• Zheng Wu, Fengwei Tan, Zhuoyu Yang, Fei Wang, Wei Cao, Chao Qin, Xuesi Dong, Yadi Zheng, Zilin Luo, Liang Zhao, Yiwen Yu, Yongjie Xu, Jiansong Ren, Jufang Shi, Hongda Chen, Jiang Li, Wei Tang, Sipeng Shen, Ning Wu, Wanqing Chen, Ni Li, and Jie He.
• Office of Cancer Screening, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
• Chin. Med. J. 2022 Jun 5; 135 (11): 1331-1339.

BackgroundNon-smokers account for a large proportion of lung cancer patients, especially in Asia, but the attention paid to them is limited compared with smokers. In non-smokers, males display a risk for lung cancer incidence distinct from the females-even after excluding the influence of smoking; but the knowledge regarding the factors causing the difference is sparse. Based on a large multicenter prospective cancer screening cohort in China, we aimed to elucidate the interpretable sex differences caused by known factors and provide clues for primary and secondary prevention.MethodsRisk factors including demographic characteristics, lifestyle factors, family history of cancer, and baseline comorbidity were obtained from 796,283 Chinese non-smoking participants by the baseline risk assessment completed in 2013 to 2018. Cox regression analysis was performed to assess the sex difference in the risk of lung cancer, and the hazard ratios (HRs) that were adjusted for different known factors were calculated and compared to determine the proportion of excess risk and to explain the existing risk factors.ResultsWith a median follow-up of 4.80 years, 3351 subjects who were diagnosed with lung cancer were selected in the analysis. The lung cancer risk of males was significantly higher than that of females; the HRs in all male non-smokers were 1.29 (95% confidence interval [CI]: 1.20-1.38) after adjusting for the age and 1.38 (95% CI: 1.28-1.50) after adjusting for all factors, which suggested that known factors could not explain the sex difference in the risk of lung cancer in non-smokers. Known factors were 7% (|1.29-1.38|/1.29) more harmful in women than in men. For adenocarcinoma, women showed excess risk higher than men, contrary to squamous cell carcinoma; after adjusting for all factors, 47% ([1.30-1.16]/[1.30-1]) and 4% ([7.02-6.75]/[7.02-1])) of the excess risk was explainable in adenocarcinoma and squamous cell carcinoma. The main causes of gender differences in lung cancer risk were lifestyle factors, baseline comorbidity, and family history.ConclusionsSignificant gender differences in the risk of lung cancer were discovered in China non-smokers. Existing risk factors did not explain the excess lung cancer risk of all non-smoking men, and the internal causes for the excess risk still need to be explored; most known risk factors were more harmful to non-smoking women; further exploring the causes of the sex difference would help to improve the prevention and screening programs and protect the non-smoking males from lung cancers.Copyright © 2022 The Chinese Medical Association, produced by Wolters Kluwer, Inc. under the CC-BY-NC-ND license.

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