Most cases of lung cancer in non-smokers treatable with drugs that target mutations – Washington University School of Medicine in St. Louis

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Available FDA Approved Drugs May Be Effective in Targeting About 80% of Lung Tumors in Non-smokers

Washington University School of Medicine

Despite the well-known role of smoking in lung cancer, a significant number of patients who develop lung tumors have never smoked. While scientists are still struggling to understand what causes cancer in so-called “never-smokers,” a study by scientists at the Washington University School of Medicine in St. Louis demonstrates new possibilities for treating these. puzzling tumors.

The new analysis suggests that 78% to 92% of lung cancers in patients who have never smoked can be treated with precision drugs already approved by the Food and Drug Administration to target specific mutations in a tumor. patient. The researchers found that the lung tumors of most non-smokers had so-called conductor mutations, specific errors in the DNA that fuel tumor growth and which can be blocked with a variety of drugs. In contrast, only about half of tumors in people who smoke have driver mutations.

The study appears Sept. 30 in the Journal of Clinical Oncology.

“Most genomic studies of lung cancer have focused on patients with a history of smoking,” said senior author Ramaswamy Govindan, MD, professor of medicine. “And even studies of the disease in patients who have never smoked have not systematically looked for specific and exploitable mutations in these tumors. We have found that the vast majority of these patients have genetic alterations that doctors can treat today with drugs that are already approved for use. The patient should undergo a high-quality biopsy to ensure that there is sufficient genetic material to identify key mutations. But testing these patients is essential. There’s a good chance these patients have a workable mutation that we can look for with specific therapies. “

In the United States, about 10 to 15% of lung cancers are diagnosed in people who have never smoked, and this proportion can reach 40% in parts of Asia.

The researchers analyzed the lung tumors of 160 patients with pulmonary adenocarcinoma but without a history of smoking. They also compared data from these patients to data from smokers and non-smokers from The Cancer Genome Atlas and the Clinical Proteomic Tumor Analysis Consortium, projects led by the National Institutes of Health (NIH) to characterize different types of cancer. Scientists verified non-smoker status by looking at mutation patterns in these patients and comparing them to mutation patterns in lung cancers from patients who had smoked. Previous work led by Govindan and colleagues found that lung tumors from smokers have about 10 times more mutations than lung tumors from non-smokers.

“Smoking causes characteristic changes in tumor cells, so we can look for telltale signs of smoking or signs of significant exposure to second-hand smoke, for example,” said Govindan, who treats patients at the Siteman Cancer Center. Barnes-Jewish Hospital and Washington University School of Medicine. “But very few tumors from these patients showed these signs, so we were able to verify that it was indeed a sample of cancerous lung tumors from patients who had never smoked or had been heavily exposed to the tobacco smoke. “

The researchers also found that only about 7% of these patients had evidence of mutations present at birth that increased the risk of cancer – hereditary or randomly occurring – deepening the mystery of what causes lung cancer in non-smokers.

“There seems to be something unique about lung cancer in people who have never smoked,” Govindan said. “We did not find a major role for inherited mutations, and we do not see evidence of a large number of mutations, which would suggest exposure to second-hand smoke. About 60% of these tumors are found in women and 40% in men. Cancer in general is more common in men, but lung cancer in non-smokers, for unexplained reasons, is more common in women. It is possible that additional genes are involved in predispositions to cancers of this type, and we just don’t know what it is yet.

The study also shed light on the immune profiles of these tumors, which may help explain why most of them don’t respond well to a type of immunotherapy called checkpoint inhibitors. Unlike the lung tumors of smokers studied, very few tumors of non-smokers included immune cells or immune checkpoint molecules that these drugs trigger to fight cancer.

“The most important finding is that we have identified workable mutations in the vast majority of these patients, between 80% and 90%,” said Govindan. “Our study highlights the need to obtain high quality tumor biopsies for clinical genomic testing in these patients, so that we can identify the best targeted therapies for their individual tumors.”

This work was supported by the National Institutes of Health (NIH), grant numbers 2U54HG00307910 and U01CA214195; and the Mesothelioma Biomarker Discovery Laboratory.

Devarakonda S, et al. Genomic profiling of pulmonary adenocarcinoma in non-smokers. Journal of Clinical Oncology. September 30, 2021.

The 1,700 physicians on the Washington University School of Medicine faculty are also on the medical staff at Barnes-Jewish and St. Louis Children’s Hospitals. The School of Medicine is a leader in medical research, education, and patient care, consistently ranking among the nation’s top medical schools by US News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s Hospitals, the School of Medicine is linked with BJC HealthCare.

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