In 2022 The George Pantziarka TP53 Trust had its ten-year anniversary. This has provided us with an opportunity to look back and reflect on the developments over the past ten years – in Li Fraumeni Syndrome (LFS) research, in clinical services and the role of the Trust as an organisation that works to further the interests of people with LFS. It has also raised questions of where we want to be in ten years from now, and what we might feasibly achieve during that time. In taking this time to reflect, we can identify where the gaps are now and how people with LFS and their families, along with the Trust, clinicians and researchers can work together to achieve our goals – better outcomes for people with LFS.
Perhaps the most significant development over this ten-year period has been in the management protocols for people diagnosed with LFS. In 2012, there was very little in the way of clinical interventions or patient support for those newly-diagnosed. But, how easy was it to even get a diagnosis in the first place?
Testing
Ten years ago, we would often find that a young child with cancer was not tested for germ line defects, or an adult with a family history of cancers was refused testing. The Trust was sometimes contacted by families where a parent or a child had tested positive for LFS, but they were struggling to convince doctors to test their other child/children.
One reason given for refusal was that LFS was incurable and there was really nothing much that could be done, therefore there was no point in knowing, as it would only increase anxiety. However, families were already anxious about what might be. At this point in time, a testing and management protocol had actually been prepared by Professor Nazneen Rahman and her colleagues at the Institute of Cancer Research Genetics and Epidemiology. It was this protocol that gave the Trust something to point to when we received enquiries from patients. And, thankfully, it often resulted in the requested testing being carried out.
It was finally in 2021 that the NHS began offering Whole Genome Sequencing (WGS) for children with cancer.
‘WGS is offered to all children and young people who have or may have cancer, suspected cancer, or non-cancerous tumours.’ (NHS England Information Guide for Parents Carers and Families).
This protocol of testing has been put into operation for children, but there still sometimes remains resistance to testing adults – those who have close family members with LFS, or a history of family members who have died from cancers associated with LFS. We need to close the gaps and ensure everyone in these situations can get access to testing if they so wish, especially as there are now increased opportunities for monitoring people with LFS through regular screening.
Screening/monitoring
The cancers that occur most often in people with LFS are brain, breast, sarcomas, and adrenocortical carcinoma. Screening for these cancers has traditionally involved separate MRIs, ultrasounds and bloodwork.
In 2011, Dr David Malkin and a team of dedicated researchers and clinicians from the Sick Kids Hospital in Toronto had carried out a trial of a protocol of screening of people with LFS. They followed them for an average of 2 years each and found that 100% in the screened group were still alive after 3 years, whereas only 21% of the control group survived. Hence, the Toronto protocol, which included Whole Body MRI (WBMRI), became the first screening protocol recommended for people with LFS. Clinicians and researchers in countries outside Canada embarked on clinical trials to try and replicate Malkin’s results.
In 2017, the SIGNIFY trial was completed in the UK. It had set out specifically to explore whether WBMRI was successful as an early cancer-detection tool for people with LFS, and to look at the feasibility of it being introduced in the UK. It also investigated the psychological effects of regular screening on patients. Results from SIGNIFY confirmed both that WBMRI was useful for early detection, and that the psychological effects on patients were positive.
In November 2019 a paper titled Psychosocial effects of whole-body MRI screening in adult high-risk pathogenic TP53 mutation carriers: a case-controlled study (SIGNIFY) appeared in a BMJ (British Medical Journal) publication, Journal of Medical Genetics (Vol 57 issue 4). In its conclusion, it stated:
‘WB-MRI screening is very acceptable to carriers and is associated with minimal medium-term adverse psychosocial outcomes. The presence of a TP53 pv [pathogenic variant, i.e. a TP53 gene mutation associated with cancer] is well known to cause adverse psychosocial outcomes for some, but there is no evidence that WB-MRI screening exacerbated cancer worry or depression. There was evidence of a transient increase in anxiety pre-MRI, but this might have been due to anticipation of what screening might detect, rather than undergoing MRI. The study population had a high level of satisfaction with the WB-MRI screening process.’
Then, in 2020, the Trust was involved in patient recruitment for a survey at the University of Cardiff, enquiring into the attitudes of LFS patients to whole body MRI. This also found a very positive view of screening from people with LFS.
The current recommended screening protocol for people with LFS in the UK was agreed and laid out in the UK Cancer Genetics Group’s paper in the Journal of Medical Genetics in July 2018. The Trust took part in, and contributed financially to, the meeting of UK-wide geneticists to develop and agree the protocol. Sadly, it has still not been implemented nationally. There are several reasons for this, including lack of equipment to carry out WBMRI, lack of expertise needed to interpret WBMRI (this is a specialist skill) and funding. The Trust continues to work towards its UK-wide adoption. It is hoped that the MILI trial will go a long way to making this happen (more on MILI later in this article).
Meanwhile, SIGNIFY has been followed by SIGNIFIED, an ongoing trial at the time of writing, which continues to investigate the effects of offering WBMRI to LFS patients and to develop the case that it is cost-effective for the NHS to adopt it nationally.
Screening is not the only means by which individuals with LFS are monitored for cancer development. Physical examination on a three-to-four-monthly basis is part of the recommended protocol for children with LFS. In addition, in 2018, Great Ormond Street Hospital (GOSH) and the Trust developed a list of Red Flags warning signs in children. Discussion is ongoing in relation to adults with LFS, about how to alert GPs to these red flags. The Trust is hoping to make inroads into this problem with the help of the University of Oxford Cancer Centre.
All the above interventions suggest that things are moving forward, and that we may indeed be looking at a time in the near future when WBMRI will be part of managing every person with LFS. The development of a system for enabling the medical profession to be alert to ‘red flags’ – ensuring swift investigation or advising avoidance of certain treatments (such as radiotherapy) – is vital and on the Trust’s agenda.
Research
Whilst the best outcome for people with LFS would be therapy to correct the mutated gene, when we formed the Trust we knew that realistically this was a long way off, if it was possible at all. Research is ongoing that tries to better understand the many functions of TP53 and the processes that take place. This has enabled research that aims to correct some of the mutant proteins produced by the gene. Some studies in this area have been successful, but there have been no clinical trials in people with LFS yet.
Although this type of research is extremely important, the Trust felt its efforts should be focused on research that could offer direct benefit to patients in the short to medium term by leading to cancer risk-reducing strategies, until therapies at the gene process level could be found. Consequently, our first research strategy formulated in 2013 proposed a focus on surveillance, scanning and early diagnosis of cancer, plus cancer-prevention strategies.
Following this, in 2013 the Trust put forward its first research paper Li Fraumeni, cancer and senescence: a new hypothesis written by our chair and co-founder Pan Pantziarka and published in the journal Cancer Cell International. This paper drew attention to aspects of LFS that lead to a kind of accelerated aging at the cell level, caused by oxidative stress. The hypothesis was expanding on the ongoing effects of a mutated TP53 gene and its proteins in the cells of people with LFS, which might in turn suggest there were interventions that could help reduce cancer risk.
In 2015, the Trust increased its focus on the elevated cancer risk resulting from a mutated TP53. Pan wrote a paper entitled Primed for Cancer: Li Fraumeni Syndrome and the pre-cancerous niche, which was published in the journal ecancermedicalscience. It discussed how the existence of a pre-cancerous environment to the cells of people with LFS could be contributing to cancer risk. And it proposed that more research needed to be done into repurposing existing drugs to target issues such as chronic inflammation, oxidative stress and tumour immunity. The pre-cancer niche is now a topic of interest in many areas of oncology, not just in relation to cancer in people with Li Fraumeni Syndrome but in all cancers.
A key relationship established by the Trust has been with Professor Sarah Blagden from The University of Oxford Cancer Centre, who has a major interest in cancer prevention as well as treatment. In particular, she is focused on the idea of ‘precision prevention trials’ – stopping the development of cancer in specific high-risk populations. Meanwhile, Oxford University with the support of the Trust had been working since 2018 to develop the MILI (Metformin in Li Fraumeni) trial and seek funding for it. In 2021 the National Institute of Health Research, along with Cancer Research UK, agreed to fund the trial – with a contribution for patient travel added by the Trust.
MILI is a randomised clinical trial, meaning all those enrolled will have regular screening, but half will also be randomly selected to receive the anti-diabetes drug metformin. There was discussion of whether a placebo pill (a dummy pill) could be used for those patients not assigned to metformin, but after consulting with the LFS community the Trust provided evidence to show that patients preferred not to take a dummy pill. Both groups in the trial will get full screening, including annual WBMRI (hence some of the gaps in the current WBMRI provision will be filled as part of the trial). Participants will be in the trial for five years and will then be followed up for another five years. The aim is to compare the two groups and ascertain whether metformin reduces cancer risk in people with LFS. The trial will be based at the University of Oxford Cancer Centre, with Professor Sarah Blagden leading it, and the Trust has been involved at a patient advisory level. MILI begins recruiting in October 2023.
In 2022, Pan and Professor Blagden published a paper in the journal Cancers, laying out the rationale for the MILI trial. Inhibiting the Priming for Cancer in Li Fraumeni Syndrome reviewed the evidence for how cancer starts in people with LFS. It laid out the reasoning and evidence for repurposing common drugs such as aspirin and the anti-diabetes drug, metformin, to prevent the development of a pro-cancer environment at the cell level.
The journey from Pan’s first paper to the current MILI trial has been a long one. Will metformin reduce cancer risk? If so, then it will be of benefit to many more people than those with LFS. In fact, any research that demonstrates a way to reduce cancer risk in LFS sufferers will likely be of benefit to other groups too. MILI is just a first step on the road to repurposing drugs for cancer risk reduction, but it offers considerable hope to the LFS community.
Another ongoing study that the Trust has been involved with is the LiFTS (Li Fraumeni over Time) study being carried out at the Sanger Institute, Cambridge. The aim of LiFTS is to understand why the frequency of cancer – and the age at which it occurs in people with LFS – varies depending on where the cancer arises. It will also look at why some TP53 mutations are associated with a higher risk of developing cancer than others. To achieve this, new methods will be used to analyse alterations in the DNA of cells over a person’s lifetime. Samples will be taken from participants and changes tracked over a number of years. Hopefully this study will improve our understanding of cancer development.
ICED (Inherited cancers – early diagnosis) is a study, based at The Royal Marsden Hospital, looking at early detection of cancer in people with inherited cancer predisposition syndromes, including LFS. Early detection will be enabled by the development of a liquid biopsy (blood and/or urine test). Participants will give blood and urine samples up to three times over a year, and the analysis of samples will be matched with scans and other surveillance. Early detection offers more likelihood of survival.
The SIGNIFIED study is also on-going, as discussed previously. The Trust maintains a register of all active trials and projects on its website at http://www.tp53.co.uk/projects/.
The wheels of research turn slowly. Of necessity, discoveries and medical interventions must be well-evidenced, proven to work and shown to be safe. Lives are at stake. Juxtaposed to this, however, is the urgency of the situation for those living with LFS. People with LFS are beginning to make their presence felt, not just as patients receiving treatment, but as patient representatives in research projects, on committees of patient organisations and as ambassadors for the Trust. Although these roles are often described as ‘patient representatives’, these individuals are actively contributing to their own futures and that of their families. As a patient support organisation, The George Pantziarka TP53 Trust will do whatever it can to keep research moving in the right direction – where it will ultimately benefit people with LFS, and as soon as possible. To this end, we have begun to set up LiNCR (Li Fraumeni Network for Clinicians and Researchers), which will look at how we can all work together to achieve better outcomes for people with LFS, through research and also through the services offered to people with LFS.
LiNCR (Li Fraumeni Network for Clinicians and Researchers)
In April 2023, the Trust sent out an invitation via email to a number of researchers to attend an online meeting, with the aim of creating a network of LFS researchers. During the meeting it became clear that many participants were primarily clinicians, and so it was decided that LiNCR should also include non-research clinicians working with patients with LFS.
Arising from the discussions, the Trust laid out the aims of LiNCR members – to be collaborative, non-competitive, share best practice and avoid duplication, whilst aiming to provide the best possible services to people with LFS. Issues highlighted as requiring attention included development of a national register of people with LFS, carrying out an audit of WBMRI availability and developing multi-consent processes for clinical trials to avoid the need for individuals to attend multiple appointments for consent, blood tests etc.
LiNCR has only just been created, but we are hopeful that it will be enormously useful for researchers, clinicians and, consequently, people with LFS.
University of Oxford, Cancer Centre
In 2022, the Trust was contacted by the University of Oxford Cancer Centre, with a view to creating a mutually beneficial partnership. Amongst areas discussed were:
- Developing a forum for sharing best practice in patient/public involvement (PPI)
- Identifying ‘lost’ patients with LFS
- Using electronic health records to flag up individuals with LFS to GPs
- Developing a LFS UK register
- Raising awareness of LFS amongst clinical nurse specialists
- A buddying scheme to connect Oxford PhD students (carrying out LFS-related research) with individuals with LFS
We will be following up these areas with Oxford in the coming year.
Support and advice
One of the primary functions of the Trust over the past ten years has been to provide information and offer advice and support to patients. In 2011, when George Pantziarka died from his third cancer, there was no patient support organisation in the UK for people with LFS. Pan and Irene – George’s parents – knew how isolating it can be for families whose members test positive for LFS, and at a time when anxiety levels are raised about the present and the future. For this reason, in 2012 they co-founded The George Pantziarka TP53 Trust and became the Chair and Vice-Chair respectively. The tp53 website was created, providing information and articles related to LFS. In the early days, it also contained a forum. Since then, social media has become an important vehicle for people with LFS and for the Trust – to communicate, share information and draw attention to important issues. Hopefully, this kind of instant communication has gone a long way to counteract isolation. People have formed a community of sorts, and the Trust, as part of that community, has a presence on Facebook, Instagram, Twitter (now X) and LinkedIn.
In 2014, we published our Patient Information Leaflet and sent it to genetic testing centres throughout the UK. We have continued to maintain contact with these centres and newly-diagnosed patients are usually pointed in our direction.
Over the years, Pan has been contacted by many people who either had LFS or had family members with a positive test and were seeking advice. We are grateful to Dr Helen Hanson at Royal Devon and Exeter Hospital for always being available to help with medical advice beyond our remit.
In 2016, we held our first national conference in London, to enable people with LFS and their families to meet together face-to-face. We have continued to hold the conference annually (apart from 2020, due to Covid 19). It allows people to hear about the latest research and services, to meet with others in similar situations and to socialise informally, as well as talk to clinicians/researchers who attend.
Alongside the national conference, we have held some informal lunch gatherings in London, and hope to continue to do this for those interested.
In 2022, we established and funded a monthly virtual support group for people with LFS, which is run by Maggie’s, a charity providing cancer support and information.
Over the years, we have also seen the autonomous development of patient-led organisations in other countries, and are in contact with some of these, including Living LFS, LFS Association America, LFS Association Germany and LFS Association Australia. We are keen to encourage co-operation and sharing of information between our organisations. We take part annually in the LFS Awareness Day #wearblueforLFS that was started by Living LFS in the USA. We also represent people with LFS in the Sarcoma Patient Advocacy Global Network (SPAGN), the international network of sarcoma support organisations – in fact we are the only cancer predisposition organisation among the 60+ sarcoma member organisations in SPAGN.
LFS Patient support organisations throughout the world have an important role to play in offering support to people with LFS – ensuring they can access information and the services they need, as well as providing emotional support. We can also work with the clinical and research communities to ensure that together we are serving the needs of people with LFS. We have a role in lobbying for change, in ensuring patients are properly represented and in supporting research – financially or otherwise. Working alongside people with LFS and their families, clinicians and researchers, we have begun to make a difference and can continue to do so.
In 2023 the Trust recruited its first three ambassadors to support the work of the charity, to be patient representatives and to be on hand for any individuals with LFS who would like to talk to someone in a similar situation. We hope to expand our ambassador team in the future.
So where are we at in 2023?
Whilst no one would deny that there is still a long way to go, it is clear that there have been significant changes for the better for people with LFS over the past ten years – in testing, in monitoring, in patient support and in listening to patients with LFS. In 2012, when The George Pantziarka TP53 Trust was formed, there were no LFS patient-support organisations, children with cancer were not regularly tested, Whole Body MRI was only beginning to be recognised as a useful monitoring tool. People with LFS were not included regularly on advisory panels or clinical trials committees. Testing positive for LFS was isolating and offered very little hope of action to prevent cancer. Only a small percentage of the suspected number of people with LFS, were actually diagnosed. Things have changed – for the better. The horrendous cancer incidence statistics that are associated with LFS are also likely to go down – simply because in the past only people with cancer tended to get diagnosed with LFS and therefore the cancer incidence was incredibly high. Now that more people are being diagnosed with LFS without cancer we can expect the cancer incidence statistics to go down – though they are still likely to be higher than the general population level. The Trust remains committed to bringing together people with LFS, clinicians and researchers to continue to push the boundaries and improve services and outcomes.
What can we realistically hope for in the next ten years?
Could we be looking at the ultimate prize – gene therapy? Probably not. There’s a long way to go on this one. But gene therapy is not the be-all and end-all. There are other avenues that are offering positive ways to make living with LFS a more acceptable reality. And more research is being carried out that will enable new strategies for early detection and prevention of cancer to be developed.
What is likely to happen?
- As more people are tested, the number of people diagnosed will grow.
- Awareness of LFS will grow amongst the medical profession – partly due to increased diagnosis, but the Trust is also committed to achieving this. This should result in better knowledge of how to monitor a patient with LFS and which treatments to avoid.
- The influence of The George Pantziarka Trust will continue to increase.
- People with LFS will become more involved and more vocal in research into LFS.
- WBMRI will likely be UK-wide and, consequently more cancers will be caught early.
- Liquid biopsies will become an important tool for non-invasive detection of very early stage cancers
- The mortality figures are likely to go down, as cancers are caught early.
- Knowledge of how cancer develops in people with LFS will be increased, which could mean not just earlier detection, but new cancer-prevention strategies could be created.
The future is not all rosy by any means, but there has been considerable progress. Now we need to increase momentum. With the help of people with LFS and their families, The George Pantziarka Trust will continue to push forward towards a future where LFS is not a devastating diagnosis.