由循环肿瘤DNA（ctDNA）分析定义的等位基因频率异质性的存在预示着非小细胞肺癌（NSCLC）患者总体生存率不佳。
Presence of allele frequency heterogeneity defined by ctDNA profiling predicts unfavorable overall survival of NSCLC.
作者信息
Liu Zhichao, Xie Zhanhong, Zhao Shen, Ye Dawei, Cai Xiuyu, Cheng Bo, Li Caichen, Xiong Shan, Li Jianfu, Liang Hengrui, Chen Zisheng, Liang Peng, Liu Jun, He Jianxing, Liang Wenhua
机构信息
Department of Thoracic Surgery and Oncology, the First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, Guangzhou 510120, China.
Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, China.
出版信息
Transl Lung Cancer Res. 2019 Dec;8(6):1045-1050. doi: 10.21037/tlcr.2019.12.10.
BACKGROUND
The generation of subclonal (low-frequency) mutations is driven by tumor mutations and the relationship between the heterogeneity of tumor mutation abundance and non-small cell lung cancer (NSCLC) remains unknown. We investigate the role of allele frequency heterogeneity (AFH) defined by circulating tumor DNA (ctDNA) profiling in predicting prognosis in advanced NSCLC patients.
METHODS
Publicly available data set of POPLAR (N=211) and OAK (N=642) trials were used for analyzing. A low ratio of allele frequency (AF) of a mutation to the maximum-somatic-allele-frequency (MSAF) was used to define the presence of AFH. The prognostic value of AF/MSAF ratio that was below a defined cutoff point in overall survival (OS) was evaluated using Cox-proportional hazards regression; and the structural break point was determined by LOESS regression and Chow test. The derived AFH was also explored in an independent cohort (N=259) of advanced NSCLC receiving first-line EGFR-TKIs from the First Affiliated Hospital of Guangzhou Medical University.
RESULTS
In the POPLAR and OAK cohort, low AF/MSAF ratio was found to be significantly associated with unfavorable OS in univariate and multivariate analysis. The structural break point analysis demonstrated that AF/MSAF <10% could yield the optimal value to stratify patients with poor OS, which was applied for defining the presence of AFH. The presence of AFH significantly correlated with unfavorable OS in advanced NSCLC regardless of treatment arms (overall: HR 1.52, immunotherapy: HR 1.81, chemotherapy: HR 1.32, all P<0.05). In the exploratory EGFR-TKIs cohort, the presence of AFH was also significantly associated with shorter OS (HR 1.72, P=0.039).
CONCLUSIONS
Our results demonstrate that the presence of AFH predict unfavorable prognosis in advanced NSCLC despite which drug the patients used. The presence of AFH defined by ctDNA might provide an easily-accessible biomarker for risk stratification in the current clinical practice.
背景
亚克隆（低频）突变的产生由肿瘤突变驱动，而肿瘤突变丰度异质性与非小细胞肺癌（NSCLC）之间的关系尚不清楚。我们研究了通过循环肿瘤DNA（ctDNA）分析定义的等位基因频率异质性（AFH）在预测晚期NSCLC患者预后中的作用。
方法
使用公开可用的POPLAR（N = 211）和OAK（N = 642）试验数据集进行分析。用突变的等位基因频率（AF）与最大体细胞等位基因频率（MSAF）的低比率来定义AFH的存在。使用Cox比例风险回归评估AF/MSAF比率低于定义的截止点对总生存期（OS）的预后价值；并通过局部加权回归（LOESS）和邹氏检验确定结构断点。还在广州医科大学第一附属医院接受一线EGFR-TKIs治疗的晚期NSCLC独立队列（N = 259）中探索了推导的AFH。
结果
在POPLAR和OAK队列中，单因素和多因素分析发现低AF/MSAF比率与不良OS显著相关。结构断点分析表明，AF/MSAF<10%可产生用于对OS不良患者进行分层的最佳值，该值用于定义AFH的存在。无论治疗组如何，AFH的存在与晚期NSCLC的不良OS显著相关（总体：HR 1.52，免疫治疗：HR 1.81，化疗：HR 1.32，均P<0.05）。在探索性EGFR-TKIs队列中，AFH的存在也与较短的OS显著相关（HR 1.72，P = 0.039）。
结论
我们的结果表明，无论患者使用何种药物，AFH的存在均预示晚期NSCLC预后不良。由ctDNA定义的AFH的存在可能为当前临床实践中的风险分层提供一种易于获得的生物标志物。
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