Identifying and tracking somatic mutations in cell-free DNA (cfDNA) by next-generation sequencing (NGS) has the potential to transform the clinical management of subjects with advanced non-small cell lung cancer (NSCLC). Baseline tumor tissue (n = 47) and longitudinal plasma (n = 445) were collected from 71 NSCLC subjects treated with chemotherapy. cfDNA was enriched using a targeted-capture NGS kit containing 197 genes. Clinical responses to treatment were determined using RECIST v1.1 and correlations between changes in plasma somatic variant allele frequencies and disease progression were assessed. Somatic variants were detected in 89.4% (42/47) of tissue and 91.5% (407/445) of plasma samples. The most commonly mutated genes in tissue were TP53 (42.6%), KRAS (25.5%), and KEAP1 (19.1%). In some subjects, the allele frequencies of mutations detected in plasma increased 3–5 months prior to disease progression. In other cases, the allele frequencies of detected mutations declined or decreased to undetectable levels, indicating clinical response. Subjects with circulating tumor DNA (ctDNA) levels above background had significantly shorter progression-free survival (median: 5.6 vs 8.9 months, respectively; log-rank p = 0.0183). Longitudinal monitoring of mutational changes in plasma has the potential to predict disease progression early. The presence of ctDNA mutations during first-line treatment is a risk factor for earlier disease progression in advanced NSCLC.

中文翻译：

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基于血浆的纵向突变监测可作为晚期非小细胞肺癌腺癌患者疾病进展的潜在预测指标。

通过下一代测序（NGS）识别和跟踪无细胞DNA（cfDNA）中的体细胞突变，具有改变晚期非小细胞肺癌（NSCLC）患者临床管理的潜力。基线肿瘤组织（n = 47）和纵向血浆（n = 445）来自接受化学疗法治疗的71名NSCLC受试者。使用包含197个基因的靶向捕获NGS试剂盒富集了cfDNA。使用RECIST v1.1确定对治疗的临床反应，并评估血浆体细胞变异等位基因频率变化与疾病进展之间的相关性。在89.4％（42/47）的组织和91.5％（407/445）的血浆样本中检测到了体细胞变异。组织中最常见的突变基因是TP53（42.6％），KRAS（25.5％）和KEAP1（19.1％）。在某些科目中 在疾病进展之前，血浆中检测到的突变的等位基因频率增加了3-5个月。在其他情况下，检测到的突变的等位基因频率下降或下降到不可检测的水平，表明临床反应。循环肿瘤DNA（ctDNA）水平高于背景水平的受试者的无进展生存期明显较短（中位数分别为5.6个月和8.9个月；对数秩p = 0.0183）。纵向监测血浆突变的变化有可能尽早预测疾病的进展。一线治疗期间ctDNA突变的存在是晚期非小细胞肺癌早期疾病进展的危险因素。指示临床反应。循环肿瘤DNA（ctDNA）水平高于背景水平的受试者的无进展生存期明显较短（中位数分别为5.6个月和8.9个月；对数秩p = 0.0183）。纵向监测血浆突变的变化有可能尽早预测疾病的进展。一线治疗期间ctDNA突变的存在是晚期非小细胞肺癌早期疾病进展的危险因素。指示临床反应。循环肿瘤DNA（ctDNA）水平高于背景水平的受试者的无进展生存期明显较短（中位数分别为5.6个月和8.9个月；对数秩p = 0.0183）。纵向监测血浆突变的变化有可能尽早预测疾病的进展。一线治疗期间ctDNA突变的存在是晚期非小细胞肺癌早期疾病进展的危险因素。