151. Metformin and insulin impact on clinical outcome in patients with advanced hepatocellular carcinoma receiving sorafenib: Validation study and biological rationale.
- Author
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Casadei Gardini A, Faloppi L, De Matteis S, Foschi FG, Silvestris N, Tovoli F, Palmieri V, Marisi G, Brunetti O, Vespasiani-Gentilucci U, Perrone G, Valgiusti M, Granato AM, Ercolani G, Negrini G, Tamburini E, Aprile G, Passardi A, Santini D, Cascinu S, Frassineti GL, and Scartozzi M
- Subjects
- Adult, Aged, Aged, 80 and over, Antineoplastic Agents adverse effects, Carcinoma, Hepatocellular enzymology, Carcinoma, Hepatocellular mortality, Carcinoma, Hepatocellular pathology, Databases, Factual, Diabetes Mellitus, Type 2 diagnosis, Diabetes Mellitus, Type 2 mortality, Disease-Free Survival, Drug Interactions, Drug Resistance, Neoplasm, Female, Humans, Hypoglycemic Agents adverse effects, Immunohistochemistry, Insulin adverse effects, Italy, Kaplan-Meier Estimate, Liver Neoplasms enzymology, Liver Neoplasms mortality, Liver Neoplasms pathology, Male, Metformin adverse effects, Middle Aged, Niacinamide adverse effects, Niacinamide therapeutic use, Phenylurea Compounds adverse effects, Protein Kinase Inhibitors adverse effects, Retrospective Studies, Sirtuin 3 analysis, Sorafenib, Time Factors, Treatment Outcome, Antineoplastic Agents therapeutic use, Carcinoma, Hepatocellular drug therapy, Diabetes Mellitus, Type 2 drug therapy, Hypoglycemic Agents therapeutic use, Insulin therapeutic use, Liver Neoplasms drug therapy, Metformin therapeutic use, Niacinamide analogs & derivatives, Phenylurea Compounds therapeutic use, Protein Kinase Inhibitors therapeutic use
- Abstract
Purpose: In 2015, we published a study on a small series of patients with hepatocellular carcinoma (HCC) treated chronically with metformin for type II diabetes mellitus (DM2) who showed a poorer response to sorafenib. The aim of the present study was to validate the prognostic significance of metformin in HCC patients treated with sorafenib, providing a biological rationale for the mechanism of resistance to sorafenib in patients on chronic metformin therapy, and to clarify the role of sirtuin-3 (SIRT-3), a protein involved in metabolic diseases and acknowledged as a tumour suppressor in HCC, in this resistance., Patients and Methods: We analysed 279 patients consecutively treated with sorafenib for the clinical analysis. Of the 86 (30%) patients with DM2, 52 (19%) were on chronic treatment with metformin and 34 (12%) with insulin. We included 43 patients with HCC for the biological study: 19 (44.1%) were diabetic and 14 (73.7%) of these received metformin for DM2. SIRT-3 expression was investigated by immunohistochemistry (IHC) in formalin-fixed and paraffin-embedded (FFPE) samples., Results: In HCC patients undergoing chronic treatment with metformin, the use of sorafenib was associated with poor progression-free survival (PFS) and overall survival (OS) (1.9 and 6.6 months, respectively) compared to 3.7 months and 10.8 months, respectively, for patients without DM2 and 8.4 months and 16.6 months, respectively, for patients on insulin (P < .0001). We also observed that SIRT-3 protein expression was significantly higher in patients treated with metformin than in those not taking this medication (65% versus 25%, respectively) (P = .013)., Conclusions: Our findings could be attributed to increased tumour aggressiveness and resistance to sorafenib caused by chronic treatment with metformin., (Copyright © 2017 Elsevier Ltd. All rights reserved.)
- Published
- 2017
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