Forming International Collaborative Efforts to Assess Metformin Use in LFS

Prior findings have inspired a shared protocol design for a randomized, non-placebo-controlled trial intended to assess whether the addition of metformin to cancer screening can impact cancer incidence among patients with LFS.

Organizing a multidisciplinary strategy to evaluate the use of metformin in Li-Fraumeni syndrome (LFS) may show that primary prevention beyond risk-reducing mastectomy can have “an equally important voice” when it comes to treating patients, according to Payal Khincha, MBBS, MSHS.¹

Khincha, a Lasker Clinical Research Scholar in the Division of Cancer Epidemiology and Genetics at the National Cancer Institute (NCI), spoke at the 7th International LFS Association Symposium about facilitating comprehensive, collaborative research efforts in LFS—a rare cancer predisposition hereditary disorder—and similar syndromes. In her presentation, Khincha specifically highlighted the ongoing work of an international network of researchers who aim to evaluate the ability of metformin to potentially prevent the development of cancer among at-risk individuals with LFS.

When it comes to forming a multidisciplinary approach in the field, Khincha first outlined the role of screening for LFS or germline TP53 variants. Although screening may help detect cancers early in this population, this method is not universally accessible. Additionally, patients and their families may have a degree of burden if they choose to undergo screening.

“We’re both worried. After you’ve seen [cancer] happen, and you’ve seen it happen to her, her father, her sister, you know where you finish the race; you just don’t know when you’re finishing the race,” according to a testimonial that Khincha highlighted to demonstrate how the cancer screening process may confer feelings of apprehension to patients and their families.²

The uncertainty of whether you are going to come out on the other side of screening, Khincha said, is a real feeling among patients and their loved ones. Consequently, this limitation associated with screening has prompted investigators to consider how to design human clinical trials assessing intervention with drugs, compounds, or vaccines in LFS.

“How do we best design and conduct a primary prevention trial in individuals with LFS?” Khincha asked. “How do we balance the scientific rigor of what we want to study? What outcomes are we picking? Are we going to have statistical power? Is this going to be relevant for clinical practice with the real-world challenges of rare disease, such as sample sizes?”

As part of facilitating the advancement of collaborative research in cancer prevention among patients with LFS on a global scale, Khincha outlined the rationale for evaluating metformin as a potentially viable option. She noted that individuals with LFS have elevated oxidative phosphorylation compared with a more general population and that disrupting mitochondrial metabolism may reverse abnormal signaling while potentially increasing survival. Additionally, metformin can inhibit mitochondrial respiration, thereby activating antiproliferation signaling in those with LFS.

On top of this mechanism, Khincha highlighted findings from a pilot study demonstrating the ability of metformin to suppress mitochondrial function in patients with LFS.³ Data from this study also showed that metformin was generally tolerable, with grade 1 and 2 adverse effects, respectively, including diarrhea (50% vs 12%), nausea (46% vs 12%), and malaise (42% vs 0%).

These findings have inspired a shared protocol design for a randomized, non-placebo-controlled trial intended to assess whether the addition of metformin to cancer screening can impact cancer incidence among patients with LFS.

In the United Kingdom, investigators are conducting the Metformin in the Li-Fraumeni Precision Prevention (MILI) trial (ISRCTN16699730). The trial population will consist of 224 adults with LFS at risk of cancer who will be randomly assigned 1:1 to receive annual whole-body MRI alone (n = 112) or in combination with metformin at up to 2 mg per day for a maximum of 5 years (n = 112). The trial’s clinical end points include cancer-free survival, overall survival at 5 years, and quality of life (QOL). Additionally, investigators are assessing how the addition of metformin may affect different signaling pathways and circulating biomarkers such as cell-free DNA.

Similarly, in the United States, investigators from the NCI are organizing the MILI-NCI trial, in which approximately 310 patients with confirmed pathogenic or likely pathogenic TP53 variants and no active cancer will receive screening with or without metformin. With a 2-year accrual period and a planned follow-up period of 5 years, investigators will primarily assess cancer incidence and 5-year cancer-free survival; the trial will also include correlative studies for end points such as biomarkers, metabolic profiling, and alternative screening strategies.

As these trials operate on an international scale, Khincha described how this pharmaco-prevention research may serve as a foundation for future progress in the LFS or TP53 variant field. As patients enroll on these trials and biospecimens are collected, these processes may facilitate future work in metabolomics, cancer screening and radiology, and alternative screening strategies. These potential advancements may, in turn, inspire further risk modifier studies and trials focused on screening-associated distress, emotional well-being, or biobehavioral research.

Regarding other metformin-focused research across the world, Khincha highlighted that investigators in Germany have received funding from German Cancer Aid to conduct a trial consisting of 300 children and adults with TP53 variants. Investigators anticipate commencing this trial, MILI-G, in the first quarter of 2025.

Additionally, researchers in Canada are actively applying for funding for their MILI-Paed (MILI-Ped) trial, in which intervention with metformin and screening or screening alone will be assessed among approximately 200 children with LFS. These researchers are currently discussing their trial with the United Kingdom’s Experimental Cancer Medicines Centres trials network.

Based on the shared protocol for the MILI-NCI trial in the United States, the MILI trial in the United Kingdom, the MILI-PAED trial in Canada, and the MILI-G trial in Germany, investigators across the world plan to conduct an international meta-analysis. With an approximate pooled population of more than 900 patients across these trials, members of an international biostatistics committee will collaborate to further evaluate how metformin may impact cancer-free survival in LFS.

“Let’s go deeper. Let’s dive deeper than what we can do as individuals,” Khincha said, emphasizing collaboration as a key component of the ongoing research in the LFS field. “This is going to be key to [seeing] what the outcome is.”

References

1. Khincha PP. Metformin as a pharmacopreventive agent in Li-Fraumeni syndrome (MILI): update on international efforts. Presented at the 7th International Li-Fraumeni Syndrome (LFS) Association Symposium; October 19-22, 2024; Philadelphia, PA.
2. Young JL, Pantaleao A, Zaspel L et al. Couples coping with screening burden and diagnostic uncertainty in Li-Fraumeni syndrome: connection versus independence. J Psychosoc Oncol. 2019;37(2):178-193. doi:10.1080/07347332.2018.1543376.
3. Walcott FL, Wang PY, Bryla CM, et al. Pilot study assessing tolerability and metabolic effects of metformin in patients with Li-Fraumeni syndrome. JNCI Cancer Spectr. 2020;4(6):pkaa063. doi:10.1093/jncics/pkaa063.