Personeni Nicola, Fieuws Steffen, Piessevaux Hubert, De Hertogh Gert, De Schutter Jef, Biesmans Bart, De Roock Wendy, Capoen An, Debiec-Rychter Maria, Van Laethem Jean-Luc, Peeters Marc, Humblet Yves, Van Cutsem Eric, Tejpar Sabine
Digestive Oncology Unit, University Hospital Gasthuisberg, Leuven, Belgium.
Clin Cancer Res. 2008 Sep 15;14(18):5869-76. doi: 10.1158/1078-0432.CCR-08-0449.
To evaluate the usefulness and the pitfalls inherent to the assessment of the epidermal growth factor receptor (EGFR) gene copy number (GCN) by fluorescence in situ hybridization (FISH) for outcome prediction to cetuximab in metastatic colorectal cancer. The value of testing KRAS mutation status, in addition to EGFR GCN, was also explored.
FISH analysis of 87 metastatic colorectal cancer patients treated with cetuximab was done, recording individual GCN per cell and using different samples per tumor. Performances of published cutoff points and different summaries of EGFR GCN distribution were assessed for response prediction.
In our data set, two published cutoff points performed less well than in their training set, yielding positive predictive values and negative predictive values between 40.0% and 48.3% and between 81.0% and 86.5%, respectively. Among summaries of GCN distribution explored, mean and right-tailed distribution of GCN yielded the highest performances. A mean EGFR GCN > or = 2.83 provided an area under the curve of 0.71. Important heterogeneity of repeated measures of mean EGFR GCN was observed within tumors (intraclass correlation, 0.61; within-class SD, 0.40), leading to potential misclassifications of FISH status in 7 of 18 (38.8%) patients if a cutoff point were used. In multivariable analysis, EGFR GCN testing provided significant information independent of the KRAS status to predict response (P = 0.016) and overall survival (P = 0.005).
We confirm the association between increased EGFR GCN and outcome after cetuximab. However, because of reproducibility concerns, any decision making based on published cutoff points is not warranted.
评估通过荧光原位杂交（FISH）检测表皮生长因子受体（EGFR）基因拷贝数（GCN）对转移性结直肠癌患者西妥昔单抗治疗疗效预测的实用性及存在的问题。同时探讨检测KRAS突变状态（除EGFR GCN外）的价值。
对87例接受西妥昔单抗治疗的转移性结直肠癌患者进行FISH分析，记录每个细胞的个体GCN，并对每个肿瘤使用不同样本。评估已发表的截断点和EGFR GCN分布的不同汇总指标对疗效预测的性能。
在我们的数据集中，两个已发表的截断点在预测疗效时表现不如其训练集，阳性预测值和阴性预测值分别在40.0%至48.3%以及81.0%至86.5%之间。在所探讨的GCN分布汇总指标中，GCN的均值和右尾分布表现最佳。平均EGFR GCN≥2.83时曲线下面积为0.71。在肿瘤内观察到平均EGFR GCN重复测量存在重要的异质性（组内相关系数，0.61；组内标准差，0.40），如果使用截断点，18例患者中有7例（38.8%）的FISH状态可能会被错误分类。在多变量分析中，EGFR GCN检测提供了独立于KRAS状态的显著信息来预测疗效（P = 0.016）和总生存期（P = 0.005）。
我们证实EGFR GCN增加与西妥昔单抗治疗后的疗效相关。然而，由于对可重复性的担忧，基于已发表的截断点进行任何决策都是不合理的。
