Lung Cancer In Non-Smokers, A Hidden Threat

As per WHO estimates, lung cancer was noted as the most common cancer worldwide in 2022, accounting for 12.4% of all newly diagnosed cancer cases. In India, it is the fourth most frequent cancer at 5.8% and the fourth leading cause of cancer-related death at 8.7%. Although lung cancer is classically associated with smoking, global and Indian data are signifying a developing trend towards higher rates in non-smokers. The US Centers for Disease Control and Prevention uses the term 'never-smoker' or 'non-smoker' for people who have smoked <100 cigarettes in their lifetime, and LCINS (lung cancers occurring in individuals who have never smoked) is defined as lung cancer arising in such individuals. By contrast, a current smoker has smoked >100 cigarettes in a lifetime and still reports smoking every day or some days.

Difference between LCINS & tobacco-related lung cancer

Tobacco-related lung cancer is more strongly associated with squamous cell carcinoma and small-cell lung cancer, whereas the majority of LCINS cases are found to have adenocarcinoma. The majority of the cases of adenocarcinoma in LCINS are found to have targetable driver mutations such as EGFR compared to tobacco-related lung cancer. This disease can be managed with drugs acting at these genetic aberrations. However, PD-L1 expression is lower in LCINS than in tobacco-related lung cancer; hence, immunotherapies may be of less value in LCINS.

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Risk Factors

There are several suspected risk factors for lung cancer in non-smokers.

• Age: Older age is generally a risk factor for many cancers and is also seen in LCINS. However, individuals are also being increasingly diagnosed under the age of 50 years.
• Familial & genetic factor: Family history of any cancer, especially in first-degree relatives diagnosed at age <50 years, is associated with an increased risk of lung cancer, also in LCINS. As per a study, first-degree relatives showed a 25% higher likelihood of developing any type of cancer compared to the general population. Additionally, among relatives who smoked, there was a notable increase in the risk of early-onset lung cancer, with diagnoses occurring before the age of 50.
• Environmental exposures: Environmental exposures such as asbestos, chromium, radon and arsenic are implicated in the development of LCINS. Radon gas is a radioactive decay of uranium and may be found in rocks, soil and water. In countries like the United States radon testing is recommended for all houses below the third floor.
• Air pollution & second-hand smoke: Air pollution and second-hand smoke exposure to indoor biomass fuel usage may also be leading to a higher rate of LCINS, which is highly prevalent in Southeast Asia, including India. Long-term exposure to PM2.5 may increase mortality in lung cancer and other diseases. It is important to note that air pollution and particulate matter have been designated as level 1 carcinogens by WHO's International Agency for Research on Cancer (IARC). PM2.5 levels are seen to be positively correlated with EGFR-mutant rates of lung cancer as well. As per studies, second-hand smoke increases the risk of LCINS by 20-25% and is estimated to be responsible for about 3500 lung cancer-related deaths in the US alone every year.

Prevention

• Do not smoke.
• Avoid exposure to second-hand smoke, diesel exhaust, and other air pollution, as well as radon, asbestos, arsenic, and some forms of silica and chromium.
• Currently, screening for lung cancer in non-smokers is not recommended. However, a study in Taiwan found that low-dose CT scan (LDCT) had a high invasive lung cancer detection rate at 1 year after baseline LDCT in individuals who never smoked or had less than 10 pack-years history and stopped smoking 15 years ago and had other risk factors such as second-hand smoke exposure, family history of lung cancer, and history of pulmonary tuberculosis.

Summary Points

• Lung cancer among non-smokers is on the rise.
• Adenocarcinoma is more frequently observed in non-smokers, whereas squamous cell carcinoma and small cell lung cancer are more commonly associated with heavy smokers.
• Non-smokers with lung adenocarcinoma are more commonly found to have clinically actionable driver alterations compared to smokers.
• Risk factors include age, family history of cancer, and environmental and second-hand exposure to carcinogens.
• Preventive strategies include avoiding exposure to carcinogens, and not starting to smoke.

(Dr. P.N. Mohapatra- Director Medical Oncology, Apollo Cancer Centre, Kolkata)

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