratios for IGF-I were around unity, except for subsets of heaviest smokers and those who had quit smoking for the longest period of time, in whom there were elevated risks in the second to fourth quartiles of IGF-I relative to the first quartile (odds ratios, 2.21-2.91), although again, none achieved statistical significance. For younger subjects, IGF-I was inversely associated with lung cancer risk in the models that also controlled for IGFBP-3. Elevated risks for lung cancer were noted in the highest quartile of IGFBP-3 level, and these tended to be higher in current smokers and more recent quitters. These results do not support the conclusions of our prior case-control study. It is possible that current smoking or recent cessation may exert a suppressive effect on IGF-I levels (notably in younger subjects with higher baseline levels) that may obscure a relatively modest association between IGF-I level and lung cancer risk. On the other hand, risks associated with elevated IGFBP-3 level tended to be higher in current smokers and more recent quitters. This trend toward a positive association with IGFBP-3 level is unexpected and requires further investigation. Finally, from these data, we cannot exclude the possibility that risk of lung cancer in nonsmokers may be related to IGF-I levels.