BACKGROUND-AIM:
The ultimate benefit of lung cancer screening (LCS) is limited by the overwhelming competing risks of death in heavy smokers, but LCS represents a significant opportunity to stop smoking. This study evaluated the cumulative long-term mortality changes achieved by smoking cessation in three prospective LCS trials.

METHODS:
The association between smoking status and overall mortality was analysed in participants to the MILD, BioMILD, and SMILE trials using Cox proportional hazards models, with smoking status treated as a time-dependent exposure. Baseline sociodemographic (age and sex) and clinical characteristics were summarized as counts (%) for categorical variables and medians with interquartile ranges [IQR] for continuous variables. Age was categorized into tertiles (≤55, 56–60, and >60 years), and clinical biomarkers were classified using standard thresholds: Coronary Artery Calcium score (CAC) >400; Forced Expiratory Volume in 1 second (FEV₁) <80% of predicted value; and Tiffeneau Index (TIF) <70%. Participants contributed person-time to the categories “Smokers”, “Ex-smokers”, or “Quitters” according to changes in smoking behavior during follow-up. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated, adjusting for age and sex, using Smokers as the reference group. The cumulative hazard of overall mortality was graphically depicted according to changes in smoking status over time.

RESULTS:
A total of 7459 individuals were included, with a median follow-up of 9.5 years and 766 deaths; among them, 1827 (24.5%) had stopped smoking before LCS start (Ex-smokers) and 5632 (75.5%) were active smokers. During follow-up, 4040 (54.2%) continued to smoke (Smokers), and 1592 (21.3%) stopped smoking (Quitters). Smoking status was strongly associated with mortality across all clinical subgroups examined. Compared with Smokers, Ex-smokers and Quitters had substantially lower mortality risk, with overall 10-year mortality HRs of 0.64 (95%CI 0.5-0.81) and 0.63 (0.47-0.85), respectively. In clinical subgroups, HRs were 0.50 (0.32-0.77) and 0.44 (0.25-0.79) for 1001 CAC>400, 0.59 (0.37-0.94) and 0.50 (0.28-0.89) for 1031 FEV₁<80%, and 0.55 (0.37-0.8) and 0.47 (0.29-0.76) for 1735 TIF<70%.

CONCLUSIONS:
Overall, these findings demonstrate a consistent and robust mortality reduction associated with smoking cessation, whether occurring before LCS or during follow-up. The benefit was even more pronounced in individuals with clinical markers indicative of chronic cardio-pulmonary disease.