A new mechanism has been identified through which very small pollutant particles in the air may trigger lung cancer in people who have never smoked, paving the way to new prevention approaches and the development of novel therapies, according to late-breaking data reported by Charles Swanton, MBBS, PhD, and colleagues at the European Society for Medical Oncology (ESMO) Congress 2022 (Abstract LBA1). The particles, which are typically found in vehicle exhaust and smoke from fossil fuels, are associated with non–small cell lung cancer (NSCLC) risk, accounting for over 250,000 lung cancer deaths globally per year, according to data published by Liu et al in Frontiers in Medicine and by Turner et al in CA: A Cancer Journal for Clinicians. 

Charles Swanton, MBBS, PhD

“The same particles in the air that derive from the combustion of fossil fuels, exacerbating climate change, are directly impacting human health via an important and previously overlooked cancer-causing mechanism in lung cells. The risk of lung cancer from air pollution is lower than from smoking, but we have no control over what we all breathe. Globally, more people are exposed to unsafe levels of air pollution than to toxic chemicals in cigarette smoke, and these new data link the importance of addressing climate health to improving human health,” said Dr. Swanton, of the Francis Crick Institute and Cancer Research UK Chief Clinician, who presented the research results at the ESMO 2022 Presidential Symposium on Saturday, September 10.

Effect on EGFR and KRAS Mutations

The new findings are based on human and laboratory research on mutations in the EGFR gene, which are seen in about half of people with lung cancer who have never smoked. In a study of nearly half a million people living in England, South Korea, and Taiwan, exposure to increasing concentrations of airborne particulate matter (PM) 2.5 μm in diameter was linked to an increased risk of NSCLC with EGFR mutations.

In the laboratory studies, Francis Crick Institute scientists showed that the same pollutant particles (PM2.5) that promoted rapid changes in airway cells with mutations in EGFR also affected those with mutations in the KRAS gene, driving them toward a cancer stem cell–like state. They also found that air pollution drives the influx of macrophages which release the inflammatory mediator, interleukin-1β, driving the expansion of cells with EGFR mutations in response to exposure to PM2.5, and that blockade of interleukin-1β inhibited lung cancer initiation.

These findings were consistent with data from a previous large clinical trial published by Ridker et al in The Lancet showing a dose-dependent reduction in lung cancer incidence when people were treated with the anti-IL1β antibody canakinumab. In a final series of experiments, the Francis Crick team used state-of-the-art, ultradeep mutational profiling of small samples of normal lung tissue and found EGFR and KRAS driver mutations in 18% and 33% of normal lung samples, respectively.

“We found that driver mutations in EGFR and KRAS genes, commonly found in lung cancers, are actually present in normal lung tissue and are a likely consequence of aging. In our research, these mutations alone only weakly potentiated cancer in laboratory models. However, when lung cells with these mutations were exposed to air pollutants, we saw more cancers, and these occurred more quickly than when lung cells with these mutations were not exposed to pollutants, suggesting that air pollution promotes the initiation of lung cancer in cells harboring driver gene mutations. The next step is to discover why some lung cells with mutations become cancerous when exposed to pollutants while others don’t,” said Dr. Swanton.

Expert Commentary

Tony S.K. Mok, MD

Commenting on the results, Tony S.K. Mok, MD, of the Chinese University of Hong Kong, who was not involved in the study, said, “This research is intriguing and exciting as it means that we can ask whether, in the future, it will be possible to use lung scans to look for precancerous lesions in the lungs and try to reverse them with medicines such as interleukin-1β inhibitors. We don’t yet know whether it will be possible to use highly sensitive EGFR profiling on blood or other samples to find nonsmokers who are predisposed to lung cancer and may benefit from lung scanning, so discussions are still very speculative.”

Like Dr. Swanton, Dr. Mok stressed the importance of reducing air pollution to lower the risk of lung diseases, including cancer. “We have known about the link between pollution and lung cancer for a long time, and we now have a possible explanation for it. As consumption of fossil fuels goes hand-in-hand with pollution and carbon emissions, we have a strong mandate for tackling these issues—for both environmental and health reasons,” Dr. Mok concluded.

Disclosure: For full disclosures of the study authors, visit oncologypro.esmo.org.