Liquid biopsy tests could help treat children and young people with cancer

A new blood test that uncovers hidden changes inside cancer cells could help doctors find the best treatments for children and young people with cancer.

The test is a type of liquid biopsy, similar to the ones NHS England is rolling out to help diagnose and treat lung cancer and breast cancer in adults. It works like a high-tech fishing net, catching and analysing telltale scraps of DNA that cancer cells release into the bloodstream.

This circulating tumour DNA (ctDNA) can contain vital information about the mutations driving a cancer. By revealing it to doctors, the new liquid biopsy could help them find the best targeted drugs for young patients whose cancer comes back.

Researchers at the Institute of Cancer Research (ICR) in London developed the test as part of the SMPaeds (Stratified Medicine Paediatrics) programme, which we co-fund with Children with Cancer UK. Their first study, published in Cancer Discovery, confirmed that the liquid biopsy can be used alongside traditional tests on small samples of cancer tissue (tissue biopsies) to give doctors a more complete picture of children’s and young people’s cancers. Now the team is moving on to the next phase of the research, where they’ll see if that extra information can help doctors find more effective treatments when the standard options stop working.

That’s just one of the test’s potential benefits. As liquid biopsies don’t require surgery to directly remove tumour tissue, they’re also much kinder on growing bodies. Although the technology behind it is currently only available in research labs, doctors could one day use the test to keep monitoring patients and tweaking treatments as part of standard care.

The SMPaeds programme

Led by Professor Louis Chesler at the ICR, SMPaeds is a precision medicine programme focused on finding targeted drugs that can help children and young people when their cancer returns or starts growing again (relapses) after initial treatment.

In its first phase, SMPaeds did that by running genomic tests on tissue biopsies from newly relapsed patients and sending the results straight to doctors. Doctors then used that information to find any new treatments or clinical trials that had the potential to help the children and young people in their care.

Alongside that, the SMPaeds team also investigated their new liquid biopsy testing approach, which makes it possible to do genomic tests of many cancers using blood samples. That work led to the Cancer Discovery paper.

Now, in SMPaeds 2, the team will provide doctors with results from both tests when their patients relapse. From there, ICR researchers will monitor how the extra information from the liquid biopsy helps doctors tailor their treatment decisions.

“We’ve shown that ctDNA offers complementary information to tissue sequencing,” says Dr Sally George, who led the development of the test.

“For lots of tumours, if there’s enough ctDNA present in the blood, we often find much more information from the [blood] plasma-based sequencing than we find in the tumour biopsy.

“SMPaeds1 has validated that this test that is ready to go, so in SMPaeds2 we will look at the value of reporting back ctDNA test results at the time of relapse or disease progression. This is the first step towards making ctDNA testing more widely available.”

Kira’s story

SMPaeds has already made all the difference for some young people.

Kira was 11 when she was first diagnosed with neuroblastoma in 2014. Despite high-dose chemotherapy, multiple surgeries and even specialised proton beam therapy, her cancer kept growing. Over the next five years, she relapsed seven times.

At the start of 2019, when it became clear that proton beam therapy hadn’t worked, Kira, her mum Aud and her oncologist decided to try zeroing in on her cancer cells with a new targeted drug: an ALK inhibitor called lorlatinib.

Though it had previously only been used to treat adults, lorlatinib works by blocking the specific changes that were driving Kira’s cancer.

At that point, Kira also joined SMPaeds1. That meant doctors could keep track of any important changes if she relapsed again.

Unfortunately, after two years, Kira’s cancer started to show signs that it was growing. Doctors took samples and sent them off to the SMPaeds team to find out what their next step should be.

Aud picks up the story there: “The results showed the ALK gene mutation, which was causing Kira’s cancer to multiply and grow, was still there and had in fact increased. So, we knew it was crucial to remain on the ALK inhibitor and add in an additional therapy such as chemoimmunotherapy.”

That combination made a lasting difference. After six months of lorlatinib and chemoimmunotherapy, Kira’s tumour became inactive. It has stayed that way ever since.

Two photos of Kira: one of her in hospital while receiving cancer treatment, and one of her on her 21st birthday. — Kira in hospital during her treatment (left) and on her 21st birthday.

“Kira’s story is an important example of precision medicine having the desired effect on cancer and allowing her to live life as a typical 21-year-old,” says Aud. “We wish to extend our gratitude to Cancer Research UK and Children with Cancer UK for accelerating this people-centred approach to cancer care. It’s imperative we tailor treatments that are the right fit for our children to give them the best possible chance of survival. Every child deserves this.”

“Having cancer nine times has undoubtedly shaped me,” says Kira, “but I still live life large at every opportunity. I always squeeze the joy out of life as I go in between treatments.”

The advantages of liquid biopsies

Liquid biopsy testing can reveal more about cancers because it picks up DNA from cells all across tumours.

“As you can imagine, if you biopsy one tiny piece of tumour, you might miss the mutation that’s over on the other side,” explains George, who is also a group leader at the ICR and a consultant at the Royal Marsden NHS Foundation Trust. “A liquid biopsy can give us a much broader overview.”

Testing with a traditional tumour biopsy is a bit like studying an archaeological site by digging one small hole straight down into it. That’s a good way to find out a lot about one particular building, but it probably won’t help you understand how it connects to anything else. The ctDNA test is more like using radar to map out an entire ancient town from above.

Both approaches have their advantages. Some matter more for children and young people. In the same way radar imaging leaves the ground undisturbed, liquid biopsies put much less strain on young patients.

“These patients are often children who require general anaesthetic for procedures – small people who go through a lot,” says George. “Their tumours could be in areas that are risky or problematic to get to, and you can’t keep taking tissue from a child. Having less invasive tests that can help us understand how their tumours change is really, really important.”

Powering precision medicine

The initial study of the liquid biopsy has also identified some mutations that become more prominent when certain cancers relapse. Scientists can now use that information to prioritise research into new targeted treatments.

In the future, George and the rest of the SMPaeds team hope to use their new test to find more changes that we could target with new drugs. Because the test is so much less invasive, there’s also potential for doctors to use it to track tumours and direct treatment in something closer to real time.

“This could be a really powerful way of understanding, actually in patients, how treatments change cells,” says George.

That’s especially important for children and young people, whose cancers are different than the cancers that usually affect adults.

“One of the reasons why childhood cancers are so difficult to treat is because they are reminiscent of embryonal cells, which can change into lots of different cell types,” George explains. “We can’t currently track how those cells change, but it could be possible to use multiple liquid biopsies to see exactly how they adapt to evade treatments.

“So, if we find out, for example, that neuroblastoma cells change in a specific way to evade normal chemotherapy, then we can begin to identify new treatments to target those changes.”