Abstract 1053: Circulating tumor DNA from cerebrospinal fluid (CSF) allows for characterization and monitoring of glioma patients
Authors: Nandakumar Subhiksha , Kreitzer Christoph , Hertz Charli Ann , Rafailov Johnathan , Song Timothy , Socci Nicholas D. , Brannon A. Rose , Arcila Maria E. , Solit David B. , Berger Michael F. , Schultz Nikolaus , Mellinghoff Ingo K. , Miller Alexandra M. 
Published: April 2023

Intro: High-Grade Gliomas (HGGs) are the most common and aggressive primary brain tumors in adults and are almost always fatal. Liquid biopsy provides a noninvasive window into the cancer genome and the underlying biology of the tumor. Circulating-tumor DNA (ctDNA) is a versatile analyte for tumor diagnosis, monitoring treatment response, detecting resistance, and tracking tumor evolution. The central hypothesis of our work is that detection of cerebrospinal fluid (CSF) ctDNA correlates with clinically significant events and can be used as a surrogate for tissue biopsy to guide treatment decisions in the clinic.

Methods: Our study includes CSF ctDNA samples from 140 recurrent glioma patients at Memorial Sloan Kettering Cancer Center who underwent collection of CSF as part of their clinical evaluation for neurological signs and symptoms. For each patient, glioma subtype and grade were confirmed by a neuropathologist. Overall survival was calculated as the time interval between the date of diagnosis and the date of death. All samples were sequenced using the MSK-IMPACT targeted sequencing assay (468 genes). Allele-specific copy number calls were assessed using the FACETS algorithm. Mutations were classified as drivers based on OncoKB. To evaluate the relationship between CSF ctDNA detection and clinico-pathologic correlates, CSF ctDNA status was determined positive by the presence of at least one somatic mutation and CSF ctDNA status was correlated with clinico-pathologic features.

Results: Within this cohort, we found 68 CSF ctDNA positive and 72 CSF negative samples. The most frequently mutated genes were: TERT (58.2%), TP53 (47.8%), IDH1 (20.9%) and EGFR (26.9%). We observed a concordance between contemporaneously sampled tumor and CSF. In a multivariate analysis accounting for established prognostic factors including: % extent of resection at diagnosis; tumor burden at the time of lumbar puncture; and IDH status, we found that CSF ctDNA positivity was negatively correlated with overall survival (HR: 2.52, p &lt;0.0001). Patients with CSF positive samples had an overall survival of 3.35 months vs 11.91 months for those with CSF negative samples (p &lt; 0.0001).

Conclusion: ctDNA from CSF depicts a powerful analyte with the potential to alter the standard of care. We have established a robust liquid biopsy program across the neuro-oncology department at MSK, and MSK-IMPACT is now certified by NYS DOH for use on CSF ctDNA enabling routine integration into clinical care. In summary, we are now able to monitor the changing genome along the disease course and have the potential to detect disease occurrence at an earlier time point, however further validation of CSF ctDNA for disease monitoring is needed. Additionally, our data suggests that CSF ctDNA may be used as a prognostic biomarker for survival, but confirmation requires further validation in a prospective study.

Citation Format: Subhiksha Nandakumar, Christoph Kreitzer, Charli Ann Hertz, Johnathan Rafailov, Timothy Song, Nicholas D. Socci, A. Rose Brannon, Maria E. Arcila, David B. Solit, Michael F. Berger, Nikolaus Schultz, Ingo K. Mellinghoff, Alexandra M. Miller. Circulating tumor DNA from cerebrospinal fluid (CSF) allows for characterization and monitoring of glioma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1053.