Zhang Jiubing, Liu Guanzheng, Wang Dayang, Bu Chaojie, Lv Guangming, Zhang Ziyue, Guo Guangzhong, Gao Yushuai, Yan Zhaoyue, Ma Chunxiao, Liu Gang, Zhao Ruijiao, Wang Meiyun, Bu Xingyao
Department of Neurosurgery, Zhengzhou University People's Hospital, Henan Provincial People's Hospital, Zhengzhou, China.
Glioma Engineering Research Center for Precision Diagnosis and Treatment of Henan Province, Henan Provincial People's Hospital, Zhengzhou, China.
Neurosurgery. 2025 Mar 5;97(3):671-80. doi: 10.1227/neu.0000000000003384.
BACKGROUND AND OBJECTIVES: Glioblastoma (GBM) recurrence after surgery remains a significant clinical challenge because of limited early detection methods and effective molecular markers. This study investigates the potential of dynamic tumor in situ fluid circulating tumor DNA (TISF-ctDNA) as a tool for monitoring molecular residual disease and evaluating treatment efficacy in postsurgical patients with GBM. METHODS: In this prospective cohort study, 75 resectable glioma patients were enrolled between October 2019 to June 2023. Primary tumor tissues and postsurgical TISF samples were collected, along with cranial imaging. TISF-ctDNA was identified through targeted next-generation sequencing, with positivity defined by the presence of one or more variants in the TISF matching those of the primary tumors or an increase of ≥10 single-nucleotide variants across consecutive assessments. RESULTS: TISF-ctDNA positivity was identified in 62.2% of patients in the early postsurgical period, indicating a high prevalence of molecular residual disease. Patients with positive TISF-ctDNA showed a significantly higher risk of recurrence (hazard ratio 2.512, 95% CI 1.264-4.993, P = .0054). Conversion to TISF-ctDNA negativity post-treatment was associated with improved overall survival, highlighting its role in evaluating treatment response. Multivariate analysis revealed that TISF-ctDNA positivity was an independent predictor of progression-free survival during adjuvant therapy, with high predictive accuracy (sensitivity 86.2%, specificity 100%). Importantly, TISF-ctDNA positivity preceded imaging signs of recurrence by a median of 71 days. In this study, no significant impact of specific tumor markers in each subcohort (EGFR, TP53, PTEN, NF1) on progression-free survival or overall survival was observed. CONCLUSION: TISF-ctDNA is a promising biomarker for monitoring GBM recurrence and evaluating clinical benefit. It provides insight into tumor genomic evolution and identifies patients who may benefit from adjuvant chemotherapy. TISF-ctDNA positivity is a robust prognostic indicator for patient outcomes and a marker for molecular recurrence after frontline therapy.
背景与目的：由于早期检测方法和有效分子标志物有限，胶质母细胞瘤（GBM）术后复发仍是一项重大临床挑战。本研究探讨动态肿瘤原位液体循环肿瘤DNA（TISF-ctDNA）作为监测GBM术后患者分子残留疾病及评估治疗疗效工具的潜力。 方法：在这项前瞻性队列研究中，2019年10月至2023年6月期间纳入了75例可切除的胶质瘤患者。收集了原发性肿瘤组织和术后TISF样本以及头颅影像学资料。通过靶向二代测序鉴定TISF-ctDNA，阳性定义为TISF中存在一个或多个与原发性肿瘤匹配的变异，或连续评估中单个核苷酸变异增加≥10个。 结果：术后早期62.2%的患者被鉴定为TISF-ctDNA阳性，表明分子残留疾病的高患病率。TISF-ctDNA阳性的患者复发风险显著更高（风险比2.512，95%置信区间1.264 - 4.993，P = 0.0054）。治疗后转化为TISF-ctDNA阴性与总体生存期改善相关，突出了其在评估治疗反应中的作用。多变量分析显示，TISF-ctDNA阳性是辅助治疗期间无进展生存期的独立预测指标，预测准确性高（敏感性86.2%，特异性100%）。重要的是，TISF-ctDNA阳性比影像学复发迹象提前出现的中位时间为71天。在本研究中，未观察到各亚组（EGFR、TP53、PTEN、NF1）中特定肿瘤标志物对无进展生存期或总体生存期有显著影响。 结论：TISF-ctDNA是监测GBM复发和评估临床获益的有前景的生物标志物。它为肿瘤基因组进化提供了见解，并识别出可能从辅助化疗中获益的患者。TISF-ctDNA阳性是患者预后的有力预后指标，也是一线治疗后分子复发的标志物。
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