基于基因表达的分类对神经母细胞瘤的预后影响。

Prognostic impact of gene expression-based classification for neuroblastoma.

机构信息

University of Cologne, Cologne, Germany.

出版信息

J Clin Oncol. 2010 Jul 20;28(21):3506-15. doi: 10.1200/JCO.2009.27.3367. Epub 2010 Jun 21.

DOI:10.1200/JCO.2009.27.3367

PMID:20567016

Abstract

PURPOSE

To evaluate the impact of a predefined gene expression-based classifier for clinical risk estimation and cytotoxic treatment decision making in neuroblastoma patients.

PATIENTS AND METHODS

Gene expression profiles of 440 internationally collected neuroblastoma specimens were investigated by microarray analysis, 125 of which were examined prospectively. Patients were classified as either favorable or unfavorable by a 144-gene prediction analysis for microarrays (PAM) classifier established previously on a separate set of 77 patients. PAM classification results were compared with those of current prognostic markers and risk estimation strategies.

RESULTS

The PAM classifier reliably distinguished patients with contrasting clinical courses (favorable [n = 249] and unfavorable [n = 191]; 5-year event free survival [EFS] 0.84 +/- 0.03 v 0.38 +/- 0.04; 5-year overall survival [OS] 0.98 +/- 0.01 v 0.56 +/- 0.05, respectively; both P < .001). Moreover, patients with divergent outcome were robustly discriminated in both German and international cohorts and in prospectively analyzed samples (P <or= .001 for both EFS and OS for each). In subgroups with clinical low-, intermediate-, and high-risk of death from disease, the PAM predictor significantly separated patients with divergent outcome (low-risk 5-year OS: 1.0 v 0.75 +/- 0.10, P < .001; intermediate-risk: 1.0 v 0.82 +/- 0.08, P = .042; and high-risk: 0.81 +/- 0.08 v 0.43 +/- 0.05, P = .001). In multivariate Cox regression models based on both EFS and OS, PAM was a significant independent prognostic marker (EFS: hazard ratio [HR], 3.375; 95% CI, 2.075 to 5.492; P < .001; OS: HR, 11.119, 95% CI, 2.487 to 49.701; P < .001). The highest potential clinical impact of the classifier was observed in patients currently considered as non-high-risk (n = 289; 5-year EFS: 0.87 +/- 0.02 v 0.44 +/- 0.07; 5-year OS: 1.0 v 0.80 +/- 0.06; both P < .001).

CONCLUSION

Gene expression-based classification using the 144-gene PAM predictor can contribute to improved treatment stratification of neuroblastoma patients.

摘要

目的

评估基于预定义基因表达分类器在神经母细胞瘤患者临床风险评估和细胞毒性治疗决策中的作用。

方法

通过微阵列分析对 440 个国际收集的神经母细胞瘤标本进行基因表达谱研究，其中 125 个标本进行了前瞻性检查。通过先前在 77 例患者的独立组中建立的 144 个基因预测分析微阵列（PAM）分类器，将患者分为有利或不利两类。将 PAM 分类结果与当前的预后标志物和风险评估策略进行比较。

结果

PAM 分类器可靠地区分了具有相反临床病程的患者（有利[ n = 249]和不利[ n = 191]；5 年无事件生存率[EFS]分别为 0.84 +/- 0.03 和 0.38 +/- 0.04；5 年总生存率[OS]分别为 0.98 +/- 0.01 和 0.56 +/- 0.05，均 P <.001）。此外，在德国和国际队列以及前瞻性分析的样本中，能够可靠地区分具有不同结局的患者（对于每个 EFS 和 OS，P <or=.001）。在临床低、中、高危死亡的亚组中，PAM 预测因子显著区分了具有不同结局的患者（低危 5 年 OS：1.0 比 0.75 +/- 0.10，P <.001；中危：1.0 比 0.82 +/- 0.08，P =.042；高危：0.81 +/- 0.08 比 0.43 +/- 0.05，P =.001）。基于 EFS 和 OS 的多变量 Cox 回归模型中，PAM 是一个显著的独立预后标志物（EFS：危险比[HR]，3.375；95%CI，2.075 至 5.492；P <.001；OS：HR，11.119，95%CI，2.487 至 49.701；P <.001）。该分类器的最大潜在临床影响见于目前被认为非高危的患者（ n = 289；5 年 EFS：0.87 +/- 0.02 比 0.44 +/- 0.07；5 年 OS：1.0 比 0.80 +/- 0.06；均 P <.001）。