Cancer Precision-Prevention trial of Metformin in adults with Li Fraumeni syndrome (MILI) undergoing yearly MRI surveillance - a randomised controlled trial protocol

Sep 21, 2026

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Li-Fraumeni syndrome (LFS) is a rare autosomal dominant condition driven by inherited or de novo germline TP53 pathogenic variants, with a reported 70–100% lifetime cancer risk. The study protocol addresses the lack of licensed chemoprevention for LFS by evaluating metformin’s potential anticancer effects. Methods: 224 adults (≥16 years) are randomised 1:1 to metformin plus yearly whole-body and brain MRI surveillance versus yearly MRI surveillance alone for up to 5 years.

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Abstract

Background

Methods

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Dixon‑Zegeye et al. Trials (2024) 25:103 [https://doi.org/10.1](https://doi.org/10.1) 186/s13063‑024‑07929‑w Trials STUDY PROTOCOL Open Access Cancer Precision‑Prevention trial of Metformin in adults with Li Fraumeni syndrome (MILI) undergoing yearly MRI surveillance: a randomised controlled trial protocol Miriam Dixon‑Zegeye1, Rachel Shaw2, Linda Collins2, Kendra Perez‑Smith3, Alexander Ooms4, Maggie Qiao4, Pan Pantziarka5, Louise Izatt6, Marc Tischkowitz7, Rachel E. Harrison8, Angela George9, Emma R. Woodward 10,11, Simon Lord 1, Lara Hawkes 12, D. Gareth Evans 10,11, James Franklin 13, Helen Hanson 14,15 and Sarah P. Blagden 1,2* Abstract Background Li‑Fraumeni syndrome (LFS) is a rare autosomal dominant disease caused by inherited or de novo ger‑ mline pathogenic variants in TP53 . Individuals with LFS have a 70–100% lifetime risk of developing cancer. The current standard of care involves annual surveillance with whole‑body and brain MRI (WB‑MRI) and clinical review; however, there are no chemoprevention agents licensed for individuals with LFS. Preclinical studies in LFS murine models show that the anti‑diabetic drug metformin is chemopreventive and, in a pilot intervention trial, short‑term use of metformin was well‑tolerated in adults with LFS. However, metformin’s mechanism of anticancer activity in this context is unclear. Methods Metformin in adults with Li‑Fraumeni syndrome (MILI) is a Precision‑Prevention phase II open‑labelled unblinded randomised clinical trial in which 224 adults aged ≥ 16 years with LFS are randomised 1:1 to oral met‑ formin (up to 2 mg daily) plus annual MRI surveillance or annual MRI surveillance alone for up to 5 years. The primary endpoint is to compare cumulative cancer‑free survival up to 5 years (60 months) from randomisation between the intervention (metformin) and control (no metformin) arms. Secondary endpoints include a comparison of cumulative tumour‑free survival at 5 years, overall survival at 5 years and clinical characteristics of emerging cancers between trial arms. Safety, toxicity and acceptability of metformin; impact of metformin on quality of life; and impact of baseline lifestyle risk factors on cancer incidence will be assessed. Exploratory end‑points will evaluate the mecha‑ nism of action of metformin as a cancer preventative, identify biomarkers of response or carcinogenesis and assess WB‑MRI performance as a diagnostic tool for detecting cancers in participants with LFS by assessing yield and diag‑ nostic accuracy of WB‑MRI. Discussion Alongside a parallel MILI study being conducted by collaborators at the National Cancer Institute (NCI), MILI is the first prevention trial to be conducted in this high‑risk group. The MILI study provides a unique opportunity to evaluate the efficacy of metformin as a chemopreventive alongside exploring its mechanism of anticancer action and the biological process of mutated P53‑driven tumourigenesis. *Correspondence: Sarah P. Blagden [sarah.blagden@oncology.ox.ac.uk](sarah.blagden@oncology.ox.ac.uk) Full list of author information is available at the end of the article © The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit [http://creativecommons.or

FAQs

What condition does the trial target, and why is prevention needed?

The trial targets Li-Fraumeni syndrome (LFS), a TP53-driven, high-penetrance cancer predisposition with a 70–100% lifetime risk. There are no licensed chemoprevention agents for individuals with LFS, motivating evaluation of metformin.

How is the study designed and who is enrolled?

MILI is a Precision-Prevention phase II open-label, unblinded randomised clinical trial enrolling 224 adults aged ≥16 years with LFS. Participants are randomised 1:1 to metformin (up to 2 mg daily) plus annual MRI surveillance or annual MRI surveillance alone for up to 5 years.

What are the primary and key secondary outcomes?

The primary endpoint compares cumulative cancer-free survival up to 5 years (60 months) between metformin and control arms. Secondary endpoints include cumulative tumour-free survival, overall survival, and clinical characteristics of emerging cancers, alongside assessments of safety and quality of life.

Sep 21, 2026

Uploaded by Himbo