ERCC1-Positive Circulating Tumor Cells in the Blood of Ovarian Cancer Patients as a Predictive Biomarker for Platinum Resistance
ERCC1-Positive Circulating Tumor Cells in the Blood of Ovarian Cancer Patients as a Predictive Biomarker for Platinum Resistance
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DOI：
10.1373/clinchem.2014.224808
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发表时间：
2014-10-01
影响因子：
9.3
通讯作者：
Kasimir-Bauer, Sabine
中科院分区：
文献类型：
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作者：
Kuhlmann, Jan Dominik;Wimberger, Pauline;Kasimir-Bauer, Sabine
背景：铂类耐药是卵巢癌最常见的临床挑战之一。值得注意的是，通过免疫组织化学检测原发性肿瘤切除修复交叉互补组1（ERCC 1）蛋白最近被证明是不准确的铂耐药性的预测。基于先前的发现，即卵巢癌患者血液中的循环肿瘤细胞（CTC）具有显著的病理学意义，并且鉴于我们的假设，即CTC的负面预后影响可能源于与铂耐药相关的细胞表型，我们想知道切除修复交叉互补组1（ERCC 1）的表达是否CTC中ERCC 1转录物形式的基因可能是铂耐药的合适的血液生物标志物。通过免疫磁性CTC富集分析CTC的存在（n = 143例患者）靶向上皮表位上皮细胞粘附分子（EPCAM）（也称为GA 733 -2）和粘蛋白1，细胞表面相关的（MUC 1），随后进行多重逆转录PCR以检测转录物EPCAM、MUC 1和粘蛋白16，细胞表面相关（MUC 16）（也称为CA 125），包括ERCC 1转录物。采用免疫组化方法检测ERCC 1在原发性肿瘤中的表达。结果：在原发性肿瘤中，CTC的检出率为14%，CTC是总生存率的独立预测因子（P = 0.041）。在8%的患者中观察到ERCC 1阳性CTC（ERCC 1（+）CTC），不仅是OS的独立预测因子，也是无进展生存期（PFS）的独立预测因子（分别为P = 0.026和P = 0.009）。更有趣的是，我们发现初步诊断时ERCC 1（+）CTC的存在同样是铂类耐药的独立预测因素（P = 0.010），而ERCC 1在相应原发肿瘤组织中的表达既不能预测铂类耐药也不能预测预后。ERCC 1（+）CTC的存在可以作为基于血液的诊断生物标志物，用于预测卵巢癌初步诊断时的铂类耐药。(C)2014年美国临床化学协会
BACKGROUND: Platinum resistance constitutes one of the most recognized clinical challenges for ovarian cancer. Notably, the detection of the primary tumor-based excision repair cross-complementation group 1 (ERCC1) protein by immunohistochemistry was recently shown to be inaccurate for the prediction of platinum resistance. On the basis of the previous finding that circulating tumor cells (CTC) in the blood of ovarian cancer patients are prognostically significant, and given our hypothesis that the negative prognostic impact of CTC may arise from a cellular phenotype associated with platinum resistance, we asked whether expression of the excision repair cross-complementation group 1 (ERCC1) gene in the form of the ERCC1 transcript in CTC may be a suitable blood-based biomarker for platinum resistance.METHODS: The presence of CTC was analyzed by immunomagnetic CTC enrichment (n = 143 patients) targeting the epithelial epitopes epithelial cell adhesion molecule (EPCAM) (also known as GA733-2) and mucin 1, cell surface associated (MUC1), followed by multiplex reverse-transcription PCR to detect the transcripts EPCAM, MUC1, and mucin 16, cell surface associated (MUC16) (also known as CA125), including ERCC1 transcripts in a separate approach. ERCC1 expression in primary tumors was comparatively assessed by immunohistochemistry, using the antibody 8F1.RESULTS: At primary diagnosis, the presence of CTC was observed in 14% of patients and constituted an independent predictor of overall survival (OS) (P = 0.041). ERCC1-positive CTC (ERCC1(+)CTC) were observed in 8% of patients and constituted an independent predictor, not only for OS but also for progression-free survival (PFS) (P = 0.026 and P = 0.009, respectively). More interestingly, we discovered the presence of ERCC1(+)CTC at primary diagnosis to be likewise an independent predictor of platinum resistance (P = 0.010), whereas ERCC1 expression in corresponding primary tumor tissue predicted neither platinum resistance nor prognosis.CONCLUSIONS: The presence of ERCC1(+)CTC can serve as a blood-based diagnostic biomarker for predicting platinum resistance at primary diagnosis of ovarian cancer. (C) 2014 American Association for Clinical Chemistry