Lung cancer in nonsmokers: The latest research

Smoking is the No. 1 cause of lung cancer. Yet, about 20% of lung cancers deaths occur in people who have never smoked, according to the American Cancer Society. Researchers here at MD Anderson, and across the U.S., are working to understand how and why lung cancer develops in non-smokers.

“We know that nonsmokers have a very different landscape of genetic changes in their cancer than smokers do,” says Humam Kadara, Ph.D. “It’s an important area of focus because lung cancer cases are rising in both nonsmokers and in light, or social, smokers.”

Lung cancer tumor mutations found in many nonsmokers

Most lung cancers diagnosed in people who have never smoked are non-small cell lung cancers (NSCLC), the most common type of lung cancer. Researchers already know that non-small cell lung cancer has a lot of variety at the molecular level, which can impact treatment options.

30% of NSCLC cases are driven by genetic mutations that are treatable with targeted therapies. Lung cancers found in never-smokers are more likely to have certain biomarkers, such as EGFR or ALK mutations, which can be treated through drugs designed to target those specific mutations.

“Non-smoking lung cancers are very heterogeneous,” Kadara says. “Some are very aggressive. Others are very responsive to targeted therapy and curable if caught early because we now know their Achilles heel.”

Advances in targeted therapies have helped improve lung cancer survival rates in recent years, which is why MD Anderson recommends molecular profiling for newly diagnosed lung cancer patients, especially those without a history of smoking.

On the other hand, advances in immunotherapy haven’t had as great of an impact for non-smoking lung cancer patients. That’s because immune targets, such as PD-L1, a protein targeted by immune checkpoint inhibitors, are more common in tumors caused by smoking. 

Currently, little is known about the immune landscape of non-smoking lung cancer. A better understanding of the immune landscape in non-smoking tumors could help pave the way for development of new immunotherapies.

Current and future research looks at lung cancer differences in smokers and nonsmokers

Kadara’s lab is taking a deeper look at the immune landscape of early-stage lung cancer including understanding the differences in the genetic and immune landscape of lung cancer in smokers and nonsmokers. They’re using an advanced type of technology called single-cell sequencing, which allows them to study the genetic material of individual cancer cells, one cell at a time.

Ansam Sinjab, Ph.D., a postdoctoral fellow in Kadara’s lab, will  share early results from this research at the  AACR Annual Meeting 2021 (Abstract 130). By analyzing more than 186,000 individual cells from early-stage lung cancer specimens and multiple normal samples at different regions in the lung each from five patients, they were able to pinpoint exactly where certain immune cells were more likely to gather – closer to the tumor itself or near the periphery of the healthy lung tissue. The study also provides an early glimpse at how lung cancer evolves, and which cells could be key to identifying lung cancer at its earliest stages before the disease spreads and becomes harder to treat.  

Next steps include analyzing additional samples and comparing the data from patients with and without a smoking history to better understand the differences in the immune microenvironment and cellular landscape between each group. Kadara’s lab is also conducting longitudinal studies with mouse models to understand how lung cancer grows over time from early to advanced disease. 

“We’re using preclinical models and human tissue samples for both smoking and non-smoking lung cancer,” Kadara says. “It’s important to study both groups at the same time, using the same tools and methods. Having a similar comparison leads to more robust data, and confidence in the disease signatures that we identify.”

Biomarkers may help identify screening opportunities and other risk factors

The long-term goal of this ongoing research is to find potential biomarkers that could be used to identify and screen nonsmokers at risk for lung cancer, and to devise early detection strategies for non-smokers with suspicion of cancer.

“Most early detection efforts are focused on smoking because we know it’s the top risk factor for lung cancer,” Kadara says. “There’s tremendous room for collaboration between epidemiologists, surgeons, oncologists and basic science researchers to identify markers and risk factors for non-smoking lung cancer.”

Studies have pointed to several other possible risk factors for lung cancer, including exposure to:

• Secondhand smoke
• Radon
• Pollution
• Asbestos, arsenic, chromium, or other chemicals

Family history may also play a role in non-smoking lung cancer. While family and smoking history are typically documented in medical records, that’s not always the case for other potential risk factors. 

“If you’re a non-smoker who’s been newly diagnosed with lung cancer, think about anything you’ve been exposed to that might be helpful for us to document, especially secondhand smoke,” Kadara says. “Consider participating in a clinical trial – making progress depends on patients, physicians and researchers collaborating together.”  

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