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Li Fraumeni Syndrome and the start of precision cancer prevention

Tim Gunn
by Tim Gunn | In depth

19 September 2023

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Steph Phillips, Dr Miriam Dixon-Zegeye & Professor Sarah Blagden
Steph Phillips (left), Dr Miriam Dixon-Zegeye (centre) and Professor Sarah Blagden are all bringing their knowledge and experience to a new type of precision cancer prevention trial for people with Li Fraumeni Syndrome. Photo by Alison Birkett.


Clinical trials do more than test treatments. Trials are where scientists turn problems we don’t understand into questions we can answer, where participants pull hope out from fear. 

Li Fraumeni Syndrome (LFS) can bring a lot of fear. It’s a genetic condition that increases people’s risk of certain childhood and adult cancers. It’s extremely rare, so data is limited, but it’s been reported that 1 in 5 children born with LFS will develop cancer before their fifth birthday.

The risk keeps climbing from there. People with LFS have a 2 in 5 chance of getting cancer by the time they’re 18. Soon, cancer becomes more likely than not. Studies suggest that fewer than 1 in 10 people with LFS will reach 70 without experiencing it.  

Researchers estimate that there are a few thousand people in the UK with LFS, though only around 500 to 700 people have received a diagnosis. Almost all of them are close to someone else with the condition. Many will have lost someone they love because of it. LFS runs in families.

Together around the dinner table; building sandcastles at the beach, families with an LFS diagnosis are constantly learning to live with cancer. And there’s currently no treatment that can reduce their risk. 

We’re funding a trial that could change that. 

The Metformin in Li Fraumeni Syndrome trial

That’s where the hope comes in. 

The MILI (Metformin in Li Fraumeni Syndrome) trial is investigating whether an anti-diabetic drug called metformin works to reduce cancer risk in people with LFS. 

It’s the first of a new kind of precision cancer prevention trial being run by researchers at the University of Oxford. With our funding, they’re developing ways to either prevent cancer or detect it sooner. Their emphasis on precision could make all the difference. 

“In the old style of doing prevention studies, you would need tens of thousands of patients, and the population with Li Fraumeni Syndrome is too small,” says Professor Sarah Blagden, who is leading the research.  

Sarah Blagden

Professor of Medical Oncology, University of Oxford

Professor Sarah Blagden leads Oxford University’s Oncology Clinical Trials Office (OCTO), which designs and runs clinical trials to investigate the anticancer drugs of the future. She also heads a translational research team exploring cancer biology. We recently invested £1m to help OCTO and Oxford’s Primary Care Clinical Trials Unit become the UK’s first centre specialising in precision cancer prevention and early cancer detection studies.

In fact, people with LFS are often excluded from larger prevention studies. Their cancer risk levels are so much higher than the general population that they can skew the results.  

“We’re turning the whole idea of these trials on its head,” says Blagden.  

It’s something everyone can benefit from. People with LFS might have a higher cancer risk than those who don’t, but the reasons they get cancer aren’t necessarily that different. They’re born with a variation in a tumour suppressor gene called TP53. Similar changes happen in half of all cancers, either causing the cancer to develop in the first place or making it more aggressive and harder to treat. 

“We’re really focusing in on very high-risk patients who can give us a better insight into the biology of cancer,” Blagden explains. “And they’re the ones who are most motivated to contribute – they want an intervention more than anyone else.” 

The Phillips family and Li Fraumeni Syndrome 

Blagden has seen that motivation first-hand, from people like Steph Phillips, a mum of two from Swansea.  

At just 18 months, Steph’s daughter Ava was diagnosed with, and then successfully treated for, a type of soft tissue sarcoma called rhabdomyosarcoma. 

A decade later, in 2019, Steph’s husband (and Ava’s dad) Ceri was diagnosed with another rare soft tissue sarcoma, liposarcoma. By then, it was too late for doctors to operate. He died just seven weeks after his diagnosis, when he was 43 years old. 

With two rare sarcomas in the family, both at a young age, doctors asked Steph if she wanted Ava to be tested for a genetic risk factor 

“It was in the middle of COVID,” remembers Steph. “Everything was really tense.”  

Ceri Phillips
Ceri Phillips died shortly after he was diagnosed with liposarcoma in 2019. No one knew at the time, but it was linked to Li Fraumeni Syndrome.

From the other side of a face mask, the doctor told Steph and Ava that the test had come back positive for Li Fraumeni Syndrome. 

“I’d never heard of it before. But my first response was, ‘What are we going to do about this? This is something that she’ll live with, so what are the options?’” 

There weren’t many. 

“It’s very blunt,” Steph says. “There’s this formal diagnosis, and then nothing. You just go home knowing that you have this risk. It’s this ticking time bomb that could go off at any point, and that’s heavy to live with, particularly for children.” 

Ava’s younger sister Amber was diagnosed with LFS a few months later. Steph found strength in the fact it wasn’t hidden any more.  

“I think knowledge is power, and the starting point for me was: if we understand, we can do something about it.” 

Watching for cancer

In 2017, the Cancer Research UK-funded SIGNIFY trial showed that whole-body MRI scans can be used to regularly screen people with LFS for cancer. It’s an effective way to find the disease early, when treatment is most likely to be successful. 

Steph started there. “My immediate thought was I need to know that there’s nothing wrong: I need to have a scan that says they’re fine and gives me a baseline.” 

Yearly MRI checkups are now recommended for all people in the UK with LFS, but some hospitals still don’t have funding from the NHS to provide them. And, because LFS is so rare, some still might not know how they can help. It can fall to people with LFS to organise their own care.

Steph contacted the George Pantziarka TP53 Trust, the UK’s only LFS charity, to ask about organising screening for Ava and Amber. Dr Pan Pantziarka, the head of the Trust, put Steph in contact with experts at Great Ormond Street Hospital. With their support, she was able to set up a yearly screening programme with her local Paediatric Oncology team in Cardiff. 

“Amber and Ava were both so young at the time,” says Steph. “I just tried to keep it age appropriate. I would say, ‘This is how I’ll keep you safe.’” 

That’s also how Steph and her daughters think about eating healthily, exercising regularly and using sun cream. They’re doing all they can to take control and move forward, but the scans are a reminder that the past never fully goes away. 

“It’s horrific, the waiting. Scanxiety is a very real thing. Not because there are symptoms or anything has changed, but because you’ve lost your innocence. You know that you can be called into a room for a conversation, and you know where that conversation can lead. That’s where your mind goes. It takes a lot of work, a lot of mental toughness, and I’m definitely not always there. 

“But I know if the scan showed something, it would be early, and we could do something about it.” 

Ceri, Ava and Amber on a snowboarding holiday.
Ceri, Ava (centre) and Amber on a snowboarding holiday.

Supporting people with Li Fraumeni Syndrome

Steph found power from knowledge, and she worked hard to set up a screening programme for her daughters. But should she have had to? 

“You’ve already gone through a lot by the time you’re looking for screening,” she says. “You’re already pretty battered. It shouldn’t be so difficult.” 

It’s far from the only difficult thing. The one risk-reducing option currently available for women with LFS is breast removal (mastectomy). It’s something they might need to consider from their 20th birthday. As it stands, doctors don’t have much data to help with the decision. 

And the hard choices start even before diagnosis. Knowledge gives us power when there’s something we can do with it; knowledge we can’t act on takes our power away. It can feel like fate, or a trap. Because treatment options are so limited, some people with strong family histories of LFS choose not to be tested for it themselves. 

“The worst thing is to be told you’ve got this and there’s nothing we can do about it,” says Steph “How do you draw hope from that? How do you motivate yourself to keep going? I can completely understand the logic of saying, ‘I’d rather not know; I’ll just live my life.’” 

Trials like MILI can turn knowledge of LFS into the power to do something about it. And the trial itself is more powerful because it’s being run in other countries too. That means it can recruit more participants, gather more data and, ultimately, create more understanding. Researchers in Canada are also setting up a version for children under 16. 

Professor Blagden has heard from people who are more willing to be tested simply because the trial exists.  

Ava, now 16, and old enough to enrol, will be taking part. 

Steph, Amber and Ava
Steph, Ava and Amber (right) at the Isle of Wight Festival.

“A clinical trial gives hope,” says Steph. “It brings this overwhelming sense that people care, that they’re saying, ‘This isn’t acceptable’, and that they want to do something about it. Scans are really important, but getting ahead of cancer and asking how we can prevent it is literally lifechanging.” 


What’s metformin? How could it help?

Animal research has shown that metformin, the drug being tested in the MILI trial, can keep mice with TP53 mutations cancer-free for longer. We know it’s safe to use because it’s one of the most common treatments for type 2 diabetes. Smaller, short-term studies have shown that it changes people with LFS’s metabolism, which could link its anti-diabetes and cancer risk-reducing effects, but we still don’t know whether it can help people with LFS over the long-term – or even exactly why or how it works.  

In fact, unlike most other cancer drugs, metformin has hardly changed for more than 100 years. It’s a lab-made version of chemicals found in a herb called goat’s rue, or galega. In medieval times, the plant was used to treat snake bites and plague.  

It’s only recently, as they’ve learned more about how cancer starts, that scientists realised metformin might help reduce people’s cancer risk. MILI will test that theory over at least five years. 

“Metformin wasn’t custom-made as an anti-cancer or even an anti-diabetes drug,” explains Blagden. “So there’s lots of questions about how it could work. There’s huge interest in it as a way of preventing cancer, but until we solve these questions, we can’t really put our hands on our hearts and say that we understand it. Once we do, though, we can come back with a better version.” 


 

Precision cancer prevention: a new type of trial 

As well as testing metformin, MILI will bring together a database of scans and samples that can be used to find better ways of detecting early-stage cancer in people with LFS and inform the use of risk-reducing mastectomies. By looking more closely at how these cancers start, researchers may even be able to find other ways to intercept them. 

But the trial won’t just be for people with LFS. Those taking part will also be helping researchers learn about cancer in the general population.  

We know TP53, the gene that is changed in LFS, is vital to preventing cancer. One of its discoverers – our former chief scientist, Professor Sir David Lane – even named it “the guardian of the genome”.  

It’s still guarding some of its own secrets, too.  

In people without LFS, changes to TP53 usually happen alongside multiple other changes in cancer cells. That makes it difficult for researchers to tell exactly what TP53 mutations do to help cancers grow or change how they act. By closely monitoring people with LFS, researchers should be able to pick out the other changes TP53 mutations make possible. 

That monitoring is dependent on NHS-funded MRI scans. Without the George Pantziarka TP53 Trust, Professor Blagden wouldn’t have known how difficult it can be for people with LFS to get them. That problem needs solving. But, as Steph would say, the problems we know about are the ones we can fix. 

That’s not the only way the LFS community has helped make MILI possible. Through the George Pantziarka TP53 Trust, people with LFS have helped plan and prepare the trial, and even raised funds to help pay for participants’ travel. 

“This study has changed how we run clinical trials,” says Blagden. “We’ve decided to knit all of this into our unit’s DNA – to make sure that our priorities are always aligned with those of the people we’re working with.” 

Where hope takes us

Blagden has worked particularly closely with Steph and Ava.

As part of a new TP53-focused buddying scheme, Steph has been paired up with Dr Miriam Dixon-Zegeye, one of Blagden’s PhD students.  

It’s given Steph new understanding, and Miriam more motivation. “It’s tough to turn up in a lab every day and keep going – to try this, which doesn’t work, and try that, which doesn’t work – when you don’t have that human side in front of you,” says Steph. “Now Miriam can say, I know who I’m doing this for.” 

Ava even joined Blagden for work experience. As part of that, she adapted information about MILI for Instagram, making the trial more visible to younger people with LFS.  

The hope MILI offers means much more when it’s Ava who’s sharing it. 

“Particularly when it comes to childhood cancer awareness, there is nothing more powerful in my view than saying, Look at these people that are out there to help you,’” says Steph. “Ava’s seeing what the future of cancer prevention and treatment could look like.” 

And Ava wants to become an oncologist. Like so many others in the LFS community, she wants to help, too. 

Tim

    Comments

  • Patrick McGuire
    22 September 2023

    This is such a great example of the power of research and credit to CRUK for putting patients and their families at the centre of everything you do. It inspires me to keep volunteering and fundraising knowing this is how the money is being spent. Research is where hope starts.

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    Comments

  • Patrick McGuire
    22 September 2023

    This is such a great example of the power of research and credit to CRUK for putting patients and their families at the centre of everything you do. It inspires me to keep volunteering and fundraising knowing this is how the money is being spent. Research is where hope starts.

Tell us what you think

Leave a Reply

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Read our comment policy.