Lung cancer in never smokers: Change of a mindset in the molecular era

Lung cancer is a leading cause of cancer-related mortality across the world. Although the majority of lung cancer is attributed to tobacco smoke, approximately 25% of lung cancers worldwide occur in lifelong never smokers. Over the past decades, the bulk of research on this disease suggested that several genetic, environmental, hormonal, and viral factors might increase the risk of lung cancer among never smokers. However, there has been no dominant risk factor whose significance has been validated across racial and ethnic groups. However, this subset of lung cancers has received renewed attention due to the introduction of the epidermal growth factor receptor-tyrosine kinase (EGFR-TK) inhibitors showing the dramatic therapeutic response on selected patients with activating EGFR mutations which occur more commonly in never smokers. The treatment strategy blocking EGFR pathway in EGFR-mutant lung cancer represents a remarkable example of molecular targeted therapies which completely repress tumor by inhibition of driving oncogenes. More recently, a surprising positive effect of an ALK inhibitor on EML4–ALK-positive lung cancer has been suggested that lung cancer in never smokers is likely to be an assemblage of molecularly defined subsets which would be a good candidate for personalized diagnostic and therapeutic approaches.