Lung cancer patients who have never smoked make up a significant and growing share of global lung cancer cases, yet remain an understudied group, according to a new review written by UCL (University College London) researchers.
In 2020, lung cancer in never-smokers (LCINS) was the fifth most common cause of cancer death worldwide (the most common cause was tobacco-related lung cancer).
Published in Trends in Cancer, the review calls for increased funding for the screening and study of lung cancer in never-smokers (LCINS), which is accounting for an ever-larger proportion of cases as smoking rates decline. Evidence from studies of several thousand lung cancer patients in the US and UK suggests absolute numbers of lung cancer in never-smokers have also risen. Cases in the UK study doubled between 2008 and 2014.
Currently, the overwhelming majority of lung cancer screening resources are directed towards smokers. In the UK, there is no routine lung cancer screening for people who have never smoked.
As a result, LCINS is often diagnosed later, leading to poorer outcomes for patients. In addition, treatments commonly used for smoking-related lung cancer, such as immunotherapy, are significantly less effective in people who have never smoked.
The authors argue that these differences highlight the need to treat LCINS as a distinct form of lung cancer, with greater investment in dedicated research, screen and clinical trials.
The review's first author, Dr Deborah Caswell (UCL Respiratory Medicine), believes a new strategy is needed to look at risk prediction, earlier detection and prevention of LCINS.
She said: "Underdiagnosis is the biggest problem because lung cancer in never-smokers does not fit the expected profile. If a young female non-smoker goes to her GP with shoulder pain, it may not even occur to the healthcare professional that lung cancer could be the cause.
"Lung cancer in never-smokers is not currently thought of as a different kind of lung cancer which is making it more difficult to intercept at an early stage. Fewer people today are smoking, which is a good thing, but that has led to the proportion of lung cancer in never-smokers increasing, meaning we need better screening programmes and a better understanding of the causes."
The review argues that LCINS has distinct causes and biology that requires a different approach. It recommends lung cancer assessments be pushed towards risk-based screening rather than relying primarily on smoking history.
Emerging risk factors such as genetics, clonal haematopoiesis (where abnormal cells multiply in the bone marrow), and environmental exposures like air pollution, radon (a radioactive gas from rocks and soil) and second-hand smoke are contributing a significant number of deaths to the global disease burden each year.
However, the relative risk associated with each of these factors is modest, meaning the justification for screening becomes more difficult.
Never-smokers with lung cancer are more likely to develop an adenocarcinoma, a cancer type that often grows from the outer parts of the lung. Adenocarcinomas are more likely to be driven by a single genetic mutation, meaning they can be treated with therapies targeting this faulty gene. Studies show around 80% of lung adenocarcinomas have actionable mutations but respond less effectively to immunotherapy compared to smokers.
Up to 4.5% of people with lung adenocarcinoma carry inherited genetic variants that increase cancer risk. Some mutations such as EGFR T790M can cause cancers to appear earlier in life and in several places at once, while changes in the APOBEC3 gene family – normally part of the body's antiviral defence – can also raise risk, highlighting the importance of genetic screening.
Another potential at-risk group are those with clonal hematopoiesis, an age-related condition where a genetic change in a blood stem cell leads to abnormal cells multiplying in bone marrow. Researchers say this can raise lung cancer risk regardless of smoking history by driving chronic inflammation that supports tumour growth.
While early evidence suggests anti-inflammatory treatments may reduce risk in high-risk individuals, there are currently no routine guidelines for screening or managing this condition in cancer prevention.
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, clonal haematopoiesis of indeterminate potential (CHIP), or inflammatory diseases
- Public health interventions such as radon monitoring and reducing exposure to air pollution and second-hand smoke
