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Online First: In the Pipeline: Glioma Status Monitored Using Liquid CSF Biopsy, DNA Sequencing


BY KURT SAMSON

Using next-generation genomic sequencing, researchers at Memorial Sloan Kettering Cancer Center have successfully tracked the evolution of some gliomas with liquid biopsy of cerebrospinal fluid (CSF) for circulating tumor cell DNA.

The process, though it requires a lumbar puncture, is less invasive than surgery for a biopsy of tissue, the authors of the new study noted. They found circulating tumor DNA (ctDNA) was detected in almost half of the patients they tested, and it was associated with increased disease burden and poorer outcomes. The findings were published in the January 23 online edition of Nature.

A wide range of genetic alterations were detected in CSF and these closely matched those collected using regular tumor biopsies. Patients with tumor DNA had a fourfold higher risk of death than those who did not, but there was no significant association between ctDNA-positive CSF and glioma grade, disease duration, or prior therapy. No oncogenic variants were found in the CSF of seven patients who had non-malignant neurological conditions.

Circulating ctDNA remained a statistically significant prognostic factor, even after adjustment for the extent of the original resection site, tumor burden at the time of CSF collection, and status of IDH mutation, which is implicated in gliomas. Tracking gliomas currently requires surgical or punch biopsies, repeated over the course of the cancer.

The assay could also be used for genotype-specific clinical trials of potential targeted therapies and to detect biomarkers, said co-author Alexandra M. Miller, MD, PhD, a neuro-oncologist at Memorial Sloan Kettering Cancer Center.

"When tumors recur, a lumbar puncture is a simpler and safer procedure than a second craniotomy. However, shedding of tumor DNA into the CSF does not appear to be a universal property of diffuse glioma, even in previously treated patients," Dr. Miller told Neurology Today.

"In patients who have a tumor that cannot be approached surgically, a lumbar puncture offers an opportunity to obtain a molecular signature and potentially a definitive diagnosis. The procedure, while not pleasant, is much better than brain surgery."

Study Design

Forty-two of 85 patients who participated in the study had at least one tumor-derived genetic alteration detectible in their CSF. Almost all had undergone surgery, radiation treatment, and/or chemotherapy. The gene sequencing assay (MSK-IMPACT) is approved by the Food and Drug Administration and can identify 410 known cancer-associated gene mutations.

There was little difference between the results of CSF DNA analysis and genetic data from tissue biopsies, or in the plasma of 19 patients.

To establish a benchmark the researchers compared data from 553 glioma biopsy samples at the institution, and blood and tissue biopsy samples when available.

Among patients who also underwent surgical biopsy, tumor cells exactly matched those in their CSF, the researchers found. Patients with larger tumors were more likely to have tumor cells in their CSF. It was unclear why 43 patients lacked any evidence of tumor cell shedding in their CSF.

Among tumor types, 54 percent were grade IV glioblastomas; 31 percent were grade III gliomas; and 15 percent were grade II gliomas. Most patients positive for ctDNA did not have detectible malignant cells using standard CSF cytopathologic analysis.

All of the patients underwent glioma treatment before CSF was collected, and all underwent brain MRIs before and directly after the initial resection. The results were later reviewed by a blinded neuroradiologist.

"Our study shows that tumor-derived DNA in CSF provides a comprehensive and genetically faithful representation of the tumor genome at the time of collection, and the frequency and type of alterations in the CSF closely resembled the genomic landscape of diffuse glioma," said Dr. Miller.

For more on the study, look for the February 21 issue of Neurology Today.

LINK UP FOR MORE INFORMATION:

Miller AM, Shah RH, Pentsoval EI, et al. Tracking tumour evolution in glioma through liquid biopsies of cerebrospinal fluid. Nature 2019; Epub 2019 Jan 23.

Changcun P, Diplas BH, Chen X, et al. Molecular profiling of tumors of the brainstem by sequencing of CSF‑derived circulating tumor DNA. Acta Neuropathol 2018; Epub 2018 Nov 20.