Lung cancer in never-smokers. Does smoking history matter in the era of molecular diagnostics and targeted therapy?

Lung cancer in never-smokers was recognised as a distinct clinical entity around the mid-2000s because these patients tended to be Asian women and diagnosed at a younger age with a preponderance of adenocarcinoma and better survival outcome despite a more advanced stage of presentation. It was soon discovered that lung cancer in never-smokers had a higher prevalence of activating EGFR mutations and we tend to classify lung cancer by smoking status for screening purpose. With the discoveries of many actionable driver mutations such as activating EGFR mutations and ALK rearrangement in adenocarcinoma of the lung we have switched to classifying non-small cell lung cancer into different individual molecular subgroups based on the presence of a dominant driver mutation. Although many actionable driver mutations are found in never-smokers with adenocarcinoma, this review will summarise that a substantial proportion of patients with these actionable driver mutations had a previous smoking history. Alternatively among the driver mutations that are associated with smoking history, a fair amount of these patients were never-smokers. Thus smoking status should not be used as a screen strategy for identifying driver mutations in clinical practice. Finally smoking history may have predictive and/or prognostic significance within individual molecular subgroups and identifying the difference according to smoking history may help optimise future targeted therapy.