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Clin Lung Cancer. 2017 Sep;18(5):535-542. doi: 10.1016/j.cllc.2017.01.005. Epub 2017 Jan 19.

Association Between Environmental Tobacco Smoke Exposure and the Occurrence of EGFR Mutations and ALK Rearrangements in Never-smokers With Non-Small-cell Lung Cancer: Analyses From a Prospective Multinational ETS Registry.

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Department of Haematology-Oncology, National University Health System and Cancer Institute of Singapore, Singapore, Singapore.
Division of Respiratory Medicine and Allergology, Aichi Medical University School of Medicine, Nagakute, Japan.
Center for Advanced Medicine and Clinical Research, Nagoya University Hospital, Nagoya, Japan. Electronic address:
Department of Respiratory Medicine/Medical Oncology, Osaka City University, Osaka, Japan.
Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Chao Family Comprehensive Cancer Center, University of California Irvine, Orange, CA.



Molecular studies have demonstrated actionable driver oncogene alterations are more frequent in never-smokers with non-small-cell lung cancer (NSCLC). The etiology of these driver oncogenes in patients with NSCLC remains unknown, and environmental tobacco smoke (ETS) is a potential cause in these cases.


We assembled clinical and genetic information for never-smoker patients with NSCLC accrued in Japan, Korea, Singapore, and the United States. To determine an association between cumulative ETS and activating EGFR mutations or ALK rearrangements, the Mantel extension test was used. Multivariate analysis on activating EGFR and ALK gene rearrangements was performed using the generalized linear mixed model with nations as a random effect.


From July 2007 to December 2012, 498 never-smokers with pathologically proven NSCLC were registered and tested for the association between ETS and EGFR and ALK status. EGFR mutations were more frequent in the ever-ETS cohort (58.4%) compared with the never-ETS cohort (39.6%), and the incidence of EGFR mutations was significantly associated with the increment of cumulative ETS (cETS) in female never-smokers (P = .033), whereas the incidence of ALK rearrangements was not significantly different between the ever-ETS and never-ETS cohorts. Odds ratio for EGFR mutations for each 10-year increment in cETS was 1.091 and 0.89 for female and male never-smokers (P = .031 and P = .263, respectively).


Increased ETS exposure was closely associated with EGFR mutations in female never-smokers with NSCLC in the expanded multinational cohort. However, the association of ETS and ALK rearrangements in never-smokers with NSCLC was not significant.


ALK gene rearrangements; EGFR mutations; Lung cancer; Never smoker; Passive smoking

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