Although air pollution is associated with lung cancer, not much has been known about how one leads to the other. For the first time, researchers have identified a mechanism by which particulate matter in the air triggers non–small cell lung cancer (NSCLC) in people who have never smoked. Moreover, the same air pollutants linked to climate change are implicated in the development of NSCLC in never-smokers, according to these findings.

Globally, air pollution is responsible for over 7 million deaths per year. These new data link the importance of addressing climate health to improving human health.

— Charles Swanton, FRCP, FRS, MBPhD

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The study was presented during a Presidential Symposium at the European Society for Medical Oncology (ESMO) Congress 2022 in Paris by Charles Swanton, FRCP, FRS, MBPhD, the Francis Crick Institute and Cancer Research UK Chief Clinician, London.1 The data showed that exposure to airborne particulate matter ≤ 2.5 μm in diameter increases the risk of NSCLC with EGFR mutations, the most common mutation-driven type of NSCLC. Air pollution drives the release of the inflammatory mediator interleukin-1 beta (IL-1β) from epithelial cells and macrophages, which acts on cells with EGFR mutations to promote lung cancer development. 

Linking Climate Health to Human Health

These particles are typically found in vehicle exhaust and smoke from fossil fuels. Exposure to these pollutants can trigger NSCLC in cells with EGFR and KRAS gene mutations. EGFR mutations are seen in lung cancers of about 50% of never-smokers, and this new research may pave the way to new prevention approaches, according to experts.

“The same particles in the air that derive from the combustion of fossil fuels are directly impacting human health via an important and previously overlooked cancer-causing mechanism on lung cells. The risk of lung cancer from air pollution is at least 10-fold lower than from smoking [cigarettes], but we have no control over what we breathe. Globally, more people are exposed to unsafe levels of air pollution than to toxic chemicals in cigarette smoke, with air pollution responsible for over 7 million deaths globally. These new data link the importance of addressing climate health to improving human health,” said Dr. Swanton.

The findings are derived from basic and human research on mutations in EGFR and lung epithelial biology. The study included almost 474,000 people from England, South Korea, and Taiwan to look at the association between exposure to air pollution in these regions and the development of NSCLC. Increasing levels of particulate matter ≤ 2.5 μm in diameter were associated with an increased risk of EGFR-mutated NSCLC and mesothelioma, among other diseases.

The researchers performed ultradeep profiling of 247 normal lung tissue samples and analyzed normal lung tissue from humans following exposures to particulate matter. EGFR and KRAS driver mutations were found in 15% and 53% of the normal lung tissue samples, respectively.

“Particulate matter promotes a macrophage response and a progenitor-like state in lung epithelium harboring mutant EGFR. Consistent with these findings, exposure to particulate matter increased tumor burden in EGFR- or KRAS-driven lung cancer models in a dose-dependent manner,” Dr. Swanton explained.

“These results shed light on the etiology of EGFR-mutated NSCLC, particularly in never-smokers…, in the absence of classic carcinogen-driven mutagenesis,” Dr. Swanton said. “The next step is to discover why some lung cells with mutations become cancerous when exposed to air pollutants, whereas others don’t.”

Comment on the Study

“This research is intriguing and exciting, as it means that we can ask whether, in the future, it will be possible to use low-dose CT [computed tomography] scans to look for precancerous lesions in the lungs and try to reverse them with ­medicines such as IL-1β inhibitors. We don’t yet know whether it will be possible to use highly sensitive EGFR profiling on blood or other samples to identify the high-risk nonsmokers who are predisposed to lung cancer and may benefit from screening low-dose CT scan, so discussions are still very preliminary and more work needs to be done,” said Tony S.K. Mok, MD, FRCPC, FASCO, of the Chinese University of Hong Kong, who was not involved in the study.

“As consumption of fossil fuels goes hand in hand with pollution and carbon emissions, we have a strong mandate for tackling these issues—both for environmental and health reasons,” Dr. Mok stated. 

DISCLOSURE: Dr. Swanton served as director, officer, partner, employee, advisor, consultant, or trustee for Cancer Research UK and National Cancer Research Institute; has received research grants from Pfizer, AstraZeneca, and Bristol Myers Squibb; has a 5% or greater equity interest in ApoGen Biotechnologies, Epic Bioscience, Grail, and Achilles Therapeutics; and has received income in an amount equal to or greater than $250 from Boehringer Ingelheim, Eli Lilly, Novartis, Roche-Genentech, GlaxoSmithKline, Pfizer, Bristol Myers Squibb, Celgene, AstraZeneca, and Illumina. Dr. Mok has a leadership role in Sanomics Limited, Hutchison MediPharma, and AstraZeneca; has stock/other ownership interests in Sanomics Limited and Hutchison MediPharma; has received honoraria from AstraZeneca, Roche/Genentech, Lilly, Bristol Myers Squibb, Boehringer Ingelheim, Novartis, Merck Sharp & Dohme, Pfizer, Merck Serono, SFJ Pharmaceuticals Group, ACEA Biosciences, Vertex, Celgene, Ignyta, Fishawack Facilitate, Takeda, Janssen, and Hutchison MediPharma; is a consultant/advisor for AstraZeneca, Roche/Genentech, Lilly, Merck Serono, Bristol Myers Squibb, Pfizer, Boehringer Ingelheim, Novartis, Clovis Oncology, Vertex, SFJ Pharmaceuticals Group, ACEA Biosciences, Merck Sharp & Dohme, GeneDecode, OncoGenex, Celgene, Ignyta, Cirina, and Hutchison MediPharma; and has received institutional research funding from AstraZeneca, Boehringer Ingelheim, Pfizer, Novartis, SFJ Pharmaceuticals Group, Roche, Merck Sharp & Dohme, Clovis Oncology, Bristol Myers Squibb, and Xcovery. 

REFERENCE

1. Swanton C, Hill W, Lim E, et al: Mechanism of action and an actionable inflammatory axis for air pollution induced non-small cell lung cancer: Towards molecular cancer prevention. ESMO Congress 2022. Abstract LBA1. Presented September 10, 2022.