Molecular prediction of response to 5-fluorouracil and interferon-α combination chemotherapy in advanced hepatocellular carcinoma
Molecular prediction of response to 5-fluorouracil and interferon-α combination chemotherapy in advanced hepatocellular carcinoma
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DOI：
10.1158/1078-0432.ccr-04-0243
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发表时间：
2004-09-15
影响因子：
11.5
通讯作者：
Monden, M
中科院分区：
文献类型：
--
作者：
Kurokawa, Y;Matoba, R;Monden, M
目的：肝细胞癌（HCC）的预后很差，特别是肿瘤侵犯门静脉主要分支的患者。动脉内5-氟尿嘧啶联合皮下干扰素- α联合化疗治疗此类晚期HCC已显示出良好的效果，但重要的是建立准确预测化疗反应的能力。实验设计：我们使用基于聚合酶链反应的阵列分析了20例在复位术后接受联合化疗的HCC患者的3080个基因的表达。在非监督分析的基础上，构建了一种预测化疗反应的监督分类方法。为了尽量减少预测基因的数量，我们使用随机排列检验只选择显著（P < 0.01）的基因。留一交叉验证证实了基因选择。我们还准备了另外11个案例来验证预测性能。结果：对所有3080个基因进行分层聚类分析和主成分分析，揭示了对联合化疗有反应（完全反应或部分反应）和无反应（疾病稳定或进展）的不同基因表达模式。使用加权投票分类方法，通过排列测试评估所有基因或仅重要基因，20例中有17例正确预测了治疗的客观反应（准确率为85%；阳性预测值为100%；阴性预测值为80%）。此外，验证数据集中的患者可以使用63个预测基因分为两个不同的预后组。结论：63个基因的分子分析可预测晚期肝癌合并门静脉肿瘤大血栓患者对5-氟尿嘧啶联合干扰素- α联合化疗的反应。
Purpose: The prognosis of hepatocellular carcinoma (HCC) is very poor, particularly in patients with tumors that have invaded the major branches of the portal vein. Combination chemotherapy with intra-arterial 5-fluorouracil and subcutaneous interferon-alpha has shown promising results for such advanced HCC, but it is important to develop the ability to accurately predict chemotherapeutic responses.Experimental Design: We analyzed the expression of 3,080 genes using a polymerase chain reaction-based array in 20 HCC patients who were treated with combination chemotherapy after reduction surgery. After unsupervised analyses, a supervised classification method for predicting chemotherapeutic responses was constructed. To minimize the number of predictive genes, we used a random permutation test to select only significant (P < 0.01) genes. A leave-one-out cross-validation confirmed the gene selection. We also prepared an additional 11 cases for validation of predictive performance.Results: Hierarchical clustering analysis and principal component analysis with all 3,080 genes revealed distinct gene expression patterns in responders (those with complete response or partial response) and nonresponders (those with stable disease or progressive disease) to the combination chemotherapy. Using a weighted-voting classification method with either all genes or only significant genes as assessed by permutation testing, the objective responses to treatment were correctly predicted in 17 of 20 cases (accuracy, 85%; positive predictive value, 100%; negative predictive value, 80%). Moreover, patients in the validation dataset could be classified into two distinct prognostic groups using 63 predictive genes.Conclusions: Molecular analysis of 63 genes can predict the response of patients with advanced HCC and major portal vein tumor thrombi to combination chemotherapy with 5-fluorouracil and interferon-alpha.