New Genetic Discoveries Shed Light on Lung Cancer in Nonsmokers

In another precision medicine advancement using whole-genome sequencing, National Cancer Institute researchers identified new lung cancer subtypes specific to nonsmokers

The reasons behind lung cancer in never-smokers have eluded doctors and patients for years. Now a new study by the National Cancer Institute (NCI) has identified lung cancer-related genetic mutations that are specific to patients who have never smoked. This discovery sheds light on how lung cancer develops in never-smokers and may soon open the door for hospitals to provide new precision medicine-based lung cancer treatments specifically targeted to those who have never smoked.

An international team of researchers led by the Maria Teresa Landi, MD, PhD, from the NCI, part of the National Institutes of Health (NIH), studied the genetic basis of lung cancer in nonsmokers. The study, which was published in Nature Genetics, as part of the article “Genomic and Evolutionary Classification of Lung Cancer in Never Smokers,” sought to fill a void in lung cancer research, addressing the genetic underpinnings of lung cancer in nonsmokers, specifically.

“What we’re seeing is that there are different subtypes of lung cancer in never smokers that have distinct molecular characteristics and evolutionary processes,” said Landi in an NIH statement. “In the future we may be able to have different treatments based on these subtypes.” Landi is Associate Professor of Epidemiology at the Johns Hopkins Bloomberg School of Public Health and received tenure in the Division of Cancer Epidemiology and Genetics (DCEG) at the NCI in 2006.

Possible Answers to Questions About Origin of Lung Cancer in Nonsmokers

The NCI study used whole-genome sequencing in over 230 patients with lung cancer who had never smoked and examined the genetic bases of nine different types of lung cancers. Analysis of the genetic data showed three distinct genetic subtypes that are not found in lung cancer patients who smoke.

“We’re starting to distinguish subtypes that could potentially have different approaches for prevention and treatment,” Landi explained. “We’re at the beginning of understanding how these tumors evolve. This analysis shows that there is heterogeneity, or diversity, in lung cancers in never smokers.”

One important area this study addressed was nonsmokers with secondhand smoke exposure. Sixty-two of the patients in the lung cancer study had significant secondhand smoke exposure, and the study results showed that these patients’ cancers were primarily driven by nonsmoker-related genetics rather than genetic changes associated with smoking.

The secondhand smoking findings, however, were limited by the small number of patients being sampled. “We need a larger sample size with detailed information on exposure to really study the impact of secondhand tobacco smoking on the development of lung cancer in never smokers,” Landi said.

Natural Versus Environmental Influences in Lung Cancer

The lung cancer in never smokers (LCINS) study also importantly showed that the genetic changes influencing the development of lung cancer in nonsmokers are primarily related to natural changes that occur within the body, and not to external, environmental influences.

While the study did not immediately identify any actionable treatments for the genetic subtypes identified, it does come at a time when new precision medicine treatments for lung cancer are becoming more prevalent. A recently approved medication called sotorasib, also known as Lumakras, has shown promise for a subtype of lung cancer patients.

Sotorasib is designed to suppress specific genetic mutations that are only present in 13% of patients with adenocarcinomas, a common type of lung cancer. In June 2021, a Phase 2 clinical trial using the precision medicine treatment showed that this drug shrank lung cancer in 82% of the patients that participated in the trial.

“This is a group of patients whose tumors have been difficult to treat and for whom we did not have targeted therapies,” said Ramaswamy Govindan, MD , co-senior author and the Anheuser-Busch Endowed Chair in Medical Oncology at Washington University in a Washington University School of Medicine statement. “The new drug is addressing an unmet need for these patients, targeting the most common mutation that we can go after. We’re also continuing to investigate this drug in combination with other experimental drugs to see if we can further improve responses and survival.”

While the NCI study is the first step in developing precision medicine treatment for lung cancer in nonsmokers, continuing advances in personalized lung cancer treatments indicate that actionable treatments may soon follow. Hospital, oncology, and pulmonology leaders will benefit from following the research that builds on this innovative study and the treatments that may emerge from it.

—Caleb Williams