Major trial sheds light on why never-smokers develop lung cancer

Major findings on air pollution and lung cancer presented at ESMO 2022 provide an explanation as to why never-smokers develop the disease but also have much wider implications for the molecular and inflammatory mechanisms of carcinogenesis and potential cancer prevention agents, experts say.

Delivering the ESMO 2022 meeting’s presidential address in Paris, Professor Charles Stanton of the Francis Crick Institute, London, presented study findings showing that increasing exposure to 2.5 µm particulate matter (PM2.5) increases the risk of non-small-cell lung cancer in non-smoking individuals with EGFR mutations.

Contrary to the classical mutation model in which a carcinogen causes DNA mutations and tumour growth, he explained that this effect is driven by an influx of macrophages and an increase in the inflammatory mediator interleukin-1β.

Professor Stanton said work by collaborative groups in the UK and Canada has shown that IL1B promotes carcinogenesis in airway cells in both animal and human models.

And as a tumour promoter it was likely acting on pre-existing mutations in latent cells, he postulated. This was feasible because EGFR driver mutations were found in 15% of normal lung samples, while KRAS mutations were found in 53%, he told the meeting.

These mutations increased with age in never smokers and could be the link between pollution and ILB1 tumour initiation, he said.

This theory was tested in experiments that showed that pollution-induced tumour initiation was blocked by anti-ILB1 agents such as the anti-inflammatory drug canakinumab.

Professor Stanton stressed that the inflammatory-mediated carcinogenic effects of fine particle air pollution were a 20-fold order of magnitude less than those of tobacco smoke. Nevertheless, given that most of the world’s population lived in environments with high PM2.5 exposure, air pollution could be responsible for a large absolute number of lung cancers.

And unlike tobacco smoke, millions of people had no choice or control over their exposure to air pollution, he noted.Therefore, aside from measures to control air pollution, there may be potential preventive benefits from anti-ILB1 agents, he suggested.

In the ESMO/meeting discussion session, attended by the limbic, Professor Suzette Delaloge of the Cancer Interception Programme, Villejuif, said the research provided new evidence to support an inflammatory mechanism through which non-smokers can get lung cancer.

“This is a very big step forward (with) a great impact on our vision of carcinogenesis. A very elegant first demonstration of the alternative non-mutagenic carcinogenic promotion hypothesis for fine particular matter,” she said.

“The major mechanism involved in this promotion is the attraction of macrophages,  secretion of IL1B, promotion of AT2-type progenitor capacity of EGFR mutation cells,” she added.

Prof Delaloge said the findings had implications for ‘cancer interception’ in which a combination of early detection and bio marker-driven prevention therapies could eradicate cancers before their clinical phase.

Based on these data and the CANTOS trial results, it could be argued that the anti-IL1B drug canakizumab could be repositioned as an anti-cancer drug, she suggested.

Commenting on the potential implications of these findings, Prof. Tony Mok of the Chinese University of Hong Kong says that the promise of molecular screening for lung cancer risk in non-smokers is still premature.

“We can say that in the future, it may be possible to further improve cancer prevention by first identifying non-smokers with EGFR mutations in their cells before using low-dose computed tomography (LD-CT) to screen for presence of lesions or pre-malignant ground-glass opacity,” he said.

“Before this, we need to determine if the presence of EGFR mutations can be detected in normal cells in non-smokers using ultrasensitive methods and whether LD-CT can detect premalignant changes. Future research could investigate whether these lesions can be targeted with interleukin-1β inhibitors. There are still a lot of unknowns, but these data are exciting and intriguing and may signal a new era of chemoprevention in lung cancer.”

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