Evaluation of a 30-gene paclitaxel, fluorouracil, doxorubicin, and cyclophosphamide chemotherapy response predictor in a multicenter randomized trial in breast cancer.
Evaluation of a 30-gene paclitaxel, fluorouracil, doxorubicin, and cyclophosphamide chemotherapy response predictor in a multicenter randomized trial in breast cancer.
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DOI：
10.1158/1078-0432.ccr-10-1265
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发表时间：
2010-11-01
期刊：
影响因子：
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通讯作者：
Pusztai L
中科院分区：
文献类型：
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作者：
Tabchy A;Valero V;Vidaurre T;Lluch A;Gomez H;Martin M;Qi Y;Barajas-Figueroa LJ;Souchon E;Coutant C;Doimi FD;Ibrahim NK;Gong Y;Hortobagyi GN;Hess KR;Symmans WF;Pusztai L
我们在一项前瞻性、随机、国际临床试验中检查了先前定义的30个基因预测因子（DLDA-30）对术前每周紫杉醇和氟尿嘧啶、多柔比星、环磷酰胺（T/FAC）化疗的病理完全缓解（pCR）的表现，并评估了DLDA-30是否也预测了对仅FAC-only化疗的敏感性增加。我们比较了T/FAC与FAC×6术前化疗后的pCR率。我们还进行了探索性分析，以确定新的候选基因，差异预测反应在两个治疗组。273名患者被随机分配接受每周紫杉醇× 12，随后FAC × 4（T/FAC，n=138）或FAC × 6（n=135）新辅助化疗。所有患者均接受了肿瘤的预处理FNA活检，以进行基因表达谱分析和治疗反应预测。T/FAC组和FAC组的pCR率分别为19%和9%（p<0.05）。在T/FAC组中，基因组预测因子的阳性预测值（PPV）为38%（95%CI：21-56%），阴性预测值（NPV）为88%（CI：77-95%），AUC为0.711。在FAC组中，PPV为9%（CI：1-29%），AUC为0.584。这表明基因组预测因子可能具有方案特异性。其性能类似于基于临床变量的预测列线图。在这项国际试验中，基因表达谱用于前瞻性缓解预测是可行的。30个基因预测因子可以识别对T/FAC化疗敏感性高于平均水平的患者。然而，它捕获了临床表型的分子等价物。下一代预测标记物将需要针对乳腺癌的不同分子子集单独开发。
We examined in a prospective, randomized, international clinical trial the performance of a previously defined 30-gene predictor (DLDA-30) of pathologic complete response (pCR) to preoperative weekly paclitaxel and fluorouracil, doxorubicin, cyclophosphamide (T/FAC) chemotherapy, and assessed if DLDA-30 also predicts increased sensitivity to FAC-only chemotherapy. We compared the pCR rates after T/FAC versus FAC×6 preoperative chemotherapy. We also performed an exploratory analysis to identify novel candidate genes that differentially predict response in the two treatment arms. 273 patients were randomly assigned to receive either weekly paclitaxel × 12 followed by FAC × 4 (T/FAC, n=138), or FAC × 6 (n=135) neoadjuvant chemotherapy. All patients underwent a pretreatment FNA biopsy of the tumor for gene expression profiling and treatment response prediction. The pCR rates were 19% and 9% in the T/FAC and FAC arms, respectively (p<0.05). In the T/FAC arm, the positive predictive value (PPV) of the genomic predictor was 38% (95%CI:21–56%), the negative predictive value (NPV) 88% (CI:77–95%) and the AUC 0.711. In the FAC arm, the PPV was 9% (CI:1–29%) and the AUC 0.584. This suggests that the genomic predictor may have regimen-specificity. Its performance was similar to a clinical variable-based predictor nomogram. Gene expression profiling for prospective response prediction was feasible in this international trial. The 30-gene predictor can identify patients with greater than average sensitivity to T/FAC chemotherapy. However, it captured molecular equivalents of clinical phenotype. Next generation predictive markers will need to be developed separately for different molecular subsets of breast cancers.