Casadei Gardini Andrea, Faloppi Luca, De Matteis Serena, Foschi Francesco Giuseppe, Silvestris Nicola, Tovoli Francesco, Palmieri Vincenzo, Marisi Giorgia, Brunetti Oronzo, Vespasiani-Gentilucci Umberto, Perrone Giuseppe, Valgiusti Martina, Granato Anna Maria, Ercolani Giorgio, Negrini Giulia, Tamburini Emiliano, Aprile Giuseppe, Passardi Alessandro, Santini Daniele, Cascinu Stefano, Frassineti Giovanni Luca, Scartozzi Mario
Department of Medical Oncology, Istituto Scientifico Romagnolo per Lo Studio e Cura Dei Tumori (IRST) IRCCS, Meldola, Italy.
Department of Medical Oncology, University of Cagliari, Italy.
Eur J Cancer. 2017 Nov;86:106-114. doi: 10.1016/j.ejca.2017.09.003. Epub 2017 Oct 3.
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.
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.
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).
Our findings could be attributed to increased tumour aggressiveness and resistance to sorafenib caused by chronic treatment with metformin.
2015年，我们发表了一项关于一小系列慢性使用二甲双胍治疗II型糖尿病（DM2）的肝细胞癌（HCC）患者的研究，这些患者对索拉非尼的反应较差。本研究的目的是验证二甲双胍在接受索拉非尼治疗的HCC患者中的预后意义，为长期接受二甲双胍治疗的患者对索拉非尼耐药机制提供生物学依据，并阐明参与代谢疾病且在HCC中被认为是肿瘤抑制因子的沉默调节蛋白3（SIRT-3）在这种耐药中的作用。
我们对连续接受索拉非尼治疗的279例患者进行了临床分析。在86例（30%）DM2患者中，52例（19%）长期接受二甲双胍治疗，34例（12%）接受胰岛素治疗。我们纳入了43例HCC患者进行生物学研究：19例（44.1%）患有糖尿病，其中14例（73.7%）因DM2接受二甲双胍治疗。通过免疫组织化学（IHC）在福尔马林固定石蜡包埋（FFPE）样本中研究SIRT-3表达。
在长期接受二甲双胍治疗的HCC患者中，与未患DM2的患者（分别为3.7个月和10.8个月）以及接受胰岛素治疗的患者（分别为8.4个月和16.6个月）相比，使用索拉非尼与无进展生存期（PFS）和总生存期（OS）较差相关（分别为1.9个月和6.6个月）（P <.0001）。我们还观察到，接受二甲双胍治疗的患者中SIRT-3蛋白表达明显高于未服用该药物的患者（分别为65%和25%）（P = 0.013）。
我们的发现可能归因于长期使用二甲双胍治疗导致肿瘤侵袭性增加和对索拉非尼耐药。
