Cancer and Cell Biology, Translational Genomics Research Institute, Phoenix, USA.
J Thorac Oncol. 2010 Aug;5(8):1273-8. doi: 10.1097/JTO.0b013e3181dea6be.
Although the majority of patients with small cell lung cancer (SCLC) respond to initial chemotherapy, those with disease progression at first response assessment (chemoresistance) have inferior outcomes. There is a need for predictive biomarkers to aid investigators in designing future clinical trials that better stratify patients beyond standard clinical and laboratory parameters and to identify new treatments for this patient subpopulation. We hypothesized that tumor microRNAs (miRNAs) could serve as predictive biomarkers for chemoresistance and prognostic biomarkers for survival of patients with SCLC treated with systemic chemotherapy.
SCLC samples annotated with clinical characteristics and baseline comorbidities were available. miRNA microarray profiling was performed on diagnostic SCLC tumor samples, and analysis was performed using XenoBase, a data integration and discovery tool. Confirmation of the top 16 miRNA candidates was performed using quantitative real-time polymerase chain reaction followed by analyses to determine clinical and miRNA biomarkers associated with chemoresistance and survival.
miRNAs significantly associated with chemoresistance were miR-92a-2* (p = 0.010), miR-147 (p = 0.018), and miR-574-5p (p = 0.039). By stepwise multivariate analysis, only gender and miR-92a-2* contributed significantly to survival (p = 0.023) and (p = 0.015), respectively. Baseline comorbidities were not associated with chemoresistance or survival.
Higher tumor miR-92a-2* levels are associated with chemoresistance and with decreased survival in patients with SCLC. Tumor miR-92a-2* may have application in screening patients with SCLC at risk for de novo chemoresistance in an effort to design more tailored clinical trials for this subpopulation. Further validation in independent sample sets is warranted.
尽管大多数小细胞肺癌（SCLC）患者对初始化疗有反应，但在首次反应评估时（化疗耐药）疾病进展的患者预后较差。需要预测生物标志物来帮助研究人员设计未来的临床试验，以便在标准临床和实验室参数之外更好地对患者进行分层，并为这一患者亚群确定新的治疗方法。我们假设肿瘤 microRNAs（miRNAs）可以作为化疗耐药的预测生物标志物和 SCLC 患者接受系统化疗的生存预后生物标志物。
有标注临床特征和基线合并症的 SCLC 样本可用。对诊断性 SCLC 肿瘤样本进行 miRNA 微阵列分析，并使用 XenoBase（一种数据集成和发现工具）进行分析。使用定量实时聚合酶链反应（PCR）对前 16 个 miRNA 候选物进行验证，然后进行分析以确定与化疗耐药和生存相关的临床和 miRNA 生物标志物。
与化疗耐药显著相关的 miRNAs 是 miR-92a-2*（p=0.010）、miR-147（p=0.018）和 miR-574-5p（p=0.039）。通过逐步多变量分析，只有性别和 miR-92a-2* 对生存有显著影响（p=0.023）和（p=0.015）。基线合并症与化疗耐药或生存无关。
肿瘤 miR-92a-2* 水平较高与 SCLC 患者的化疗耐药和生存降低相关。肿瘤 miR-92a-2* 可能在筛选 SCLC 患者对新的化疗耐药的风险方面具有应用价值，以努力为这一亚群设计更具针对性的临床试验。需要在独立样本集中进一步验证。
