Crossing barriers with CSF-based sequencing for leptomeningeal disease in EGFR mutant NSCLC

This case report highlights the critical role of cerebrospinal fluid (CSF)-based sequencing in precision oncology for a 64-year-old female with metastatic Epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC) with leptomeningeal metastases spread. Isolating cell-free DNA (cfDNA) and capturing true live single circulating tumor cells (sCTCs) from CSF fluid is extremely challenging due to rapid degradation of DNA and extremely low abundance of sCTCs. In progressive disease, we successfully extracted cfDNA and sCTCs in CSF that revealed actionable mutations such as EGFR Exon 19 deletion and ERBB2 amplification. The findings guided personalization of precision therapy, including intrathecal trastuzumab combined with systemic treatments, leading to significant clinical improvement and effective control of leptomeningeal disease.

CSF profiling opens a new diagnostic avenue in identifying resistance mechanism, when blood analysis showed no actionable information. This case demonstrates the transformative potential of CSF-based liquid biopsies to uncover critical mutations, monitor disease progression, and optimize outcomes for central nervous system metastases. Sequential molecular profiling and CSF analysis were instrumental in effective therapeutic strategies for this complex clinical case.