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

## TL;DR

This study identifies risk factors for lung cancer in never-smokers, including pollution and rheumatoid arthritis, and highlights regional differences in risk.

## Contribution

The study quantifies global risk factors for lung cancer in never-smokers and identifies regional variations, such as family history differences between East Asia and the West.

## Key findings

- Female sex, rheumatoid arthritis, and pollution are significant risk factors for lung cancer in never-smokers.
- Family history of lung cancer is a risk factor in East Asia but not in Western countries.
- The study analyzed 16 million never-smokers across 54 studies to identify these risk factors.

## Abstract

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.

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.

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]).

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.

Together with a group of patient representatives, the authors in this study designed an infographic to highlight key factors associated with LCINS as identified in the systematic review and meta-analysis that will be of interest to health care professionals and members of the public.