Hereditary Cancers

Changing the standards of care in early detection of Li Fraumeni Syndrome (LFS)

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Home Research Spotlight Hereditary Cancers – Li Fraumeni Syndrome

I feel so honoured to be working on the ATLAS study because the patients and families are so freely giving of their time and expertise to be involved. There is a huge clinical need for improved early detection strategies in Li Fraumeni Syndrome and this study is working to make it accessible for all.

Dr Emma Woodward

Consultant Clinical Geneticist at St Mary’s Hospital, Manchester University NHS Trust and Honorary Senior Clinical Lecturer at The University of Manchester

What is LFS?

Li Fraumeni Syndrome or LFS is caused by a TP53 germline mutation, which was one of the first hereditary cancer predisposition genes identified in the 1990s. Around 1 in 5,000 people in the UK have this inherited condition, which results in a high cancer lifetime risk. This means around 80% of people with this syndrome will develop cancer by age 70 (greater than a 70% chance for men and 80% chance in women). In addition, 40-49% of individuals with LFS have a risk of developing a second cancer.

Five cancer types account for the majority of tumours caused by LFS, including tumours located in the adrenal glands, breast, central nervous system, bones and soft tissues. Young women with LFS commonly develop breast cancer, while children and young adults with the syndrome can be seen to develop sarcomas, and brain tumours.

The average onset of cancers in individuals with LFS is in early adulthood with one study showing the average age at onset of the first cancer being around 25 years, with around 20% of carriers having developed a cancer by age just 5 years and 40% by age 18 years. Furthermore, 40-50% of individuals will go on to further primary cancers. As such, there is a need to identify adolescents, children and young adults with TP53 mutations.

Inheritance of LFS

50% of children will inherit this gene alteration if it is present in just one of their parents. Additionally, the germline mutation rate – changes to DNA that are inherited from the egg and sperm cells during conception – is quite high at 15%, meaning there are many children who are the first to present with LFS in their families.

It is thought that about 1 in 5,000 people in the UK have LFS. The presence of LFS syndrome in both males and females is equal, but because breast cancer is one of the more common features, more women are seen in clinical cohorts.

How is LFS detected?

There are currently two ways in which LFS is detected. The first way is when an individual sadly presents with a cancer and they then receive a follow-up genetic test to look for the genetic mutation that indicates LFS.

The second way is where there is known to be LFS in the family (a germline TP53 mutation), so these family members are offered predictive genetic testing for the familial TP53 gene alteration and surveillance offered to those testing positive.

Current screening practices in LFS patients

A whole-body magnetic resonance image (WBMRI) is used to screen for the presence of cancers in patients with LFS and is an annual occurrence. For children of parents with LFS, their annual screening starts in childhood. However, these are challenging to deliver due to requiring specialist hardware and radiologists to interpret the images.

Additionally, due to the magnetic coils in the WBMRI, patients’ arms and legs – where many sarcomas can occur – may be missed from the images, so an additional annual clinic appointment is still necessary to rule out these cancer occurrences, where the doctor will perform a physical examination to feel for any lumps.

The need for early detection

Current outcomes for a patient with LFS are dependent on catching the disease early. Due to the progress of delineating cancer risks thanks to the work of Professor Evans and many others, research in LFS is shifting towards early detection. This shift in focus means that we are now moving in an optimistic direction in regard to a patients LFS diagnosis and offering these patients the opportunity to participate in cutting edge research.

Outcomes from onset of breast cancer in women have improved remarkably, and for these women, there is now an incentive to improve the risk assessment of them developing a second primary cancer. For example, around 95% of women will survive their breast cancer for one year after their diagnosis, with 75% surviving for 10 years or more after.

However, even though there has been a shift from 20-30 years ago where patients would unfortunately die from their first cancer, patients are now living longer but are at risk of developing a second cancer. There is therefore a need for continued surveillance to monitor these patients.

ATLAS study

Changing LFS cancer detection and treatment options

The ATLAS study, run by Dr Emma Woodward, Consultant Clinical Geneticist at St Mary’s Hospital, Manchester University NHS Trust and Honorary Senior Clinical Lecturer at The University of Manchester and ACED (International Alliance for Early Cancer Detection) co-director of research, is designed to improve the accessibility and effectiveness of annual cancer screening for individuals with the highest cancer risks in the world: carriers of LFS. This study was co-funded by Cancer Research UK (CRUK) and Ontario Institute for Cancer Research (OICR), and aims to enrol 160 patients split across these two centres.

The ATLAS study aims to detect cancers earlier in LFS carriers through analysis of blood circulating free DNA (cfDNA). It will establish a common platform to accelerate the clinical use of circulating free DNA (cfDNA) screening for early detection of all cancers in LFS as an upfront test before a patient receives the less accessible WBMRI surveillance.

It is hoped that this test could be used to detect abnormalities prior to a WBMRI scan. Thus, these blood tests would be used as supplementary screening tools in conjunction with the WBMRI. This test would also act to indicate the need for further screening in patients who have presence of cfDNA showing a concerning signal in their samples.

The inception of this study came in early 2022 when Emma was invited to an online meeting organised by CRUK in conjunction with Ontario Institute for Cancer Research (OICR) in Toronto. This meeting covered a presentation by Dr. Raymond Kim taking about the use of cfDNA as a means of early detection in LFS. Following this, Emma contacted Raymond and the two put in a formal bid between OICR and CRUK with Dr Trevor Pugh as the main PI for OICR. This study then officially began between the two centres in March 2023.

Possible outcomes

The success of this study would see the extraction and analysis of cfDNA from a cohort of Manchester patients. This analysis would determine if there are any preliminary data to demonstrate if an early cancer signal is being detected in a blood test through the presence of an abnormal signal in the cfDNA. This study is a 12-month trial, with samples being analysed in parallel with results being collected. Final results are expected in March 2024.

This would provide patients with reassurance of the international research importance of improving outcomes for those with a hereditary cancer predisposition.

Working with patient focus groups

ATLAS has worked to integrate a patient focus group into its research with the research team forming a LFS patient focus feedback group specifically for this study. The LFS patient focus group informed the study design through feedback regarding the acceptability and feasibility of collection of blood samples.

This group have also contributed insightful opinions on how they feel about receiving a blood test compared to receiving standard WBMRI imaging. Patients reported that they receive an additional level of comfort from coming to the hospital in person once a year for the WBMRI and would see this test being supplementary to current screening, rather than acting as a stand-alone test.