Joerger M, van Schaik R H N, Becker M L, Hayoz S, Pollak M, Cathomas R, Winterhalder R, Gillessen S, Rothermundt C
Department of Medical Oncology and Hematology, Cantonal Hospital, St Gallen, Switzerland.
Department of Clinical Chemistry, Erasmus University Medical Center Rotterdam/ Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
Prostate Cancer Prostatic Dis. 2015 Jun;18(2):167-72. doi: 10.1038/pcan.2015.8. Epub 2015 Mar 10.
This study was initiated to explore the impact of organic cation transporter 1 (OCT1) and multidrug and toxin extrusion transporter 1 (MATE1) genetic polymorphisms on toxicity, and clinical activity of metformin in patients with castration-resistant prostate cancer (CRPC).
The SAKK 08/09 trial included 44 patients with CRPC to receive single-agent metformin 1000 mg two times a day until disease progression or unwanted toxicity. Drug pathway-associated gene polymorphisms of OCT1 (rs622342) and MATE1 (rs2289669) were assessed. The primary objective of this study was to define the relationship between mutations in OCT1, MATE1 and progression-free survival (PFS) at 12 weeks absolute PFS and PSA response in consenting patients of SAKK 08/09. The secondary objective of this study was to analyze the association between mutations in OCT1, MATE1, metformin-related toxicity, PSA response at 12 weeks and overall survival.
Thirty-six patients were evaluable for pharmacogenetic analysis. Homozygous carriers of the polymorphic OCT1 C-allele had no metformin-related toxicity as compared with 41.9% for any metformin-related toxicity in carriers of at least one wild-type A-allele (P=0.07). Disease progression according to RECIST (Response Evaluation Criteria In Solid Tumors) was significantly more frequent in homozygous carriers of the polymorphic OCT1 C-allele (80%) as compared with carriers of at least one wild-type A-allele (28.6%) (P=0.002). Disease progression according to RECIST was also more frequent in carriers of at least one polymorphic MATE1 A-allele (44%) as compared with homozygous carriers of the wild-type G-allele (12.5%) (P=0.07). OCT1 and MATE1 were not associated with PFS.
The polymorphic OCT1 C-allele has been shown to be associated with less metformin-related toxicity and a higher risk of tumor progression in patients with CRPC receiving metformin as an anticancer treatment. Polymorphisms in metformin drug transporters are attractive molecular markers to serve as potential predictors of efficacy in future clinical studies.
本研究旨在探讨有机阳离子转运体1（OCT1）和多药及毒素外排转运体1（MATE1）基因多态性对去势抵抗性前列腺癌（CRPC）患者中二甲双胍毒性及临床活性的影响。
SAKK 08/09试验纳入44例CRPC患者，接受单药二甲双胍，每日2次，每次1000mg，直至疾病进展或出现不良毒性反应。评估OCT1（rs622342）和MATE1（rs2289669）的药物途径相关基因多态性。本研究的主要目的是确定SAKK 08/09试验中符合条件的患者中，OCT1、MATE1突变与12周无进展生存期（PFS）、绝对PFS及PSA反应之间的关系。本研究的次要目的是分析OCT1、MATE1突变与二甲双胍相关毒性、12周时的PSA反应及总生存期之间的关联。
36例患者可进行药物遗传学分析。与至少携带一个野生型A等位基因的患者中41.9%出现任何二甲双胍相关毒性相比，OCT1多态性C等位基因的纯合携带者未出现二甲双胍相关毒性（P = 0.07）。与至少携带一个野生型A等位基因的患者（28.6%）相比，OCT1多态性C等位基因的纯合携带者中根据实体瘤疗效评价标准（RECIST）出现疾病进展的情况更为频繁（80%）（P = 0.002）。与野生型G等位基因的纯合携带者（12.5%）相比，至少携带一个MATE1多态性A等位基因的患者中根据RECIST出现疾病进展的情况也更为频繁（44%）（P = 0.07）。OCT1和MATE1与PFS无关。
已表明OCT1多态性C等位基因与接受二甲双胍作为抗癌治疗的CRPC患者中较低的二甲双胍相关毒性及较高的肿瘤进展风险相关。二甲双胍药物转运体的多态性是有吸引力的分子标志物，可作为未来临床研究中疗效的潜在预测指标。
