What are liquid biopsies?

By Emily Farthing

Back in 400BC, the Greek doctor Hippocrates described using the colour, consistency and smell of urine to diagnose different conditions.  

He was pretty spot on. We now know there’s a treasure trove of information available in our urine and other body fluids, like blood and saliva.  

Today’s technologies let us scour these fluids for molecular clues to gain valuable insight about what’s going on inside our bodies.  

When it comes to cancer, this sort of test is called a liquid biopsy.  

Liquid biopsies search for cancer-specific biomarkers – the traces of material that cancer leaves in the blood and other body fluids. While solid biopsies can be challenging for patients – especially if the tumour is in a hard-to-reach place like the lung – liquid biopsies offer a non-invasive alternative that can provide real-time information about a tumour.

The NHS rolled out its first liquid biopsy earlier this year to help match people to the best treatment for their cancer type.  

Another potential use of liquid biopsies is to diagnose cancer earlier, when treatment is more likely to be successful. But that application remains a little further from the clinic.  

So, where are we with liquid biopsies? How do liquid biopsies work? And what could the future hold?   

How do liquid biopsies work?

Detecting tumour cells

As a tumour grows, it leaks a range of substances into the blood and other fluids, which can be detected by liquid biopsies.  

For example, cancer cells can break away from a growing tumour, potentially to spread to elsewhere in the body. 

Once they're in the blood, these cells become circulating tumour cells, or CTCs.  

Detecting them isn’t easy. Someone with advanced lung cancer would have around 25 million red blood cells for every one CTC.  

But advances in technology mean we are now able to detect CTCs in people with some advanced tumours. The presence and number of CTCs can be used to predict a person’s prognosis and determine whether their treatment is working.  

Detecting tumour DNA

As some tumours become more advanced, they leak old, dead cells into the blood, where they break down.  

This releases tiny fragments of tumour DNA, known as circulating tumour DNA (ctDNA).

Analysing ctDNA in the blood of people with advanced disease can unlock valuable information about their tumour.  

For example, this approach can predict the likelihood of advanced lung cancer returning after treatment, or whether a person with bowel cancer should receive chemotherapy after surgery. It might also be able to determine whether a person with advanced melanoma should switch therapies, before their cancer has become resistant to their current treatment.

Most of these tests are still in clinical studies. But so far, evidence suggests liquid biopsies capture more information about a whole tumour than a solid biopsy can. This is because tumours are typically made of a patchwork of different cells that a solid biopsy may not capture.

Liquid biopsies, on the other hand, can analyse ctDNA once it’s released into the blood, to build a fuller picture of the tumour.  

Eventually, this sort of information could support doctors in tailoring treatment for their patients.  

Early diagnosis: searching for a needle in a haystack 

Most liquid biopsies in clinical studies aim to provide information about an already diagnosed tumour.  

But what about detecting cancer at an earlier stage?  

This is where it gets a bit trickier.  

Generally, the more advanced a cancer is, the more ctDNA can be found in the blood. Earlier stage cancers may only release very few fragments of tumour DNA. Additionally, healthy tissues can also release fragments of DNA when their cells die.  

All of this means the ctDNA signal is diluted by many other molecules in the blood.  

That’s tougher than looking for a needle in a haystack. It’s more like trying to find a specific snowflake during a blizzard.  

Although we are still a way off using liquid biopsies for early cancer detection in the clinic, technological advances are inching us closer.  

For example, a clinical trial recently showed that the Galleri test can detect ctDNA in the blood of people with some early-stage cancers. However, more research is needed to understand the accuracy of the test and whether it should be adopted by the NHS.  

Looking to the future: promising technologies for liquid biopsies 

Determining cancer origin from DNA methylation  

Researchers at the Cancer Research UK National Biomarker Centre are taking a new approach: looking for specific patterns of tags, called methylation, in ctDNA.  

Methylation helps regulate cell development by switching genes on or off in different parts of the body – which is why lung cells differ from stomach cells, for example.  

The team have developed a test called CUPiD, which can detect specific patterns of methylation in very low levels of ctDNA, and predict which part of the body the ctDNA came from.  

This could be valuable when diagnosing people with a cancer of unknown primary (CUP) – when there is evidence that a cancer has spread, but doctors can’t pinpoint where it started.  

People with CUP currently face a lengthy, often inconclusive diagnostic pathway to determine the origin of their cancer and the best course of treatment.  

But if successful, the CUPiD test could streamline diagnosis for these people and quickly match them to the most appropriate treatment.  

What about fluids other than blood?

Beyond blood tests, urine also holds a wealth of information.  

At the University of Cambridge, our scientists have developed the world’s first urine test for lung cancer. In mice, it can detect some of the earliest signs of the disease.  

The test looks for a molecule produced by senescent cells – those which aren’t quite dead but no longer grow like healthy cells.  

When senescent cells accumulate, they can remodel their surroundings and make it easier for cancer cells to grow. This is often one of the earliest steps of cancer development.  

Currently in the final stage of validation before being tested in people, the test could eventually help to spot this very early sign of lung cancer, far before the onset of symptoms.  

Could tears hold the key to detecting brain tumours earlier?  

Unlike most other parts of the body, the brain presents a unique challenge when it comes to diagnosing a tumour.  

It’s surrounded by the blood-brain barrier, a protective shield that keeps harmful substances out. But it also traps tumour material inside.  

By the time tumour material escapes into the bloodstream in detectable amounts, a cancer is often already advanced. 

If blood isn’t an option for early detection – what about tears?  

Tears are produced by glands located above each eye. They also contribute to the eyes’ immune health.  

As a brain tumour grows, it reshapes the immune system in the brain. This affects the eye glands and, in turn, affects the composition of the tears.  

At the University of Manchester, our researchers have shown this change can be detected using a modified test used for dry eye disease, to predict the presence of a brain tumour.  

They are now running a clinical study to see if their tear test can reliably detect brain tumours in a larger group of people. 

Eventually, the test could provide GPs with a simple, effective tool to help decide whether a patient needs to be referred for urgent MRI scanning. 

Where could we go next?  

We’ve come a long way in recent years. Just a few decades ago, the idea of liquid biopsies guiding treatment decisions might have sounded like science fiction. 

Today, clinical studies are proving the value of liquid biopsies so that they may help doctors stay one step ahead of an evolving tumour.  

And we’re edging ever closer to something even more remarkable: liquid biopsies that could potentially spot cancer at its earlier, more treatable stages. 

Although we’re a little way off these entering the clinic, there’s genuine reason for optimism, with technologies that offer new opportunities to delve deeper into the fluids of the body to gain better insight as to what’s going on inside. 

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