Abstract CT156: Safety and tolerability of metformin for chemoprevention in Li-Fraumeni syndrome (LFS)
Notice bibliographique
Résumé
Abstract 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.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,001 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,001 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,005 | 0,001 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».