A blood test signature made up of 14 proteins signals key inflammatory changes that precede lung cancer, and could help identify people to trial new cancer prevention drugs.
An artistic representation of the extraction of a plasma signature predictive of lung cancer. Inflamed red alveoli are separated from white healthy ones, and from these inflamed alveoli a 14-protein plasma signature is extracted. Credit: Jeroen Claus (Phospho Biomedical Animation).
Just over one third of lung cancer cases are diagnosed at an early stage (stage 1 or stage 2) and after this, options for curative treatment narrow and survival falls. Targeted screening has begun to shift the dial, increasing early-stage diagnoses, but there’s a way to go.
The Crick’s Clinical Director Charlie Swanton believes the next shift could come earlier still, by identifying the biological conditions in which cancer can be triggered, and intervening before a tumour forms.
His team at the Crick and UCL have brought scientists and clinicians a step closer to realising this, identifying a signature of 14 proteins in the blood, that can predict lung cancer risk more than five years before diagnosis.
Their work, funded by Cancer Research UK and the European Research Council and published today in Cell, links this blood signal to the inflammatory processes that trigger cancer initiation, and importantly, suggests how it could be used in future precision cancer prevention.
As we age, our cells acquire cancer-causing mutations. But mutations alone are rarely enough to start a tumour. An additional trigger is often required and that can come from the environment.
Charlie’s team, who are supported by the National Institute for Health and Care Research UCLH Biomedical Research Centre, have previously shown that exposure to air pollution can create a chronic inflammatory state that triggers mutated cells to become cancerous.
Current approaches to lung cancer screening only capture part of the risk: offered to people over a certain age with a history of smoking, but missing never-smokers and individuals exposed to high levels of pollutants.
Tej Pandya, a clinical PhD student in the team, sought out a measurable signal of the inflammatory environment that precedes lung cancer.
“We used machine learning to analyse plasma protein data from more than 48,000 UK Biobank participants, linking this to cancer registry records to identify those who went on to develop lung cancer,” he explains. “Alongside age, smoking status and previous lung disease, our algorithm identified 14 key proteins that could predict a future diagnosis within five years.”
Tej and the team also validated this signature, showing it was consistent across eight independent datasets worldwide.
Importantly, the signature does not appear to originate from the tumour itself. Instead, it reflects an altered inflammatory lung environment that exists before cancer develops. The same signal was also increased in people who develop idiopathic pulmonary fibrosis or chronic obstructive pulmonary disease (COPD), suggesting it may capture a shared, pre-disease state of lung inflammation.
The findings connect directly to the lab’s earlier work on how exposure to air pollution initiates cancer through release of the inflammatory signal interleukin-1 beta (IL-1β).
In this latest study, pollution exposure also increased the 14-protein signature and expanded a population of so-called ‘KAC cells’, an adaptive cell state that emerges after injury but can become cancerous if mutations are present.
The team showed that blocking IL-1β in mice exposed to pollution, reduced the number of KAC cells and slowed early tumour development, suggesting that targeting this pathway could interrupt cancer before it begins. They also showed that components of the 14-protein signature are induced by IL-1β, pollution or cancer mutations.
“We've shown that the signature reflects an altered inflammatory lung environment before cancer takes hold," explains Tej. “It’s a proof of concept that, one day, we could use this signature to offer preventive treatment to people at risk of lung cancer.”
Image credit: Michael Schwimmer and Jeroen Claus (Phospho Biomedical Animation).
“The idea of preventing lung cancer with drugs has so far remained out of reach, in part because of the difficulty of identifying who would benefit,” explains Charlie. “Drugs like statins have transformed the prevention of cardiovascular disease used to treat individuals with a high LDL, but we don’t yet have an LDL-like marker of risk or a statin for lung cancer.”
In 2017, the CANTOS trial, run by Norvartis, tested the IL-1β blocker canakinumab to prevent cardiovascular disease, and reported a reduction in lung cancer as an exploratory finding. But the benefit was modest at a population level. Because their 14-protein signature reflected an inflammatory, partly IL-1β-driven state, the team worked with Novartis to investigate whether a high signature expression in blood at trial entry might predict those individuals most likely to benefit from canakinumab in CANTOS.
Re-analysing data from 4,651 CANTOS participants, the researchers found that the effect of lung cancer risk reduction was concentrated in those with high levels of the 14-protein signature, with risk of lung cancer almost halved in this group.
“Restricting treatment to this high-risk group meant you would only need to treat 55 people to prevent one case of lung cancer, a level comparable to established cardiovascular prevention approaches such as statins,” adds Charlie.
“This has given us insight into this window opportunity, when preventative treatment could work best. This work supports a relatively new idea in the field, that some common age-related diseases, causing a high burden of disease in the community, share a common, presymptomatic state of inflammation. We think the signature could in the future help to predict and help prevent lung cancer and other lung diseases.”
“This research moves us beyond thinking about cancer purely as a disease that we diagnose and treat, towards one that we may be able to predict and prevent. It points to a future where we can identify the biological changes that occur years before a tumour forms and intervene before cancer takes hold,” adds Iain Foulkes, Executive Director of Research and Innovation at Cancer Research UK and CEO of Cancer Research Horizons.
“This study is particularly powerful is because it links a measurable signal in the blood to the underlying inflammatory processes implicated in cancer development. By combining large-scale population data, advanced computational approaches and fundamental biological insights, it opens the door to a new era of precision prevention, where preventive treatments can be targeted to those most likely to benefit.”
