Pharmacogenomic predictor of sensitivity to preoperative chemotherapy with paclitaxel and fluorouracil, doxorubicin, and cyclophosphamide in breast cancer
Pharmacogenomic predictor of sensitivity to preoperative chemotherapy with paclitaxel and fluorouracil, doxorubicin, and cyclophosphamide in breast cancer
复制标题
DOI：
10.1200/jco.2006.05.6861
复制
发表时间：
2006-09-10
影响因子：
45.3
通讯作者：
Pusztai, Lajos
中科院分区：
文献类型：
--
作者：
Hess, Kenneth R.;Anderson, Keith;Pusztai, Lajos
PurposeWe开发了一个多基因预测的病理完全反应（pCR）术前每周紫杉醇和氟尿嘧啶，阿霉素，环磷酰胺（T/FAC）化疗，并评估其预测准确性独立cases.Patients和MethodsOne一百三十三例I-III期乳腺癌患者。用寡核苷酸微阵列对细针穿刺标本进行预处理基因表达谱分析。我们开发的预测pCR从82例，并评估51个独立的cases.ResultsOverall OCR率为26%，在两个队列的准确性。在训练集中，56个探针被鉴定为在pCR与残留疾病之间差异表达，错误发现率为1%。我们在完全交叉验证中检查了780个不同分类器（基因集+预测算法）的性能。许多预测者表现同样出色。选择名义上最佳的30探针组对角线性判别分析分类器进行独立验证。它显示出显着更高的敏感性（92%比61%）比临床预测因素，包括年龄，等级，和雌激素受体状态。阴性预测值（96% v86%）和曲线下面积（0.877 v0.811）名义上更好，但没有统计学意义。基因组和临床信息的组合产生的预测因子与单独的基因组预测因子没有显著差异。在31个样本中，RNA杂交重复与所得的预测是97%concordant.ConclusionA 30探针集药物基因组学预测预测pCR T/FAC化疗具有较高的敏感性和阴性预测值。该测试正确地鉴定了除一名患者外的所有达到pCR的患者（13名患者中的12名），并且除一名被预测具有残留疾病的患者外的所有患者都具有残留癌症（28名患者中的27名）。
PurposeWe developed a multigene predictor of pathologic complete response (pCR) to preoperative weekly paclitaxel and fluorouracil-doxorubicin-cyclophosphamide (T/FAC) chemotherapy and assessed its predictive accuracy on independent cases.Patients and MethodsOne hundred thirty-three patients with stage I-III breast cancer were included. Pretreatment gene expression profiling was performed with oligonecleotide microarrays on fine-needle aspiration specimens. We developed predictors of pCR from 82 cases and assessed accuracy on 51 independent cases.ResultsOverall OCR rate was 26% in both cohorts. In the training set, 56 probes were identified as differentially expressed between pCR versus residual disease, at a false discovery rate of 1%. We examined the performance of 780 distinct classifiers (set of genes + prediction algorithm) in full cross-validation. Many predictors performed equally well. A nominally best 30-probe set Diagonal Linear Discriminant Analysis classifier was selected for independent validation. It showed significantly higher sensitivity (92% v 61%) than a clinical predictor including age, grade, and estrogen receptor status. The negative predictive value (96% v 86%) and area under the curve (0.877 v 0.811) were nominally better but not statistically significant. The combination of genomic and clinical information yielded a predictor not significantly different from the genomic predictor alone. In 31 samples, RNA was hybridized in replicate with resulting predictions that were 97% concordant.ConclusionA 30-probe set pharmacogenomic predictor predicted pCR to T/FAC chemotherapy with high sensitivity and negative predictive value. This test correctly identified all but one of the patients who achieved pCR (12 of 13 patients) and all but one of those who were predicted to have residual disease had residual cancer (27 of 28 patients).