PO.CL01.05 · 临床研究
通过循环肿瘤DNA监测非小细胞肺癌免疫治疗期间的分子应答
Monitoring of molecular response during immunotherapy by circulating tumor DNA in non-small cell lung cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：非小细胞肺癌(NSCLC)患者可能从靶向PD-1/PD-L1的免疫检查点阻断(ICB)中获益。然而，仅有20-40%的患者对ICB有应答。血浆中循环肿瘤DNA(ctDNA)分析提供了一种用于治疗监测的非侵入性生物标志物。既往研究已表明，ctDNA检测能够比标准影像学评估更早预测临床应答。
目的：本研究旨在评估在早期治疗周期中ctDNA内体细胞肿瘤特异性DNA变异的检测和动态变化，以识别分子应答模式。
方法：前瞻性纳入33例接受ICB治疗的III-IV期NSCLC患者。在基线及治疗期间最多五个时间点纵向分析ctDNA水平。基于初始肿瘤测序，根据致病性分类和变异等位基因频率选择四至十五个患者特异性体细胞变异。使用超灵敏测序检测(Simsen Diagnostics)在每个时间点监测这些变异。开发了一种基于ctDNA的应答评估模型，并与ICB起始后每三个月进行的CT扫描按RECIST标准定义的临床结局进行比较。结果：总体而言，应用分子应答模型时，78.8%(26/33)的患者ctDNA结果与CT影像一致。13例基线ctDNA不可检测的患者与基线ctDNA阳性患者相比总生存显著更长，且独立于3个月时的影像学应答。6例患者出现早期进展，ctDNA在CT扫描临床评估前最多六周即检测到。纵向ctDNA模式因转移部位和采样时间点而异。使用互补方法进一步探索了无应答者的基因组图谱。
结论：基于选择信息性肿瘤特异性DNA变异的ctDNA监测，为评估NSCLC治疗应答提供了一种灵敏工具。ctDNA动态与临床结局良好相关，并能比影像学更早检测进展或应答。纵向ctDNA分析强调了频繁采样的重要性，并凸显其在常规临床实践中改善患者管理的潜力。
查看英文原文 English abstract
Background: Patients with non-small cell lung cancer (NSCLC) may benefit from immune checkpoint blockade (ICB) targeting PD-1/PD-L1. However, only 20-40% of patients respond to ICB. Circulating tumor DNA (ctDNA) analysis in plasma offers a non-invasive biomarker for treatment monitoring. Previous studies have shown that ctDNA detection can predict clinical response earlier than standard radiological evaluation.
Objective: This study aimed to evaluate the detection and dynamics of somatic tumor-specific DNA variants in ctDNA during early treatment cycles, with the goal of identifying molecular response patterns.
Methods: Thirty-three stage III-IV NSCLC patients treated with ICB were prospectively included. ctDNA levels were analyzed longitudinally at baseline and up to five timepoints during treatment. Based on initial tumor sequencing, four to fifteen patient-specific somatic variants were selected according to pathogenicity classification and variant allele frequency. These variants were monitored at each timepoint using ultrasensitive sequencing assays (Simsen Diagnostics). A model for ctDNA-based response assessment was developed and compared with clinical outcomes defined by RECIST criteria from CT scans performed every third month after ICB initiation. Results Overall, 78.8% (26/33) of patients showed ctDNA results concordant with CT imaging when applying the molecular response model. Thirteen patients with non-detectable ctDNA at baseline had significantly longer overall survival compared with baseline ctDNA-positive patients, independent of radiological response at 3 months. Six patients experienced early progression, which was detected by ctDNA up to six weeks before clinical evaluation by CT scan. Longitudinal ctDNA patterns varied depending on metastatic site and sampling timepoint. The genomic landscape of non-responders was further explored using complementary methodologies.
Conclusion: ctDNA monitoring, based on the selection of informative tumor-specific DNA variants, provides a sensitive tool for evaluating treatment response in NSCLC. ctDNA dynamics correlated well with clinical outcomes and enabled earlier detection of progression or response compared with radiological imaging. Longitudinal ctDNA analysis underscores the importance of frequent sampling and highlights its potential to improve patient management in routine clinical practice.
利益披露 Disclosure
J. Svensson, None..
M. Yhr, None..
P. Torstensson, None..
L. Akyürek, None..
A. Hallqvist, None..
S. Raghavan, None..
A. Rohlin, None.