Abstract 535: Molecular profiling of brainstem gliomas by liquid biopsy

Abstract

Background: Brainstem gliomas are heterogeneous diseases, many of which are difficult to safely resect and have limited treatment options due to their location. These constraints pose challenges to biopsy, which limits the use of routine molecular profiling and identification of personalized therapies. Here, we explored the potential of sequencing of circulating tumor DNA (ctDNA) isolated from the cerebrospinal fluid (CSF) of brainstem glioma patients as a less invasive approach for tumor molecular profiling. Cohorts and Methods:A retrospective analysis of brainstem glioma patients with CSF and tumor tissue available was completed. CSF was obtained from patients either intraoperatively (91.2%, 52/57), from ventricular-peritoneal shunt (3.5%, 2/57), or by lumbar puncture (5.3%, 3/57), all prior to surgical manipulation of the tumor. Deep panel sequencing of glioma-associated genes was performed on CSF-derived ctDNA and, where available, matched blood and tumor DNA from 57 patients, including nine medullary and 23 diffuse intrinsic pontine gliomas (DIPG). In addition, we have now completed a prospective study, in which 12 preoperative CSF samples were obtained from lumbar puncture and used to isolate and characterize ctDNA. Results: In the retrospective analysis, at least one tumor-specific mutation was detected in over 82.5% of CSF ctDNA samples (47/57). In cases with primary tumors harboring at least one mutation, alterations were identified in the CSF ctDNA of 97.3% of cases (36/37). In over 83% (31/37) of cases, all primary tumor alterations were detected in the CSF, and in 91.9% (34/37) of cases, at least half of the alterations were identified. Among ten patients found to have primary tumors negative for mutations, 30% (3/10) had detectable somatic alterations in the CSF. Finally, mutation detection using plasma ctDNA was less sensitive than sequencing the CSF ctDNA (38% vs. 100%, respectively). In the prospective study, at least one tumor-specific mutation was detected in over 83.3% of CSF ctDNA samples (10/12), which is consistent with the data from the retrospective cohort. Conclusion: Our study indicates that deep sequencing of CSF ctDNA is a reliable technique for detecting tumor-specific alterations in brainstem tumors. This approach may offer an alternative approach to stereotactic biopsy for molecular profiling of brainstem tumors. Citation Format: Changcun Pan, Tian Li, Liping Jiang, Hai Yan, Liwei Zhang. Molecular profiling of brainstem gliomas by liquid biopsy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 535.