化疗仍是小细胞肺癌（SCLC）的主要治疗方法。液体活检为监测SCLC患者疾病进展提供了方便、非侵入性的检测方法。我们对69名广泛期（ES）SCLC患者的159个血浆样本进行了新一代测序。循环肿瘤DNA（ctDNA）水平以每毫升单倍体基因组当量（hGE/mL）计量。采用MuTect2检测单个核苷酸变异和短插入/缺失。采用“clusterProfiler”R包中的“enrichKEGG”功能扩增在疾病进展期间出现的突变基因。在我们的队列研究中，69个患者中有66个（95.7％）诊断时的血浆样本检测到有突变情况；TP53（89％）和RB1（56％）是最常见的突变，以及一些常见的SCLC相关基因的拷贝数变异，如RB1。与仅依靠组织检测相比，组合ctDNA和组织检测改善了可操作突变的总体检测率，从19.4％提高到26.9％。此外，ctDNA水平在治疗过程中动态变化，并与进展无瘤生存显著相关。值得注意的是，可操作突变在诊断和疾病进展期间均可检测到。我们的研究通过连续的ctDNA检测揭示了动态的体细胞突变谱，并证实ctDNA水平可以反映肿瘤负担并预测广泛期SCLC患者的进展无瘤生存。此外，我们证明了血浆ctDNA检测可以提供关于SCLC潜在靶向治疗的体细胞突变实时信息。版权所有©2023 Elsevier B.V.。保留所有权利。

Chemotherapy remains the mainstay of treatment for small-cell lung cancer (SCLC). Liquid biopsies provide a convenient and non-invasive detection method for monitoring disease progression in patients with SCLC.We performed next-generation sequencing of 159 plasma samples from 69 patients with extensive-stage (ES)-SCLC. Circulating tumor (ct)DNA levels were quantified in haploid genome equivalents per mL (hGE/mL). MuTect2 was used to detect single nucleotide variants and short insertions/deletions. The "enrichKEGG" function in the "clusterProfiler" R package was used to enrich the mutated genes that only appeared during disease progression.In our cohort, 66 of 69 (95.7%) plasma samples at the time of diagnosis had detectable somatic mutations; TP53 (89%) and RB1(56%) were the most frequent mutations, as well as copy number variations in some common SCLC-related genes such as RB1. Combination ctDNA and tissue testing improved the overall detection rate of actionable mutations from 19.4% to 26.9% compared with that of tissue detection alone. In addition, ctDNA levels changed dynamically during the course of treatment and were significantly associated with decreased progression-free survival. Notably, actionable mutations were detected at the time of diagnosis and during disease progression.Our study revealed a dynamic somatic mutation profile through continuous ctDNA detection and confirmed that ctDNA levels can reflect tumor burden and predict PFS in patients with extensive stage-SCLC. Furthermore, we demonstrated that plasma ctDNA assays can provide real-time information on somatic mutations for potential targeted therapies for SCLC.Copyright © 2023 Elsevier B.V. All rights reserved.