Tumor DNA Mutations From Intraparenchymal Brain Metastases Are Detectable in CSF

Abstract

PURPOSE Discordant responses between brain metastases and extracranial tumors can arise from branched tumor evolution, underscoring the importance of profiling mutations to optimize therapy. However, the morbidity of brain biopsies limits their use. We investigated whether cell-free DNA (cfDNA) in CSF could serve as an effective surrogate marker for genomic profiling of intraparenchymal (IP) brain metastases. METHODS CSF and blood were collected simultaneously from patients with progressive brain metastases undergoing a craniotomy or lumbar puncture. Mutations in both biofluids were measured using an error-suppressed deep sequencing method previously published by our group. Forty-three regions of 24 cancer-associated genes were assayed. RESULTS This study enrolled 14 patients with either IP brain metastases (n = 12) or cytology-positive leptomeningeal disease (LMD, n = 2) and two controls with normal pressure hydrocephalus. Primary cancer types were lung, melanoma, renal cell, and colorectal. cfDNA was measurable in all sixteen samples of CSF. Cancer-associated mutations were found in the CSF of ten patients (eight with IP [67%] and two with LMD [100%]) and plasma of five patients (five with IP [42%] and none with LMD). All patients with plasma cfDNA had extracranial tumors. Among the five patients in the cohort who also had mutation data from time-matched brain metastasis tissue, four patients (80%) had matching mutations detected in CSF and brain, whereas only one patient (20%) had matching mutations detected in plasma and brain. CONCLUSION The detection of mutational DNA in CSF is not restricted to LMD and was found in two thirds of patients with IP brain metastases in our cohort. Analysis of CSF can be a viable alternative to biopsy for detection of somatic mutations in brain metastases.

A systematic review of CSF biomarker discovery in neuro-oncology: A roadmap to standardization and clinical application

“…The mutation detection rates in CSF of brain metastasis patients using gene panels of 16 to 525 somatic mutations range from 63-95%. 10,11,25,27,125 In a proof-of-principle study, DNA methylation signatures have also been shown to distinguish BrM from other CNS malignancies with an AUROC of 0.93 (95% CI: 0.71-1.0). 17 metastases and other intracranial malignancies.…”

Systematic Review of Cerebrospinal Fluid Biomarker Discovery in Neuro-Oncology: A Roadmap to Standardization and Clinical Application

“…11 ddPCR also has better cfDNA mutation sensitivity than Sanger sequencing and NGS at the cost of reduced multiplex capacity. 9,11,20,[32][33][34][35] Burgeoning NGS technologies that use error suppression strategies and duplex sequencing have promise in pushing detection limits further. 36,37 RNA miRNA and mRNA unique to CNS malignancy exist in the total and EV (Data Supplement) fractions of CSF.…”

“…cfDNA mutation biomarkers are not confounded by nonspecific processes, and there is excellent concordance between mutation profiles in CSF and tumor tissue. 20,[33][34][35] The caveat with cfDNA biomarkers is low sensitivity; however, this can be offset by selective CSF sampling 11 and more sensitive profiling methods (eg, ddPCR).…”

Cerebrospinal fluid: A unique source of circulating tumor DNA with broad clinical applications

“…Ommaya ventricular port) [27] . Although genetic alterations from both leptomeningeal disease and intraparenchymal tumors may be detected in the CSF, success rates are greater when there is leptomeningeal or direct ventricular involvement [ 7 , 12 , [28] , [29] , [30] , [31] ]. Similar to observations in plasma ctDNA studies, analysis of ctDNA from CSF allows a more comprehensive assessment of the genomic landscape of heterogeneous tumors compared to direct tissue sampling of a lesion, which may reflect only focal changes [ 6 , 9 , [32] , [33] , [34] , [35] ].…”