The link was first suggested decades ago and was long 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 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 conference. “Due to environmental carcinogens, this causes mutations in the DNA, activates a driver event, and the tumor starts.” “But there are some big problems with this model,” he pointed out. For example, research has shown that normal healthy tissue harbors mutated clones with cancer driver mutations, without 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 model of tumor promotion in which tumors were driven in a two-step process — via an initiator and a promoter. “And you need both together to start tumors in mice. One is insufficient to cause cancer,” he explained. “So we know that air pollution is associated with lung cancer risk, and lung cancer in nonsmokers does not have DNA mutations caused by environmental carcinogens,” Swanton said. “So could air pollution drive lung cancer through this model of tumor promotion?” Swanton and his colleagues argued that to be true, certain 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 almost half a million people living in the UK, Swanton’s team found that increasing exposure to PM2.5 (particulate matter 2.5 micrometres in diameter) was associated with an increased 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 Laryngeal carcinomas: HR 1.26
Looking specifically at EGFR-mutated cancer, they found that there was a significant association between lung cancer incidence and PM2.5 concentrations. In addition, they 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, exposed the mice to PM2.5 for several weeks, and then evaluated their lungs for tumors. They found that cancers were more likely to start in cells carrying these mutations when exposed to air pollution. Investigating further, Swanton’s team 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 results from 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 canakinomab (Ilaris). Finally, they wanted to show how pollution could cause cancer without directly causing DNA mutation. For the tumor promotion model to be correct, tumor promoters must act on a preexisting mutation, Swanton said. “This must mean… there will be EGFR and KRAS mutations in the normal tissue of an apparently healthy adult.” Using advanced 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 KRAS-activating mutations. These mutations, Swanton said, occur precisely through 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 pollution.” The findings underscore the importance of reducing air pollution in order to reduce the risk of lung diseases, including cancer, Swanton said, noting that between 7 and 9 million deaths a year are due 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 is “at least on par with tobacco in terms of global mortality benefit,” he said. “He’s really, I think, the silent killer.” “We don’t have a choice in 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 limit of PM2.5. ESMO discussant Suzette Delaloge, MD, MSc, of the Gustave Roussy Cancer Interception Program in Vellejuif, France, called the study “a very important demonstration — from epidemiological data to preclinical models — of the role of PM2.5 pollutants in promoting of lung cancer. And it gives us very important answers about the mechanism by which non-smokers can get lung cancer.” Revelations Swanton has disclosed relationships with Pfizer, AstraZeneca, Bristol Myers Squibb (BMS), Ventana, Boehringer-Ingelheim, Ono Pharmaceuticals, Archer, Novartis, GlaxoSmithKline, MSD, Amgen, Illumina, Sarah Canon Research Institute, Roche0Genicxicycle, Rail, Therapeutics, Metabomed , Roche Innovation Center Shanghai, Apogen Biotechnologies, Epic Bioscience and Achilles Therapeutics. Discuss disclosed relationships with 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, European Commission, French Government, ARCm Pfizer Foundation, Novartis, AstraZeneca and Seagen.
