Zhichao Liu1,2, Zhanhong Xie1, Shen Zhao3, Dawei Ye4, Xiuyu Cai5, Bo Cheng1, Caichen Li1, Shan Xiong1, Jianfu Li1, Hengrui Liang1, Zisheng Chen6, Peng Liang1, Jun Liu1, Jianxing He1, Wenhua Liang1. 1. 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. 2. Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, China. 3. Department of Medical Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China. 4. Cancer Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. 5. Department of General Internal Medicine, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China. 6. Department of Respiratory Medicine, the Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan 511518, China.
Abstract
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. 2019 Translational Lung Cancer Research. All rights reserved.
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. 2019 Translational Lung Cancer Research. All rights reserved.
Entities:
Keywords:
Non-small cell lung cancer (NSCLC); circulating tumor DNA (ctDNA); heterogeneity
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