EARLY RESEARCH SUGGESTS A PATH TO PREDICT AND PREVENT LUNG CANCER

Scientists have made a discovery that may help prevent some people from developing lung cancer, which kills more people worldwide than any other cancer.

A team of more than 80 researchers working across four continents have identified a set of proteins in the blood that accurately predict lung cancers more than five years before diagnosis. The scientists also found early evidence that an existing anti-inflammatory drug could significantly reduce lung cancer risk in people with elevated concentrations of these proteins, which they linked to inflammation.

More research is needed before a test based on these proteins could be ready for use in patients. And scientists would still need to run a randomized trial to determine whether the drug prevents lung cancers. Still, outside experts said the findings, which were published on Thursday in the journal Cell, offer a promising starting point toward a long-held public health goal.

“Preventing lung cancer has been a missing holy grail for a very, very long time,” said Dr. Douglas Arenberg, a professor of medicine at the University of Michigan who was not involved in the study. The authors may have identified a biological marker that “not only predicts risk but also predicts the probability of benefit from a given drug” for prevention, he said.

Over the past two decades, the medical community has made much progress on lung cancer, due in large part to screening programs that detect it sooner and to targeted drugs and immunotherapies that can extend life even in patients with late-stage disease. Still, lung cancer is the most commonly diagnosed cancer worldwide, and fewer than one-third of people diagnosed survive past five years.

“Prevention is the solution in my mind,” said Dr. Charles Swanton, an oncologist and clinical director of the Francis Crick Institute in the United Kingdom who was the senior author of the paper.

Led by Dr. Swanton, Dr. Tej Pandya, a Ph.D. student, and other researchers took a set of 48,000 blood samples from the UK Biobank and used machine learning to identify 14 proteins associated with the development of lung cancer. When the researchers looked at the presence of those proteins and also took into account a patient’s age, smoking status and history of lung disease, they were able to predict who would develop lung cancer more accurately than the best risk assessment models currently in use.

The researchers validated the 14-protein “signature” in eight additional data sets from around the world, including one data set from Taiwan that primarily included people who had never smoked.

Using mouse and cell models, the scientists showed that these proteins increased when a specific inflammatory pathway was activated. Smoking and air pollution can activate that pathway.

This adds to the evidence that it isn’t just genetic mutations caused by smoking, pollution or other factors that are driving lung cancers. Rather, Dr. Swanton said, the findings suggest that “smoke causes mutations and inflammation, which together cause cancer.” They also found that the signature was increased in people who later developed chronic obstructive pulmonary disease and pulmonary fibrosis, pointing to a common inflammatory environment upstream of all three diseases.

That’s exciting to scientists because inflammation is an issue that they could potentially target before a cancer develops. To explore that idea, the researchers looked back at data from 4,650 patients who were included in a randomized controlled trial of canakinumab, a drug that targets the same inflammatory pathway associated with the 14-protein signature. That trial showed only a modest benefit in reducing heart attacks, but it did show that patients who took the drug happened to have a reduced incidence of lung cancer.

The researchers found that canakinumab nearly halved the risk of lung cancer among 2,300 patients in the trial who had higher-than-average expression of the 14 proteins. (Dr. Swanton recently joined the board of Novartis, the maker of canakinumab.)

Dr. Swanton likened the drug’s promise to that of statins: Doctors can identify patients who have a specific marker (high LDL cholesterol) for treatment with statins that significantly reduce their risk of heart attack and stroke. “This is sort of equivalent to an LDL for cancer,” Dr. Swanton said.

Scientists still need to validate the protein signature with further studies, and they would also need to develop a test for it to be used in patients. Most importantly, they need to run a clinical trial testing canakinumab for lung cancer prevention.

“This is the big ‘if,’” said Dr. Roy S. Herbst, chief of medical oncology and hematology at the Yale School of Medicine. “Will it be clinically significant? Will we be able to block this sufficiently at the right stage to prevent cancer?”

Canakinumab can have significant side effects, including increased risk of infection and sepsis, Dr. Peter Mazzone, a pulmonologist at the Cleveland Clinic, said. Even within a narrow population, it could still be too toxic for the benefit to outweigh the harms. It’s possible that a different medicine that targets the same pathway could work and would be safer, he said.

Beyond treatment, the protein signature could also help better define the pool of people who are most likely to benefit from lung cancer screening with low-dose CT scans. Right now, U.S. doctors recommend annual screening for anyone aged 50 to 80 who has a 20 pack-year smoking history and currently smokes or has quit within the past 15 years.

But many people who are eligible don’t get scans, Dr. Mazzone said. If doctors could use a blood test to identify the people most likely to benefit, that might help get more people in the door. A blood test could also help identify others who aren’t covered by the eligibility criteria but may be at increased risk.

In particular, there is “a big need” to better detect lung cancers in people who never smoked, Dr. Mazzone said. The new paper suggested that some components of the protein signature could help identify nonsmokers who are at increased risk of lung cancer, but more data is needed to show whether that’s possible.

Dr. Herbst said that, over the course of his 30-year career, he had seen lung cancer change from an incurable disease to a curable condition in some patients.

But the “greatest benefit is still going to be getting it at the earliest stages, or even preventing it,” he said. “This is a step forward in that direction.”