Predicting response to bevacizumab in ovarian cancer: a panel of potential biomarkers informing treatment selection.
Predicting response to bevacizumab in ovarian cancer: a panel of potential biomarkers informing treatment selection.
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DOI：
10.1158/1078-0432.ccr-13-0489
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发表时间：
2013-09-15
期刊：
影响因子：
--
通讯作者：
Banks RE
中科院分区：
文献类型：
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作者：
Collinson F;Hutchinson M;Craven RA;Cairns DA;Zougman A;Wind TC;Gahir N;Messenger MP;Jackson S;Thompson D;Adusei C;Ledermann JA;Hall G;Jayson GC;Selby PJ;Banks RE
本研究的目的是鉴定和验证作为III期国际ICON 7临床试验一部分治疗的上皮性卵巢癌（EOC）患者的新型预测和/或预后血清蛋白质组学生物标志物。ICON 7是一项针对EOC的III期国际试验，证明了在标准化疗基础上添加贝伐珠单抗对无进展生存期的适度但具有统计学意义的获益。通过质谱分析来自10名接受贝伐珠单抗的患者（5名应答者，5名无应答者）的血清样品以鉴定候选生物标志物。在92例患者的独立队列中进行了免疫测定的初步验证和探索，随后是115例患者的第二个独立队列（来自试验的两个组）。三个候选的生物标志物，间皮素，fms样酪氨酸激酶-4（FLT 4）和α1-酸性糖蛋白（AGP）被确定。当在初始（p<0.02）和组合（p<0.01）验证队列中调整高风险状态时，每种都显示出独立的预后潜力的证据。在队列I中，单个生物标志物不能预测贝伐珠单抗获益;然而，当与CA-125联合使用时，开发了一种特征，可预测贝伐珠单抗应答，并区分贝伐珠单抗获益优于临床特征。该特征在验证队列II中显示出较弱的预测能力证据，但考虑到所有样本，仍具有较强的预测性（p=0.001），与标准组相比，实验组中特征阳性患者的中位PFS改善5.5个月。AGP和CA-125可能识别出更有可能从贝伐珠单抗中获益的EOC患者。这些结果需要在进一步的患者队列中进行验证。
The aim of this study was to identify and validate novel predictive and/or prognostic serum proteomic biomarkers in patients with epithelial ovarian cancer (EOC) treated as part of the phase III international ICON7 clinical trial. ICON7 was a phase III international trial in EOC which demonstrated a modest but statistically significant benefit in progression-free survival with the addition of bevacizumab to standard chemotherapy. Serum samples from 10 patients who received bevacizumab (5 responders, 5 non-responders) were analysed by mass spectrometry to identify candidate biomarkers. Initial validation and exploration by immunoassay was undertaken in an independent cohort of 92 patients, followed by a second independent cohort of 115 patients (taken from across both arms of the trial). Three candidate biomarkers were identified, mesothelin, fms-like tyrosine kinase-4 (FLT4) and α1-acid glycoprotein (AGP). Each showed evidence of independent prognostic potential when adjusting for high risk status in initial (p<0.02) and combined (p<0.01) validation cohorts. In cohort I individual biomarkers were not predictive of bevacizumab benefit; however, when combined with CA-125, a signature was developed that was predictive of bevacizumab response and discriminated benefit attributable to bevacizumab better than clinical characteristics. The signature showed weaker evidence of predictive ability in validation cohort II, but was still strongly predictive considering all samples (p=0.001), with an improvement in median PFS of 5.5 months in signature-positive patients in the experimental arm compared to standard arm. This study demonstrates a discriminatory signature comprising mesothelin, FLT4, AGP and CA-125 as potentially identifying those patients with EOC more likely to benefit from bevacizumab. These results require validation in further patient cohorts.