1. DiGiulio, Sarah

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There is much more research on lung cancer that develops in people with a history of smoking compared with never-smokers. To better understand what drives lung cancer in never-smokers-and particularly the genomic underpinnings-researchers analyzed whole-exome and RNA-sequencing data in one of the largest set of samples to date in never-smokers. The findings were published online ahead of print in the Journal of Clinical Oncology (2021; doi: 10.1200/JCO.21.01691).

Siddhartha Devarakon... - Click to enlarge in new windowSiddhartha Devarakonda, MD. Siddhartha Devarakonda, MD

The data suggest the vast majority of these tumors may have mutations that suggest patients may respond to available targeted therapies. So molecular analyses of these cancers is important. In an interview with Oncology Times, study coauthor Siddhartha Devarakonda, MD, a medical oncologist and Assistant Professor of Medicine at Washington University School of Medicine, shared his thoughts about the work.


1 Before this research, what was known about the genomic profile of lung cancer in never-smokers?

"The challenge has really been that, when we look at the genomic basis of lung cancer or try to study the pathogenesis of this disease, it's really skewed toward smoking-related lung cancer because about 90 percent of the lung cancer we see affects people who have some history of smoking. So that's part of what led to this study. We know that smoking causes genetic changes that lead to lung cancer in smokers, but what about lung cancer in never-smokers? If these people didn't smoke, what's causing them to get lung cancer?


"The Cancer Genome Atlas had a few samples from never-smoker lung cancer, but the emphasis of the study has not been [looking] at the genomic and RNA of never-smokers to see what might be leading to those tumors. So, the genomic profile of lung cancer in people with no history of smoking has been studied here and there, but not in a large, systematic way."


2 What did your data show about the genomic profiles of never-smokers?

"We had a collection of approximately 80 samples from our collaborating institutions: New York University, MD Anderson Cancer Center, and Washington University. Then we also took those samples from The Cancer Genome Atlas and the Clinical Proteomic Tumor Analysis Consortium. All together we had about 160 samples, one of the largest studies to date. We analyzed all of this data to get a sense of what really drives never-smoker lung cancer. Simultaneously, we analyzed lung cancer samples from smokers from The Cancer Genome Atlas to compare the different phenotypes (never-smoker lung cancer vs. cancer in people who have smoked).


"In the last 2 decades, we've developed many targeted therapies that go after genetic changes, like EGFR, ROS1, MET, ALK, and so on. One thing we learned in this study is that nearly 70-90 percent of patients with never-smoker lung cancer can have a genetic change that you can probably hit with a targeted therapy, which emphasizes the fact that if you see a never-smoker in your clinic and, after genetic testing you don't find something, you really have to make sure that the test was ordered and done properly. So, that has important implications for clinical care.


"The second thing that we noticed in our study was actually somewhat of a surprise. Because never-smokers have no known environmental drivers of cancer (like smoking), we might expect these people to have a genetic predisposition. But we found that germline or hereditary alterations (in cancer-predisposing genes) were present in 7 percent of individuals across never-smokers and this prevalence was almost the same across smokers. So that element doesn't explain why some never-smokers are predisposed to getting cancer. It is possible that there are other genes that are predisposing that we just don't know yet.


"The other thing that we found in our study is that, when you use RNA data to infer what the immune landscape of never smokers looks like, they're all not the same. If you try to categorize never-smoker tumors based on their immune composition, it's a heterogenous entity. Maybe there are some types of never-smoker lung cancer that might respond to immunotherapy and some that don't."


3 What's the bottom-line message about your work?

"The biggest one is be mindful of ordering genomic testing. Make sure you have good-quality biopsies. If that report comes back negative, put some thought in it. Was this a good test? Is there some chance that this could be a false-negative just given the probability that most of these patients have some mutation that could be targeted with a drug (70-90%, according to our research)?


"If you're caring for never-smokers with lung cancer, there is a chance that some of these individuals could be genetically predisposed. Genetic counseling should be considered for these individuals and their families. Make sure that you're taking a family history from your patients, especially regarding other cancers that run in the family.


"The next step is building upon this work, looking at more samples, and finding more never-smokers to ask: Is there something that we missed? We haven't found any genetic predisposition in the 160 patients we looked at from a germline alteration perspective."