Joerger M, Baty F, Früh M, Droege C, Stahel R A, Betticher D C, von Moos R, Ochsenbein A, Pless M, Gautschi O, Rothschild S, Brauchli P, Klingbiel D, Zappa F, Brutsche M
Department of Medical Oncology & Hematology, Cantonal Hospital, St. Gallen, Switzerland.
Department of Pneumology, Cantonal Hospital, St. Gallen, Switzerland.
Lung Cancer. 2014 Aug;85(2):306-13. doi: 10.1016/j.lungcan.2014.04.014. Epub 2014 May 29.
Molecular subclassification of non small-cell lung cancer (NSCLC) is essential to improve clinical outcome. This study assessed the prognostic and predictive value of circulating micro-RNA (miRNA) in patients with non-squamous NSCLC enrolled in the phase II SAKK (Swiss Group for Clinical Cancer Research) trial 19/05, receiving uniform treatment with first-line bevacizumab and erlotinib followed by platinum-based chemotherapy at progression.
Fifty patients with baseline and 24 h blood samples were included from SAKK 19/05. The primary study endpoint was to identify prognostic (overall survival, OS) miRNA's. Patient samples were analyzed with Agilent human miRNA 8x60K microarrays, each glass slide formatted with eight high-definition 60K arrays. Each array contained 40 probes targeting each of the 1347 miRNA. Data preprocessing included quantile normalization using robust multi-array average (RMA) algorithm. Prognostic and predictive miRNA expression profiles were identified by Spearman's rank correlation test (percentage tumor shrinkage) or log-rank testing (for time-to-event endpoints).
Data preprocessing kept 49 patients and 424 miRNA for further analysis. Ten miRNA's were significantly associated with OS, with hsa-miR-29a being the strongest prognostic marker (HR=6.44, 95%-CI 2.39-17.33). Patients with high has-miR-29a expression had a significantly lower survival at 10 months compared to patients with a low expression (54% versus 83%). Six out of the 10 miRNA's (hsa-miRN-29a, hsa-miR-542-5p, hsa-miR-502-3p, hsa-miR-376a, hsa-miR-500a, hsa-miR-424) were insensitive to perturbations according to jackknife cross-validation on their HR for OS. The respective principal component analysis (PCA) defined a meta-miRNA signature including the same 6 miRNA's, resulting in a HR of 0.66 (95%-CI 0.53-0.82).
Cell-free circulating miRNA-profiling successfully identified a highly prognostic 6-gene signature in patients with advanced non-squamous NSCLC. Circulating miRNA profiling should further be validated in external cohorts for the selection and monitoring of systemic treatment in patients with advanced NSCLC.
非小细胞肺癌（NSCLC）的分子亚分类对于改善临床结局至关重要。本研究评估了参加II期SAKK（瑞士临床癌症研究组）19/05试验的非鳞状NSCLC患者循环微小RNA（miRNA）的预后和预测价值，这些患者接受一线贝伐单抗和厄洛替尼统一治疗，疾病进展时接受铂类化疗。
从SAKK 19/05纳入了50例有基线和24小时血样的患者。主要研究终点是确定预后（总生存期，OS）miRNA。患者样本用安捷伦人类miRNA 8x60K微阵列进行分析，每张玻片格式化为八个高清60K阵列。每个阵列包含针对1347个miRNA中每一个的40个探针。数据预处理包括使用稳健多阵列平均（RMA）算法进行分位数归一化。通过Spearman秩相关检验（肿瘤缩小百分比）或对数秩检验（针对事件发生时间终点）确定预后和预测性miRNA表达谱。
数据预处理保留了49例患者和424个miRNA用于进一步分析。10个miRNA与OS显著相关，其中hsa-miR-29a是最强的预后标志物（HR = 6.44，95%置信区间为2.39-17.33）。hsa-miR-29a高表达患者在10个月时的生存率显著低于低表达患者（54%对83%）。根据对其OS的HR进行留一法交叉验证，10个miRNA中的6个（hsa-miRN-29a、hsa-miR-542-5p、hsa-miR-502-3p, hsa-miR-376a、hsa-miR-500a、hsa-miR-424）对干扰不敏感。各自的主成分分析（PCA）定义了一个包含相同6个miRNA的元miRNA特征，得出HR为0.66（95%置信区间为0.53-0.82）。
游离循环miRNA谱成功地在晚期非鳞状NSCLC患者中鉴定出一个具有高度预后价值的6基因特征。循环miRNA谱应在外部队列中进一步验证，以用于晚期NSCLC患者全身治疗的选择和监测。
