Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Trials
Published in: Trials 1/2024

Open Access 01-12-2024 | Metformin | Study protocol

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

Authors: Miriam Dixon-Zegeye, Rachel Shaw, Linda Collins, Kendra Perez-Smith, Alexander Ooms, Maggie Qiao, Pan Pantziarka, Louise Izatt, Marc Tischkowitz, Rachel E. Harrison, Angela George, Emma R. Woodward, Simon Lord, Lara Hawkes, D. Gareth Evans, James Franklin, Helen Hanson, Sarah P. Blagden

Published in: Trials | Issue 1/2024

Login to get access

Abstract

Background

Li-Fraumeni syndrome (LFS) is a rare autosomal dominant disease caused by inherited or de novo germline 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 metformin (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 mechanism 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 diagnostic 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.

Trial registration

ISRCTN16699730. Registered on 28 November 2022. URL: https://​www.​isrctn.​com/​ EudraCT/CTIS number 2022-000165-41.
Appendix
Available only for authorised users
Literature
1.
2.
Kratz CP, Achatz MI, Brugières L, Frebourg T, Garber JE, Greer MLC, et al. Cancer screening recommendations for individuals with Li-Fraumeni syndrome. Clin Cancer Res Off J Am Assoc Cancer Res. 2017;23(11):e38–45.CrossRef
3.
Hanson H, Brady AF, Crawford G, Eeles RA, Gibson S, Jorgensen M, et al. UKCGG Consensus Group guidelines for the management of patients with constitutional TP53 pathogenic variants. J Med Genet. 2020;58(2):135–9.CrossRefPubMed
4.
Chompret A, Brugières L, Ronsin M, Gardes M, Dessarps-Freichey F, Abel A, et al. P53 germline mutations in childhood cancers and cancer risk for carrier individuals. Br J Cancer. 2000;82(12):1932–7.PubMedPubMedCentral
5.
Saya S, Killick E, Thomas S, Taylor N, Bancroft EK, Rothwell J, et al. Baseline results from the UK SIGNIFY study: a whole-body MRI screening study in TP53 mutation carriers and matched controls. Fam Cancer. 2017;16(3):433–40.CrossRefPubMedPubMedCentral
6.
Villani A, Shore A, Wasserman JD, Stephens D, Kim RH, Druker H, et al. Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: 11 year follow-up of a prospective observational study. Lancet Oncol. 2016;17(9):1295–305.CrossRefPubMed
7.
Hafner A, Bulyk ML, Jambhekar A, Lahav G. The multiple mechanisms that regulate p53 activity and cell fate. Nat Rev Mol Cell Biol. 2019;20(4):199–210.CrossRefPubMed
8.
Light N, Layeghifard M, Attery A, Subasri V, Zatzman M, Anderson ND, et al. Germline TP53 mutations undergo copy number gain years prior to tumor diagnosis. Nat Commun. 2023;14(1):77.ADSCrossRefPubMedPubMedCentral
9.
Zhou G, Wang J, Zhao M, Xie TX, Tanaka N, Sano D, et al. Gain-of-function mutant p53 promotes cell growth and cancer cell metabolism via inhibition of AMPK activation. Mol Cell. 2014;54(6):960–74.CrossRefPubMedPubMedCentral
10.
Alvarado-Ortiz E, de la Cruz-López KG, Becerril-Rico J, Sarabia-Sánchez MA, Ortiz-Sánchez E, García-Carrancá A. Mutant p53 gain-of-function: role in cancer development, progression, and therapeutic approaches. Front Cell Dev Biol. 2020;8:607670.CrossRefPubMed
11.
12.
Wang PY, Li J, Walcott FL, Kang JG, Starost MF, Talagala SL, et al. Inhibiting mitochondrial respiration prevents cancer in a mouse model of Li-Fraumeni syndrome. J Clin Invest. 2017;127(1):132–6.CrossRefPubMed
13.
Wang PY, Ma W, Park JY, Celi FS, Arena R, Choi JW, et al. Increased oxidative metabolism in the Li-Fraumeni syndrome. N Engl J Med. 2013;368(11):1027–32.CrossRefPubMedPubMedCentral
14.
Chan CS. Prevalence and penetrance of Li-Fraumeni cancer predisposition syndrome. Curr Opin Syst Biol. 2017;1:48–53.CrossRef
15.
16.
Yue X, Wu F, Li Y, Liu J, Boateng M, Mandava K, et al. Gain of function mutant p53 protein activates AKT through the Rac1 signaling to promote tumorigenesis. Cell Cycle. 2020;19(11):1338–51.CrossRefPubMedPubMedCentral
17.
Jiang N, Dai Q, Su X, Fu J, Feng X, Peng J. Role of PI3K/AKT pathway in cancer: the framework of malignant behavior. Mol Biol Rep. 2020;47(6):4587–629.CrossRefPubMedPubMedCentral
18.
19.
Hermann LS. Metformin: a review of its pharmacological properties and therapeutic use. Diabete Metab. 1979;5(3):233–45.PubMed
20.
21.
22.
Garber AJ, Duncan TG, Goodman AM, Mills DJ, Rohlf JL. Efficacy of metformin in type II diabetes: results of a double-blind, placebo-controlled, dose-response trial. Am J Med. 1997;103(6):491–7.CrossRefPubMed
23.
Higurashi T, Hosono K, Takahashi H, Komiya Y, Umezawa S, Sakai E, et al. Metformin for chemoprevention of metachronous colorectal adenoma or polyps in post-polypectomy patients without diabetes: a multicentre double-blind, placebo-controlled, randomised phase 3 trial. Lancet Oncol. 2016;17(4):475–83.CrossRefPubMed
24.
25.
Klil-Drori AJ, Azoulay L, Pollak MN. Cancer, obesity, diabetes, and antidiabetic drugs: is the fog clearing? Nat Rev Clin Oncol. 2017;14(2):85–99.CrossRefPubMed
26.
Lord SR, Cheng WC, Liu D, Gaude E, Haider S, Metcalf T, et al. Integrated pharmacodynamic analysis identifies two metabolic adaption pathways to metformin in breast cancer. Cell Metab. 2018;28(5):679-688.e4.CrossRefPubMedPubMedCentral
27.
Walcott FL, Wang PY, Bryla CM, Huffstutler RD, Singh N, Pollak MN, et al. Pilot study assessing tolerability and metabolic effects of metformin in patients with Li-Fraumeni syndrome. JNCI Cancer Spectr. 2020;4(6):pkaa063.CrossRefPubMedPubMedCentral
28.
Achatz MIW, Hainaut P, Ashton-Prolla P. Highly prevalent TP53 mutation predisposing to many cancers in the Brazilian population: a case for newborn screening? Lancet Oncol. 2009;10(9):920–5.CrossRefPubMed
29.
Sandoval RL, Polidorio N, Leite ACR, Cartaxo M, Pisani JP, Quirino CV, et al. Breast cancer phenotype associated with Li-Fraumeni syndrome: A Brazilian cohort enriched by TP53 p.R337H carriers. Front Oncol. 2022;12:836937.CrossRefPubMedPubMedCentral
30.
Evans DG, Harkness EF, Woodward ER. TP53 c.455C>T p.(Pro152Leu) pathogenic variant is a lower risk allele with attenuated risks of breast cancer and sarcoma. J Med Genet. 2023;60(11):1057–60.CrossRefPubMed
31.
Chan AW, Tetzlaff JM, Gøtzsche PC, Altman DG, Mann H, Berlin JA, et al. SPIRIT 2013 explanation and elaboration: guidance for protocols of clinical trials. BMJ. 2013;346:e7586.CrossRefPubMedPubMedCentral
32.
33.
Chan AHY, Horne R, Hankins M, Chisari C. The Medication Adherence Report Scale: a measurement tool for eliciting patients’ reports of nonadherence. Br J Clin Pharmacol. 2020;86(7):1281–8.CrossRefPubMedPubMedCentral
34.
Mai PL, Best AF, Peters JA, DeCastro R, Khincha PP, Loud JT, et al. Risks of first and subsequent cancers among TP53 mutation-carriers in the NCI LFS cohort. Cancer. 2016;122(23):3673–81.CrossRefPubMed
35.
Mai PL, Sand SR, Saha N, Oberti M, Dolafi T, DiGianni L, et al. Li-Fraumeni Exploration Consortium Data Coordinating Center: building an interactive web-based resource for collaborative international cancer epidemiology research for a rare condition. Cancer Epidemiol Biomarkers Prev. 2020;29(5):927–35.CrossRefPubMedPubMedCentral
36.
Metadata
Title
Cancer Precision-Prevention trial of Metformin in adults with Li Fraumeni syndrome (MILI) undergoing yearly MRI surveillance: a randomised controlled trial protocol
Authors
Miriam Dixon-Zegeye
Rachel Shaw
Linda Collins
Kendra Perez-Smith
Alexander Ooms
Maggie Qiao
Pan Pantziarka
Louise Izatt
Marc Tischkowitz
Rachel E. Harrison
Angela George
Emma R. Woodward
Simon Lord
Lara Hawkes
D. Gareth Evans
James Franklin
Helen Hanson
Sarah P. Blagden
Publication date
01-12-2024
Publisher
BioMed Central
Published in
Trials / Issue 1/2024
Electronic ISSN: 1745-6215
DOI
https://doi.org/10.1186/s13063-024-07929-w

Other articles of this Issue 1/2024

Trials 1/2024 Go to the issue

Study protocol

HYPofractionated Adjuvant RadioTherapy in 1 versus 2 weeks in high-risk patients with breast cancer (HYPART): a non-inferiority, open-label, phase III randomised trial

Update

Efficacy of propofol-supplemented cardioplegia on biomarkers of organ injury in patients having cardiac surgery using cardiopulmonary bypass: a statistical analysis plan for the ProMPT-2 randomised controlled trial

Review

Defining usual care comparators when designing pragmatic trials of complex health interventions: a methodology review

Study protocol

Zero Self-Harm app: a mobile phone application to reduce non-suicidal self-injury—study protocol for a randomized controlled trial

Study protocol

Virtual reality as a method of cognitive training of processing speed, working memory, and sustained attention in persons with acquired brain injury: a protocol for a randomized controlled trial

Research

Brief Educational Workshops in Secondary Schools Trial (BESST trial), a school-based cluster randomised controlled trial of the DISCOVER workshop for 16–18-year-olds: recruitment and baseline characteristics