Department of Medical Oncology, Shanghai Pulmonary Hospital, Thoracic Cancer Institute, Tongji University School of Medicine, Shanghai, P.R. China.
Department of Lung Cancer and Immunology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, P.R. China.
Theranostics. 2017 Oct 17;7(19):4753-4762. doi: 10.7150/thno.21687. eCollection 2017.
To investigate whether the mutational landscape of circulating cell-free DNA (cfDNA) could predict and dynamically monitor the response to first-line platinum-based chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC). Eligible patients were included and blood samples were collected from a phase III trial. Both cfDNA fragments and fragmented genomic DNA were extracted for enrichment in a 1.15M size panel covering exon regions of 1,086 genes. Molecular mutational burden (MMB) was calculated to investigate the relationship between molecular features of cfDNA and response to chemotherapy. In total, 52 eligible cases were enrolled and their blood samples were prospectively collected at baseline, every cycle of chemotherapy and time of disease progression. At baseline, alterations of 17 genes were found. Patients with partial response (PR) had significantly lower baseline MMB of these genes than those patients with either stable disease (SD) ( = 0.0006) or progression disease (PD) ( = 0.0074). Further analysis revealed that the mutational landscape of cfDNA from pretreatment blood samples were distinctly different among patients with PR vs. SD/PD. For patients with baseline mutation, those with PR experienced a significant reduction in MMB whereas patients with SD or PD experienced an increase after two, three or four cycles of chemotherapy. Furthermore, patients with low MMB had superior response rate and significantly longer progression-free survival than those with high MMB. This study indicated that the mutational landscape of cfDNA has potential clinical value to predict the therapeutic response to first-line platinum-based doublet chemotherapy in NSCLC patients. At the single gene level, dynamic change of molecular mutational burden of is valuable to monitor efficacy (and, therefore, might aid in early recognition of resistance and relapse) in patients harboring this mutation at baseline.
为了研究循环游离 DNA（cfDNA）的突变谱是否可以预测并动态监测晚期非小细胞肺癌（NSCLC）患者对一线铂类化疗的反应。合格的患者被纳入并从 III 期试验中采集血液样本。提取 cfDNA 片段和断裂的基因组 DNA，用于在 1.15M 大小的面板中进行富集，该面板覆盖 1086 个基因的外显子区域。计算分子突变负担（MMB）以研究 cfDNA 的分子特征与对化疗的反应之间的关系。总共纳入了 52 例合格病例，并前瞻性地在基线、每个化疗周期和疾病进展时采集了他们的血液样本。在基线时，发现了 17 个基因的改变。部分缓解（PR）患者的这些基因的基线 MMB 明显低于稳定疾病（SD）患者（ = 0.0006）或进展疾病（PD）患者（ = 0.0074）。进一步分析表明，PR 患者与 SD/PD 患者相比，cfDNA 的突变谱明显不同。对于基线 突变的患者，PR 患者的 MMB 显著降低，而 SD 或 PD 患者在两个、三个或四个化疗周期后则增加。此外，基线 MMB 较低的患者的反应率和无进展生存期明显优于 MMB 较高的患者。这项研究表明，cfDNA 的突变谱具有潜在的临床价值，可以预测 NSCLC 患者一线铂类双联化疗的治疗反应。在单个基因水平上，基线携带该突变的患者中分子突变负担的动态变化对于监测疗效（因此可能有助于早期识别耐药性和复发）具有价值。
