The mystery rise of lung cancer in non-smokers

The number of lung cancer cases in people who have never smoked is increasing. The disease is different from lung cancer caused by smoking, so what causes it?

Martha first realised that something was wrong when her cough changed and the mucus in her airways became increasingly viscous. Her doctors put it down to a rare disorder she had that caused her lungs to become chronically inflamed. "No worry, it must be that," she was told.

When she finally had an X-ray, a shadow was detected on her lung. "That set the ball rolling," Martha recalls. "First, a CT scan was done, then a bronchoscopy [a procedure that involves using a long tube to inspect the airways in a person's lungs] to take tissue samples." After the tumour was removed, about four months after she'd first reported symptoms to her GP, she received the diagnosis: Stage IIIA lung cancer. The tumour had infiltrated the surrounding lymph nodes but had not yet spread to distant organs. Martha was 59 years old.

"It was a total shock," says Martha. Although she would occasionally light up a cigarette at a party, she never considered herself a smoker.

Lung cancer is the most common cancer worldwide and the leading cause of cancer death. In 2022, about 2.5 million people were diagnosed with the disease and more than 1.8 million died. Although tobacco-related lung cancers still for the majority of diagnoses worldwide, smoking rates have been declining for several decades. As the number of smokers continues to fall in many countries around the world, the proportion of lung cancer occurring in people who have never smoked is on the rise. Between 10 and 20% of lung cancer diagnoses are now made in individuals who have never smoked.

"Lung cancer in never-smokers is emerging as a separate disease entity with distinct molecular characteristics that directly impact treatment decisions and outcomes," says Andreas Wicki, an oncologist at the University Hospital Zurich, Switzerland. While the average age at diagnosis is similar to that of smoking-related lung cancers, younger patients with lung cancer are more likely to have never smoked. "When we see 30- or 35-year-olds with lung cancer, they are usually never-smokers," he says.

Another difference is the type of cancer being diagnosed. Until the 1950s and 1960s, the most common form of lung cancer was squamous cell carcinoma – a type which begins with the cells that line the lungs. In contrast, lung cancer in never-smokers is almost exclusively adenocarcinoma – a type which starts in mucus-producing cells – which is now the most common form of lung cancer in both smokers and never-smokers.

Like other forms of lung cancer, adenocarcinoma is usually diagnosed at an advanced stage. "If there's a 1cm (0.4in) tumour hidden somewhere in your lungs, you won't notice it," says Wicki. The early symptoms, which include persistent coughing, chest pain, shortness of breath or wheezing, often only appear when the tumour is larger or has spread. In addition, the historically strong link between smoking and lung cancer may inadvertently lead non-smokers to attribute symptoms to other causes, says Wicki. "Most cases in never-smokers are therefore only diagnosed at stage 3 or 4."

Lung cancer in never-smokers is also more common in women. Women who have never smoked are more than twice as likely to develop lung cancer as male never-smokers. Aside from lung anatomy and environmental exposures, at least part of the answer may lie in genetic mutations that are more common in women, especially in Asian women. One of the most prevalent is a mutation known as EGFR.

Lung cancer cells in people who have never smoked usually have a number of mutations that could be causing their cancer, explains Wicki – so-called driver mutations. These genetic changes drive tumour growth, such as the EGFR gene which codes for a protein on the surface of cells and is called epidermal growth factor receptor. The reasons why these driver mutations are more frequently found in female patients, particularly those of Asian descent, are not entirely understood. There is some evidence that female hormones may play a role, with certain genetic variants that affect oestrogen metabolism being more prevalent in East Asians. This could potentially explain the higher incidence of EGFR-mutant lung cancer in Asian women, although the data is very preliminary.

Following the discovery of mutations which can lead to lung cancer in non-smokers, the pharmaceutical industry began to develop drugs that specifically block the activity of those proteins. For example, the first EGFR inhibitors became available around 20 years ago and most patients showed an impressive response. However, treatment often led to resistant cancer cells, resulting in tumour relapse. In recent years, much effort has been put into overcoming this problem, with newer types of drugs now entering the market. 

As a result, the prognosis for patients has steadily improved. "The median survival rate of patients who carry such driver mutations is now several years," Wicki explains. "We have patients who have been on targeted therapy for more than 10 years. This is a huge step forward when you consider that the median survival rate was less than 12 months about 20 years ago." 

As the proportion of lung cancer in never-smokers increases, experts say it is crucial to develop prevention strategies for this population. A number of risk factors have been implicated. For example, studies have revealed that radon and second-hand smoke can elevate the risk of lung cancer in non-smokers. Additionally, exposure to cooking fumes or to stoves burning wood or coal in poorly ventilated rooms may also increase this risk. Since women traditionally spend more time indoors, they are particularly vulnerable to this type of indoor air pollution. However, outdoor air pollution is an even more significant factor in the development of lung cancer.

In fact, outdoor air pollution is the second leading cause of all lung cancer cases after smoking. Studies have revealed that people who live in highly polluted areas are more likely to die of lung cancer than those who do not. Particulate matter less than 2.5 microns in diameter (about a 30th of the width of a human hair), typically found in vehicle exhaust and fossil fuel smoke, seems to play an important role. And intriguingly,  research has shown a strong link between high levels of PM2.5 and lung cancer in individuals who have never smoked and who carry an EGFR mutation.

How air pollution may trigger lung cancer in never-smokers carrying the EGFR mutation has been the focus of research at the Francis Crick Institute in London. "When we think about environmental carcinogens, we usually think about them as causing mutations in the DNA", says William Hill, a post-doctoral researcher in the cancer evolution and genome instability laboratory of the Francis Crick Institute. Cigarette smoke, for example, damages our DNA, thus leading to lung cancer. "However, our [2023] study proposes that PM2.5 doesn't directly mutate DNA, rather it wakes up dormant mutant cells sitting in our lungs and starts them on the early stages of lung cancer."

In their experiments, the researchers showed that air pollutants are taken up by immune cells called macrophages. These cells normally protect the lung by ingesting infectious organisms. In response to PM2.5 exposure, macrophages release chemical messengers known as cytokines, which wake up cells carrying the EGFR mutation and causes them to proliferate. "Both air pollution and EGFR mutations are needed for tumours to grow," says Hill. Understanding how PM2.5 acts on the microenvironment of cells carrying EGFR mutations to promote tumour growth, he adds, could pave the way for new approaches to preventing lung cancer. 

The association between air pollution and lung cancer is not new. In a landmark paper establishing the link between smoking and lung cancer in 1950, the authors suggested outdoor pollutants from the burning of fossil fuels as a possible cause. But policies to date have focused almost exclusively on tobacco control. But 75 years later, air pollution is finally coming into focus.

Air pollution levels in Europe and the US have fallen in recent decades. But the effect of changes on lung cancer rates has not yet become apparent. "It probably takes 15 to 20 years for changes in exposure to be reflected in lung cancer rates, but we don't know for sure," says Christine Berg, a retired oncologist from the National Cancer Institute in Maryland, US. Moreover, the picture is not static: climate change is likely to have an impact in the future. "With the increasing risk of wildfires, air pollution and PM2.5 levels are rising again in certain regions of the US," says Berg. "At least one study has shown an association between wildfire exposure and increased incidence of lung cancer. Transitioning away from coal, oil and gas is therefore crucial not only to slow global warming but also to improve air quality."

In 2021, the WHO halved the annual mean air quality guideline for PM2.5, meaning it has adopted a more stringent approach to particulate matter. "But 99% of the world population lives in areas where air pollution levels exceed [these updated] WHO guideline limits," says Ganfeng Luo, a postdoctoral researcher at the International Agency for Research on Cancer (IARC) in Lyon, . 

In a recent study, IARC researchers estimated that approximately 194,000 cases of lung adenocarcinoma worldwide were attributable to PM2.5 in 2022. "The highest burden is estimated in East Asia, especially in China," says Luo.

In the future, the number of lung cancer deaths attributable to air pollution could increase in countries such as India, which currently has some of the highest levels of air pollution, according to the WHO. In Delhi, the average PM2.5 levels are above 100 micrograms per sq m, which is 20 times above the WHO air quality guidelines.

In the UK, 1,100 people developed adenocarcinoma of the lung as a result of air pollution in 2022, the IARC study found. "But not all of these cases will be in never-smokers," says Harriet Rumgay, an epidemiologist and a co-author of the study. Adenocarcinoma also occurs in smokers, especially in those using filtered cigarettes. "There's still a lot we don't know," says Rumgay. "More research is needed to disentangle the different factors and also to understand, for example, how long you would need to be exposed to air pollution before developing lung cancer." 

As treatments continue to improve, lung cancer in never-smokers is becoming more survivable. It is conceivable that this type of lung cancer will one day become the most common form of a disease that has historically been associated with older male smokers, changing the way we think about the disease in popular culture; "…the idea that they [patients] are at least partly to blame for their disease is unfortunately still widespread," says Wicki.

Martha was found to have an EGFR mutation and has been taking an inhibitor since her diagnosis almost three years ago. "It's definitely not a vitamin pill," she says. The drug has some nasty side effects: chronic fatigue, muscle pain, skin problems. Balancing the risks and benefits of drug treatment and maintaining a reasonable quality of life is not always easy, she says. But the drug is working.  "And the fatalistic view of the disease is changing, and that is good."

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