A clinical trial investigating the use of a drug called metformin as a way of reducing the cancer risk in people with Li Fraumeni Syndrome (LFS)

INTERVENTION: This is a randomised clinical trial for participants with LFS as per the inclusion criteria below. People with LFS should undergone yearly MRI whole‐body, breast and brain imaging but provision is erratic as not all hospitals are able to offer this service. The MILI trial will offer yearly whole‐body (and brain) imaging at one of 5 investigator sites, as well as dermatological examination, haematological testing with blood samples also being collected for translational research in order to better understand the biology of LFS. Quality of Life questionnaires will assess the participants’ well‐being during the trial. Metformin: In addition to annual surveillance, half the participants will be randomised to receive daily metformin. Research in LFS mouse models has shown that metformin can delay the emergence of cancer. It is hoped that from data pooled from this trial and also similar international trials will provide enough evidence for metformin to be prescribed as a cancer preventative for people with LFS as well as advancing research into this condition. The trial has a dose‐titration phase which will assess the safety and toxicity of metformin to ensure the side‐effect profile is consistent with that of the diabetic population. All participants randomised to metformin will begin with a daily starting dose of 500mg which will be increased at 2‐weekly intervals over a period of 9 weeks until they are taking a daily dose of 2000mg, if tolerated. They will remain on this dose for the duration of the trial. From month 6 onwards, participants in both arms will be asked the same questions via telemed calls about the known metformin side‐effects in order to assess the adverse‐event rate in each arm. Partic CONDITION: Li Fraumeni Syndrome ; Cancer PRIMARY OUTCOME: Cancer free survival – with “cancer” event defined as pathologically confirmed diagnosis of malignant cancer identified during trial participation or death from any cause up to 5 years (60 months) following randomisation INCLUSION CRITERIA: 1. Diagnosis of LFS from confirmed pathogenic TP53 variant (class IV or V by CanVIG‐UK criteria 2. Aged >16 years 3. Capable of understanding the consent process and participating in the study (including proving blood samples), in the investigators’ decision SECONDARY OUTCOME: ; 1. Tumour free survival – with a “tumour” event including pathologically confirmed diagnosis of malignant cancer or clinically/scan detected benign or premalignant lesion (e.g. ductal carcinoma in situ ‐ DCIS) identified during trial participation or death from any cause. Measured by time to development of new cancer and/or benign lesion in each trial arm within 60 months of randomisation and % events.; 2. Time from randomisation to death from any cause within 60 months post‐group allocation and % events.; 3. Number and type of emerging cancers, including size, stage and histological grade at diagnosis measured by number, type and stage of cancer diagnosed within each trial arm within 60 months post‐group allocation; 4. Relevant treatment‐emergent adverse events and clinically significant laboratory changes (per NCI CTCAE v5.0) or changes in physical exam and/or vital signs in investigation arm compared to baseline measured by number of and severity of relevant AEs in metformin trial arm within 60 months post‐group allocation; 5. MARS‐5 questionnaire score in the metformin arm from group allocation to 60 months; 6. Change in 12‐item short form survey (SF12v2), Cancer Worry Scale, Treatment Burden Questionnaire (TBQ) over 60 months post‐group allocation; 7. Baseline weight, BMI and lifestyle factors (e.g. smoking and diet);