Tarpgaard Line S, Qvortrup Camilla, Nygård Sune B, Nielsen Signe L, Andersen Diana R, Jensen Niels Frank, Stenvang Jan, Detlefsen Sönke, Brünner Nils, Pfeiffer Per
Department of Oncology, Odense University Hospital, Odense, Denmark.
Faculty of Health and Medical Sciences, Department of Veterinary Disease Biology, University of Copenhagen, Frederiksberg, Denmark.
BMC Cancer. 2016 Feb 11;16:91. doi: 10.1186/s12885-016-2124-5.
The overall purpose of this study is to provide proof of concept for introducing the anthracycline epirubicin as an effective, biomarker-guided treatment for metastatic colorectal cancer (mCRC) patients who are refractory to treatment with oxaliplatin-based chemotherapy and have TOP2A gene amplification in their tumor cells.
Epirubicin is an anthracycline that targets DNA topoisomerase 2-α enzyme encoded by the TOP2A gene. It is used for treatment of several malignancies, but currently not in CRC. TOP2A gene amplifications predict improved efficacy of epirubicin in patients with breast cancer and thus could be an alternative option for patients with CRC and amplified TOP2A gene. We have previously analysed the frequency of TOP2A gene aberrations in CRC and found that 46.6% of these tumors had TOP2A copy gain and 2.0% had loss of TOP2A when compared to adjacent normal tissue. The TOP2A gene is located on chromosome 17 and when the TOP2A/CEN-17 ratio was applied to identify tumors with gene loss or amplifications, 10.5% had a ratio ≥ 1.5 consistent with gene amplification and 2.6% had a ratio ≤ 0.8 suggesting gene deletions. Based on these observations and the knowledge gained from treatment of breast cancer patients, we have initiated a prospective clinical, phase II protocol using epirubicin (90 mg/m2 iv q 3 weeks) in mCRC patients, who are refractory to treatment with oxaliplatin.
METHODS/DESIGN: The study is an open label, single arm, phase II study, investigating the efficacy of epirubicin in patients with oxaliplatin refractory mCRC and with a cancer cell TOP2A/CEN-17 ratio ≥ 1.5. TOP2A gene amplification measured by fluorescence in situ hybridization. A total of 25 evaluable patients (15 + 10 in two steps) will be included (Simon's two-stage minimax design). Every nine weeks, response is measured by computed tomography imaging and evaluated according to RECIST 1.1. The primary end-point of the study is progression-free survival.
Eudract no. 2013-001648-79.
本研究的总体目的是为将蒽环类药物表柔比星引入作为对基于奥沙利铂的化疗难治且肿瘤细胞中具有TOP2A基因扩增的转移性结直肠癌（mCRC）患者的一种有效、生物标志物引导的治疗方法提供概念验证。
表柔比星是一种靶向由TOP2A基因编码的DNA拓扑异构酶2-α酶的蒽环类药物。它用于治疗多种恶性肿瘤，但目前未用于结直肠癌。TOP2A基因扩增预测表柔比星对乳腺癌患者疗效更佳，因此对于结直肠癌且TOP2A基因扩增的患者可能是一种替代选择。我们之前分析了结直肠癌中TOP2A基因畸变的频率，发现与相邻正常组织相比，这些肿瘤中有46.6%具有TOP2A拷贝数增加，2.0%具有TOP2A缺失。TOP2A基因位于17号染色体上，当应用TOP2A/CEN - 17比值来识别基因缺失或扩增的肿瘤时，10.5%的比值≥1.5与基因扩增一致，2.6%的比值≤0.8提示基因缺失。基于这些观察结果以及从乳腺癌患者治疗中获得的知识，我们启动了一项前瞻性临床II期方案，在对奥沙利铂治疗难治的mCRC患者中使用表柔比星（90 mg/m²静脉注射，每3周一次）。
方法/设计：本研究是一项开放标签、单臂、II期研究，调查表柔比星对奥沙利铂难治且癌细胞TOP2A/CEN - 17比值≥1.5的mCRC患者的疗效。通过荧光原位杂交测量TOP2A基因扩增。总共将纳入25例可评估患者（分两步，15例 + 10例）（西蒙两阶段极小极大设计）。每9周通过计算机断层扫描成像测量反应，并根据RECIST 1.1进行评估。该研究的主要终点是无进展生存期。
Eudract编号2013 - 001648 - 79。
