Lung cancer in never smokers presents unique molecular traits and lower mutation burdens, necessitating distinct treatment strategies and revised screening criteria.

Lung cancer in never smokers is gaining attention due to its distinct clinical, pathological, and biological features, fostering research into its molecular basis. Despite tobacco smoking being the primary risk factor for lung cancer, a significant number of cases occur in never smokers, who have different potential risk factors and molecular characteristics. Recent genome sequencing studies of tumors from never smokers have revealed that these cancers have lower tumor mutation burdens (TMB) and different oncogenic driver mutations compared to those in smokers, with implications for treatment and early detection strategies.

Studies have identified specific molecular drivers in lung cancer among never smokers, such as higher prevalence of EGFR mutations and lower incidence of KRAS mutations, influencing therapeutic approaches. Lung adenocarcinomas in never smokers also show lower PD-L1 expression, affecting their responsiveness to immunotherapy. The classification of lung cancers in never smokers into distinct molecular subtypes suggests the need for tailored treatment strategies, with some subtypes potentially benefiting from targeted therapies or immunotherapies, while others may require novel approaches.

The Sherlock-Lung study highlighted the existence of three molecular subtypes of non-small cell lung cancer (NSCLC) in never smokers, each with different genomic characteristics and potential treatment strategies. The study also found significant differences in the growth rates of these subtypes, affecting their latency periods and the timing of detection. These findings underscore the importance of considering expanded screening criteria for never smokers, as current recommendations focus on smokers, despite the increasing proportion of lung cancer cases in never smokers.

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