Background and Trial Relevance

The Metformin in Li Fraumeni (MILI) trial. This clinical trial is investigating the use of a drug called metformin as a way of reducing the cancer risk in people with Li Fraumeni Syndrome (LFS).

What is Li Fraumeni Syndrome or LFS? LFS is a rare genetic condition that predisposes people to develop one or more cancers. It is caused by a mutation in a gene called TP53, either inherited from a parent or occurring as a new mutation at conception.TP53 is the most important anticancer gene in the body – its job is to stop cells becoming cancerous after they become damaged or stressed. For most people with cancer the gene is only mutated in their cancer cells but, for people with LFS, it is mutated in all the cells in the body. This means there is a very high risk of developing cancer for people with LFS – a lifetime risk of 90% for women, and about 70% for men. Many people with LFS develop multiple cancers over their lifetimes. Cancers associated with LFS include rare bone and soft tissue sarcomas, childhood brain tumours and leukaemias, but also more common cancers such as breast cancer.

How can people with LFS protect themselves from cancer? Currently there are no treatments to reduce this high risk of cancer. For LFS women there is risk-reducing mastectomy to guard against breast cancer. Other than that, people with LFS have regular health checks and imaging – like whole-body MRI scans and check-ups with specialists – to catch any new cancers early. Research shows that, for people with LFS, spotting cancer early improves survival. Currently there is an agreed protocol for such check-ups in the UK and other countries, but many people are still not getting the care and scans they need.

Why is the MILI trial testing metformin? Metformin is a well-known and safe drug used to treat diabetes. Laboratory experiments have shown that, in mice with LFS, metformin can reduce the risk of them developing cancer. This is because metformin alters the metabolism of cells with mutated TP53 and makes them act more like normal cells. A small study was carried out in people with LFS which showed that metformin treatment caused the same kind of cellular changes that had been seen in the treated mice. However, this is not enough to conclude that metformin will reduce the risks of cancer in people with LFS. For that, a larger clinical trial is needed – involving more patients and a much longer duration of treatment.

How many people will take part in the MILI trial?  The MILI trial aims to enrol 224 patients with LFS in the UK, a large fraction of the approximate 600 people with it in the country. In order to get the numbers of patients needed to address more detailed questions, such as whether metformin is better at preventing certain types of cancer than others, the trial will be run in US, Canada, as well as the UK and the results will be pooled together. Altogether it is expected that around 600 LFS patients from around the world will be included. Half the people on the trials will take metformin every day for up to 5 years and the other half will not – all participants will have regular check-ups for cancer, including whole-body MRI. Five years has been estimated as long enough to give an early indication of  whether differences in cancer incidence are due to treatment rather than being random (i.e., chance events) although longer follow-up may be implemented in the future.

How will the trial answer whether metformin works? The data from each of the trials will be put together to create one large meta-analysis to tell us definitively whether metformin reduces the risk of cancer by comparing the number of people who developed cancer in the metformin vs non-metformin participants. In addition to answering the question about reducing cancer risk, the trial will also include regular quality of life questionnaires and biological studies to better understand what it is in the cells of people with LFS that is most associated with cancer development. If the trial is successful, and shows that metformin is effective, it can be licensed as a standard cancer prevention treatment for people with LFS. This trial will provide important information about LFS and give hope to families across the world who currently face the devastating impact of cancer on themselves and their children.

How have people with LFS been involved in designing MILI? The idea of using metformin for cancer risk reduction was first proposed in the LFS community in 2013 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3637189/) and the LFS community has been involved in the creation, development and management of this trial. In addition, money raised by the UK LFS charity, the George Pantziarka TP53 Trust, will help pay for the travel costs for participants attending clinics and taking part in the trial. All results, including interim results, will be shared with the LFS community at meetings and online.