Why Women Appear to Have Better Outcomes When Undergoing Screening for Lung Cancer

<b>Rationale:</b> Randomized controlled trials (RCTs) of lung cancer (LC) screening (LCS) using computed tomography (CT) documented LC mortality reductions between 7.2% and 29.2%, compared with a chest radiograph (CXR). Women appear to have a greater reduction than men. <b>Objectives:</b> We sought to determine why women appear to have better outcomes from LCS compared with men. <b>Methods:</b> We used a secondary analysis of the National Lung Screening Trial, an RCT comparing CXR with CT among screen-eligible individuals ages 55-74 years. Descriptive statistics and a competing risk proportional hazards model that included an interaction between sex and screening arm were used to examine differences in screening outcomes by sex. <b>Results:</b> Of 31,530 men and 21,922 women, 648 (2.1%) and 373 (1.7%) died of LC during the study, respectively. Overall mortality was higher in men: 2,771 (8.8%) versus 1,198 (5.5%). In an adjusted competing cause of death analysis, the LC mortality subdistribution hazard ratio (sHR) favoring CT was significant in women (sHR = 0.74; 95% confidence interval [CI] = 0.6-0.9; <i>P</i> = 0.003) but not men (sHR = 0.91; 95% CI = 0.78-1.06; <i>P</i> = 0.24). The interaction between screening arm and sex was not significant (<i>P</i> = 0.1). Chronic obstructive pulmonary disease and heart disease, which are more prevalent in men, were independently associated with LC death. LC deaths were consistently greater in the CT arm (vs. the CXR arm), for preexisting COPD and diabetes mellitus in men, but not women. Of those with LC, women in the CT arm had 53.7% prevalence of adenocarcinoma (AD) histology, whereas women in the CXR arm and men in both arms had approximately 36-41% AD prevalence. However, there was no overall difference between sexes in the screening difference for AD lethality. <b>Conclusion:</b> Women in the National Lung Screening Trial had a greater reduction in LC mortality that, although not statistically significant, could be the result of more prevalent comorbid disease in men, which contributed to greater all-cause and LC mortality.