Researchers presented data at the European Society of Medical Oncology Congress on Saturday about the epidemiologic rates of EGFR-mutant NSCLC in areas with high PM2.5 concentrations and examined how these particles may play a role in the development of cancer 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 tends to be present in higher concentrations in cities. Charles Swanton, chief clinician at the Francis Crick Institute and Cancer Research UK, noted in the research presentation that the link between lung cancer and air pollution has been known for decades, but his team hoped to investigate how pollution can to change normal lung cells into cancer cells. His team’s findings may “start to open some doors in terms 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 that there was a link between PM2.5 exposure and the incidence of seven different types of cancer, including lung, small bowel, larynx, anus, mesothelioma, glioblastoma and mouth cancers. They then focused on EGFR-mutated NSCLC, a disease more common in never-smokers, in the UK Biobank data and found a similar association between PM2.5 exposure and the incidence of EGFR-mutated NSCLC. 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 his colleagues visited some Asian countries with PM2.5 in the air. “We repeated it [analysis] with partners in South Korea and Taiwan, [which] have much higher levels of PM2.5, and the relationship still exists between the incidence of EGFR-mutated lung cancer and PM2.5 exposure,” Swanton said. After noticing this association in humans, researchers conducted studies in mice to try to analyze whether exposure to PM2.5 played a role in the onset of lung cancer. They induced an EGFR or KRAS mutation in the normal lung tissue of mice and then exposed them to two dose levels of diesel particulate matter. In this experiment, they found that mice exposed to higher dose levels of PM2.5 had more tumors, while control group mice not exposed to PM2.5 did not develop tumors. In the mouse models, the researchers looked for the appearance of alveolar type 2 (AT2) cells, which are thought to be the most common cell of origin for EGFR-mutated NSCLC, Swanton said. In the mice exposed to PM2.5, the inflammation caused more AT2 cells to appear in the lung tissue. “Not even air pollution [nor] An EGFR mutation alone is sufficient to increase stem cell status [in AT2]but instead, stem cell competence requires both the EGFR mutation and pollution exposure,” Swanton said. In the mice exposed to PM2.5, the researchers also found that the inflammatory mediator interleukin-1β (IL1B) was upregulated. Swanton said their research found that IL1B caused an AT2 ancestral state. Therefore, the research suggests that exposure to pollution activates IL1B, which stimulates AT2 macrophages to infiltrate lung tissue. “Clearly, IL1B seems to be the smoking gun,” Swanton said. The next step was to investigate an anti-IL1B antibody as a preventive tool in preclinical studies, Swanton said. An anti-IL1B drug in development is Novartis’ canakinumab, which was shown to reduce the incidence of lung cancer in the 2017 CANTOS study. “[In that study]we don’t know if there is a correlation with reduction [lung cancer] danger to those most exposed to pollution,” Swanton said. “But we did the same experiment in mice, where we exposed mice to the pollution and at the same time gave an IL1B antibody. We have shown that we can completely abrogate tumor growth in the presence of EGFR contamination and mutation.” In a discussion of these data, Suzette Delaloge, associate professor of medical oncology at the Gustave Roussy Institute, noted that the research was a “substantial demonstration” of the role of PM2.5 air pollution in promoting lung cancer. However, the data did not confirm that PM2.5 was mutagenic, he said, and further research is needed to clarify how common this oncogenic pathway is in humans, how much exposure is needed to initiate cancer and whether some people are more susceptible. in pollution-induced lung cancer. “It could be a very nice model for cancer prevention, a combination of early detection and prevention therapies based on early biomarkers to eliminate cancers before their clinical phase,” said Delaloge. “This means that if we could identify risk conditions, such as sensitivity or exposure, and we could monitor these patients and provide them with early detection, such as inflammation, then we could suggest a tailored systemic treatment that would avoid the development of a tumor and it will completely prevent cancer.”
