Attention Turns to Lung Cancer Cases in Those Who Never Smoked

Just under a quarter of a million new cases of lung cancer were estimated to be diagnosed in 2023, and although smoking is the number one cause of lung cancer, anywhere from 10% to 20% of new cases will occur in people who never smoked or smoked fewer than 100 cigarettes in their lifetime.^1,2

“Lung cancer in people without a smoking history is a really interesting disease entity that we have been learning a lot more about in recent years,” said Michael Grant, MD, an assistant professor of medicine at Yale School of Medicine. “It is an area emerging on oncologists’ radars a bit more because of the increased genomic understanding of lung cancer.”

There is growing interest in understanding how and if lung cancer in people who have never smoked is different than lung cancer in those with a smoking history, and whether anything can be done to capture these people earlier in their disease course.

What Are the Trends?

“It is difficult to ascertain if the absolute incidence of lung cancer in patients who have never smoked is increasing over time or if these cases just represent a greater proportion of lung cancers now that smoking rates are decreasing,” said Jaclyn LoPiccolo, MD, PhD, an attending physician at the Lowe Center for Thoracic Oncology at the Dana-Farber Cancer Institute.

For example, a study looking at self-reported smoking history among patients diagnosed with lung cancer in registries from the University of Texas Southwestern Medical Center, Parkland Hospital, and Vanderbilt University showed that the proportion of cases in patients who have never smoked almost doubled from 8.0% in 1990-1995 to 14.9% in 2011-2013.³

Further data in the study suggested that the incidence of lung cancer in the never-smoking population is also likely increasing, but Dr. LoPiccolo said that because information on individual smoking status is not available in large national epidemiologic databases, it is hard to determine what the true trends are on a larger scale.

Data also suggest that lung cancer in patients who have never smoked may be more common in women compared with men, Dr. LoPiccolo said.

Data published from the US Centers for Disease Control and Prevention National Program of Cancer Registries found a higher proportion of people who have never smoked among women with lung cancer compared with men across all age groups and races/ethnicities (15.7% vs 9.6%).⁴

Data also indicate that lung cancer rates in people who have never smoked may be higher in Asian women, according to Rajat Thawani, MBBS, an assistant professor of medicine at the University of Chicago Medicine.

“The hypothesis that lung cancer in never smokers is more common in Asian women came from data from Asia, and one of the reasons hypothesized is environmental, but whether the same environmental effects translate into Asian-American women in the [United States] is still unknown,” said Dr. Thawani.

Data from Florida’s cancer registry found the highest rates of lung cancer among people who have never smoked among Asian/Pacific Islander men and women.⁵ A study of electronic health records from two health systems in northern California enriched for Asian American, Native Hawaiian, and Pacific Islander (AANHPI) groups found that although lung cancer diagnoses among those who have never smoked varied across different AANHPI groups, “more than three-quarters of Chinese, Asian Indian, and Vietnamese female lung cancer diagnoses [occurred] among those who have never smoked.”⁶

Additionally, although the average age at diagnosis of lung cancer is not all that different between patients with a history of smoking and those without, Dr. LoPiccolo noted that among young people diagnosed with lung cancer, a greater proportion of patients have never smoked.

However, it is early days in all of the research examining trends in lung cancer rates among people who have never smoked. For example, Manali Patel, MD, an associate professor of medicine at Stanford Medicine, said that while it is generally thought that there could be a higher prevalence of all lung cancer diagnoses among women, it may be related to differences in smoking prevalence and rates of uptake and cessation.

Risk Factors

More research is being done to identify risk factors for lung cancer in people who have never smoked; some of these risk factors are likely environmental.

“Radon is a radioactive, odorless, and colorless gas that is released from rock and has geographic distribution across the [United States],” Dr. Grant said. “It is thought to contribute to a significant proportion of nonsmoking-related lung cancers.”

Indeed, decades of research have established the link between radon exposure and lung cancer. The World Health Organization estimates that radon exposure is responsible for 3% to 14% of lung cancer cases and is the leading cause of lung cancer in nonsmokers.⁷

“In some areas of the world, fine particulate matter, known as PM_2.5, is thought to be associated with lung cancer in patients who have never smoked,” Dr. LoPiccolo said.

Last year, researchers from the Francis Crick Institute in the United Kingdom discovered how this fine particulate matter may trigger lung cancers and published data showing that exposure to increased concentrations of PM_2.5 was associated with incidence of lung cancer, particularly EGFR-driven lung cancer cases.⁸

Other links being explored include industrial pollution, radiation exposure, and wildfires.

“Some people have looked at obesity as a risk factor, but the linkage is not clear,” said Dr. Patel. “I know that some researchers are looking at a potential association with hormonal exposure, but there are not a lot of data on these areas.”

It is also possible that the lung cancers that occur in people without a history of smoking may be different than those that occur in people with a history.

A genomic analysis of lung cancer in people who have never smoked found that these tumors could occur as a result of the accumulation of mutations in the body. Using whole-genome sequencing in people with lung cancer who had never smoked—predominantly of European descent—researchers found three subtypes of disease based on somatic copy number alterations that were profoundly different from adenocarcinomas diagnosed in smokers.⁹ The majority of tumor genomes in these patients had mutational signatures associated with damage from natural processes occurring in the body.¹⁰

“There are genetic subsets of risk factors that can be inherited from parents,” Dr. Grant said. “These include gene mutations in EGFR; mutations in BRCA, which can be associated with other cancers; mutations in MET, TP53, PTEN…but these make up only a small percentage of nonsmoking-related lung cancers.”

Unique Disease?

The majority of nonsmoking-related lung cancers are adenocarcinomas, with only about 10% to 20% having squamous cell histology.² Additionally, about 90% of adenocarcinomas in people who have never smoked have a known driver mutation, Dr. Grant said.

One small genomic profiling study of lung cancer found that while only about half of patients with a history of smoking had clinically actionable driver mutations, between 78% and 92% of people without a history of smoking had actionable mutations.¹¹ Another single-center study found that after comprehensive next-generation sequencing 78% of people without a history of smoking had actionable driver mutations compared with 47% of people with a history of smoking.¹²

For the most part, a pathologist cannot tell a smoking-related cancer or a nonsmoking-related cancer apart just by looking under the microscope, Dr. Grant said. However, there are subsets of non-small cell lung cancer (NSCLC) where certain features stand out under the microscope, one of which is sarcomatoid histology.

“When you see sarcomatoid features, there is a higher likelihood that you will find a MET alteration called a MET exon 14-skipping alteration, for which there are [US Food and Drug Administration]-approved oral treatments available,” Dr. Grant said. “Whenever I see sarcomatoid carcinoma and it doesn’t pick up a MET mutation, I really make sure we are looking hard enough because of the enrichment seen in this specific subset of NSCLC.”

Clinicians may need to obtain another biopsy or get information from cell-free DNA in cases where there are certain features with high suspicion for targetable driver mutations. This information can affect treatment options and the length of patient lives.

Expanded Screening

People without a history of smoking do not currently qualify for lung cancer screening, explained Dr. Thawani.

“Usually, these patients are diagnosed once they have become symptomatic versus people who smoke who are offered annual screening,” Dr. Thawani said. “That means the likelihood of them being diagnosed at a more advanced stage is higher, which could have an effect on prognosis.”

The need to adjust screening guidelines to capture a larger number of people at potential risk for lung cancer is a big debate in the field, according to Dr. Patel.

“We need to adapt screening guidelines to make sure we are not inadvertently creating disparities either by gender or race and ethnicity,” he said, citing research that showed that prior screening guidelines that required a 30 pack-year history excluded a larger proportion of women compared with men and minorities compared with non-Hispanic White individuals.¹³

Dr. LoPiccolo and colleagues at Dana-Farber, in collaboration with GO2 for Lung Cancer and the Addario Lung Cancer Medical Institute, are conducting a study to look at germline genetic risk for lung cancer based on family history, which will also collect detailed information on past medical and exposure histories, called INHERIT (Investigating Hereditary Risk in Thoracic Cancers). The study will pilot computed tomography screening in a subset of people with a family history of lung cancer or those who are known to be at higher genetic risk for lung cancer, a significant proportion of whom are expected to be those without known tobacco exposure.

Dr. Grant is interested in harnessing the power of artificial intelligence (AI) to capture more people at risk for lung cancer.

“There are AI projects within radiology where a model is looking at scans to see if there are commonalities to the structure of the lung or other radiographic features that can predict cancer development,” Dr. Grant said. “Training these machine learning models can potentially lead to better screening techniques in the future, which is interesting and exciting.”

Addressing Stigma

Finally, any discussion of lung cancer in people who have never smoked should address the fact that there is a still a stigma attached to the diagnosis.

“Clinicians are still not well trained on how to be more sensitive when it comes to asking about smoking,” Dr. Patel said. “Even if the intent is not to be stigmatizing—because that is important information that we need and we must ask—when we frame it in the context of a lung cancer diagnosis there is a concern among patients, as shown in our research, that we, as clinicians, may be attributing blame.”

The International Association for the Study of Lung Cancer released a language guide in 2021 to promote best practices in all written and spoken language related to people with lung cancer. The guide focuses on not defining patients by their disease. The guide includes simple suggestions like the use of “person who doesn’t smoke” instead of “nonsmoker.”¹⁴

Using language that does not assign blame is important whether addressing someone with or without a history of smoking, Dr. Patel emphasized.

“When I give lectures to medical students and other trainees, I discuss why certain patient populations have higher smoking rates, for example, the veteran population,” Dr. Patel said. “There are upstream factors that led to that, including availability of cigarettes in commissary packets and the socialization that accompanies [smoking] during their service.”

There has also been a lack of advocacy for patients with lung cancer because of the stigma that surrounds the disease. In fact, studies have shown that lung cancer research consistently receives less funding than other cancers like breast cancer, despite more people in the United States dying from lung cancer.¹⁵ Dr. Patel said she has seen more groups focused on the targeted mutations, such as The ROS1ders and EGFR Resisters, who advocate for lung cancer while also addressing the issue of stigma.

Moving forward, Dr. Patel said that there is definitely more work to be done to evaluate all the potential factors that are increasing rates of lung cancer.

“There is a lot of investment being poured into novel treatments for lung cancer, but we have to move upstream to address what the etiology is,” Dr. Patel said. “Even though it will be harder, it is what we have to address to help get rid of the disease.”

Leah Lawrence is a health writer and editor based in Delaware.

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