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ESMO Study Explores Role of Air Pollution in EGFR-Mutant NSCLC in Non-Smokers


PARIS – An international study discovered an association between air pollution and the development of EGFR-mutant non-small cell lung cancer in non-smokers and suggested that the concentration of PM2.5 air pollution particles may play a role in cancer initiation.

Researchers presented data at the European Society for Medical Oncology Congress on Saturday on the epidemiological rates of EGFR-mutant NSCLC in areas with high PM2.5 concentrations, and they examined how these particles may play a role in cancer development in mice.

PM2.5 are air particles that are 2.5 micrometers and are often caused by burning fossil fuels, such as diesel engines. PM2.5 tend to exist in higher concentrations in cities.

Charles Swanton, chief clinician at the Francis Crick Institute and Cancer Research UK, noted in his presentation of the research that the association between lung cancer and air pollution has been known for decades, but his team hoped to dive into how pollution can change normal lung cells into cancerous cells.

His group's findings might "start to open some doors in the context of molecular cancer prevention in high-risk populations," Swanton said.

First, Swanton and colleagues analyzed data from more than 447,000 lung cancer patients included in the UK Biobank. They found there was a relationship between PM2.5 exposure and the incidence of seven different cancer types including lung, small intestine, larynx, anal, mesothelioma, glioblastoma, and mouth cancers. They then focused on EGFR-mutant NSCLC, a disease that is more common in never smokers, in the UK Biobank data and found a similar association between PM2.5 exposure and EGFR-mutant NSCLC incidence.

EGFR-mutated NSCLC is also more prevalent in Asian than in Western populations. To further test the association between environmental and genomic factors, Swanton and colleagues homed in on certain Asian countries with PM2.5 in the air. "We repeated this [analysis] with collaborators in South Korea and Taiwan, [which] have much higher levels of PM2.5, and the relationship still exists there between EGFR-mutant lung cancer incidence and PM2.5 exposure," Swanton said.

After observing this association in humans, the researchers conducted mouse studies to try to parse whether PM2.5 exposure played a role in lung cancer initiation. They induced an EGFR or KRAS mutation into normal lung tissue of the mice and then exposed them to two dose levels of diesel particulates. In this experiment, they found that the mice exposed to higher PM2.5 dose levels had more tumors, while the mice in the control group not exposed to PM2.5 didn't develop any tumors.

In the mouse models, researchers looked for the emergence of alveolar type 2 (AT2) cells, which are thought to be the most common cell of origin for EGFR-mutant NSCLC, Swanton said. In the mice exposed to PM2.5, inflammation caused more AT2 cells to appear in lung tissue.

"Neither air pollution [nor] an EGFR mutation alone is sufficient to augment a stem cell state [in AT2], but instead, the stem cell capacity is requiring both the EGFR mutation and pollution exposure," Swanton said.

In the mice exposed to PM2.5, researchers also found that the inflammatory mediator interleukin-1β (IL1B) was upregulated. Swanton said their research found that IL1B induced an AT2 progenitor state. As such, the research suggests that exposure to pollution activates IL1B, which induces AT2 macrophages to infiltrate the lung tissue.

"Clearly, IL1B looks like it's the smoking gun," Swanton said.

The next step was to explore an anti-IL1B antibody as a preventive tool in preclinical studies, Swanton said. One anti-IL1B drug in development is Novartis' canakinumab, which appeared to reduce lung cancer incidence in the 2017 CANTOS study.

"[In that study], we don't know if there's an association with reduction in [lung cancer] risk for those most exposed to pollution," Swanton said. "But we did the same experiment in mice, where we exposed mice to pollution and simultaneously gave an IL1B antibody. We showed we can completely abrogate tumor growth in the presence of pollution and the EGFR mutation."

In a discussion of this data, Suzette Delaloge, an associate professor of medical oncology at the Institute Gustave Roussy, noted that the research was a "meaningful demonstration" of the role of PM2.5 air pollution in the promotion of lung cancer.

However, the data did not confirm that PM2.5 was mutagenic, she said, and there is further research needed to elucidate how common this oncogenic pathway is in humans, how much exposure is needed for cancer initiation, and whether some people are more susceptible to pollution-induced lung cancer.

"It could be a very nice model towards cancer interception, a combination of early detection and early biomarker-driven prevention therapies to eradicate cancers before their clinical phase," Delaloge said. "This means that if we were able to identify risk situations, such as susceptibility or exposure, and were able to watch these patients and provide them with early detection, such as of inflammation, then we would be able to propose a customized systemic treatment that would avoid the growth of a tumor and totally prevent cancer."