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PARIS -- Fine particulate matter from the combustion 0f fossil fuels seemed to trigger non-small cell lung cancer (NSCLC) in never smokers through a process of "tumor promotion," 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 thr Francis Crick Institute and UCL Hospitals in London.

"If you would have asked me 2 years ago how a tumor starts, I would have said it is obvious," Swanton said in a presentation at the European Society for Medical Oncology (ESMO) annual congress. "Due to environmental carcinogens, this causes mutations in DNA, activates a driver event, and the tumor starts."

"But there are some major problems with this model," he pointed out. For example, research has shown that normal health 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 an article published in 1947 by biochemist Isaac Berenblum, MD, who proposed a tumor promotion model in which tumors were driven in a two-step process -- through an initiator and a promoter. "And you need the two together to initiate tumors in mice. Either one is insufficient to induce cancer," he explained.

"So, we know air pollution is associated with lung cancer risk, and lung cancer in never smokers has no environmental carcinogen-induced DNA mutations," Swanton said. "So could air pollution drive lung cancer through this tumor promotion model?" Swanton and 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 with air pollution levels. In a study of nearly half a million people living in the U.K., Swanton's group found increasing PM2.5 (airborne particulate matter 2.5 micrometres in diameter) exposure was associated with an increased risk of seven cancer types:

• Mesothelioma: hazard ratio 1.19
• Lung: HR 1.16
• Anal: HR 1.23
• Small intestine: HR 1.30
• Glioblastoma: HR 1.19
• Lip, oral cavity and pharynx: HR 1.15
• Laryngeal carcinomas: HR 1.26

Looking specifically at EGFR-mutated cancer, they determined there was significant association between lung cancer incidence and PM2.5 concentrations, In addition, they found the relationship between cancer incidence and PM2.5 in South Korea and Taiwan was comparable to that in the U.K.

Next, the researchers wanted to prove causation. They conducted animal studies in which they induced EGFR or KRAS mutations into mice lung epithelium, proceeded to expose the mice to PM2.5 over several weeks, and then assessed their lungs for tumors. They found 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 a blockade of IL-1β can inhibit lung cancer initiation. The finding was consistent with results from the trial, which demonstrated a dose-dependent reduction in lung cancer incidence 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 mutation.

For 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 tissue of a seemingly healthy adult."

Using state-of-the-art mutational profiling of small samples of normal lung tissue, the researchers found 15% of the samples had EGFR driver mutations, and more than 50% had KRAS activating mutations. These mutations, Swanton said, occur just through process of aging.

"I think we are getting closer to establishing a link between PM2.5 and EGFR-mutated lung cancer," Swanton said. "And we are beginning to explain why there may be an absence of mutagenic signature associated with pollution."

The findings underscore the importance of reducing air pollution in order to lower the risk of lung disease, including cancer, Swanton said, pointing out that between 7 and 9 million deaths annually are due to PM2.5s.

While these deaths are due to a number of diseases -- including cardiovascular disease, dementia, and diabetes -- in addition to lung cancer, PM2.5s are "at least equivalent to tobacco in terms of its global mortality benefit," he said. "It really is, I think, the silent killer."

"We have no choice in the air we breathe," Swanton observed, noting that 99% of the world's population now live in areas of the world where pollution levels are above the safe PM2.5 limit.

ESMO discussant Suzette Delaloge, MD, MSc, of Cancer Interception Program, Gustave Roussy in Vellejuif, France, called the study "a very meaningful demonstration -- from epidemiological data to preclinical models -- of the role of PM2.5 pollutants in the promotion of lung cancer. And it provides us with very important answers on the mechanism through which non-smokers can get lung cancer."

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