Liquid Biopsies Enable Pediatric Brain Cancer Monitoring

Liquid biopsies may enable physicians to monitor treatment effectiveness for children with brain cancer, enabling detection of progression earlier than MRI imaging, according to a small study published Oct. 15 in Clinical Cancer Research. The authors say this is the first evidence of the feasibility and clinical utility of ctDNA for longitudinal surveillance in pediatric brain cancers.

Pediatric diffuse midline glioma (DMG) are highly malignant tumors with poor clinical outcomes, particularly for the estimated 70 percent of patients that harbor the histone 3 p.K27M (H3K27M) mutation.

Currently, imaging and clinical-based disease monitoring are the standard of care. Complete surgical resection of DMG is not possible and while biopsy at presentation can be feasible, rebiopsy at the time of tumor progression is rare due to risks, sensitive anatomic location, costs, and clinical regulations.

"The inability to accurately assess disease response and treatment-related molecular changes confer significant challenges, particularly for emerging biologically targeted strategies such as immunotherapy," write the authors led by Eshini Panditharatna, from Children's National Health System in Washington, D.C.

Researchers assessed the clinical utility of H3K27M in ctDNA of 48 newly diagnosed patients with DMG to evaluate the feasibility of tumor genomic profiling of biopsies and treated patients. Mutations were assessed using droplet digital polymerase chain reaction (ddPCR) in 110 specimens (30 cerebrospinal fluid [CSF], 79 plasma, and one cyst fluid sample). Blood was collected from for ctDNA analysis at the time of initial diagnosis, as well as with each MRI. ddPCR was chosen as it has high sensitivity and can enable detection and quantification of rare mutations.

The researchers found that both CSF and plasma are suitable sources for detection of ctDNA, although CSF was more enriched. H3K27M mutations were identified in 88 percent of DMG patients, a level comparable to detection with traditional biopsy. Additionally, multiplexing was feasible enabling detection of H3K27M and additional driver mutations.

The authors note that mutations were identified in 80 percent of known pretreatment biopsies. They speculate that the four patients in whom a known mutation was not detected could be because of the "high blood brain barrier integrity" and the resulting lack of ctDNA in plasma samples. However, in two of these patients with initially undetectable H3K27M mutations, longitudinal samples subsequently had a detectable histone mutation.

A significant decrease in H3K27M plasma ctDNA was detected and agreed with MRI assessment of tumor volume in response to radiotherapy in 10 of 12 of patients.

Additionally, ctDNA analysis was conducted for nine patients enrolled in a clinical trial for precision therapy. Researchers found a decrease in plasma ctDNA from biopsy through early cycles of precision therapy and a subsequent increase in plasma ctDNA with disease progression.

"There is an urgent need for the development of ctDNA assays for clinical applications in pediatric central nervous system [cancer] patients," writes senior author Javad Nazarian, Ph.D., from George Washington University in Washington, D.C. "Tumor-associated ctDNA can be quantified using ddPCR, which will allow for a rapid and more sensitive method for surveying tumor mutations. This represents a key advance particularly for tumors with limited tissue acquisition, or prohibitive sampling at multiple time points."

Takeaway: This is the first evidence for the utility of monitoring pediatric brain cancer mutations and tumor progression using ctDNA found in plasma and CSF. This marks and advance in the ability to use liquid biopsies for assessing tumors that may be unable to biopsied.