PGY-5 Neurosurgery Resident Barrow Neurological Institute Phoenix, Arizona, United States
Disclosure(s):
Charuta G. Furey, MD: No financial relationships to disclose
Introduction: Effective drug development in glioblastoma (GBM) requires visualization of tumor evolution in response to experimental therapy. Today, genetic and epigenetic mechanisms of tumor resistance are undetected in clinical trials. Here, we establish the feasibility of a liquid biopsy paradigm in tracking tumor evolution in response to a novel therapeutic using an intra-cavitary reservoir for serial cerebrospinal fluid (CSF) collection.
Methods: We conducted a Phase 0/2 clinical trial of niraparib, a new-in-class PARP1/2 inhibitor, in newly-diagnosed GBM patients (NCT05076513). Intra-cavitary reservoirs were placed in select patients following tumor resection. Monthly outpatient CSF samples were collected to longitudinally examine cell-free tumor DNA (cfDNA) using a 293-gene amplicon-based next-generation sequencing (NGS) panel and circulating tumor cells using single cell RNA-sequencing (scRNA-seq). Concordance analysis was performed using paired tumor tissue samples against multiple liquid biopsies.
Results: Tumor-derived cfDNA and circulating tumor cells were successfully isolated from all patients at regular intervals for the duration of the clinical trial. No adverse events were observed during liquid biopsy acquisition. CSF sequencing data was highly concordant with NGS analyses of tumor tissue. DNA and RNA analyses from serial CSF samples reflected the disparate evolution of GBM patient tumors in the face of PARP1/2 inhibition.
Conclusion : This is the first reported experience of serial CSF liquid biopsy to monitor DNA- and RNA-based tumor evolution in the context of an experimental therapy. Our data demonstrate the feasibility of cfDNA NGS and scRNA-seq using longitudinal CSF sampling of clinical trial patients. This new strategy for serial tumor profiling will be an important component of future drug development efforts targeting the moving biology of glioblastoma.