As smoking rates fall, lung cancer in never-smokers (LCINS) represents an increasing share of lung cancer diagnoses. These cancers are frequently detected at a late stage, when they are less treatable. In a new paper, publishing February 11 in the Cell Press journal Trends in Cancer, researchers outline the importance of identifying risk factors, developing better screening tests, and discovering more effective treatment approaches for these cancers.
"LCINS is a growing global health challenge, and it's biologically and clinically distinct from smoking-related lung cancer," says corresponding author Deborah Caswell of the Lung Cancer Prevention Laboratory at University College London. "Prevention and screening strategies that work for smokers don't automatically translate to never-smokers, and identifying non-smoking risk factors is essential to finding the subgroups who could benefit from targeted screening and prevention."
The symptoms of LCINS—such as coughing, fatigue, and difficulty swallowing—are often vague and are frequently attributed to benign causes in those who lack a smoking history. As a result, both patients and clinicians may be unlikely to suspect cancer. The authors say that increasing awareness of the risk of LCINS could lead to earlier clinical evaluation, such as imaging tests and referrals to specialists. This would, in turn, shorten the time to diagnosis and increase the chance that these cancers are found at a stage where curative treatment is possible.
"Symptom awareness reinforces the idea that 'never-smoker' does not mean 'no risk,'" Caswell says, noting that there is rapidly evolving evidence on who is at risk and how LCINS develops. This awareness could lead to guidelines for targeted screening in those who may have risk factors beyond smoking.
"Newer lines of research focus on inherited gene variants that may increase risk, as well as environmental drivers like air pollution, radon, second-hand smoke, and radiation exposure," Caswell adds. "By studying these factors, we could develop future risk models and prevention trials."
The paper also explores the molecular differences between smoking-related lung cancers and LCINS and how these differences impact treatment strategies. For example, LCINS is more likely to be adenocarcinoma and more likely to carry "driver" alterations that can be targeted with drugs. These drivers include EGFR mutations and ALK fusions. In addition, LCINS tends to have fewer mutations overall, making it less likely to respond to immune checkpoint inhibitors.
The authors highlight the promise of developing interventions for preventing LCINS, including the following:
Targeted prevention in those with an inherited predisposition
Anti-inflammatory strategies for those with inflammation due to pollution exposure, CHIP, or inflammatory diseases
Public health interventions such as radon monitoring and reducing exposure to air pollution and second-hand smoke
"We anticipate that raising awareness of LCINS will lead to an increased interest in defining 'high-risk never-smoker' subgroups, the development of cost-effective screening protocols for those subgroups, and the building of prevention/interception trials in which the benefits clearly outweigh the harms," Caswell says.
