Lung Cancer in Never-Smokers: Risk Factors, Driver Mutations, and Therapeutic Advances

Our plain-English summary of Lung Cancer in Never-Smokers: Risk Factors, Driver Mutations, and Therapeutic Advances, by P.M. Chen, Y.H. Huang, C.Y. Li (Diagnostics, 2026).

The study

• Authors: P.M. Chen, Y.H. Huang, C.Y. Li
• Journal: Diagnostics
• Published: 2026;16(2)
• Type of article: Review
• Cited by: 10 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background and Objectives: Lung cancer in never-smokers (LCINS) has become a major global health concern, ranking as the fifth leading cause of cancer-related mortality. Unlike smoking-related lung cancer, LCINS arises from complex interactions between environmental carcinogens and distinct genomic alterations. This review summarizes current evidence on environmental risks, molecular features, and therapeutic progress shaping lung cancer management. Methods: A narrative review was conducted to examine risk factors for lung cancer in non-smokers. Studies reporting driver mutations in never-smokers and smokers were identified across major lung cancer histological subtypes, including small-cell lung cancer (SCLC), lung adenocarcinoma (LUAD), squamous cell carcinoma (SCC), and large-cell carcinoma (LCC). In addition, PubMed was searched for phase III trials and studies on targeted therapies related to driver mutations published between 2016 and 2025. Results: Environmental factors such as cooking oil fumes, radon, asbestos, arsenic, and fine particulate matter (PM2.5) are strongly associated with LCINS through oxidative stress, DNA damage, and chronic inflammation. EGFR, PIK3CA, OS9, MET, and STK11 mutations are characteristic of never-smokers, in contrast to TP53 mutations, which are more common in smokers. Recent advances in targeted therapy and immunotherapy have improved survival and quality of life, emphasizing the importance of molecular profiling for treatment selection. Conclusions: LCINS represents a distinct clinical and molecular entity shaped by complex interactions between environmental exposures and genetic susceptibility. Genetic alterations promote tumor immune evasion, facilitating cancer development and progression. Continued advances in air quality control, molecular diagnostics, and precision therapies are essential for prevention, early detection, and reduction of the global disease burden.

In plain English

This article was a narrative review of lung cancer in people who never smoked, and it reported no new data. The authors searched PubMed for studies published from January 2016 to October 2025 on gene mutations in never-smokers and smokers, and on phase III treatment trials. They also described earlier research on risk factors such as cooking oil fumes, fine particulate matter (PM2.5), radon, arsenic and asbestos. Asbestos was covered briefly, by summarizing other studies. The review stated that chrysotile and amphibole fibers cause chronic lung inflammation. It also stated that combined asbestos and cigarette smoke exposure raises lung cancer risk up to fivefold compared with unexposed nonsmokers. In the earlier studies the authors compiled, EGFR and some other mutations were more common in never-smokers, and TP53 was more common in smokers. In one small-cell lung cancer study, TP53 was found in 59% of never-smokers versus 85% of current or former smokers. The authors concluded that lung cancer in never-smokers is a biologically distinct disease. They noted that study selection may be biased and that evidence quality was not formally assessed.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Narrative review of published literature; no new data were collected
• Who was studied: Published studies found through PubMed, January 2016 to October 2025: studies of driver mutations by smoking status across small-cell lung cancer, lung adenocarcinoma, squamous cell carcinoma and large-cell carcinoma, and phase III treatment trials
• Exposure: Environmental risk factors for lung cancer in never-smokers, described from other studies: cooking oil fumes, PM2.5, radon, arsenic, secondhand smoke and asbestos. Asbestos is discussed only in a brief passage that names chrysotile and amphiboles.
• Main results:
  • Citing earlier work (reference 67), the review stated that combined exposure to asbestos and cigarette smoke raises lung cancer risk up to fivefold compared with unexposed nonsmokers. This is not a finding of this review's own analysis.
  • In a cited small-cell lung cancer study, TP53 mutations were less frequent in never-smokers than in current/former smokers: 32/54 (59%) vs 518/608 (85%), p less than 0.001
  • In cited lung adenocarcinoma studies, EGFR mutations were more common in never-smokers than in smokers: 62% vs 13% in a small cohort and 65% vs 41% in a large cohort (both p less than 0.001)
  • In a cited large-cell carcinoma study, there were no significant differences between never-smokers and current/former smokers in EGFR, KRAS, ALK or PIK3CA mutation frequencies
  • In a cited 2016 phase III trial of pembrolizumab in metastatic NSCLC with PD-L1 of 50% or more, no progression-free survival improvement was reported among never-smokers, whereas improvement was observed among smokers
• The authors' conclusion: The authors concluded that lung cancer in never-smokers is a biologically distinct entity driven by interactions between environmental carcinogens and specific genomic alterations
• Limitations the authors state:
  • As a narrative rather than systematic review, the choice of included studies and trials may be subject to selection bias
  • Environmental exposure studies differ substantially in methods, exposure measurement and region, which complicates comparison
  • Associations with environmental exposures may be influenced by confounders
  • The quality of included evidence was not formally assessed, and relevant studies may have been missed

Topics

Medical terms in this study, explained in our Lexicon: Lung Cancer, Histological Subtype, Lung Adenocarcinoma, Squamous Cell Carcinoma, Carcinoma, Oxidative Stress, Chronic Inflammation, EGFR.

Related studies

• Association between lung cancer somatic mutations and occupational exposure in never-smokers — C. Paris, P. Do, et al. (2017)
• Pulmonary adenocarcinoma with epidermal growth factor receptor-mutations in asbestos exposed non-smokers: A case series — R.L. Kradin, J. Iafrate, et al. (2017)
• Lung cancer in never smokers: a review — J. Subramanian, R. Govindan (2007)
• Expiratory and inspiratory forced vital capacity and one-second forced volume in asymptomatic never-smokers in Norway — A. Gulsvik, T. Tosteson, et al. (2001)
• Driver Gene and Novel Mutations in Asbestos-Exposed Lung Adenocarcinoma and Malignant Mesothelioma Detected by Exome Sequencing — S. Mäki-Nevala, V.K. Sarhadi, et al. (2016)
• YAP/TAZ activation predicts clinical outcomes in mesothelioma and is conserved in in vitro model of driver mutations — R. Cunningham, S. Jia, et al. (2023)

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