Cell-free DNA (cfDNA) derived from cerebrospinal fluid (CSF) can be used as a biomarker of measurable residual disease (MRD) in medulloblastoma, according to research published in Cancer Cell.

Researchers evaluated the clinical utility of assessing tumor-associated copy number variations (CNVs) in CSF-derived cfDNA as a surrogate marker for detection of MRD in children with medulloblastoma.

The team analyzed 476 CSF samples collected from 123 patients enrolled in the phase 3 SJMB03 trial (ClinicalTrials.gov Identifier: NCT00085202).

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Using low-coverage whole-genome sequencing, the researchers were able to detect MRD at baseline in 64% of patients with baseline samples (67/105), 85% of patients with metastatic disease (29/34), and 54% of patients with localized disease (38/71). On the other hand, there were no cfDNA-derived CNVs in the 7 control samples from noncancer patients.

The percentage of MRD-positive patients declined with therapy. MRD was detected in 39% of samples available after radiotherapy (30/77), 28% mid-chemotherapy (21/75), and 34% at the end of therapy (20/68).

MRD detection at baseline was not prognostic for progression-free survival (hazard ratio [HR], 1.36, 95% CI, 0.67-2.76; P =.4).

However, MRD positivity during or after treatment was associated with significantly worse progression-free survival. This was true for MRD detected after radiotherapy (HR, 6.53; 95% CI, 3.22-13.26; P <.0001), mid-chemotherapy (HR, 6.35, 95% CI, 3.06-13.19; P <.0001), or at the end of therapy (HR, 8.94; 95% CI, 4.10-19.49; P <.0001).

In 50% of patients who had achieved complete radiographic response before relapse (16/32), detection of MRD in the absence of radiographic and/or cytologic abnormalities preceded relapse by a median of 8.3 months (range, 3.0-29.4 months).

For patients who had MRD-positive CSF at both an early time point (baseline or post-radiotherapy) and at disease progression, the researchers compared CNV profiles derived from patient-matched CSF samples. The comparison revealed divergent chromosomal aneuploidy suggestive of clonal selection or evolution in 80% of patients (12/15), and loss of chromosome 10q was identified as a recurrent event at relapse.

Based on the overall study results, the researchers advocated for prospective assessment of CSF-derived liquid biopsies in future trials of medulloblastoma.

“[O]ur findings provide a solid foundation for the future deployment of CSF-derived liquid biopsies as an actionable biomarker for malignant CNS tumors in children,” the researchers wrote.


Liu APY, Smith KS, Kumar R, et al. Serial assessment of measurable residual disease in medulloblastoma liquid biopsies. Cancer Cell. Published online October 19, 2021. doi:10.1016/j.ccell.2021.09.012