Unknown Long-Term Effects of E-Cigarettes Generates Questions in Lung Cancer

Nagashree Seetharamu, MD, MBBS

Due to the lack of data around the long-term safety profile of electronic cigarettes (e-cigarettes), the National Cancer Institute has issued grant P50CA180890 to further the research. These products have already been linked to blood vessel damage, and experts who treat lung cancer have raised concern about e-cigarettes and their correlation with lung cancer risk.^1,2

The FDA also recently published general safety concerns including what risks one should be aware of if using e-cigarettes, vaporizers, or other tobacco products. While studies suggest e-cigarettes may be less harmful than combustible cigarettes, the FDA notes that there is not yet enough evidence to support claims that e-cigarettes and other electronic nicotine delivery systems are effective tools for smoking cessation.³

“There are no safe tobacco products, including [electronic nicotine delivery systems]. In addition to exposing people to risks of tobacco-related disease and death, FDA has received reports from the public about safety problems associated with vaping products,” wrote the FDA.

To date, there are no e-cigarettes approved as a cessation device or authorized to make a modified risk claim. Because of this, more research is needed to gauge the potential risks and benefits these products may offer to those who use them. According to authors in an article published in the ASCO Daily News,² led by Wint Yan Aung, MD, internal medicine resident at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, “[a]t this time, the attributable risk of e-cigarettes is yet to be determined, and current practice lags behind in terms of capturing e-cigarette usage.”

Among the few studies that have examined the adverse effects of e-cigarette use, a growing body of evidence suggests that exposure these products will result in changes to the pulmonary environment and contribute to chronic lung conditions.

“E-cigarette use has been attributed to the outbreak of e-cigarette or vaping product use–associated lung injury, resulting in over 2800 hospitalizations and 68 deaths. These findings highlight the potential for e-cigarettes to cause acute pulmonary toxicity,” wrote authors in the article published in the ASCO Daily News.² “Evidence also suggests that e-cigarette use may relate to long-term risk of cancer beyond the known carcinogenic effect of nicotine and its metabolites.

Between 2016 to 2017 and 2017 to 2018, there was an increase in the prevalence of e-cigarette use, especially in young adults, adolescents, and children in middle school.^4,5 According to research published in the ^{JAMA Network}, the national prevalence of e-cigarette use in 2018 increased to 5.4%, meaning approximately 13.7 million individuals are using these devices in the United States.

In 2018, the popularity of these devices increased with an estimated 4.9% of middle school children and 20.7% of high school children using e-cigarettes. According to Nagashree Seetharamu, MD, MBBS, there are multiple reasons as to why they have increased in popularity over the years.

“Because of the flavors [e-cigarettes come in], it makes them much more attractive. The colors, the flavors, the social media, and the peer pressure perhaps all add to it. We want to dig deeper into what we know about it and what are the harms of it. Of course, it's too early to know exactly what it causes, but e-cigarettes have been associated with lung injury, resulted in significant hospitalizations, and a few hundred deaths,” stated Seetharamu, professor of hematology and medical oncology at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, in an interview with Targeted Oncology^TM.

With an observed shift toward daily use of e-cigarettes among younger adults and students, experts wonder what product use–associated lung injuries, including lung cancer, may be observed in e-cigarette users down the road.

Impact of E-Cigarettes on Lung Health

While the full effects of e-cigarettes and vaping on the impact of lung cancer are not known, preclinical data have demonstrated negative outcomes when used in mouse models. For clinicians like Seetharamu, there is an unsettling theory that, with what has been reported in preclinical data on mice, e-cigarettes will have the same negative impacts on humans.

“We only know from preclinical studies that there's a lot of inflammatory response that occurs in the lungs when exposed to vaping. In mouse models, there have been reports of cancer developing in cell lines when exposed to vaping products. That risk will take a while before we see the actual impact of vaping on cancers because carcinogenesis takes a few years, so we may not know about it until maybe another 10 years.”

Some preclinical studies that highlight the adverse effects of e-cigarettes include evaluating the oxidative stress and inflammatory response in lung epithelial cells.

A study published by Proceedings of the National Academy of Sciences sought to evaluate the effects of e-cigarettes on mice, following previous studies performed by the group which demonstrated that mice who were exposed to e-cigarettes developed lung adenocarcinoma and bladder urothelial hyperplasia. Because the threat e-cigarettes pose to humans has been studied so little, investigators led by Tang et al, further tested the carcinogenicity of e-cigarettes in mice.⁶

What they found was that 9 out of 40 mice (22.5%) who were exposed to e-cigarette smoke with nicotine for 54 weeks developed lung adenocarcinoma vs none of the mice in the control group. While these data seem alarming, it is not yet known whether this correlates with humans, warranting future in-depth studies.

Then, a study examined the regulation of genes and associated molecular pathways, genome-wide, in oral cells of e-cigarette users and cigarette smokers vs nonsmokers. What investigators found was that there were overlapping patterns of gene expression changes, with most of this overlap falling under cancer-related pathways and functions.⁷

Another study suggested that using e-cigarettes at the same time as receiving chemotherapy may correlate with poor treatment outcomes, similar to smoking tobacco. This was found in an in vitro study of patients with head and neck squamous cell carcinoma.⁸

Here, it was observed that tumor cells which were exposed to e-cigarette aerosols had an altered expression of cisplatin transporters. Further, there was an increased drug resistance in oral cancer cells. This effect observed in the study was independent of nicotine concentration, indicating that the ingredients found in e-cigarettes have the potential to induce cancer as well as impact treatment response.

Each of these preclinical studies may provide evidence of the carcinogenic effects of e-cigarettes, but since these are from preclinical models, the correlation between e-cigarettes and their impact on cancer incidence will most likely not be evident for over a decade.

What’s Next?

“There are some ongoing clinical trials looking at e-cigarettes as a mode of smoking cessation. A lot of groups have started putting out strong statements against use of e-cigarettes until we know more about the safety of these products. From the manufacturers, they want objective data to say that their products are harmful. Studies that have already been conducted perhaps will shed light, but until those studies and results are available, I would be extremely cautious,” noted Seetharamu.

At the University of Texas MD Anderson Cancer Center, there is an ongoing, randomized, clinical trial (NCT05144542) evaluating the risks and benefits of e-cigarettes in older adult smokers who are at high risk for developing lung cancer.⁹

The primary end point of the trial is to characterize the effects of switching from combustible cigarettes to e-cigarettes regarding use of the product, product acceptability, and reinforcement among daily, adult cigarette smokers at high risk for lung cancer. The secondary end point of the trial will be to characterize the effects of switching from combustible cigarettes to e-cigarettes on biomarkers of inflammation and oxidative stress.

There is also a pilot trial of e-cigarettes in patients with lung or head and neck cancer (NCT05412875) at the Ohio State University Comprehensive Cancer Center. The trial is currently recruiting patients to investigate the acceptability of e-cigarettes for smoking cessation and the reduction of surgery-related complications in this patient population.¹⁰

Until there are objective data about the long-term effects and benefits (if any) of e-cigarettes on lung cancer, Seetharamu advises her patients with and without lung cancer to stay away from any tobacco product due to their potential harm.

“I discourage patients from using e-cigarettes as a replacement. I strongly advise all young people who've never been exposed to any type of tobacco to refrain from it. We can only do that with the help of industry, with the help of collective thinking, and making sure that our youngsters are not attracted to products like this by highlighting in schools, colleges, and social media that there are other cool things to do that are not harmful to health,” added Seetharamu.

Overall, with limited data and the large number of different tobacco products available, the ingredients which may lead to lung toxicity or be associated with cancer risk remain in question. Based on current knowledge from preclinical trials and emerging data, it is clear that a variety of these products have the potential to negatively impact health for patients with and without lung cancer and increase the risk of cancer development.

“We have focused and spent so much money on discovering new drugs and targets in advanced disease for curing stage IV lung cancer, but how about prevention? That takes a backseat a lot of times, and I'm particularly interested in that arena. From what we know, vaping is dangerous and a hazard. But at the same time, can it be effectively used for tobacco cessation? If so, how can you best use it? That is still a work in progress. Analysis of recently completed and ongoing clinical trials will shed light and, as time goes on, we will know more about their true impact on lung function and their impact on causing lung cancer,” concluded Seetharamu.

References:

1. NIH-funded studies show damaging effects of vaping, smoking on blood vessels. News release. National Institutes of Health. October 26, 2022. Accessed November 15, 2022. https://bit.ly/3Ey22BP

2. Aung WY, Neumann M, Seetharamu N. The impact of E-cigarettes on cancer and treatment: questions and controversies. ASCO Daily News. https://bit.ly/3Exorzg

3. E-Cigarettes, Vapes, and other Electronic Nicotine Delivery Systems (ENDS). FDA. Updated June 6, 2022. Accessed October 31, 2022. https://bit.ly/3DlP60e

4. Huerta TR, Walker DM, Mullen D, Johnson TJ, Ford EW. Trends in E-Cigarette Awareness and Perceived Harmfulness in the U.S. Am J Prev Med. 2017;52(3):339-346. doi:10.1016/j.amepre.2016.10.017

5. Obisesan OH, Osei AD, Uddin SMI, et al. Trends in e-Cigarette Use in Adults in the United States, 2016-2018. JAMA Intern Med. 2020;180(10):1394-1398. doi:10.1001/jamainternmed.2020.2817

6. Tang MS, Wu XR, Lee HW, et al. Electronic-cigarette smoke induces lung adenocarcinoma and bladder urothelial hyperplasia in mice [published correction appears in Proc Natl Acad Sci U S A. 2019 Nov 5;116(45):22884]. Proc Natl Acad Sci U S A. 2019;116(43):21727-21731. doi:10.1073/pnas.1911321116

7. Tommasi S, Caliri AW, Caceres A, et al. Deregulation of Biologically Significant Genes and Associated Molecular Pathways in the Oral Epithelium of Electronic Cigarette Users. Int J Mol Sci. 2019;20(3):738. Published 2019 Feb 10. doi:10.3390/ijms20030738

8. Manyanga J, Ganapathy V, Bouharati C, et al. Electronic cigarette aerosols alter the expression of cisplatin transporters and increase drug resistance in oral cancer cells. Sci Rep. 2021;11(1):1821. Published 2021 Jan 19. doi:10.1038/s41598-021-81148-0

9. Risk and benefits of electronic cigarettes to older smokers at high risk for lung cancer. ClinicalTrials.gov Updated October 20, 2022. Accessed November 1, 2022. https://clinicaltrials.gov/ct2/show/NCT05144542?term=e-cigarettes&cond=lung&draw=2&rank=2

10. Pilot trial of E cigarettes in pts diagnosed with cancer of the head, neck, and lung. ClinicalTrials.gov. Updated August 24, 2022. Accessed November 1, 2022. https://clinicaltrials.gov/ct2/show/NCT05412875?term=e-cigarettes&cond=lung&draw=3&rank=11