ATS Breathe Easy - Delving into the Research on Lung Cancer in People Who Have Not Smoked

 Lung cancer is commonly associated with smoking. However, among people diagnosed with lung cancer, the proportion who have never smoked has been increasing, and there are many reasons why a person who has never smoked may develop this disease. Lori Sakoda, PhD, MPH, ATSF, a research scientist and epidemiologist at Kaiser Permanente Northern California, explains what factors may come into play, what the ongoing research shows, and what knowledge gaps exist on this topic. Patti Tripathi hosts. 

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Conversations in Pulmonary, Critical Care and Sleep Medicine by the American Thoracic Society

non: [00:00:00] You are listening to the A TS Breathe Easy podcast brought to you by the American Thoracic Society.
Patti: Hello and welcome. I'm your host Patty Pathy. Lung cancer is the leading cause of cancer death worldwide, and the third most common cancer following breast and prostate as smoking rates. Actually decline. We are seeing an overall decline in lung cancer rates. However, the rate of lung cancer in non-smokers is reportedly increasing.
Joining us is Dr. Laurie Sakoda, who's a research scientist at PhD in the division of Research at Kaiser Permanente in Northern California. Dr. Sakoda, when discussing lung cancer and non-smokers, it classically refers to those who smoked less than 100 cigarettes. [00:01:00] In their lifetime. Generally when people hear about lung cancer, they automatically assume the person is a smoker.
So, but more than half of women, or 50% or more, uh, with lung cancer are non-smokers presently, worldwide. Is that correct? Correct. And what are some of the risk factors for developing lung cancer?
Lori: So risk factors for lung cancer in individuals who do not have a smoking history include both environmental risk factors as well as genetic risk factors.
The environmental risk factors include exposure to rate on gas. Which is the second leading cause of lung cancer after tobacco smoking, exposure to secondhand smoke and exposure to occupational carcinogens, including various gases, natural elements, fumes and particulate matter, as well as materials such as asbestos.
We also [00:02:00] know that exposure to air pollution, both outdoor and indoor air pollution, increases risk for lung cancer. Um, and outdoor air pollution is commonly measured by far the levels of fine particulate matter. So particulate matter that is, uh, 2.5 micro meters or. Smaller in diameter, um, exposure to indoor air pollution largely arises from burning coal as well as cooking oil fumes from high temperature frying.
And that inf that data largely comes from studies in East Asia. We also know that irradiation to the chest, such as from treatment for breast cancer, increases risk for lung cancer. And that having a, a history of chronic lung conditions, including COPD, pneumonia and tuberculosis also is a risk factor. As for genetic factors, having a family history of lung [00:03:00] cancer can increase your risk for lung cancer.
Um, and there are some hereditary or rare hereditary mutations in certain genes such as the epidermal growth factor receptor gene or EGR gene. Um, that. Increases risk for lung cancer. And in this gene there's a particular mutation, um, that is known to increase risk, uh, risk for lung cancer, uh, known as the T 9 7 90 M mutation.
Um, we also know that female sex and Asian ethnicity are associated with risk for lung cancer among individuals who have never smoked. So based on our current knowledge, what is most likely is that. Lung cancer rises in individuals who have never smoked, um, based on interactions between genetic susceptibility and environmental exposures.
Patti: Okay, that pretty much covers it all. Everybody can get cancer. Um, what are some of the symptoms they should be [00:04:00] looking for?
Lori: Sure. So common symptoms of lung cancer are often quite general, so they can often be overlooked. Um, early symptoms vary between individuals but tend to include a persistent cough that worsens over time.
Especially if they're coughing up blood, um, they could experience a shortness of breath or wheezing, having chest pain that worsens with breathing deeply, coughing or even laughing, um, an unexplained hoarseness in your voice. Um, having frequent respiratory infections such as bronchitis and pneumonia. Um, having feeling weak or fatigued for any reason.
Um, having unexplained weight loss, um, and a loss of appetite. So these common symptoms arise and persist [00:05:00] for at least several weeks, is highly recommended that someone, um, seek. Care from their primary care provider.
Patti: And those symptoms really are common in many ailments. Correct. So it's probably, it's hard to diagnose or Exactly.
Um, if someone has a history of cancer in their family, is screening recommended And what do you suggest homes out to be checked for radon too.
Lori: Sure. So currently in the United States, screening for lung cancer with low dose CT is not currently recommended for individuals without a smoking history, and that's because.
As a whole, uh, the benefit of finding lung cancer, uh, in these individuals does not outweigh the potential harms. And so for individuals, particularly with a family history of lung cancer, they could consider genetic counseling or testing.
Patti: And, and what is a [00:06:00] biomarker testing that you spoke of?
Lori: So with regards to radon, um, homes are commonly tested for radon levels when they're bought or sold.
Um, but if you haven't had your home tested for radon, it's advisable to do so, and if levels are detected, systems can be installed to mitigate it.
Patti: Okay. And, and so you had spoken about biomarker testing. What does that mean?
Lori: So biomarker testing, or what is often referred to as molecular testing involves analyzing, um, either tumor tissue, preferably, or blood for certain genetic alterations and specific proteins.
Biomarker testing has become increasingly more important. Um. To en ensure that individuals diagnosed with lung cancer receive the most effective and optimal treatment. So specifically, their targeted therapies that are appropriate for [00:07:00] individuals who have certain genetic mutations and immunotherapy may also be appropriate depending on levels of, uh, protein known as PD L one.
Patti: Okay. What is the protocol or the treatment plan for somebody with early stage uh, lung cancer?
Lori: Sure the recommended treatment for individuals diagnosed with early stage lung cancer is surgical resection. However, testing for certain biomarkers, including EGFR mutations and alk rearrange rearrangements is recommended to guide treatment decisions, um, with regards to both neoadjuvant adjuvant treatment.
So that's treatment before or after surgery. I
Patti: imagine biopsy is done before that, correct.
Lori: So a biopsy can be done, um, beforehand to identify potential biomarkers that are present.
Patti: Okay. And for clinic clinicians and [00:08:00] researchers listening in, what are the biggest unanswered questions or research gaps you feel?
Lori: Sure. That's an excellent question. Um, as I mentioned screening for lung cancer, um, using low dose CT in the United States is not currently recommended for individuals, uh, without a smoking history. So one of the biggest questions is how to identify individuals without a smoking history who are at high risk for developing lung cancer and could potentially benefit.
From screening, and so what this entails is actually having a better understanding about the etiology of lung cancer among individuals who have not smoked before. We also don't know why lung cancer is more common among non-smoking women, especially women of Asian ancestry. And so there's data to indicate that Asian American women who have never smoked have a.
Twofold, [00:09:00] higher incidents of lung cancer compared to women who have never smoked of other Asian, uh, other racial and ethnic backgrounds. And so using data from our own system at Kaiser Permanente in Northern California, um, we looked at trends in lung cancer incidents by smoking history between 2007 and.
2018. And what we found is that incidents of lung cancer among those who have smoked, has been declining over time, which is what has been reported, um, more broadly in the US population. But incidents of lung cancer among individuals who have, who don't have a smoking history, has remained relatively. The only subgroup in which we found a slight increase in risk, uh, or increase in incidences of lung cancer was among Asian individuals who have never smoked.
Mm. So there's this question of why lung cancer incidents is HI is higher and potentially [00:10:00] increasing among Asian Americans who have never smoked.
Patti: That is what you are doing your research on right now at the moment, correct?
Lori: Yes. Currently. So we're in, we're collaborating in a study called Fans, which stands for Female Asian, never Smokers.
Um. With colleagues at UCSF, uc, Davis and Stanford, and the objective is to identify both. Environmental and genetic risk factors that increase risk for lung cancer among Asian American women who have never smoked. Um, we've enrolled over a thousand Asian American women, about half have been diagnosed with lung cancer, and we're currently analyzing the data and are hopeful that we can, um, gain new insights to improve our understanding of the etiology of lung cancer in this population.
Patti: Right. We'll have to have you back on, um, to sp speak about that. The FDA, uh, this year announced that it's removing the dangerous black box [00:11:00] warning on hormone replacement therapy during menopause. It was, uh, uh, they said the data was inconclusive or dated, um, earlier they thought that it caused cancer. Uh, and, uh, what do you feel about that?
Lori: Honestly, it's a little difficult for me to comment definitively on this just because I'm not an expert on hormone replacement therapy. Um, however, I would say that in general with using any drug, it's important to have a discussion about the potential risks and benefits of using a drug with your primary care physician and to determine whether the.
Risk, um, or the benefits outweigh the risks of taking that drug. With regards to lung cancer, the evidence is relatively mixed on the use of hormone replacement therapy and risk of lung cancer. So it's another area of, uh, that could benefit from increased research. Correct.
Patti: And so with [00:12:00] advances in the understanding of the molecular biology of cancer or substantial differences between lung cancer in smokers versus non-smokers, some scientists think that they ought to be looked at, uh, as a completely different entity.
Is that correct?
Lori: That is definitely correct. Um, and that's because we see differences in the epidemiology and molecular features of lung cancer that arises in individuals. Um. Who do not have a smoking history compared to those who do would suggest that the underlying biology between these of lung cancer, between these two groups, um, are distinct.
Um, and as I've mentioned earlier, in terms of lung cancer, lung cancer occurs twice as frequently. Among non-smoking women compared to non-smoking men, uh, globally, the highest incidence rates of lung cancer. Non-smoking women are reported in e in East Asian countries and in the United States. As I mentioned, lung [00:13:00] cancer incidents in Asian American women who have not smoked, um, are twice as high compared to women of other racial and ethnic, uh, groups who have never smoked.
Patti: But the survival rate is higher too compared to men. Is that correct?
Lori: Correct.
Patti: Correct.
Lori: Yes. And why
Patti: is that?
Lori: We don't know. We actually don't know why that is. And so, uh, I think one of the important questions to answer is also why is lung cancer more common? Right. Among, uh, Asian American or among non-smoking women, especially women of Asian descent.
Patti: Okay. Okay. Um, are patients often misdiagnosed? Uh, what can non-smokers do to advocate for themselves?
non: Or
Lori: non-smoking individuals can advocate for themselves, especially if they're experiencing some symptoms that we've discussed, um, to ask their physician if they've been, if they've considered or evaluated them for lung [00:14:00] cancer.
And if they haven't, to be very direct and asking for an evaluation of lung cancer. I would say it's also important to. To share the symptoms that you're experiencing as well as how long they've been occurring, and to disclose any risk factors that someone might have been exposed to or have including a family history of lung cancer.
Patti: As you had said, if you have lungs, you can get cancer. Correct. Just curiosity. Um, uh, news anchor Peter Jennings had quit. He actually, it's been 20 years since he passed away. It was surprising and, uh, that he had quit 20 years earlier and then, uh, started smoking. During nine 11. So even with the lapse of 20 years as being a non-smoker, but not defined non-smokers as 100 cigarettes for less, um, he immediately got lung cancer.
Is that, is that, does [00:15:00] that surprise you?
Lori: It doesn't surprise me. Um, we know that quitting smoking is definitely beneficial for your health, and that smoking cessation substantially reduces your risk of lung cancer at any age. Um, especially after quitting. Over 10 years ago. Um, but we also know that your lung, your risk of lung cancer does not go down to zero once you quit smoking.
And that the damage from smoking is long lasting. And, and so certain DNA mutations can lead to lung cancer even without continuing. Continuing smoking. Um, and it's possible that he was also exposed to other percent potential carcinogenic exposures. Um, but I think what you're getting at and what this highlights is that there are other causes to lung cancer besides tobacco smoking.
And as you mentioned, it's important to recognize that anyone with lungs, including that's [00:16:00] everyone can, can develop lung cancer.
Patti: Yes. And there was a lot of stress at that time. I was in the newsroom myself when 9, 9 11 happened. Um, so thank you so much. Uh, what we know is that, uh, the seriousness and risks associated with the disease is, uh, quite high.
Um, do you have anything to add?
Lori: No, I don't have anything more to add. It's been a pleasure to have this conversation, and I hope people have learned something about lung cancer today.
Patti: Okay, Dr. Lori Sakoda, thank you so much for joining us.
non: Thank you for joining us today. To learn more, visit our [e-mail]. Find more a TS Breathe Easy Podcasts on transistor, YouTube, apple podcasts, and Spotify. Don't forget to like, comment, and subscribe so you know. Ever miss a show?
Lori: I also mentioned that lung cancer differs based on [00:17:00] molecular features. We see that patterns of lung cancer histology differ over 90% of lung cancers in individuals who have not, not smoked, are of adenocarcinoma histology. This is in comparison to smoking related cancers, which include adenocarcinoma, squamous, cell carcinoma, and small cell, uh, histologies.
Both squamous cell and small cell lung cancers are more strongly associated with smoking. Another distinction is that lung cancer in individuals who have not smoked tend to be more enriched for targetable genomic alterations, um, such as EGFR mutations and alk rearrangements, and these alterations are present in about 80 to 90% of tumors.
This is in contrast to smoking related. Lung cancers where the prevalence of these alterations are much lower, around 30 to 50%, and they mainly consist of KRAS and other gene [00:18:00] mutations. Another distinction is tumor mutation burden, which is the number of mutations found in DNA of tumor cells and the and tumor mutation burden that we know is substantially higher among lung, uh, smoking related lung cancers.
There are also genomic mutation signatures associated with tobacco smoking, uh, which consists of single based substitutions, uh, caused by tobacco carcinogens, which are exclusively found in smoking related lung cancers. PD L one expression, which is commonly measured in biomarker testing, is often much higher among smoking related lung cancers as well.
Patti: So it, it makes sense to scientists like you, uh, think that, that, uh, it should be looked completely as a different entity, possibly.
Lori: Correct? Yes. I mean, they're very distinct and so the etiology and biology of, of lung [00:19:00] cancer is different between these populations.