Abstract：
Disease progression is a major problem in ovarian cancer. There are very few treatment options for patients with platinum-resistant ovarian cancer (PROC), and therefore, these patients have a particularly poor prognosis. The aim of the present study was to identify markers for monitoring the response of 123 PROC patients enrolled in the Phase I/II GANNET53 clinical trial, which evaluated the efficacy of Ganetespib in combination with standard chemotherapy versus standard chemotherapy alone. In total, 474 blood samples were collected, comprising baseline samples taken before the first administration of the study drugs and serial samples taken during treatment until further disease progression (PD). After microfluidic enrichment, 27 gene transcripts were analyzed using quantitative polymerase chain reaction and their utility for disease monitoring was evaluated. At baseline, ERCC1 was associated with an increased risk of PD (hazard ratio [HR] 1.75, 95% confidence interval [CI]: 1.20-2.55; p = 0.005), while baseline CDH1 and ESR1 may have a risk-reducing effect (CDH1 HR 0.66, 95% CI: 0.46-0.96; p = 0.024; ESR1 HR 0.58, 95% CI: 0.39-0.86; p = 0.002). ERCC1 was observed significantly more often (72.7% vs. 53.9%; p = 0.032) and ESR1 significantly less frequently (59.1% vs. 78.3%; p = 0.018) in blood samples taken at radiologically confirmed PD than at controlled disease. At any time during treatment, ERCC1-presence and ESR1-absence were associated with short PFS and with higher odds of PD within 6 months (odds ratio 12.77, 95% CI: 4.08-39.97; p < 0.001). Our study demonstrates the clinical relevance of ESR1 and ERCC1 and may encourage the analysis of liquid biopsy samples for the management of PROC patients.
摘要：
疾病进展是卵巢癌的主要问题。铂耐药卵巢癌（PROC）患者的治疗选择很少，因此,这些患者的预后特别差。本研究的目的是确定用于监测参与I/II期GANNET53临床试验的123名PROC患者的反应的标志物，评估了Ganetespib联合标准化疗与单独标准化疗的疗效。总的来说,收集了474份血液样本，包括在首次施用研究药物之前采集的基线样品和在治疗期间采集的系列样品，直到进一步的疾病进展（PD）。微流体富集后，使用定量聚合酶链反应分析了27种基因转录本，并评估了它们在疾病监测中的实用性。在基线,ERCC1与PD的风险增加相关（风险比[HR]1.75，95％置信区间[CI]：1.20-2.55；p=0.005），而基线CDH1和ESR1可能具有降低风险的作用(CDH1HR0.66,95%CI:0.46-0.96;p=0.024;ESR1HR0.58,95%CI:0.39-0.86;p=0.002).ERCC1的观察频率明显更高(72.7%vs.53.9%；p=0.032）和ESR1的频率明显较低（59.1%与78.3％；p=0.018）在放射学证实的PD时比在受控疾病时取的血样中。在治疗期间的任何时候，ERCC1的存在和ESR1的缺失与6个月内较短的PFS和较高的PD几率相关（比值比12.77，95％CI：4.08-39.97；p<0.001）。我们的研究证明了ESR1和ERCC1的临床意义，并可能鼓励分析液体活检样本以管理PROC患者。
