Why Is Lung Cancer Increasing in Never-Smokers?

The reason why lung cancer is increasing in never smokers, especially young women, isn't clear. That said, we do have some idea what is not causing the rise, as well as risk factors that might play a role but don't entirely explain why rates should be rising (such as genetic predisposition).

Unfortunately, the stigma of lung cancer as being a "smoker's disease," and the relative lack of funding compared with other common cancers, are leaving critical questions unanswered. There are risk factors, however, that have been essentially ruled out, and many potential causes need further investigation.

Lung Cancer in Lifetime Never Smokers Is Increasing

For several years, physicians have noted what appears to be an increase in non-small cell lung cancer in people who have never smoked. The average age of lung cancer is 71, but support groups began to be filled with young parents coping with lung cancer, even women who were diagnosed while pregnant.

Studies have now confirmed that this impression is backed by facts. A significant portion of this increase has taken place from 1990 to the present, though a little digging suggests this has been going on much longer.

The first comment many people make when hearing of the rising rate of lung cancer in never smokers is that it must be the proportion. As smoking rates decline, perhaps the percent of people who never smoked is growing. Again, recent studies suggest this isn't a proportion problem and a true increase (and the consequences of such) is at stake.

Never Smokers vs. Non-Smokers Definition

When reviewing the literature it's important to make a distinction between never smokers and non-smokers. The term non-smokers includes both people who have never smoked and former smokers, those who once smoked but may have quit long ago. At the current time, the majority of people who develop non-small cell lung cancer are non-smokers; they have quit smoking or never smoked.

In contrast, the definition of a never smoker is someone who has smoked less than 100 cigarettes in their lifetime. In the United States, around 20% of women who develop lung cancer are never smokers, with that number rising to over 50% worldwide.

The Statistics

Several studies have now documented the increasing rate of lung cancer in never smokers. A 2017 study published in the Journal of the National Cancer Institute found what appears to be a true increase in lung cancer in never smokers.

Researchers looked at non-small cell lung cancer in never smokers at three different cancer centers in the U.S.

This increase was not believed to be due to an increased proportion of never smokers versus smokers/former smokers.

Further evidence from this study that shows this is a true increase as rising rates were seen only in non-small cell lung cancer. For lung cancers that are more strongly correlated with smoking, including small cell lung cancer and squamous cell lung cancer, there was no change in the proportion of smokers and never smokers diagnosed.

While Asians who develop cancer are more likely to be never smokers, and there was an increase in the proportion of Asians during the study period, the increase was not responsible after controlling for race/ethnicity.

Never smoking young adult women: Non-small cell lung cancer in never smokers is seen more commonly in women, with 17.5% being women compared with 6.9% of men. This difference was not seen among people with small cell lung cancer.

Young adults: Yet another difference noted in this study (and seen previously) was that lung cancer in never smokers tended to occur at a younger age than lung cancer that occurred in smokers or former smokers.

Similar Findings in the UK

A 2017 study in the U.K. also found a true increase in the incidence of lung cancer in never smokers. Over a six-year period, there was more than a doubling in the annual frequency of lung cancer in never smokers, increasing from 13% in 2008 to 28% in 2014.

Similar to the U.S. study, this increase was not just due to an increased proportion of never smokers, but an actual increase in the number of cases.

It May Have Been Increasing Much Longer

While the increase in lung cancer in never smokers is thought of as fairly recent, with the greatest increase since 2000, there is some evidence that the increase began long before this time.

A 1979 study published in the Journal of the National Cancer Institute looked at the incidence in never smokers between 1914 and 1968. The researchers found that for white males between the age of 35 and 84, the incidence in never smokers rose 15-fold with the relative increase between the ages of 65 and 84 rising 30-fold.

For white women between the ages of 35 and 84, the increase was seven-fold. Some of the increase prior to 1935 is thought to be related to diagnostic methods, but still, an increase was seen.

A few other studies have previously noted an increase in lung cancer in never smokers as well. A Swedish study found that lung cancer in never smokers increased from the 1970s to the 1990s. A U.S. study around the time also found an increase, with lung cancer in never smokers more prevalent in the 1980s and 1990s than the 1960s. In the United States, however, this was statistically significant only in women.

Scope of the Problem

An increase in the incidence of any lung cancer is of great concern as lung cancer is the leading cause of cancer-related deaths in both men and women. And while smoking cessation campaigns have been very successful in reducing the rate of smoking, they will do little to reduce the risk in lifelong never smokers.

Considering the Causes

While there is speculation regarding the increase in lung cancer in never smokers, there are few solid answers as to the possible causes. As awareness improves, and more people realize that lung cancer can and does happen to anyone with lungs, it's likely that potential causes will be evaluated in greater depth.

Until that time, it's important to take a careful look at what might be underlying this increase. After all, people are being diagnosed today and we may not have that data for a few decades.

In looking at risk factors, it's helpful to understand that lung cancer in never smokers is a different disease in many ways.

People who have smoked are much more likely to have KRAS or TP53 mutations.

A greater understanding of the genomics of lung cancer from tests such as next-generation sequencing and genome-wide association studies will likely tease out further differences between lung cancer in never smokers and that in smokers. For example, it's known that tobacco carcinogens are associated with KRAS mutations.

Factors Unlikely to Be Responsible

A good first step at looking at the potential causes of the rising rate of lung cancer in never smokers is to look at what isn't responsible. There are many factors that can't explain the increase.

Closet Smoking

A potential reason for an increased rate of lung cancer in never smokers is misreporting (if people were smokers but claimed not to be). Not only does this not fit with the studies above (rates increased in non-small cell lung cancer but not small cell), but researchers found that the characteristics of the tumors in never smokers differed from those in smokers.

Even if the never smokers in these studies were mostly closet smokers, there is yet another problem with this solution. Never smokers are more likely to be diagnosed at a younger age than smokers.

The latency period (the amount of time between exposure to a carcinogen and the development of cancer) is such that the average of lung cancer diagnosis is age 71. For closet smoking to be responsible, many of these people would have had to start closet smoking as young children, or even in the womb.

Secondhand Smoke

Not only did people in the never-smoking group claim lower rates of secondhand smoke exposure, but the rate of secondhand smoke exposure is also dropping due to fewer people smoking and tighter regulations on smoking in public. Research in both Europe and Asia looking at lung cancer in never smokers found, in addition, that the mutational signature (the types of acquired mutations in the tumor cells) did not fit with secondhand smoke.

Obesity

Recent frightening statistics found that several types of cancer are increasing in young adults. Unlike the types of cancer noted, however, lung cancer is not considered an obesity-related cancer, and obesity has actually been associated with a lower risk of the disease.

Potential Causes and Risk Factors

There are a number of potential causes of lung cancer in never smokers. In the U.K., current estimates of factors that contribute to lung cancer in never smokers are as follows:

• Secondhand smoke (around 15%)
• Occupational carcinogen exposure (roughly 20.5% in men and 4.3% in women)
• Outdoor pollution (around 8%)
• Medical radiation (0.8%)
• Radon exposure (0.5%)

This differs from numbers quoted by the Environmental Protection Agency (EPA), in which radon is listed as the number one cause of lung cancer in never smokers.

Other risk factors have also been identified such as family history of the disease/genetics, other lung diseases (asthma, tuberculosis, COPD), autoimmune diseases, indoor air pollution (cooking fumes and cleaning products), excess estrogen exposure, dietary factors, and HPV.

It is helpful to look at these risk factors when pondering the question we are asking, but there is another question that needs to be considered at the same time and is rarely asked.

It's important to keep this question in mind as we explore potential causes, beginning with one risk factor that's often cited as a possible answer: genetic predisposition.

Genetic Predisposition

A genetic predisposition plays a greater role in lung cancer risk in never smokers than people who have smoked. People who have a family history of lung cancer are at greater risk, especially those who have a first-degree family member (parent, sibling, or child) who developed lung cancer (or any cancer for that matter) before the age of 50.

With genetic testing, some of the underlying causes are being identified. Women who have a BRCA2 gene mutation (one of the genes usually associated with breast cancer risk) are more likely to develop lung cancer. Roughly half of all people with non-small cell lung cancer who have an EGFR T790M mutation at the time of diagnosis may have a germline mutation (hereditary) rather than a somatic (acquired) mutation.

There are several other genetic associations that have now been examined. Most of these mutations (such as BRCA mutations) are in tumor suppressor genes, genes that code for proteins that fix damaged DNA (or result in the death of the cell) so that abnormal cells cannot persist and become cancer cells. There are also likely genetic variations that result in people having different susceptibilities when exposed to carcinogens associated with lung cancer.

While a genetic predisposition may play a significant role in lung cancer in never smokers, especially in women and young adults, it wouldn't account for the increasing incidence of the disease within a generation.

Radon

Radon exposure is often quoted as the leading cause of non-small cell lung cancer in people who have never smoked (and the second-leading cause in smokers). Elevated radon levels have been found in homes in all 50 states and around the world. Since it is an odorless, colorless gas, the only way to know if you are at risk is to test your home or have it tested.

Radon gas is released from the normal breakdown of uranium in the soil beneath homes. Particles of radioactive radon are inhaled and become trapped in the lungs, releasing alpha particles that can directly damage DNA (cause mutations).

There has been some debate over whether the type of mutations caused by radon results in the types of mutations seen in lung cancers in never smokers. In other words, does residential radon play a role in the molecular signature of lung cancer in never smokers?

A 2013 study did not find an association between EGFR mutations and radon, but newer studies looking at several mutations common in never smokers suggest a different story.

A 2018 study published in the Journal of Thoracic Oncology looked at three areas in France based on average radon exposure. It was found that the type of driver alterations commonly found in never smokers, including EGFR mutations, ROS1 rearrangements, BRAF, and HER2 were significantly more common in the high radon exposure area. In contrast, the prevalence of KRAS mutations (mutations often found in lung cancers in people who have smoked) was much more common in the low radon exposure area.

A different 2016 study found that people who had ALK positive lung cancer had residential radon levels that were twice as high as those who had ALK negative tumors. This study did not find significant difference overall based on radon levels, but radon levels were two-fold higher in people who had exon 19 deletions when compared with people who had exon 21 (L858R) substitution mutations.

Radon Levels and the Increase in Lung Cancer in Never Smokers

Knowing that radon may be associated with lung cancer in never smokers begs the question, "Could radon somehow account for the increasing risk? Is radon in homes increasing for some reason?"

A 2019 study suggests the answer is yes. Researchers looked at 11,727 residential buildings in North America, linking more modern construction features and behaviors to an increase in the amount of radon concentration in the home. Examples include:

• Increased square footage
• Higher ceilings
• Fewer stories
• The presence of basements
• More time spent in a closed indoor space (thanks to air conditioning)
• Infrequent window opening

Other theories say measures to improve the porosity in the soil around homes (done to reduce the likelihood of water damage) can make it easier for radon to enter homes and become trapped. Studies done in Italy have found that radon levels in homes can vary depending on the time (and building methods) that structures are built.

Even some of the advances in addressing radon could potentially be a factor. Homes are now built to be radon-resistant. Radon resistance, however, does not mean radon proof, and homes that are radon-resistant may still need radon mitigation (though it is easier as the basics are in place). It's possible that this could create a false sense of security that radon testing is not needed.

There are many more questions than answers but, with the current information, it's important that these questions are addressed.

Occupational Exposures/Home Exposures

Occupational exposures as a cause of lung cancer have been considered important for many years among never smokers (as well as smokers) who develop the disease.

Overall, it's thought that these exposures play a role in lung cancer in 13% to 29% of men, with lower numbers among women. The increased risk now seen in more never-smoking women could relate to more women in the workforce, or perhaps increased susceptibility to known carcinogens. That said, measures to protect workers have also improved substantially.

This brings up concerns about potential home exposures, though there is little to no research looking at the potential of cleaning products or even personal care products as an issue. Perhaps if lung cancer didn't carry the stigma of being a smoker's disease, studies evaluating these issues would be in place.

Air Pollution

Air pollution is now considered a known risk factor for lung cancer in both smokers and never smokers, with the risk varying significantly by geography and whether people live in urban or rural areas. In some regions of the world, this could easily account for an increase in the disease in never smokers, though in the U.S., this is thought to be less of an issue than some other areas.

HPV

A connection between human papillomavirus (HPV) and lung cancer has been found in a number of studies, but at the current time it's not known if this is causation or simply correlation. Certainly cancers (such as head and neck cancer) related to HPV have increased.

That said, the mutational signature of lung cancer in never smokers is very different from that seen with HPV related cancers such as those of the head and neck, cervix, and other regions.

Hormones

An association has also been noted between estrogen and lung cancer, though the research is confusing. A 2010 study published in Cancer Epidemiology Biomarkers and Prevention found that women who experienced early menopause (before the age of 44) were 39% more likely to develop lung cancer, while women who had used oral contraceptives (birth control pills) for more than five years were 22% more likely. The effect, however, was greater in smokers and associated more strongly with small cell lung cancer.

Looking Forward

At the current time, most lung cancers in never smokers cannot be clearly linked with environmental risk factors.

The Hunt for Environmental Carcinogens

Now that more is known about the unique mutational signature of non-small cell lung cancer in never smokers, it will be easier to evaluate potential causes, and some researchers are focusing on just this issue. For example, Dr. Alice Berger at Fred Hutchinson Cancer Center in Seattle recently received a grant to study this area.

Finding Answers

There are many more steps that can be taken, and epidemiological research is urgently needed to address this rising trend. Looking at other cancers that are increasing and any possible associations is one step.

For example, multiple myeloma, a cancer often thought of as being largely environmental in causation, has significantly increased in the past three decades, including in occupations such as bakers, pastry chefs, and cosmetologists. More research is needed to look into the role substances like chlorinated solvents, pesticides, etc. may play.

A Word From Verywell

While we don't know the causes, we do know that never smokers are much more likely to have treatable mutations that can sometimes significantly extend and improve quality of life. At the same time, far too few people are being treated or even tested for genomic alterations in their tumors.

If you have been diagnosed with lung cancer, it's important to be your own advocate. Oncology is changing so rapidly that it's nearly impossible for any physician to stay on top of the changes in lung cancer, more or less all cancers. Fortunately, remote second opinions are now available at many of the large National Cancer Institute-designated cancer centers so that people can find out if they need to travel to take part in the newest treatments or participate in a clinical trial.