Background: Metformin is FDA approved for the treatment of type II diabetes. Frequently reported side effects of metformin use in diabetics are abdominal cramping, nausea, and diarrhea. Lactic acidosis, a life-threatening accumulation of lactic acid in the blood, is also a potential adverse effect of metformin. The primary goal of this phase I study was to assess the safety and tolerability of metformin in non-diabetic patients with germline mutations in TP53 and a clinical diagnosis of LFS. LFS is a highly-penetrant, autosomal dominant, cancer predisposition disorder characterized by early onset of breast, sarcoma, adrenocortical, brain, and other cancers. Further, LFS patients have been shown to have increased oxidative phosphorylation capacity in skeletal muscle and oxidative stress markers. Evidence suggests metformin inhibits oxidative phosphorylation in mitochondria, reducing available energy for cancer cell proliferation, and decreasing the production of reactive oxygen species that can cause DNA damage. Although metformin is used safely in non-diabetic individuals for off -label indications such as polycystic ovarian syndrome and infertility, its use in non-diabetic patients with germline TP53 mutations has never been documented.

Objectives: To assess safety and tolerability of metformin dosages from 500 mg to 2000 mg per day in patients with germline mutations in TP53 and a clinical diagnosis of LFS.

Methodology: Adult LFS patients (?18 years old) with documented germline mutation in TP53 were enrolled for 20 weeks. Patients with a history of cancer had to be in remission (surgery and chemotherapy completed 6 and 12 months prior respectively). Patients could not have a history of diabetes or prior metformin use. Metformin was initiated at 500 mg per day and increased in 500 mg dose increments every two weeks to a maximum dose of 2000 mg by week 8. Patients were maintained on 2000 mg of metformin for six additional weeks (week 14). For the last six weeks of the study, patients were taken off metformin (week 20). The targeted accrual goal was ?22 subjects.

Results: Of 24 non-diabetic, LFS patients enrolled, 18 (75%) were female, and 6 (25%) were male. Thirteen (54%) females and 1 male (16%) had a prior history of cancer. The age range for females and males was 25-52 and 20-54 years old respectively. One patient developed cancer, and 2 withdrew from the study before starting treatment; 1 dropped out of the study due to personal issues after reaching a dose of 1500 mg. Of the remaining 20 patients, 1 dropped out of the study due to intolerable dyspepsia/reflux at a dose of 500 mg and 1 patient could only tolerate a maximum dose of 1500 mg due to headaches and nausea; the remaining 18 patients tolerated 2000 mg of metformin. Of 22 patients who took metformin, 20 (90%) experienced abdominal pain/nausea/diarrhea. Five patients (22%) experienced headaches. Three patients (13%) experienced reflux/dyspepsia. Two patients experienced one episode of vomiting (9%). None of the patients experienced lactic acidosis. Fasting glucose at week 14 on 2000 mg of metformin daily for females ranged from 76-96 mg/dL and for males 86-98 mg/dL.

Conclusions: Metformin was safe and tolerable in non-diabetic LFS patients with germline mutations in TP53. LFS patients report similar side effects as diabetic patients on metformin. No cases of lactic acidosis occurred.

Citation Format: Farzana Lukmanji Walcott, Paul M. Hwang, Ping-yuan Wang, Sharon A. Savage, Phuong Mai, Seth M. Steinberg, Michael N. Pollak, Christina Annunziata, Antonio T. Fojo. Safety and tolerability of metformin for chemoprevention in Li-Fraumeni syndrome (LFS). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT156.