Detailed information about the current and former smoking habits of patients with non-small cell lung cancer (NSCLC) can shed light on the best way to treat them—whether with a combination of chemotherapy and immunotherapy, or with immunotherapy alone, according to new research from Harvard T.H. Chan School of Public Health.
Co-authors of the study, published Dec. 21 in the Journal for ImmunoTherapy of Cancer, included first author Xinan Wang, Xihong Lin, and David Christiani of Harvard T.H. Chan School of Public Health.
“By understanding how smoking history affects response to different treatments, doctors can identify which patients need the more intensive combination of chemotherapy and immunotherapy when they start treatment and which patients might do just as well with immunotherapy alone—allowing those patients to potentially avoid the unnecessary side effects and toxicity associated with chemotherapy,” Christiani said.
The researchers analyzed data from 4,157 patients with advanced NSCLC who were treated with immunotherapy alone or with a combination of chemotherapy and immunotherapy at Dana-Farber Cancer Institute and Memorial Sloan Kettering Cancer Center between 2010 and 2023. They looked at associations between detailed smoking history and clinical outcomes and explored several biological and genomic indicators known to be related to smoking, to see how they may be related to patients’ outcomes from particular treatments.
The study found that patients who are current smokers or have a history of heavy smoking tend to live longer when treated with a combination of chemotherapy and immunotherapy. This result occurred regardless of certain gene mutations (STK11, KEAP1, and KRAS) in the patients’ tumors that are associated with tobacco exposure.
The researchers also looked at a group of patients with tumors that had high levels of a protein marker called PD-L1—which can allow cancer cells to evade the immune system—and that didn’t have EGRF/ALK gene alterations, which cause uncontrolled cell growth. As this group of patients started treatment, those who never smoked tended to benefit more from the combination of chemotherapy and immunotherapy, while patients with a smoking history had similar outcomes whether they got the combination or immunotherapy alone.
In addition, the scientists were able to detect tobacco smoking’s mutational signature in DNA from tumors, which independently predicted how well immunotherapy would work—valuable information in cases where the patient’s self-reported smoking history is unavailable.
The study also found that tobacco smoking is associated with more DNA mutations in tumors, higher levels of PD-L1, more immune cells infiltrating the tumor, higher levels of immune-related proteins in the blood, and altered patterns in how cancer cells handle metabolism and signaling.
“By identifying specific biological mechanisms, changes in both the tumor’s surrounding environment and blood protein profiles throughout the body, our work provides new directions for discovering biomarkers that could further improve treatment selection in the future,” Christiani said.
For next steps, Christiani would like to see the development of novel, accurate biomarkers to help characterize groups of patients based on their different smoking histories—information that could help clinicians optimize treatment approaches while taking into account patients’ quality of life.
