Lung cancer in never smokers: a different disease

Abstract

Lung cancer in never smokers (LCINS) is often considered a different disease entity with a distinct molecular sub-classification. Notably, actionable mutations in epidermal growth factor receptor (EGFR), v-Ki-ras2 Kirsten Rat sarcoma viral oncogene homolog (KRAS) and anaplastic lymphoma kinase (ALK)-rearrangement are three major recurrent oncogenic alterations in LCINS. HER2 and BRAF mutations, ROS1 and RET rearrangements are also included, although these are known to occur with low frequencies. Although the overall response rate (ORR) to EGFR tyrosine kinase inhibitors (TKIs) in unselected patients was only 10 %, subgroup analyses revealed comparatively higher response rates and survival in women, never smokers and Asians harbouring EGFR mutations, suggesting a predictive and/or prognostic significance among patients with mutated EGFR by smoking status. Differences in the prevalence of KRAS mutations between subgroups have also been described: 8 % of never smokers versus 57 % of former/current smokers with lung adenocarcinoma harbour KRAS mutations, and although 3 % to 5 % of unselected patients with lung adenocarcinoma have ALK rearrangements, the frequency appears to be more pronounced in never smokers. There is a suggestion that prognostic and predictive relevance of KRAS mutations varies by smoking status, but it is still less characterized as well as the smoking-related prognostic and predictive value of ALK rearrangement and the other alterations, which are still largely unknown. Clinical trials of lung cancer patients should always be stratified by smoking history and the identification of differences according to smoking status may help optimize future targeted therapies.