The Rising Cases of Lung Cancer in Non-Smokers

The incidence of lung cancer among people who have never smoked is increasing. This form of the disease differs from that linked with smoking, so what exactly causes it?

Martha noticed a change when her cough intensified, and the mucus in her airways grew thicker. Initially, doctors attributed her symptoms to a rare disorder causing chronic lung inflammation. “No need to worry, it must just be that,” she remembers being told.

However, an X-ray later revealed a shadow on her lung. “That was the catalyst,” Martha reflects. Following up with a CT scan and a bronchoscopy — a procedure using a tube for airway inspection — tissue samples were collected. After four months since she first approached her GP, she learned she had Stage IIIA lung cancer, as the tumor had affected surrounding lymph nodes but hadn’t metastasized further. At the time, Martha was 59.

“It was completely shocking,” she admits, noting that while she might have smoked occasionally at parties, she never identified as a smoker.

Lung cancer ranks as the most prevalent cancer globally and the primary cause of cancer-related deaths. In 2022 alone, about 2.5 million new cases were reported, with over 1.8 million deaths. While lung cancer tied to tobacco use remains predominant, smoking rates have been decreasing steadily over the past few decades. As a growing number of smokers quit, lung cancer cases in non-smokers are starting to rise. Currently, between 10 to 20% of lung cancer diagnoses are among those who have never touched a cigarette.

“Lung cancer in non-smokers is emerging distinctively, with unique molecular traits affecting treatment and patient outcomes,” says Andreas Wicki, an oncologist at the University Hospital Zurich. Although the age of diagnosis is similar to that of smokers, younger patients with lung cancer tend to be non-smokers. “When we see patients in their 30s or 35s, they often have never smoked,” he points out.

Moreover, the types of lung cancer being diagnosed have shifted. Up until the 1950s and 1960s, squamous cell carcinoma, starting from lung lining cells, was the most common. In contrast, lung cancer in non-smokers is predominantly adenocarcinoma, which originates in mucus-producing cells and has become the most frequently diagnosed type in both smokers and non-smokers.

Similar to other lung cancers, adenocarcinoma is generally detected at a later stage. “A hidden tumor of just 1 cm (0.4 inches) may go unnoticed,” Wicki explains. Early symptoms like persistent cough, chest pain, or shortness of breath often arise only after the tumor grows or spreads. The strong historical connection between smoking and lung cancer might lead non-smokers to misinterpret symptoms as caused by other factors, Wicki adds. “Thus, most cases in non-smokers are diagnosed at Stage 3 or 4.”

Interestingly, lung cancer in non-smokers tends to be more prevalent among women. Female non-smokers face more than twice the risk of lung cancer compared to their male counterparts. Factors here might include anatomical lung differences and environmental exposures, but genetic mutations are also at play, especially common among Asian women. One notable mutation is called EGFR.

Wicki explains that lung cancer cells in non-smokers frequently exhibit various mutations contributing to their development, known as driver mutations. These genetic changes propel tumor growth, one being the epidermal growth factor receptor gene. The reasons for the higher occurrence of these mutations in females, particularly of Asian descent, remain unclear. Preliminary evidence suggests female hormones might influence this, as certain genetic variations impacting estrogen metabolism are more common in East Asians.

In response to the identification of these mutations, the pharmaceutical industry has begun developing targeted therapies. The first EGFR inhibitors were available about two decades ago, showing remarkable initial responses in most patients. However, treatment could lead to resistant cancer cells and eventual relapse. Recently, a variety of new drugs have made their way to the market to tackle this issue.

This progress has led to improved patient outcomes. “Currently, the median survival rate for those with driver mutations is several years,” explains Wicki. “Some patients have benefited from targeted therapy for over ten years. Compared to just 20 years ago, when the median survival was below 12 months, that’s a significant advancement.”

With the rise of lung cancer cases in non-smokers, experts stress the importance of developing preventive measures for this demographic. Various risk factors have been connected, such as radon exposure and second-hand smoke, which can heighten lung cancer risk in non-smokers. Furthermore, inhaling cooking fumes or using wood or coal-burning stoves in poorly ventilated areas poses additional threats. Notably, women, often spending more time indoors, may be particularly susceptible to this indoor air pollution. However, outdoor air pollution appears to be an even more significant contributor to lung cancer development.

Indeed, outdoor air pollution ranks as the second leading cause of lung cancer, trailing only behind smoking. Research indicates that individuals living in heavily polluted regions face greater risk of lung cancer mortality compared to those in cleaner areas. Particulate matter smaller than 2.5 microns — about a thirty-second the width of a human hair, commonly resulting from vehicle emissions and fossil fuel combustion — is especially culpable. There’s also compelling evidence connecting high PM2.5 levels to lung cancer in never-smokers who possess EGFR mutations.

Research at the Francis Crick Institute in London is examining how air pollution could trigger lung cancer in non-smokers with the EGFR mutation. “Environmental carcinogens often lead to DNA mutations,” shares William Hill, a postdoctoral researcher there. For instance, cigarette smoke inflicts DNA damage, leading to lung cancer. Their recent study posits that PM2.5 may not directly cause DNA mutations; instead, it appears to activate dormant mutant cells in the lungs, instigating the early stages of lung cancer.

Experiments indicate that air pollutants are absorbed by immune cells called macrophages, which typically defend the lungs against infections. Upon PM2.5 exposure, these cells release cytokines that awaken cells harboring the EGFR mutation and encourage their proliferation. “Both air pollution and EGFR mutations are crucial for tumor development,” asserts Hill. Understanding how PM2.5 influences the microenvironment of EGFR-mutated cells might lead to groundbreaking lung cancer prevention strategies.

This longstanding association between air pollution and lung cancer dates back to a pivotal 1950 study linking smoking to the disease, which identified outdoor pollutants from fossil fuel combustion as potential culprits. Yet, measures taken since have primarily focused on tobacco control. Now, 75 years later, air pollution is gradually gaining attention.

Air quality in Europe and the US has seen improvement over the years, although the effects on lung cancer rates may take years to unfold. “Changes in exposure might take 15 to 20 years to reflect in lung cancer statistics, but that’s not definitive,” cautions Christine Berg, a retired oncologist with the National Cancer Institute in Maryland. With climate change affecting future conditions, Berg also notes increased wildfire risks contributing to elevated air pollution next in line. “At least one study has associated wildfire exposure with rising lung cancer rates. It’s crucial to transition from coal, oil, and gas to both fortify air quality and combat climate change.”

The World Health Organization has revised its annual mean air quality guideline for PM2.5, adopting stricter standards. Yet, alarmingly, 99% of the global population lives in regions exceeding these updated limits, remarks Ganfeng Luo, a postdoctoral researcher at the IARC.

Recent IARC research estimated that in 2022, around 194,000 adenocarcinoma cases worldwide were linked to PM2.5 exposure, with East Asia, particularly China, facing the greatest burden.

In the coming years, lung cancer deaths due to air pollution may rise significantly, particularly in countries like India, where pollution levels are among the highest globally, according to the WHO. In Delhi, average PM2.5 levels are alarmingly high, exceeding WHO guidelines by 20 times.

In the UK, approximately 1,100 adenocarcinoma cases in 2022 were tied to air pollution, according to IARC data. However, Harriet Rumgay, an epidemiologist, notes that this does not mean all cases were non-smokers since adenocarcinoma also affects smokers, especially those using filtered cigarettes. “There’s so much still unknown,” she admits. “Further research is vital to unraveling these multifaceted factors, including how long exposure might lead to lung cancer.”

With advances in treatment, lung cancer among non-smokers is becoming increasingly manageable. There might come a day when this variant overtakes lung cancer historically linked with older male smokers, altering public perception of the disease. “Sadly, the notion that patients bear some responsibility for their illness persists,” laments Wicki.

Martha discovered she had an EGFR mutation and has been on targeted therapy since her diagnosis nearly three years ago. “It’s certainly no walk in the park,” she comments, describing the drug’s harsh side effects: fatigue, muscle aches, skin issues. Judging the trade-offs of treatment while maintaining quality of life can be challenging, but she notes the efficacy of the treatment. “And I see a shift in thinking regarding the disease, which is definitely a positive change.”