Spotlight

lung cancer: lung cancerGiven that smoking is the leading cause of lung cancer, many may assume that as a non-smoker they are not at risk. And while the majority of individuals who develop lung cancer have a history of tobacco smoking, about 10-20 percent of those diagnosed with the disease have never smoked. Understanding the reasons why this happens is crucial for both patient education and effective disease management. A study of more than 12,000 lung cancer patients conducted in 2017 observed an increase in the proportion of never-smokers from 8 percent in 1990-1995 to 14.9 percent in 2011-2013 (J Natl Cancer Inst 2017; doi:10.1093/jnci/djw295). The CDC defines never-smokers as anyone who has smoked less than 100 cigarettes in their lifetime. Some lung cancers in never-smokers may be the result of environmental factors—such as exposure to secondhand tobacco smoke, radon, air pollution, and asbestos—or genetics, but, overall, the root causes of these cases remain unclear. “To date, we have examined the genomes of more than 1,000 lung cancer samples, but the vast majority of these are from smokers,” noted Siddhartha Devarakonda, MBBS, MD, Assistant Professor of Medicine at the Washington University School of Medicine. “And so, never-smoker lung cancer has been somewhat understudied. There is still a lot to learn about what predisposes these individuals to this disease. How these tumors differ from smoking-related cancer has also not been well-characterized.” Current Research Recognizing the need to better understand this patient population, researchers continue to explore the origins of lung cancer in never-smokers. One such study, led by scientists at Washington University School of Medicine in St. Louis and recently published in the Journal of Clinical Oncology, offered new insights and treatment possibilities (2021; doi:10.1200/JCO.21.01691). The researchers collected samples from 88 self-reported never-smokers who were diagnosed with lung adenocarcinoma between 2007 and 2014. They performed whole-exome sequencing on these patients; tumor samples from 69 patients in this cohort underwent RNA-sequencing. To verify never-smoker status, the researchers developed a scoring model using tumor mutation burden and mutation signatures characteristic of tobacco smoke exposure. This information was analyzed alongside data from 76 never-smokers and 299 smoker lung adenocarcinoma samples that were sequenced by The Cancer Genome Atlas and Clinical Proteomic Tumor Analysis Consortium. The data revealed a high prevalence of clinically actionable driver alterations in never-smokers with lung adenocarcinoma (78-92%) compared to their smoker counterparts (49.5%), according to Devarakonda, the first author of the study. “Our study demonstrated that the genes mutated in never-smoker lung cancer and those mutated in smoker lung cancer are actually very similar, but the frequency at which these genes are mutated is quite different,” he explained, while emphasizing the clinical implications of these findings. “We identified driver mutations in about 78-92 percent of never-smoker samples, while only about half of smoker lung cancer samples readily showed them. The vast majority of these mutations have FDA-approved treatments, underscoring the importance of sequencing all lung cancer samples—especially in never-smokers.” The researchers also noticed that, although they initially didn't find a mutation in some samples, a deeper dive uncovered that there were in fact alterations. “We think that the mutation was initially missed because the sample was not of adequate quality,” he noted. “And if this can happen in the research setting, it can also happen in the clinical setting.” Based on the evidence that there is a high likelihood of driver mutations among never smokers with lung cancer, Devarakonda urges clinicians caring for these patients to carefully review their findings and make sure that the samples are not only adequate, but also that testing was conducted properly. “Diagnostic technologies are evolving at a rapid pace and oncologists today have a lot of sophisticated tests at their disposal,” he stated. Elaborating on this topic, he emphasized the need for clinicians to understand these various tests and their limitations to ensure that they can provide effective patient care. Another observation in the study was that the frequency of samples showing germline variants in cancer predisposing genes was similar between the two groups: 6.4 percent in smokers and 6.9 percent in never-smokers. They also found that there was a subset of never-smoker samples (5.9%) that had mutation signatures suggestive of passive exposure to cigarette smoke. This study also shed light on the immune profiles of never-smoker tumors. “We know that patients with never-smoker lung cancers typically do not respond well to immunotherapy, but the reasons behind this are not fully understood,” noted Devarakonda. “One explanation that's often been offered, as our study and others have shown, is that the amount of damage that the DNA has is much more limited in never-smokers compared to those who smoke. “However, the explanation may be more complicated than that,” he added. “Our paper revealed that not all never-smoker lung cancers have the same immune composition. So, gaining more of an understanding of this through future studies will help us use immunotherapies better in this patient population.” Future Directions As researchers continue to improve their understanding of these patients, Devarakonda noted that the next big step is examining more samples. “Our goal eventually is to conduct an analysis with a much larger set of samples,” he noted. “We are starting to appreciate that never-smoker lung cancer may not be just one disease,” he continued. “It is probably a collection of different diseases and, to get a better sense of what is going on in these patients, we need a much broader representation of each type of never-smoker lung cancer.” Other areas of future exploration include studies that examine the epigenetics of the DNA, as well as the differences between how lung cancer in smokers and never-smokers differs at the protein level, according to Devarakonda, who noted that advancements in technology make this research possible. “We are beginning to get a clear picture of these tumors and how they evolve,” concluded Devarakonda. “Ongoing study of lung cancers in never-smokers will provide further insight into this patient population and hopefully effective avenues for screening and treatment.” Catlin Nalley is a contributing writer.