Why is there an increase in lung cancer among women who have never smoked?

Lung cancer cases are increasing in people who have never smoked, especially in women, a new study by the World Health Organization’s cancer agency has found.

The findings, published in The Lancet Respiratory Medicine, reveal that lung adenocarcinoma, the most common type of lung cancer among non-smokers, accounts for nearly 60% of lung cancer cases in women compared to 45% in men.

About 2.5 million new lung cancer cases were diagnosed worldwide in 2022 – an increase of 300,000 since 2020. The study suggests that environmental factors, particularly air pollution, along with genetic predisposition and immune responses, may be driving this rise in non-smoking-related lung cancer.

One of the most significant risk factors for lung cancer in non-smokers is genetic mutations, especially mutations in the EGFR gene. This gene provides instructions for producing a protein on the surface of cells involved in growth and division.

Mutations in this gene drive uncontrolled cell division and tumour growth. They are found in 50% of lung adenocarcinomas in non-smoking Asian women and 19% in non-smoking Western women – compared with 10–20% in non-smoking men.

Read more: We need to talk about cancer

Advances in genetic testing have made it easier to detect these mutations. However, rising exposure to air pollution, which is known to trigger EGFR mutations – may also be contributing to their increasing prevalence.

Other genetic changes that drive tumour growth include mutations in the genes ALK and ROS1, which are found in about 5% of lung cancer cases in non-smokers. These mutations are more often seen in younger non-smoking women, particularly in Asia. Thankfully, improved screening programmes, especially in East Asian countries, have helped detect these mutations more frequently.

Mutations in TP53, a crucial tumour-suppressing gene, also appear to be more commonly found in non-smoking women than in men. This gene prevents cells from becoming cancerous, and its mutation leads to out-of-control cell growth. The hormone oestrogen can interact with TP53 mutations, making lung cancer more likely to develop in women over time.

Another gene that is worth mentioning is KRAS. Mutations in this gene are usually associated with smoking-related lung cancer, however, they are increasingly being found in non-smokers – particularly women.

Recent studies suggest that exposure to tiny particles in the air, or PM2.5 (so-called because they are 2.5 micrometres or smaller) may be responsible for these mutations in non-smoker women.

Since PM2.5 levels continue to rise in many towns and cities, exposure to these particles could be another factor not only in lung cancer but also in other types of cancers in women.

In addition to genetic predisposition, hormone fluctuations may influence tumour growth in women. Oestrogen receptors are found in lung tissue, and experimental studies suggest that oestrogen promotes tumour growth and that women who receive hormone-replacement therapy (HRT), have a lower risk of lung cancer compared with women not on HRT, suggesting that natural oestrogen cycles may provide some level of protection.

Chronic inflammation

Beyond genetics and hormones, chronic inflammation could also explain why lung cancer is rising among non-smoking women.

Women are more likely to develop autoimmune diseases than men, and problems with the immune system can play a role in cancer. Persistent inflammation can cause repeated damage to tissues, leading to changes in DNA, and promoting abnormal cell growth, all of which raise the risk of cancer.

Women with autoimmune diseases like rheumatoid arthritis and lupus have a higher chance of getting lung cancer, possibly because of long-lasting inflammation in the lungs. Inflammatory molecules – like interleukin-6 and tumour necrosis factor-alpha – can exacerbate the cancer by helping tumour cells survive and spread.

Autoimmune diseases have been increasing globally, probably because of environmental changes, changes in diet and shifts in gut microbiomes (the constellation of microorganisms that live in our guts and play an important role in our health). Because women are disproportionately affected by autoimmune conditions, they may be more vulnerable to chronic inflammation-driven cancer.

As life expectancy increases, more women are accumulating years of immune system activation, leading to a higher risk of developing inflammation-related lung cancer. In addition, things like pollution, household chemicals and work-related exposures can make immune system problems worse, increasing the risk of cancer even more.

Air pollution has long been recognised as a significant factor in lung cancer risk, but emerging evidence suggests that women may be particularly vulnerable. Studies show that women’s lung anatomy and function make them more susceptible to the harmful effects of pollutants. Women’s lungs are smaller than men’s, with narrower airways, which might cause more fine particles, like PM2.5, to get trapped in their lungs.

Additionally, oestrogen has been shown to amplify inflammatory responses when exposed to pollutants, potentially making lung tissue more prone to damage that can lead to lung cancer.

Women are more exposed to air pollution than men, but in a different way. While men often face pollution from factory work, women spend more time indoors where toxic fumes from cooking and heating are more common.

Air pollution in the home, especially from things like wood, coal and kerosene, can raise the risk of lung cancer. Women working in places such as textile factories, beauty salons and hospitals are also more exposed to harmful chemicals that can damage the lungs. In rapidly growing cities, women are often in areas with high traffic and factory pollution.

More significant

Women are biologically more likely than men to develop certain genetic mutations that increase the risk of lung cancer. However, factors like rising pollution, changes in hormone levels, immune system imbalances and longer life expectancy are making these risks even more significant.

Recent research suggests that HPV, a virus, may also contribute to lung cancer in women, underscoring the need for further study and preventative measures.

Understanding the roles of immune, hormonal, genetic and viral factors is key to spotting lung cancer early, creating more effective treatments and developing better ways to prevent it. DM 

This story was first published in The Conversation. Pinar Uysal-Onganer is a Reader in Molecular Biology at the University of Westminster.