Study on Metformin for Cancer Prevention in Adolescents and Adults with Li-Fraumeni Syndrome

Li-Fraumeni syndrome (LFS) is a rare, hereditary condition that greatly increases the risk of developing cancer. Affected individuals may develop various types of cancer as early as childhood or adolescence and also have an increased risk of developing multiple independent tumors (multiple primary tumors) over the course of their lives. In most cases, the syndrome is caused by an inherited change (germline mutation) in the p53 gene. This gene is essential because it encodes the p53 protein, also known as the “guardian of the genome.” Its normal function is to repair damaged DNA or, if the damage is too severe, to trigger programmed cell death (apoptosis) to prevent the development of malignant cells. In people with LFS, this important control function is impaired due to the mutation, which can lead to uncontrolled cell division and, consequently, tumor development. Children of affected individuals have a 50% chance of also inheriting the genetic mutation. The most common tumors associated with LFS include breast cancer (often occurring at an early age), various sarcomas (such as soft tissue and osteosarcomas), brain tumors, adrenal cortical carcinomas, as well as leukemias and lymphomas. Given the nearly 100 percent lifetime risk of developing cancer, intensive, close-monitored cancer screening through comprehensive surveillance programs—often including annual whole-body MRIs and specific examinations—is of great importance for those affected in order to detect potential cancers at an early stage. To date, there are no medications that prevent or delay the onset of cancer in LFS. Metformin is a well-established medication and is primarily used to treat type 2 diabetes. However, research has shown that it may also play a role in cancer prevention, particularly in people with Li-Fraumeni syndrome (LFS). Metformin is not yet approved for treatment in this context; its use is experimental. In general, metformin is considered well tolerated.

The goal of this Phase 3b study is to determine whether the drug metformin can reduce the risk of cancer in patients with LFS. To this end, patients will be randomly assigned to two groups. In Group 1, they will receive a daily dose of up to 2,000 milligrams of metformin for the duration of the study (planned for 5 to 7 years). The medication is taken orally, either as a tablet or as a liquid, and the dose is gradually increased. In addition, patients in Group 1 will receive the recommended screening tests for early cancer detection (e.g., annual whole-body MRI). Patients in Group 2 will receive only the recommended screening tests. Follow-up as part of the study will take place over a period of 5 to 7 years. The most important outcome measure evaluated by the study is cancer-free survival. Other objectives include tumor-free survival, overall survival, quality of life, and any side effects of the treatment. The study will also examine how factors such as body weight and lifestyle may influence the treatment’s effectiveness.

Eligible participants are individuals aged 10 and older, regardless of gender, in whom LFS has been confirmed by a genetic test and a mutation in the p53 gene has been detected. Participation is not possible if cancer treatment is currently underway or was completed within the last 6 months. Patients must not have type 2 diabetes.