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Rationale: Chronic obstructive pulmonary disease (COPD) is a well-established independent risk factor for lung cancer; however, the literature on the association between asthma and lung cancer is mixed. Whether asthma-COPD overlap (ACO) is associated with lung cancer has not been studied. Objectives: We aimed to compare lung cancer risk among patients with ACO versus COPD and other conditions associated with airway obstruction. Methods: We studied 13,939 smokers from the National Lung Cancer Screening Trial who had baseline spirometry and used spirometric indices and history of childhood asthma to categorize participants into five specific airway disease subgroups. We used Poisson regression to compare unadjusted and adjusted lung cancer risk. Results: The incidence rate of lung cancer per 1,000 person-years was as follows: ACO, 13.2 (95% confidence interval [CI], 8.1-21.5); COPD, 11.7 (95% CI, 10.5-13.1); asthmatic smokers, 1.8 (95% CI, 0.6-5.4); Global Initiative for Chronic Obstructive Lung Disease-Unclassified, 7.7 (95% CI, 6.4-9.2); and normal spirometry smokers, 4.1 (95% CI, 3.5-4.8). Patients with ACO had increased adjusted risk of lung cancer compared with patients with asthma (incidence rate ratio [IRR], 4.5; 95% CI, 1.3-15.8) and normal spirometry smokers (IRR, 2.3; 95% CI, 1.3-4.2) in models adjusting for other risk factors. Adjusted lung cancer incidence in patients with ACO and COPD were not found to be different (IRR, 1.2; 95% CI, 0.7-2.1). Conclusions: The risk of lung cancer among patients with ACO is similar to those with COPD and higher than other groups of smokers. These results provide further evidence that COPD, with or without a history of childhood asthma, is an independent risk factor for lung cancer. [ABSTRACT FROM AUTHOR]