Background: Lung cancer in never smokers (LCINS) is the fifth leading cause of cancer deaths worldwide, affecting disproportionately women and Asian populations. Recent studies suggest that an increasingly higher proportion of lung cancer in female never-smokers may have been overdiagnosed in China, raising concerns about the benefit-and-harm balance of lung cancer screening in this population.
Objectives: We aimed to micro-simulate and compare the overdiagnosis estimates and benefits of various risk-factor-based lung cancer screening strategies for female never-smokers in China.
Methods: We developed a microsimulation model, which was calibrated and validated by Chinese population-based data, to simulate the lifetime overdiagnosis and benefits of lung cancer screening among 100,000 Chinese female individuals aged 45-80 years. We compared 672 screening strategies by combining initial age (45, 50, and 55 years), stopping age (74 and 80 years), different risk-factor-based screening strategies, and screening frequency (annual screening, 1-year interval, 2-year interval, 3-year interval, 4-year, and 5-year interval, once per lifetime screening). For each scenario, we calculated the number and proportion of overdiagnosed cases (O), lung cancer deaths averted by screening (D) per one overdiagnosed case (D/O ratio), and quality-adjusted life years gained (QALYG) by screening per one overdiagnosed case (QALYG/O ratio) to assess the trade-off between benefits and harms.
Results: Overdiagnosis cases per 100,000 individuals and overdiagnosis rates among 672 screening scenarios ranged from 31 and 0.8% to 1233 and 10.2%. Quantitative analyses revealed that all screening scenarios exhibited D/O ratios surpassing one (range:1.5-3.6). Stopping age of screening had the most significant impact on outcome metrics: stopping screening at 74 versus 80 years could reduce the risk of overdiagnosis by 60% and thereby elevate D/O ratios by 35% and QALYG/O ratios by 52%; whereas initial age had no significant impact. A total of 22 efficient strategies were identified, all of which included a chronic obstructive pulmonary disease diagnosis, and 77% required passive smoking exposure; 82% of them set the stopping age at 74 years; and the dominant screening intervals were 1?4 years.
Conclusion: Given the risk of overdiagnosis in screening never-smoking women, careful consideration of the screening stopping age, high-risk population definition, and screening interval is needed to optimize the tradeoff between the benefits and harms.

(A) Lung cancer deaths averted by screening per overdiagnosis cases (D/O ratios), and (B) Quality-adjusted life years (QALYs) gained by screening per overdiagnosis cases (QALYG/O ratios) among 672 risk-factor-based screening strategies.