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Lung Cancer in Never Smokers: A Complex Clinical Phenomenon

A Conversation With Nasser Hanna, MD


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Nasser Hanna, MD

Nasser Hanna, MD

Despite advances in prevention, early detection, and treatments, lung cancer remains the leading cause of cancer-related death in the United States. Although cigarette smoking is the main cause of lung cancer, about 10% of these patients are lifelong never smokers for whom the molecular composition of the disease, among other things, differs from smoking-related disease. To shed light on this interesting and complicated clinical phenomenon, The ASCO Post recently spoke with nationally regarded lung cancer expert Nasser Hanna, MD, Professor, Department of Medicine, Division of Hematology/Oncology, Indiana University School of Medicine, Indianapolis. Dr. Hanna’s research has focused on thoracic oncology, specifically the study and management of all forms of lung cancer.

Risk Factors Beyond Smoking

There has been an uptick in lung cancer in never smokers, especially in women. Do we have scientific data explaining the cause of this clinical phenomenon?

In the United States, about 20% of women with lung cancer are never smokers, and about 7% of men with lung cancer are never smokers. There is no definitive answer as to why never smokers develop lung cancer; however, there are several major risk factors outside of cigarette smoking -associated with lung cancer. Radon exposure is the number-two cause of lung cancer. Radon is ubiquitous in soil, so there is a greater incidence of exposure by those who work underground, even in people whose homes have basements in which they spend time. There is also a link between lung cancer and asbestos exposure in certain work places or older homes with concealed asbestos. Another occupational hazard is working in environments with chronic exposure to lung irritants.

There is also an increased risk for lung cancer in those who have underlying medical conditions, such as certain autoimmune disorders, and in those who develop scars in their lungs from nonmalignancy-related issues. In Asia, about 50% of women who develop lung cancer are never smokers, which may be partially related to second-hand smoke, due to the high incidence of male smokers in many Asian countries. Air pollution and high-temperature cooking techniques without adequate fume extractors are also thought to contribute to lung injury, with cancer developing later in life.

Potential Gender and Biologic Differences

Why is there such a demonstrable difference in the incidence of never-smoker lung cancer between women and men?

There are no definitive answers, but there are hypotheses. For instance, we have long considered an individual’s ability to metabolize carcinogens, as a risk for cancer, and there may be differences between individuals. So equal exposure to carcinogens may not result in equal risks.

What do we know about the biologic differences in tumors of never smokers vs smokers?

In some cases, the tumors in never smokers behave differently, and the DNA mutational spectrum looks quite different from that in smoking-related lung cancer. Never smokers who develop lung cancer almost exclusively have adenocarcinoma. Squamous and small cell cancers develop in the large airways, where smoke has caused not only DNA mutations but also chronic irritation, whereas adenocarcinoma does not typically occur in the air tubes but rather in the periphery of the lungs. 

It may be that small inhaled particles, which are not particularly caustic to the central airways, lodge in the periphery of the lungs, which may be why never smokers almost exclusively develop adenocarcinoma. Smokers do not tend to take as deep inhalation as nonsmokers, which may be why cancer-causing particles lodge in different parts of the lungs.

About 75% of the time, never smokers have a targetable mutation, as opposed to smokers, where there is a targetable mutation about 15% of the time.
— Nasser Hanna, MD

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The other difference between the tumors of never smokers and smokers comes to light when you study the DNA mutational spectrum. About 75% of the time, never smokers have a targetable mutation, as opposed to smokers, where there is a targetable mutation about 15% of the time. DNA mutations in a smoker tend to carry about 20,000 to 100,000 DNA point mutations. However, in never smokers, we see about 3,000, up to 10,000 mutations. So it is a one-log difference—90% fewer mutations among never smokers.

Moreover, never smokers are more likely to have a single oncogenic driver. In other words, they have far fewer mutations than smokers, but the ones they have really count. About half of never smokers will have a mutation in the epidermal growth factor receptor (EGFR) gene, which contrasts with smokers, in whom less than 10% have an EGFR mutation. Never smokers are also much more likely to have an anaplastic lymphoma kinase (ALK) gene abnormality and also in ROS1 and MET. In addition, HER2 and RET abnormalities are much more prevalent in never smokers. Smokers do have these mutations but at a much lower incidence level. On the other hand, smokers tend to develop mutations on the KRAS and BRAF genes more frequently than never smokers.

Response to Immunotherapy

How do never smokers and smokers respond to -immunotherapies?

Interestingly, never smokers are less likely to have high expressions of the protein programmed cell death ligand 1 (PD-L1), which is a biomarker for immunotherapies. This makes never smokers less likely to respond to these new agents. Ironically, smokers with high mutational burdens are more likely to express PD-L1, making them more responsive to immunotherapies. 

Immunotherapy tends to work better in smokers with lung cancer who have squamous cell histology and high mutational tumor burdens than in never smokers. Now there are never smokers who respond to immunotherapy, but far fewer than smokers. Never smokers tend to do better on targeted therapies than smokers.

Smoking Cessation Initiatives

Smoking-related lung cancer is still the greatest cancer killer in the United States. What’s your opinion on the current smoking cessation initiatives across the country?

To affect smoking rates in a substantial way requires consistent and relentless messaging, not intermittent and random. We really cannot let up on our efforts if we want to reduce smoking rates. Smoke-free work environments, taxation rates, restriction of tobacco access to minors, and constraints to marketing and advertising of cigarettes are all very effective antismoking strategies.

With the explosion of targeted and immunotherapies, it is not unusual for patients with metastatic disease to live 2, 3, 4 years, and beyond.
— Nasser Hanna, MD

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The Centers for Disease Control and Prevention provides general per state estimates of how to provide an effective tobacco control program. Apart from a few states, such as California, which does a good job, most states miss the mark by quite a bit in terms of their commitment to resources to cessation initiatives.

That said, as long as tobacco is a legal product, we will never get to zero use. If you look at Utah, for instance, it has the lowest smoking rate in the country (about 10%) because of its Mormon population; so if we could target a national smoking rate of 10%, I think that would be an attainable goal.

During the Obama administration, the U.S. Food and Drug Administration (FDA) was granted the power to regulate tobacco, which was a 100-year law in the making. The Agency is considering ways to dramatically reduce the amount of nicotine in cigarettes. Lowering the nicotine levels would make cigarette smoking markedly less addictive.

Closing Thoughts

Any closing thoughts on the state of lung cancer -moving forward?

We’ve made more advances in the past 5 years than in the previous 50 years combined to help a patient diagnosed with lung cancer. In the past, it was unusual to see patients with metastatic lung cancer live beyond 6 to 12 months. Over the past 5 years, with the explosion of targeted and immunotherapies, it is not unusual for patients with metastatic disease to live 2, 3, 4 years, and beyond. Moreover, we have recently seen data suggesting we are on the verge of making big advances in curing patients with earlier stages of lung cancer. The advances are based on the great DNA and immunologic scientific work, and credit should be spread around to all parties involved. We are truly in the middle of an outcomes shift in some patients with lung cancer, unfortunately not all. But the future is bright.

The most important aspect of lung cancer is realizing we could eliminate 90% of the disease if we got rid of tobacco. That, of course, is not going to happen, but with continued cessation programs, we will see major reductions in tobacco use in the United States over the coming years, which will greatly reduce the suffering and death related to lung cancer. ■

DISCLOSURE: Dr. Hanna reported no conflicts of interest.


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