Development and Validation of an Individualized Immune Prognostic Signature in Early-Stage Nonsquamous Non-Small Cell Lung Cancer
Development and Validation of an Individualized Immune Prognostic Signature in Early-Stage Nonsquamous Non-Small Cell Lung Cancer
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DOI：
10.1001/jamaoncol.2017.1609
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发表时间：
2017-11-01
期刊：
影响因子：
28.4
通讯作者：
Li, Ruijiang
中科院分区：
文献类型：
--
作者：
Li, Bailiang;Cui, Yi;Li, Ruijiang
随着近年来年度筛查计划的实施，早期非小细胞肺癌（NSCLC）的患病率预计会增加。需要可靠的预后生物标志物来识别高复发风险的患者以指导辅助治疗。目的开发一种稳健的、个体化的免疫特征，可以估计早期非鳞状NSCLC患者的预后。设计、设置和参与者这项回顾性研究分析了来自19个公开NSCLC队列的冷冻肿瘤组织样本的基因表达谱，包括癌症基因组图谱（TCGA）肺腺癌队列的18个微阵列数据集和1个RNA-Seq数据集。仅纳入具有临床注释的非鳞状NSCLC患者。样本来自2414例非鳞状NSCLC患者，分为变形训练队列（729例患者）、荟萃检验队列（716例患者）和3个独立验证队列（439、323和207例患者）。所有患者均接受手术，手术切缘阴性，未接受辅助或新辅助治疗，并有公开的基因表达数据和生存信息。数据收集于2016年7月22日至9月8日。主要结果和指标总生存率。（1205名男性[50%]，1111名女性[46%]，98名性别不详[4%];中位年龄[范围]，64 [15-90]岁），使用元训练数据集构建由40个独特基因组成的25个基因对的预后免疫标记。在荟萃检验和验证队列中，根据I期、IA期、IB期或II期疾病亚群之间和亚群内的总生存率，免疫特征将患者显著分为高风险组和低风险组，并在多变量分析中仍作为独立的预后因素（风险比范围为1.72 [95%CI，1.26-2.33; P < .001]至2.36 [95%CI，1.47-3.79; P < .001]）。几个生物过程，包括趋化性，在免疫特征的基因中富集。在TCGA数据集中，高风险免疫组的中性粒细胞浸润（5.6% vs 1.8%）和坏死（4.6% vs 1.5%）的百分比显著高于低风险组（P <0.003）。在可比的验证队列中，免疫签名比2个商业化的多基因签名（平均C-指数，0.53和0.61）获得了更高的准确性（平均一致性指数[C-指数]，0.64），用于估计存活率。当与年龄和分期等临床特征整合时，相对于单独的分子特征，复合临床和免疫特征在所有验证数据集中显示出改善的预后准确性（平均C指数，0.70 vs 0.63）和另一种商业化的临床分子特征（平均C指数，0.68 vs 0.65）.结论和相关性所提出的临床免疫特征是一种有前途的生物标志物，用于估计非鳞状NSCLC的总生存期，包括早期疾病。需要进行前瞻性研究来测试该生物标志物在非鳞状非小细胞肺癌个体化管理中的临床实用性。
IMPORTANCE The prevalence of early-stage non-small cell lung cancer (NSCLC) is expected to increase with recent implementation of annual screening programs. Reliable prognostic biomarkers are needed to identify patients at a high risk for recurrence to guide adjuvant therapy.OBJECTIVE To develop a robust, individualized immune signature that can estimate prognosis in patients with early-stage nonsquamous NSCLC.DESIGN, SETTING, AND PARTICIPANTS This retrospective study analyzed the gene expression profiles of frozen tumor tissue samples from 19 public NSCLC cohorts, including 18 microarray data sets and 1 RNA-Seq data set for The Cancer Genome Atlas (TCGA) lung adenocarcinoma cohort. Only patients with nonsquamous NSCLC with clinical annotation were included. Samples were from 2414 patients with nonsquamous NSCLC, divided into ameta-training cohort (729 patients), meta-testing cohort (716 patients), and 3 independent validation cohorts (439, 323, and 207 patients). All patients underwent surgery with a negative surgical margin, received no adjuvant or neoadjuvant therapy, and had publicly available gene expression data and survival information. Data were collected from July 22 through September 8, 2016.MAIN OUTCOMES AND MEASURES Overall survival.RESULTS Of 2414 patients (1205 men [50%], 1111 women [46%], and 98 of unknown sex [4%]; median age [range], 64 [15-90] years), a prognostic immune signature of 25 gene pairs consisting of 40 unique genes was constructed using the meta-training data set. In the meta-testing and validation cohorts, the immune signature significantly stratified patients into high-vs low-risk groups in terms of overall survival across and within subpopulations with stage I, IA, IB, or II disease and remained as an independent prognostic factor in multivariate analyses (hazard ratio range, 1.72 [95% CI, 1.26-2.33; P < .001] to 2.36 [95% CI, 1.47-3.79; P < .001]) after adjusting for clinical and pathologic factors. Several biological processes, including chemotaxis, were enriched among genes in the immune signature. The percentage of neutrophil infiltration (5.6% vs 1.8%) and necrosis (4.6% vs 1.5%) was significantly higher in the high-risk immune group compared with the low-risk groups in TCGA data set (P < .003). The immune signature achieved a higher accuracy (mean concordance index [C-index], 0.64) than 2 commercialized multigene signatures (mean C-index, 0.53 and 0.61) for estimation of survival in comparable validation cohorts. When integrated with clinical characteristics such as age and stage, the composite clinical and immune signature showed improved prognostic accuracy in all validation data sets relative to molecular signatures alone (mean C-index, 0.70 vs 0.63) and another commercialized clinical-molecular signature (mean C-index, 0.68 vs 0.65).CONCLUSIONS AND RELEVANCE The proposed clinical-immune signature is a promising biomarker for estimating overall survival in nonsquamous NSCLC, including early-stage disease. Prospective studies are needed to test the clinical utility of the biomarker in individualized management of nonsquamous NSCLC.