Risk Factors Associated With Incidence of Lung Cancer in Never-Smokers: A Systematic Review and Meta-Analysis.

OBJECTIVES

Lung cancer is the leading cause of cancer mortality globally. Although often associated with smoking, up to 25% of cases worldwide and 50% in East Asia occur in "never-smokers." There are currently no robust tools for predicting lung cancer in individuals who have never smoked (LCINS) for populations outside East Asia.Together with a group of patient representatives, the authors of this study aimed to summarise risk factors for LCINS and quantify risk in different geographical regions.

METHODS

This study was prospectively registered (PROSPERO-CRD42022379253). The systematic review and meta-analysis included studies published from 2017 and aimed to comprehensively investigate risk factors associated with LCINS incidence. Risk of bias was assessed using Newcastle-Ottawa Scale.

RESULTS

A total of 6725 reports were identified and 54 studies were included, with multivariable analysis of 192 factors in 16 million never-smokers. No studies were assessed as having high risk of bias. Of the participants, 8,241,269 (51.0%) were from Western countries.The meta-analysis found that female sex (adjusted hazard ratio [aHR] 1.28 [95% confidence interval or CI 1.12-1.47]), previous cancer (aHR 2.04 [1.95-2.13]), rheumatoid arthritis (aHR 1.41 [1.15-1.73]), passive smoking (aHR 1.30 [1.22-1.40]), PM10 (aHR 1.10 [1.09-1.11]), and PM2.5 (aHR 1.16 [1.03-1.30]) pollution were associated with LCINS. In planned subgroup analyses by region, LCINS was associated with family history of lung cancer in East Asian (aHR 1.56 [1.23-1.98]) but not Western countries (aHR 0.86 [0.35-2.11]).

CONCLUSION

We found key factors linked with LCINS, including female sex, rheumatoid arthritis, and pollution and, for the first time, quantified their association through meta-analyses of studies globally. This may be used to develop tools to detect LCINS earlier.