A new blood test for children with brain tumours offers a safer approach than surgical biopsies and may allow doctors to measure the effectiveness of treatment even before changes are identified on scans, according to research led by UCSF Benioff Children's Hospitals and Children's National Health System.

Unlike a standard brain biopsy, which entails drilling a small hole through the skull to extract a sample of the tumour, the so-called liquid biopsy is minimally invasive and involves analysing molecules in the blood or the cerebrospinal fluid, which bathes the brain and spinal cord, for the tumour's specific genetic signature.

The study appears in Clinical Cancer Research on Oct. 15, 2018.

In the study, 48 children with a high-grade brain tumour called diffuse midline glioma (DMG) underwent liquid biopsies using plasma from blood draws and cerebrospinal fluid from spinal punctures.

The investigators looked for circulating tumour DNA in these samples, using a highly sensitive technique called digital droplet polymerase chain reaction that precisely counts individual DNA molecules.

They identified a driver mutation called H3K27M in 42 of the 48 patients, a level comparable to that found using standard biopsy.

Among the 12 children who had undergone liquid biopsy before and after radiation -- standard treatment for many types of brain tumours -- the investigators discovered that the circulating tumour DNA had decreased significantly, indicating the tumour had receded.

This reduction was later confirmed by MRI in 10 of the 12 patients.

"Most diffuse midline gliomas can be surgically biopsied, but this is frequently not carried out at recurrence, due to risk," said co-senior author Sabine Mueller, MD, PhD, a paediatric neuro-oncologist at UCSF Benioff Children's Hospital San Francisco.

"Consequently, physicians rely on clinical exams and MRIs to assess response to therapy, although both of these methods are limited in sensitivity and specificity."

Subtle tumour growth may not be evident on MRI, leading to under-diagnosis in its earliest phase.

When tumour recession is detected on MRI, it is a clear indicator that the child's treatment is working, but radiation and certain other treatments can cause inflammation that masquerades as growth making it difficult to assess the impact of treatment.

Brain tumours are the most deadly form of childhood cancer, according to a 2016 report from the Centers for Disease Control and Prevention.

Close to 30 percent of childhood cancer deaths are now attributed to brain tumours.

Unlike treatments for childhood leukaemia and lymphoma, which have improved steadily for decades, advances have been modest for some types of paediatric brain tumours.

At a time when neuro-oncologists are reimagining treatment of high-grade and refractory brain tumours, and turning to targeted therapies that match a tumour's mutations, there is a heightened need to monitor tumour growth, evolution and response to treatment, said co-senior author Javad Nazarian, PhD, of Children's National Health System and George Washington University School of Medicine and Health Sciences in Washington, D.C.

"Selecting appropriate, tumour-specific treatments requires the ability to frequently monitor progression of the tumour and the genetic changes that evolve over time," Nazarian said.

"Circulating tumour DNA is increasingly used for disease monitoring in adult cancers, including the adult brain tumour glioblastoma, and melanoma, lung, breast and colon cancers. However, this is the first use of the technique in a paediatric brain tumour population in a clinical trial.

"Bringing emerging technologies to the clinic will allow us to achieve precision medicine for treating the most vulnerable patient populations," he said.

The researchers further looked at a subset of patients with an especially virulent form of DMG called diffuse intrinsic pontine glioma (DIPG).

These patients were enrolled in a trial conducted by the Pacific Pediatric Neuro-Oncology Consortium, led by Mueller.

Looking only at plasma samples -- which are less enriched than cerebrospinal fluid with circulating tumour in DNA -- the researchers detected a type of mutation at diagnosis in 16 of the 20 samples that had been identified at standard biopsy.

Following tumour progression, nine of the children with DIPG underwent precision therapy with drugs that matched the mutations identified with liquid biopsy.

The treatment led to a drop in circulating tumour DNA, indicating reduced tumour volume, which was later confirmed by MRI.

"These results are encouraging," said Mueller. "Liquid biopsies have the potential to tell us if a patient is a candidate for a targeted therapy and if that therapy is working in real time.

"Eventually, targeted therapies will lose effectiveness as the tumour 'learns' new ways to evade treatment, and new mutations and alterations will drive its growth. Over time, we anticipate that new targeted therapies will emerge that will further slow disease progression."

Source: UC San Francisco