Uncovering an association between pollution and EGFR mutant lung NSCLC

PARIS — Fine particles from burning fossil fuels appeared to trigger non-small cell lung cancer (NSCLC) in non-smokers through a process of “tumor promotion,” according to a study into the etiology of EGFR-mutant disease.

The link was first suggested decades ago and has long been overlooked, but now appears to be the most likely mechanism of action, said Charles Swanton, PhD, of the Francis Crick Institute and UCL Hospitals in London.

“If you had asked me two years ago how a tumor forms, I would have said it was obvious,” Swanton said in a presentation at the European Society for Medical Oncology (ESMO) annual meeting. “Due to environmental carcinogens, this causes mutations in the DNA, activates a driver event, and the tumor begins.”

“But there are some big problems with this model,” he pointed out. For example, research has shown that normal health tissue harbors mutant clones with cancer driver mutations without evidence of cancer. And a recent study showed that 17 out of 20 environmental carcinogens tested in mice did not cause DNA mutations.

Instead, Swanton referred to a 1947 paper by biochemist Isaac Berenblum, MD, which proposed a tumor promotion model 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. Both are not enough to induce cancer,” he explained.

“So we know that air pollution is linked to lung cancer risk, and lung cancer in non-smokers does not have DNA mutations caused by environmental carcinogens,” Swanton said. “So could air pollution promote lung cancer through this tumor promotion model?” Swanton and colleagues argued that a number of criteria had to be met for this to happen.

First, they had to explain the geographic relationship between EGFR-mutated NSCLC and air pollution. In a study of nearly half a million people living in the UK, Swanton’s group found that increasing exposure to PM2.5 (airborne particles 2.5 microns in diameter) was associated with an increased risk of seven types of cancer:

• Mesothelioma: hazard ratio 1.19
• Lungs: HR 1.16
• Anal: heart rate 1.23
• Small intestine: HR 1.30
• Glioblastoma: HR 1.19
• Lip, oral cavity and throat: HR 1.15
• Laryngeal carcinomas: HR 1.26

Concretely considered EGFR-mutant cancer, they found that there was a significant association between lung cancer incidence and PM2.5 levels. 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 carried out animal experiments in which they induced EGFR or KRAS Mutations in the lung epithelium of mice exposed the mice to PM2.5 for several weeks and then examined their lungs for tumors. They found that cancer is more likely to come from cells carrying these mutations when exposed to air pollution.

In further investigations, 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 development of lung cancer. The result was consistent with the results of the CANTOS study, which showed a dose-dependent reduction in the incidence of lung cancer when people were treated with the anti-IL-1β antibody canakinumab (Ilaris).

Ultimately, they wanted to show how pollution can cause cancer without directly causing a DNA mutation.

For the tumor promotion model to be correct, tumor promoters must act on a pre-existing mutation, Swanton said. “So that must mean…there will be EGFR and KRAS Mutations in the normal tissues of an apparently healthy adult.”

Using state-of-the-art mutation profiles of small samples of normal lung tissue, the researchers found that 15% of the samples had it EGFR Driver mutations, and more than 50% had KRAS activate mutations. These mutations, Swanton said, only occur through the aging process.

“I think we are getting closer to making a link between PM2.5 and PM2.5 EGFR-mutagenic lung cancer,” Swanton said. “And we’re beginning to explain why there might not be a mutagenic signature associated with pollution.”

The findings underscore the importance of reducing air pollution to lower the risk of lung diseases, including cancer, Swanton said, noting that between 7 and 9 million deaths annually are attributed to PM2.5.

While these deaths are due to a range of diseases — including cardiovascular disease, dementia and diabetes — in addition to lung cancer, PM2.5 emissions are “at least equivalent to tobacco in terms of global mortality advantage,” he said. “It really is, I think, the silent killer.”

“We don’t have a choice about the air we breathe,” Swanton observed, noting that 99% of the world’s population now lives in areas of the world where pollution levels are above the safe PM2.5 limit.

ESMO panellist Suzette Delaloge, MD, MSc, from Cancer Interception Program, Gustave Roussy in Vellejuif, France, called the study “a very powerful 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 by which non-smokers develop lung cancer.”