Li Fraumeni Syndrome and the start of precision cancer prevention

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.  

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.”  

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.” 

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. 

“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.”