NCCN Expands CSF Molecular Profiling Recommendation to Inoperable High-Grade Glioma

Updated NCCN Clinical Practice Guidelines in Oncology for central nervous system (CNS) cancers have expanded recommendations for cerebrospinal fluid (CSF)-based molecular tumor profiling to include patients with inoperable high-grade glioma (HGG) and glioblastoma (GBM), according to a news release from Belay Diagnostics.¹ The update, reflected in version 2.2026 of the NCCN guidelines for CNS cancers applies regardless of whether biopsy is not feasible due to patient health, patient unwillingness to undergo neurosurgical biopsy, or tumor location.

What does the NCCN now recommend for biopsy-infeasible high-grade glioma?

A new footnote added to the glioblastoma/high-grade gliomas (excluding IDH1/2-mutant gliomas) systemic therapy options section of the guidelines states that when direct tissue sampling is not feasible, CSF sampling may be pursued as an adjunctive approach to diagnosis when the clinical suspicion for a neoplastic process is high.² The addition of tumor-derived DNA (tDNA), specifically CSF-tDNA, may be considered alongside CSF cytology to increase sensitivity. For tumors whose diagnosis and treatment depend on molecular markers, including H3K27-altered tumors, CSF-tDNA testing is further recommended for consideration. A separate update to the molecular markers section of the guidelines states that when the diagnosis of diffuse midline glioma H3K27-altered is under consideration, CSF-tDNA testing should be considered for both diagnosis and assessment of response to treatment.

The expansion is described by Belay Diagnostics as the second consecutive-year update to the NCCN Guidelines in which the application of CSF-based molecular profiling has broadened to include new CNS malignancies. In March 2026, CSF liquid biopsy data in CNS lymphoma were reported demonstrating an 82% clinical impact across tested patients, illustrating the growing body of evidence supporting tumor-derived DNA analysis from CSF across multiple CNS tumor types.³ Specifically, this was observed with the Summit™ and Vantage™ CSF liquid biopsies.

What prior CNS malignancies had CSF testing recommendations?

Prior to this update, the NCCN guidelines had included CSF-based molecular testing recommendations for medulloblastoma, spinal and cranial ependymoma, CNS lymphoma, and leptomeningeal metastasis in adults. The addition of HGG and GBM extends that framework to 2 of the most common and most aggressive primary brain tumors, for which patients are frequently inoperable and have historically been managed with more limited diagnostic approaches such as imaging and CSF cytology alone.

What is CSF-based genomic profiling and how does it work?

CSF comprehensive genomic profiling uses tumor-derived DNA shed by CNS tumors into the cerebrospinal fluid, obtained via lumbar puncture, to characterize the molecular landscape of a patient’s tumor without requiring surgical tissue biopsy. In contrast to plasma-based liquid biopsy, which has been broadly adopted in solid tumor oncology, CSF is anatomically proximate to CNS tumors and contains higher concentrations of tumor-derived nucleic acids, making it better suited for CNS-specific molecular testing. The guideline update positions CSF-tDNA testing as an adjunct to tissue-based diagnosis, in cases where tissue cannot be obtained.

References

1. Belay announces update to NCCN guidelines to recommend CSF-based genomic profiling in biopsy infeasible high-grade gliomas. News release. Belay Diagnostics. June 17, 2026. Accessed June 18, 2026. https://tinyurl.com/yckckkyn
2. NCCN. Clinical Practice Guidelines in Oncology. Central Nervous System Cancers. Version 2.2026. National Comprehensive Cancer Network. Published June 10, 2026. Accessed June 18, 2026. https://tinyurl.com/5242wek6
3. Belay Diagnostics reports 82% clinical impact rate for Summit™ and Vantage™ in CNS lymphoma study. News release. Belay Diagnostics. March 24, 2026. Accessed June 18, 2026. https://tinyurl.com/y5ttcrmj