Exon 20-Mutated NSCLC: Extending the Data Set to Allow the Recognition of Potential Causes (2023)

The consortium responsible for collecting data from 175 patients with EGFR exon 20-mutant NSCLC, the European EXOTIC Registry,1Mountzios G. Planchard D. Metro G. et al.Molecular epidemiology and treatment patterns of patients with EGFR exon 20-mutant NSCLC in the precision oncology era: the European EXOTIC Registry.JTO Clin Res Rep. 2023; 4100433PubMed Google Scholar has added an important piece of information and for that we like to congratulate the authors. To make this resource even more valuable, we like to encourage the consortium to expand this important work beyond the identification of novel and better treatment approaches and to develop a plan to recognize causal factors associated with exon 20 mutations (molecular archaeology). EGFR mutations, including those affecting exon 20, are more frequent in nonsmokers and never-smokers.2Zhang Y.L. Yuan J.Q. Wang K.F. et al.The prevalence of EGFR mutation in patients with non-small cell lung cancer: a systematic review and meta-analysis.Oncotarget. 2016; 7: 78985-78993Crossref PubMed Scopus (419) Google Scholar The increasing incidence of lung cancers in nonsmokers and never-smokers has been noticed in several parts of the world, and it is a formidable challenge to identify its cause(s) and to try to translate them into public health measures. Asbestos and air pollution (particulate matter [PM]2.5) are important causes of lung cancer in nonsmokers and never-smokers, and genetic susceptibility may contribute.3McKay J.D. Hung R.J. Han Y. et al.Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes.Nat Genet. 2017; 49: 1126-1132Crossref PubMed Scopus (315) Google Scholar Moreover, in contrast to multiple studies revealing carcinogenic synergy between smoking and asbestos exposure, little is known about the interaction between exposure to secondhand smoke and asbestos. Asbestos and PM2.5 exposures are found in occupational and in environmental settings, and a recent study concluded that PM2.5 exposure and EGFR mutations are responsible for alveolar cell transformation in nonsmokers and never-smokers.4Swanton C. Hill W. Lim E. et al.LBA1 Mechanism of action and an actionable inflammatory axis for air pollution induced non-small cell lung cancer: towards molecular cancer prevention.Ann Oncol. 2022; 33: S808-S869Google Scholar Considering that the average adult inhales approximately 10,000 liters of air per day, even carcinogens present at relatively low concentrations may pose a risk factor. Healthy never-smokers, exposed to PM2.5 (at the same concentration found in polluted cities) for 2 hours, had an inflammatory response (interleukin-1β) strong enough to drive alveolar cells into an activated state, ready to further transform into EGFR-mutant NSCLC.4Swanton C. Hill W. Lim E. et al.LBA1 Mechanism of action and an actionable inflammatory axis for air pollution induced non-small cell lung cancer: towards molecular cancer prevention.Ann Oncol. 2022; 33: S808-S869Google Scholar It is also important to note that after the massive rise of asbestos consumption in the previous century, this group of minerals is now ubiquitously present in our manmade environment. This contamination may provide an explanation as to why the incidence of asbestos-related cancers fails to decline in most of the countries which have banned the use of asbestos and asbestos-containing products.5van Zandwijk N. Reid G. Frank A.L. Asbestos-related cancers: the ‘Hidden Killer’ remains a global threat.Expert Rev Anticancer Ther. 2020; 20: 271-278Crossref PubMed Scopus (22) Google Scholar It may even be theorized that small asbestos particles (length <5 μm and considerably smaller than those asbestos fibers considered capable of inducing malignant mesothelioma) might become a part of PM2.5 pollution. To attribute lung cancer to asbestos, air pollution, secondhand cigarette smoke, or a combination of these carcinogens, occupational and ideally also residential data should be collected and made available. Radiologic signs of pleural plaques and pulmonary fibrosis have been accepted as indicative of asbestos exposure in the past, and the list of occupations associated with asbestos exposure is considerable. Adding occupational, residential histories and radiologic data to the EXOTIC database might well assist the consortium in getting closer to the cause(s) of exon 20-mutated NSCLC. Nico van Zandwijk, Christopher I. Amos, Oluf Dimitri Røe, Glen Reid, Sonja Klebe: Draft writing, Review and editing. Molecular Epidemiology and Treatment Patterns of Patients With EGFR Exon 20-Mutant NSCLC in the Precision Oncology Era: The European EXOTIC RegistryJTO Clinical and Research ReportsVol. 4Issue 1PreviewReal-world evidence regarding molecular epidemiology and management patterns of patients with EGFR exon-20 mutated, advanced NSCLC outside the context of clinical trials is lacking. Full-Text PDF Open AccessExtending the EXOTIC Database to Allow the Recognition of Potential Causes of Exon 20-Mutated NSCLCJTO Clinical and Research ReportsVol. 4Issue 5PreviewWe read with great interest the Letter to the Editor by Zandwijk et al.1 regarding our recent publication on the EXOTIC real-world database focusing on molecular epidemiology and clinical outcomes of exon 20-mutated NSCLC.2 We are particularly thankful to the authors for their innovative suggestion to expand the EXOTIC consortium to include data on occupational data, residential history, and radiological features in an effort to identify potential causative environmental factors for this challenging disease entity. Full-Text PDF Open Access