Lung cancer in never smokers — a different disease

Key Points About 25% of lung cancer cases worldwide are not attributable to tobacco smoking. Thus, lung cancer in never smokers is the seventh leading cause of cancer deaths in the world, killing more people every year than pancreatic or prostate cancers. Globally, lung cancer in never smokers demonstrates a marked gender bias, occuring more frequently among women. In particular, there is a high proportion of never smokers in Asian women diagnosed with lung cancer. Although smoking-related carcinogens act on both proximal and distal airways inducing all the major forms of lung cancer, cancers arising in never smokers target the distal airways and favour adenocarcinoma histology. Environmental tobacco smoke (ETS) is a relatively weak carcinogen and can only account for a minority of lung cancers arising in never smokers. Although multiple risk factors, including environmental, hormonal, genetic and viral factors, have been implicated in the pathogenesis of lung cancer in never smokers, no clear-cut dominant factor has emerged that can explain the relatively high incidence of lung cancer in never smokers and the marked geographic differences in gender proportions. Molecular epidemiology studies, in particular of the TP53 , KRAS and epidermal growth factor receptor ( EGFR ) genes, demonstrate strikingly different mutation patterns and frequencies between lung cancers in never smokers and smokers. There are major clinical differences between lung cancers arising in never smokers and smokers and their response to targeted therapies. Indeed, non-smoking status is the strongest clinical predictor of benefit from the EGFR tyrosine kinase inhibitors. The above-mentioned facts strongly suggest that lung cancer arising in never smokers is a disease distinct from the more common tobacco-associated forms of lung cancer. Further efforts are needed to identify the major cause or causes of lung cancers arising in never smokers before successful strategies for prevention, early diagnosis and novel therapies can be implemented. Approximately 25% of lung cancer cases worldwide are not attributable to smoking, accounting for over 300,000 deaths each year. What do we know about this unique but poorly characterized disease? Although most lung cancers are a result of smoking, approximately 25% of lung cancer cases worldwide are not attributable to tobacco use, accounting for over 300,000 deaths each year. Striking differences in the epidemiological, clinical and molecular charac