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<p>Genomic profiling of central nervous system (CNS) metastases has the potential to guide treatments. In the present study, we included 584 patients with non-small-cell lung cancer and CNS metastases and performed a comprehensive analysis of cerebrospinal fluid (CSF) circulating tumor DNA (ctDNA) with clinicopathological annotation. CSF ctDNA-positive detection was independently associated with shorter survival than negative detection (hazard ratio (HR) = 1.9, 95% confidence interval (CI) = 1.56–2.39; <i>P</i> &lt; 0.0001). Matched tumor–CSF analysis characterized the CSF private molecular features causing poor survival (HR = 1.64, 95% CI = 1.15–2.32, <i>P</i> = 0.006). A multimetric CSF ctDNA prognostic model integrating CSF ctDNA features and clinical factors was developed for risk-stratifying CNS metastases and validated in an independent cohort. Among patients with treatment histories available, those positive for a driver alteration by CSF ctDNA showed a survival benefit from CSF-matched therapy (HR = 0.78, 95% CI = 0.65–0.92, <i>P</i> = 0.003). Longitudinal monitoring by CSF identified CNS-specific resistant mechanisms and a second matched targeted therapy indicating improved survival (HR = 0.56, 95% CI = 0.35–0.91, <i>P</i> = 0.018). These findings support the clinical value of CSF ctDNA for risk-stratifying CNS metastases and guiding therapy.</p>

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Cerebrospinal fluid circulating tumor DNA profiling for risk stratification and matched treatment of central nervous system metastases

  • 期刊论文

  • 发表日期：

    2025年2月27日

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  • Mei-Mei Zheng,
  • Qing Zhou,
  • Hua-Jun Chen,
  • Ben-Yuan Jiang,
  • Li-Bo Tang,
  • Guang-Ling Jie,
  • Hai-Yan Tu,
  • Kai Yin,
  • Hao Sun,
  • Si-Yang Liu,
  • Jia-Tao Zhang,
  • Fa-Man Xiao,
  • Jin-Ji Yang,
  • Xu-Chao Zhang,
  • Wen-Zhao Zhong,
  • Yi Pan,
  • Bin-Chao Wang,
  • Hong-Hong Yan,
  • Wei-Bang Guo,
  • Zhi-Hong Chen,
  • Zhen Wang,
  • Chong-Rui Xu,
  • Su-Yun Li,
  • Si-Yang Maggie Liu,
  • Lu Zeng,
  • Shang-Li Cai,
  • Guo-Qiang Wang,
  • Dong-Qin Zhu,
  • Yang-Si Li,
  • Yi-Long Wu

摘要

Genomic profiling of central nervous system (CNS) metastases has the potential to guide treatments. In the present study, we included 584 patients with non-small-cell lung cancer and CNS metastases and performed a comprehensive analysis of cerebrospinal fluid (CSF) circulating tumor DNA (ctDNA) with clinicopathological annotation. CSF ctDNA-positive detection was independently associated with shorter survival than negative detection (hazard ratio (HR) = 1.9, 95% confidence interval (CI) = 1.56–2.39; P < 0.0001). Matched tumor–CSF analysis characterized the CSF private molecular features causing poor survival (HR = 1.64, 95% CI = 1.15–2.32, P = 0.006). A multimetric CSF ctDNA prognostic model integrating CSF ctDNA features and clinical factors was developed for risk-stratifying CNS metastases and validated in an independent cohort. Among patients with treatment histories available, those positive for a driver alteration by CSF ctDNA showed a survival benefit from CSF-matched therapy (HR = 0.78, 95% CI = 0.65–0.92, P = 0.003). Longitudinal monitoring by CSF identified CNS-specific resistant mechanisms and a second matched targeted therapy indicating improved survival (HR = 0.56, 95% CI = 0.35–0.91, P = 0.018). These findings support the clinical value of CSF ctDNA for risk-stratifying CNS metastases and guiding therapy.