PARIS — Fine particulate matter from burning fossil fuels appeared to trigger non-small cell lung cancer (NSCLC) in never-smokers through a “tumor-promoting” process, according to a study on the etiology of EGFR mutated disease.
The link was first suggested decades ago and long overlooked, but now appears to be the most likely mechanism of action, said Charles Swanton, PhD, of the Francis Crick Institute and Hospitals UCL London.
“If you had asked me 2 years ago how a tumor starts, I would have said it’s obvious,” Swanton said in a presentation at the European Society of Medical Oncology (ESMO) annual congress. “Because of environmental carcinogens, this causes mutations in the DNA, activates a driver event and starts the tumor.”
“But there are some major problems with this model,” he noted. For example, research has shown that normal healthy tissue harbors mutant clones with cancer driver mutations, with no evidence of cancer. And a recent study showed that 17 of 20 environmental carcinogens tested in mice did not cause DNA mutations.
Instead, Swanton referred to a paper published in 1947 by biochemist Isaac Berenblum, MD, who proposed a model of tumor promotion in which tumors were driven in a two-step process: by an initiator and a promoter . “And you need both together to initiate tumors in mice. Neither is sufficient to induce cancer,” he explained.
“So we know that air pollution is associated with lung cancer risk, and lung cancer in never smokers does not have environmental carcinogen-induced DNA mutations,” Swanton said. “So could air pollution drive lung cancer through this model of tumor promotion?” Swanton and his colleagues reasoned that for this to be true, a number of criteria would have to be met.
First, they had to explain the geographic relationship of EGFR-mutant NSCLC to air pollution levels. In a study of nearly half a million people living in the United Kingdom, Swanton’s group found that increased exposure to PM2.5 (atmospheric particles 2.5 micrometers in diameter) was associated with increased of the risk of seven types of cancer:
- Mesothelioma: hazard ratio 1.19
- Lungs: HR 1.16
- Anal: HR 1.23
- Small intestine: HR 1.30
- Glioblastoma: HR 1.19
- Lip, oral cavity and pharynx: HR 1.15
- Carcinomas of the larynx: HR 1.26
Looking specifically at EGFR-mutated cancer, they determined that there was a significant association between lung cancer incidence and PM2.5 concentrations. They also found that the relationship between cancer incidence and PM2.5 in South Korea and Taiwan was comparable to that in the UK.
Next, the researchers wanted to prove causality. They conducted animal studies in which they induced EGFR or KRAS mutations in the lung epithelium of mice, proceeded to expose the mice to PM2.5 for several weeks, and then assessed their lungs for tumors. They found that cancers were more likely to start from cells carrying these mutations when exposed to air pollution.
Investigating further, Swanton’s group showed that interleukin-1β (IL-1β) plays a key role in the inflammatory response to PM.25 and that blocking IL-1β can inhibit the initiation of lung cancer. The finding was consistent with the results of the CANTOS trial, which showed a dose-dependent reduction in the incidence of lung cancer when people were treated with the anti-IL-1β antibody canakinumab (Ilaris).
Finally, they wanted to show how pollution could cause cancer without directly causing DNA mutations.
For the tumor promotion model to be correct, tumor promoters must act on a preexisting mutation, Swanton said. “This must mean that … there will be EGFR and KRAS mutations in the normal tissue of an apparently healthy adult.”
Using state-of-the-art mutational profiling of small samples of normal lung tissue, the researchers found that 15% of the samples had EGFR driver mutations and more than 50% had activating KRAS mutations. These mutations, Swanton said, occur only during the aging process.
“I think we’re getting closer to establishing a link between PM2.5 and EGFR-mutated lung cancer,” Swanton said. “And we’re beginning to explain why there might be an absence of a mutagenic signature associated with contamination.”
The findings underscore the importance of reducing air pollution to reduce the risk of lung diseases, including cancer, Swanton said, noting that 7 to 9 million deaths annually are due to PM2.5.
Although these deaths are due to various diseases, including cardiovascular disease, dementia and diabetes, in addition to lung cancer, PM2.5 is “at least equivalent to tobacco in terms of overall mortality benefit,” he said. “He really is, I think, the silent killer.”
“We have no choice in the air we breathe,” Swanton observed, noting that 99 percent of the world’s population now lives in areas of the world where pollution levels are above the safe limit of PM2.5.
Suzette Delaloge, MD, MSc, of the ESMO Gustave Roussy Cancer Interception Program in Vellejuif, France, called the study “a very significant demonstration, from epidemiological data to preclinical models, of the role of PM2.5 pollutants in the promotion of lung cancer. And it gives us very important answers about the mechanism through which non-smokers can get lung cancer.”
disclosures
Swanton disclosed relationships with Pfizer, AstraZeneca, Bristol Myers Squibb (BMS), Ventana, Boehringer-Ingelheim, Ono Pharmaceuticals, Archer, Novartis, GlaxoSmithKline, MSD, Amgen, Illumina, Sarah Canon Research Institute, Roche0Genentech, Novartis, GRAIL, Medicxi , Therapeutics, Metabomed, Roche Innovation Center Shanghai, Apogen Biotechnologies, Epic Bioscience and Achilles Therapeutics.
Discuss disclosed relationships and/or support from AstraZeneca, MSD, Rappta, Basins, Gilead, Elsan, Sanofi, Pfizer, Novartis, Roche Genentech, Lilly, Puma, Orion, Amgen, Servier, BMS, Pierre Fabre, Seagen, Exact Sciences, Taiho, the European Commission, the French government, the ARCm Pfizer Foundation, Novartis, AstraZeneca and Seagen.