Close-up Of Female Doctor Injecting Male Patient With Syringe To Collect Blood Sample

“It’s always been a dream for many clinicians and scientists to be able to detect cancers with a simple blood test,” says Dr Amit Roshan, a clinician scientist at the University of Cambridge who works on the early detection of melanoma skin cancer.

A blood test capable of catching any cancer at an early stage before any symptoms may sound like science fiction, but Amit says that not everyone has that impression.

“Many patients, even today, when they come to my clinic, find it very unusual that they can’t have a blood test to detect their particular type of cancer.”

Whilst Amit notes that while there can be a mismatch between people’s hopes and expectations and the reality of what’s available, significant progress has still been made in this area.

In September 2021, a new blood test that has the potential to detect over 50 kinds of cancer began trials in the NHS, sparking renewed excitement in the ‘holy grail’ of improving our ability to catch cancer early, when it’s far more treatable.

And while this test – the Galleri test – is the first of its kind to be trialled on this scale in the UK, it’s not the only player on the field.

So how close are we to these tests becoming a routine part of medicine? And are they the silver bullet some might hope them to be?

How could these tests actually work?

When searching for signs of cancer in the blood, there are many avenues to explore, but there are 3 main clues that researchers are following: metabolites, proteins, and DNA.

Cancer cells can grow in many different ways when compared to healthy cells. This often leaves a distinct imprint of metabolites. These are substances that are made or used when the body breaks down nutrients, drugs, chemicals or its own tissue. Identifying and analysing these metabolites can help to fingerprint cancer or the body’s response to treatments.

Measuring proteins

Analysing the levels of proteins in the blood is a well-known method for identifying the presence of some cancers. This is because some proteins are either produced by the cancer itself or by the body in response to the cancer (and may not be present in the same levels in healthy individuals).

CA125 is a protein often found on the surface of ovarian cancer cells and in some normal tissues. High levels can be a result of conditions like endometriosis, fibroids and even pregnancy but also ovarian cancer.

Searching for DNA

In healthy individuals, cells in the body can release fragments of DNA into the blood when they die and these fragments are known as cell-free DNA.

These fragments allow us to get an insight into the body, as levels of fragments released by different cells can be used as a marker for different conditions – including cancer.

In people with cancer, some of the cell-free DNA found in the blood comes from the death of tumour cells and is known as circulating tumour DNA (or ctDNA). Being able to identify and measure the presence of these fragments could be a non-invasive way to diagnose cancer at an early stage.

Tests designed to pick up one or more of these clues are the furthest along at the minute, but they’re not the only approaches being investigated. The best method may still be yet to come, and may involve a combination of clues rather than a single one.

And while a lot of focus has been on ‘simple’ blood tests, they’re not the only place scientists are searching. Our researchers are also looking at the potential for breath tests to pick up multiple cancers, for example. But that’s a story for another time.

What are the challenges with blood?

“We’ve already developed highly sensitive tests to detect cancers in the blood. But they’ve all been for single cancers,” says Amit.

There’s already a challenge in finding ctDNA for one cancer type – it’s a needle in a haystack.

One of the main challenges to overcome is that ctDNA analysis must detect the minute fragments of DNA released by tumour cells. These fragments are only one small fraction of all of the cell-free DNA in the blood. This means that the ctDNA ‘signal’ that is being searched for can be drowned out by lots of noise – diluted by many other molecules in the blood.

This becomes even more complex when you’re trying to detect multiple types of cancer with a single blood test.

Different tumours release different types of ctDNA and this makes it particularly difficult to detect fragments, especially at early stages of tumour development. So instead of searching for a needle in a haystack, it’s more like searching for multiple tiny needles in a haystack and then having to sort them.

However, researchers have developed tools, such as looking at groups of common mutations or methylation patterns (chemical changes to DNA) to help us differentiate ctDNA from DNA from normal cells. This means that you don’t need to know exactly what type of cancer that you’re looking for.

But it’s not enough to know that somebody has cancer, we also need to know where that cancer is most likely going to be,” says Amit. Having this information should direct follow-up tests and help speed up diagnosis.

When could we see these tests in practice?

Amit notes that some of these tests have already moved beyond lab testing and are now in large trials to see how effective they are.

Although several more are in progress, there are 3 tests which have reached advanced stages of development:

  • The Galleri test, currently in trials in the NHS being run by the Cancer Research UK-funded Clinical Trials Unit at King’s College London. This test looks at methylation patterns on ctDNA, potentially being able to detect up to 50 kinds of cancer.
  • PanSEER, a blood test that also looks at DNA methylation patterns. In a large study in China the test was reported to detect individuals who later developed one of 5 different cancers up to 4 years in advance of diagnosis.
  • CancerSEEK, one of the first multi-cancer blood tests to be trialled, beginning recruitment in 2017 and publishing results in early 2020. More trials are now being planned in the hopes of gaining regulatory approval in the US. This test looks for a mix of mutated ctDNA and proteins.

However, he still urges caution. “We’re still years away from getting enough information from these trials to tell if the tests are good enough for regular use.”

The trials needed to prove the worth of a multi-cancer blood test are very complicated.

A particular issue that tests like these face is that they’re looking for cancer in people without any signs of it. Only a small proportion of the volunteers in the trial will end up developing cancer, and for many it will be several years down the line.

And in addition to making sure the tests pick up cancer in people who have it, they also need to make sure not to tell people they have cancer when they actually don’t. This would, of course, cause much undue mental stress, and potentially unnecessary tests and treatment.

This all adds to the amount of time it will take to tell whether one of these tests can be allowed for routine use.

On top of all that, we need to remember the true purpose of developing tests like this: reducing the number of people who die from cancer by catching it a stage when it can be treated more easily.

So, is the hype warranted?

“As a scientist, it’s terribly exciting, because there’s so much potential. And the technologies themselves are advancing at a rapid pace. So certainly, the scientific possibilities are immense,” says Amit.

“With my clinician hat on, I have to be quite careful about how these tests are introduced, because sometimes initial optimism doesn’t translate into clinical benefit, and certainly might not translate into reduced mortality.”

Amit believes that, in the short term, these multi-cancer tests will complement the existing schemes for detecting cancer early in the UK, rather than replacing them.

“It is still vitally important that we continue to do screening with methods that are known and widely effective. Their sensitivity is, at the moment, much better than the multi cancer detection tests are. But I think using them in conjunction with existing screening tests gives us an opportunity to both improve the screening programmes we have, and also gives the ability to detect cancers that we currently do not have a screening test for.”

Multi-cancer early detection tests aren’t a silver bullet – just one piece of the puzzle. A range of research into new ways to detect cancer is vital to create a world where more lives are saved as a result of catching cancer early when it’s more treatable.

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