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LILLE, FRANCE — Patients with lung cancer who reside in polluted areas (ie, those affected by PM_2.5, PM₁₀, or nitrogen dioxide) have an additional 50% risk of carrying an oncogenic EGFR mutation, which is typical in nonsmoker cancers. This finding results from the KPB-2020 study, which was presented at the 28th French Language Pulmonology Congress. It confirms the findings of a major English study published in 2023.

The link between pollution and cancer has long been discussed. It was first suggested on September 30, 1950, by Richard Doll in BMJ. This English doctor's hypothesis suggested that the increase in lung cancer cases was related to either air pollution or tobacco.

The timing of this publication is not coincidental. Episodes of pollution peaks, including the famous London smog in 1952, began to be observed in the early 1950s. Their health consequences included 12,000 short-term deaths. The question of the long-term consequences of this type of pollution, however, was only resolved decades later, thanks to the inclusion of hundreds of thousands of participants in epidemiological studies.

Two major cohorts, the European Study of Cohorts for Air Pollution Effects (ESCAPE) and the ACS CPS II study by the American Cancer Society, have examined the impact of fine particles, especially those with a diameter of < 2.5 μm (PM_2.5), on the incidence and mortality of lung cancer.

These epidemiological studies demonstrate a significant link between these factors. The increase in cancer incidence is estimated at 18% per 5 µg/m³ of PM_2.5 exposure (according to ESCAPE), and the increase in mortality risk is around +15%-27% per 10 µg/m³ of exposure (according to ACS CPS II).

"This link is independent of smoking, as confirmed by cohorts of nonsmoker patients," said Alexis Cortot, MD, a thoracic oncologist at the Lille University Hospital, Lille, France. Since then, the World Health Organization's International Agency for Research on Cancer has classified PM_2.5 as a definite carcinogen.

Estimates suggest that 200,000-300,000 lung cancer deaths per year occur worldwide due to pollution.

Tobacco consumption and pollution exposure likely have synergistic effects. Moreover, these cancers in patients exposed to air pollution seem to have a poor prognosis, especially in cases of localized stage.

A Turning Point

The physiopathological mechanisms of this relationship between pollution and bronchopulmonary cancer remain largely unknown. But in 2023, a study conducted by the team of Charles Swanton, PhD, of the Francis Crick Institute in London marked a decisive turning point in understanding this link. This study, published last year in Nature, focuses on lung cancer associated with EGFR mutation, which represents 10%-15% of cases in France and 40% in Asia, mainly in nonsmokers.

Through an epidemiological analysis, the study establishes a dose-dependent association between PM_2.5 exposure and the estimated incidence of EGFR-mutated non–small cell lung cancers. This association was observed in Great Britain, Taiwan, and South Korea, even in contexts where PM_2.5 exposure is relatively low.

Using a murine model, the researchers then experimentally demonstrated the cause-and-effect relationship between PM_2.5 exposure and the development of preexisting EGFR-mutated clones via the interleukin (IL)-1 β pathway.

The researchers induced an EGFR mutation, which by itself causes few tumors. But when mice are exposed to PM_2.5, tumors appear, depending on the degree of exposure. Analysis reveals an inflammatory signature, specifically an IL-1 β-type signature, in these tumors. Mice treated with an anti-IL-1 β antibody no longer develop tumors.

New Carcinogenesis Model

The last part of the study explores how these EGFR mutations occur. Researchers performed autopsies on human lung tissue and demonstrated that in healthy lung tissue, EGFR mutations are present in 18% of patients and KRAS mutations in 53%. "This suggests a new two-step carcinogenesis theory," said Cortot. It begins with an EGFR or KRAS mutation, followed by exposure to pollution that triggers an inflammatory response mediated by alveolar macrophages and the IL-1 β pathway. This response leads EGFR-mutated cells to evolve into true EGFR-positive lung cancers.

New French Data

Research into the link between pollution and cancers, particularly lung cancer, also has been undertaken in France. Examples include the KBP study and the series of multicenter observational epidemiological cohorts conducted by the College of Pulmonologists of General Hospitals. This research has enabled an overview of new cases of bronchial cancer in France to be conducted every 10 years since 2000.

The 2020 cohort (KPB-2020) included all patients diagnosed with lung cancer in participating centers. The population totaled 8999 patients nationwide. Researchers evaluated participants' average level of exposure to various pollutants, including PM_2.5 and PM₁₀ particles, ionizing radiation such as radon, and other pollution parameters (such as soil artificialization, geohazard, and traffic density), based on their place of residence.

In collaboration with public health teams at the Lille University Hospital, this exposure level was then correlated by adjusting for smoking, a correction that was not made in the Swanton study.

"The results of this study confirm the link between exposure to PM_2.5 and PM₁₀ and the risk for carrying an EGFR mutation, with a significant relative increase of 1.5 among patients living in heavily polluted areas compared with those residing in lightly polluted areas," said Cortot, who was the study coordinator. In other words, patients residing in polluted areas have an additional 50% risk for EGFR-mutated lung cancer. "For reference, this level of risk is similar to that associated with passive smoking and 15 times lower than that of active smoking."

A similar correlation was observed with other types of pollutants sharing the same sources as PM_2.5. For PM₁₀, the risk is increased by 1.39; for nitrogen dioxide, it is increased by 1.63.

Another notable finding was the association between mutations in the tumor suppressor gene STK11 and radon.

"These findings should encourage governments to continue efforts to reduce PM_2.5 emissions," said Cortot. "While levels in France are among the lowest in the world and have been steadily decreasing for several years, other regions of the world are still heavily exposed."

Cortot declared no conflicts of interest with his presentation on KPB-202.

This story was translated from the Medscape French edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.