Blood test

If lung cancers are found at an early stage, the chance of treating them successfully is higher. In part one of this series, we discussed clinical trials that have tested if CT scans could be used for lung screening. In part two, we investigate research that’s happening right now in the hunt for better ways to detect lung cancers early and give people a better chance of surviving.

Reducing the harms of lung screening

There are two main disadvantages to screening for early lung cancers, which have mostly been discovered through research on CT scans.

Screening uses a test to detect signs of a disease in people without symptoms. But some people can end up having unnecessary tests when what’s found isn’t serious (a ‘false positive’). Others will receive unnecessary treatment for tumours that never would have caused them any harm, so-called overdiagnosis and overtreatment.

This means unnecessary surgery, radiotherapy and chemotherapy for some, which can be dangerous with long-lasting side effects – especially for older, frailer patients.

That’s why doctors and researchers have been scrutinising how to better interpret lung CT scans. In the time that has passed since the first major lung cancer screening trial was carried out, doctors have learned much more about how lung cancers might behave differently. And those results are beginning to unravel the differences between abnormalities that are more likely to be cancer and those that aren’t.

We can more accurately identify nodules that don’t need further investigation. And researchers are developing new and better software too, so computers will be able to analyse scans and give an immediate result

– Professor Sam Janes, UCL and University College London Hospitals NHS Foundation Trust

Professor Sam Janes, a specialist consultant at the Cancer Research UK Lung Cancer Centre of Excellence, is one of those doctors. And he says a lot has changed in low dose CT scans since the large US National Lung Screening Trial opened in 2002.

The characteristics of a lung abnormality (called a nodule), including its size, shape and how quickly it grows, can help tell how likely that growth is to be cancer, says Janes.

“We understand a lot better now what a harmless nodule looks and behaves like compared to an aggressive cancer.

“We can more accurately identify nodules that don’t need further investigation. And researchers are developing new and better software too, so computers will be able to analyse scans and give an immediate result.

“That will lessen the anxiety of waiting, plus computers will probably be better than the human eye at working out if a growth is risky or not,” he adds.

Experts have pulled together this information and drawn up clinical guidelines for doctors to help them identify harmless nodules, nodules that need monitoring, and those that are likely to be cancer and need further investigation. This is helping doctors give better advice on what treatment or monitoring to pursue. While the guidelines weren’t developed for screening, the information is being used to help design studies that test screening. And doctors can have these guidelines at their fingertips during clinics, thanks to a smartphone app we developed.

Janes has also just announced he will be leading the latest, and largest, UK lung cancer screening study at University College London Hospitals NHS Foundation Trust (UCLH) and UCL. Based in London, a key part of the SUMMIT study will invite around 25,000 smokers or former smokers aged 50-77 to have a CT scan as part of a lung ‘health check’.

Other researchers are trying to work out how to tailor any potential future screening invitations, by finding people whose medical history suggests they’re at higher risk of lung cancer. Professor David Baldwin is a Nottingham-based lung cancer expert we’re funding to work with researchers in the Netherlands and Leeds. They’ll be analysing large, anonymised databases of electronic GP records, looking for hallmarks of people who go on to develop lung cancer, and testing how to accurately identify others at risk.

Another long-standing challenge of screening with CT scans is that the procedure exposes people to damage from radiation, especially if they have repeat scans. But thanks to better technology that gives off lower doses of radiation, this exposure is falling.

So, research is steadily reducing the risks posed by radiation and false alarms in low dose CT screening for people at high risk of lung cancer, and working out who to invite.

In the meantime, could new technology complement the information gleaned from scans, or potentially even replace them?

New technology – blood and breath tests

One idea that scientists are pursuing is looking for small traces of cancer in blood samples.

As cancer develops and grows it can shed detectable signs into the blood, including tumour cells, strands of tumour DNA and its chemical cousin RNA, and tiny DNA-filled sacs called exosomes. Scientists want to find out if these traces can be fished out of blood samples to detect lung cancers early.

A blood test for DNA shed by cancer cells has shown potential to be better than scans at spotting early signs that a patient’s lung cancer has come back after treatment. In this scenario, researchers have a sample of the original lung tumour and know what to look for in the blood. So it’s a far-cry from using blood tests in healthy people without symptoms.

But Dr Chris Abbosh, one of the lead researchers of the Cancer Research UK-funded TRACERx study that developed the experimental test, believes the findings could be adapted for screening.

In our experience, not all tumours behave the same, some release more DNA than others. And in lung cancer the ones that release the most DNA may unfortunately be the most aggressive

– Dr Chris Abbosh, Cancer Research UK-funded scientist

“There’s lots of excitement at the possibility of finding these tiny traces of DNA in blood samples and using this information alongside other diagnostic tools such as a CT scan to bring more clarity to whether a growth is a dangerous cancer and needs treating,” he says. “But we need more research and development, as there are several barriers we need to overcome with this technology.

“Firstly, we think a tumour would have to be quite big before we’d be able to pick up these tiny traces in a small blood sample – therefore the sensitivity of current tests is an issue now. Plus, in an early detection setting, we wouldn’t have a sample of the tumour to guide what DNA mistakes to look for, so we’d need technology that can probe for hundreds of possible DNA mistakes that can occur in cancer and accurately call their presence or absence with a low degree of error.

“In our experience, not all tumours behave the same, some release more DNA than others. And in lung cancer the ones that release the most DNA may unfortunately be the most aggressive. We need to understand more about the relationship between tumour DNA release, cancer type and how a cancer behaves to determine how useful DNA detection will be for screening purposes.”

But technology is improving all the time. And researchers can now separate out small numbers of cancer cells or amounts of tumour DNA from blood that were impossible to detect even just a few years ago. In a second part of their London-based SUMMIT study, Janes and his team, working in collaboration with a US company called GRAIL, will be looking at the potential for a blood test to detect multiple cancers earlier, including lung cancer.

Researchers are also looking at alternative approaches to fishing out faulty tumour DNA – some are looking for changes in chemical tags put on DNA (called DNA methylation) and others are examining how changes in our immune system might act as a sign that cancer is developing.

Just as cancers can leave a trace in blood samples, they can also release tell-tale signs in the air we breathe out. A spin-out company from Cambridge University, called Owlstone Medical, is developing a breath test that aims to detect smelly molecules given off by lung cancers. The breath test is being studied in clinical trials to find out whether it’s accurate and sensitive enough to be considered as a potential screening test for people at high risk of lung cancer.

Another interesting area of research is looking for ‘fingerprints’ of DNA damage in a nose swab. Current and former smokers are at the highest risk of lung cancer, and some interesting research from the US has shown that patterns of genetic mistakes in the DNA of smoke-exposed cells lining the nose and upper airways might indicate lung cancer risk.

The test is still being studied in clinical trials involving people who are having a biopsy to determine if a growth is cancerous or not. And the next steps will be finding out how precise it is in people who don’t have any symptoms.

Stopping lung cancer developing

The UK’s cervical screening programme and the bowel scope test in England have a dual purpose: detect cancers early and also prevent cases.

Both cervical and bowel cancers develop from abnormal cells. And it’s these growths that the screening tests aim to find. In doing so, the tests offer a window of opportunity to remove the cells at the same time, because if they’re left untreated some will go on to become a cancer.

Could a preventative approach work for some lung cancers too?

Lung cancers develop from patches of abnormal cells, called lesions, which can be spotted with a bronchoscope that uses special fluorescent light.

People can be referred for a bronchoscopy for a variety of lung problems. It gives doctors a chance to take a closer look inside the lungs for what’s causing the issues, and sometimes they spot lesions that could develop in to cancer.

That’s why Janes is leading a clinical trial, which is still being set up so isn’t open yet, to find out if removing these potentially pre-cancerous lesions using photodynamic therapy (PDT) could reduce the person’s risk of developing lung cancer.

This wouldn’t prevent all lung cancers. But if the trial shows a positive result, it could give doctors an extra treatment option in people who have a lesion spotted during a bronchoscopy and potentially prevent some of these lesions going on to become lung cancers.

The road ahead

Tackling lung cancer is one of our urgent priorities, and one way to do this is ensuring that more lung cancers are detected at an early stage when they are more likely to be treated successfully.

Screening is being studied as a potential way to achieve this goal.

Because screening causes harm to people taking part, experts must carefully weigh up the benefits against the harms in everyone being screened. But thanks to research into CT scans and how to interpret them, those risks could be lower for people in future if screening becomes the norm.

There are several other technologies being developed that could also add to the information from a CT scan. They have the potential to give doctors a more accurate picture of the threat a growth poses, and may even replace CT scans as a more reliable test. Hopefully in the future there will be more precise and safer ways for doctors to spot potentially aggressive lung tumours.

For now, it’s a complicated picture and there’s lots to consider. But researchers are working extremely hard to bring more clarity to the situation and improve the outlook for those diagnosed with lung cancer in the future.

Emma


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