An Apoptosis Methylation Prognostic Signature for Early Lung Cancer in the IFCT-0002 Trial
An Apoptosis Methylation Prognostic Signature for Early Lung Cancer in the IFCT-0002 Trial
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DOI：
10.1158/1078-0432.ccr-11-2797
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发表时间：
2012-05-15
影响因子：
11.5
通讯作者：
Zalcman, Gerard
中科院分区：
文献类型：
--
作者：
de Fraipont, Florence;Levallet, Guenaelle;Zalcman, Gerard
目的：评估早期非小细胞肺癌(NSCLC)接受新辅助化疗的预后和预测分子生物标志物。实验设计：IFCT-0002试验比较了528例I至II期非小细胞肺癌患者的两种新辅助化疗方案。从208例接受吉西他滨-顺铂或紫杉醇-卡铂方案的患者的冰冻手术样本中提取DNA，可以鉴定出3p等位基因失衡，RAS相关结构域家族1A(RASSF1A)和死亡相关蛋白激酶1(DAPK1)启动子甲基化，以及表皮生长因子受体K-ras和TP53突变。多变量分析确定了分子改变的预后和预测效果。结果：RASSF1A甲基化与较短的无病生存期(DFS；调整后HR=1.88，95%CI：1.25~2.82，P=0.0048)和较短的中位总生存期(OS；调整后HR=2.01，95%CI：1.26~3.20，P=0.020)显著相关。采用计算机Bootstrap重抽样策略建立了包括RASSF1a、DAPK1和肿瘤分期的预后模型，将患者分为三组，中位OS从高危患者34个月(死亡危险比=3.85，95%CI：1.79~6.4)到中危患者(HR=1.85，95%CI：0.97~3.52)>84个月(参照组，P=0.00044)。此外，在接受紫杉醇-卡铂治疗的患者中，RASSF1A甲基化预测的DFS比吉西他滨-顺铂更长(校正后HR=0.47，95%CI：0.23~0.97，P交互作用=0.042)。结论：新辅助化疗后，RASSF1A甲基化对早期非小细胞肺癌的预后有负面影响。随着DAPK1甲基化和肿瘤分期，RASSF1A甲基化允许定义预后截然不同的三个亚组。相反，对于肿瘤显示RASSF1A甲基化的患者，基于紫杉醇的新辅助化疗后DFS显著延长，这表明它对I期和II期非小细胞肺癌有预测意义。临床癌症研究；18(10)；2976-86。(C)2012年AACR。
Purpose: To evaluate prognostic and predictive molecular biomarkers in early-stage non-small cell lung carcinoma (NSCLC) receiving neoadjuvant chemotherapy.Experimental Design: The IFCT-0002 trial compared two neoadjuvant regimens in 528 stages I to II NSCLC patients. DNA extraction of snap-frozen surgical samples taken from 208 patients receiving gemcitabine-cisplatin or paclitaxel-carboplatin regimens allowed for the identification of 3p allelic imbalance, Ras association domain family 1A (RASSF1A) and death-associated protein kinase 1 (DAPK1) promoter methylation, and epidermal growth factor receptor, K-ras, and TP53 mutations. Multivariate analysis identified prognostic and predictive effects of molecular alterations. A Bootstrapping approach was used to assess stability of the prognostic models generating optimism corrected indexes.Results: RASSF1A methylation correlated significantly with shorter disease-free survival (DFS; adjusted HR = 1.88, 95% CI: 1.25-2.82, P = 0.0048) and shorter median overall survival (OS; adjusted HR = 2.01, 95% CI: 1.26-3.20, P = 0.020). A computed bootstrap resampling strategy led to a prognostic model, including RASSF1A, DAPK1, and tumor stage, dividing patients into three prognostic groups, with median OS ranging from 34 months for high-risk patients (HR for death = 3.85,95% CI: 1.79-6.40) to more than 84 months for moderate (HR = 1.85,95% CI: 0.97-3.52) and low-risk patients (reference group; P = 0.00044). In addition, RASSF1A methylation predicted longer DFS in patients treated with paclitaxel-carboplatin compared with gemcitabine-cisplatin (adjusted HR = 0.47, 95% CI: 0.23-0.97, P-interaction = 0.042).Conclusions: Following neoadjuvant chemotherapy, RASSF1A methylation negatively impacted prognosis of early-stage NSCLC. Along with DAPK1 methylation and tumor stage, RASSF1A methylation allowed definition of three subgroups with strikingly different prognosis. Conversely, significantly longer DFS following paclitaxel-based neoadjuvant chemotherapy for patients whose tumors showed RASSF1A methylation suggested its predictive interest in stages I and II NSCLC. Clin Cancer Res; 18(10); 2976-86. (C) 2012 AACR.