Newswise — Children’s Hospital Los Angeles was first in the nation to offer a clinical liquid biopsy assay for pediatric solid tumors. Launched in late 2022 by CHLA’s Center for Personalized Medicine, the test is the only one of its kind using whole genome sequencing to detect copy number changes in these tumors—including brain tumors.
Katrina O’Halloran, MD, MS—a pediatric oncologist in the Neuro-Oncology Program in the Cancer and Blood Disease Institute at CHLA—was an investigator on the initial pilot study and is leading research into the team’s clinical use of this groundbreaking test for patients with brain tumors. Dr. O’Halloran presented the team’s latest data at the Children’s Oncology Group meeting in April, as well as at the 8th Biennial Pediatric Neuro-Oncology Conference in May.
She shares how the neuro-oncology team is using this liquid biopsy assay today—and how it could change the paradigm for future patient care.
How does the test work?
A liquid biopsy enables us to detect tumor DNA or other tumor markers in a minimally invasive way. Our test uses a sample of cerebrospinal fluid (CSF), which we typically obtain through a lumbar puncture.
CHLA’s liquid biopsy platform is also available for other pediatric solid tumors using a blood sample, and for retinoblastoma using the aqueous humor fluid in the eye. But for brain tumors, we use CSF because the blood-brain barrier may prevent tumor fragments from crossing into the blood.
After we collect the sample, the Center for Personalized Medicine performs low-pass whole genome sequencing. This gives us a bird’s eye view of the genome and any copy number changes—gains or losses of specific chromosomes—which help determine the presence of tumor DNA.
In addition, the lab now offers a new, targeted sequencing panel for liquid biopsy applications. Rather than looking across the whole genome, this panel zooms in on specific cancer-causing genes to detect DNA sequence-level alterations.
What types of brain tumors are you testing?
We have been routinely using it in patients with embryonal tumors, especially those with medulloblastoma. Embryonal tumors have more of the copy number changes that you see with the low-pass whole genome sequencing.
Our new targeted sequencing panel test is helpful for other types of tumors, such as diffuse midline gliomas, which tend to have single-gene changes that are disease-causing.
How is the team using liquid biopsy in clinical care?
We typically use it at diagnosis and at the end of therapy to help assess the patient’s response to treatment. For some very high-risk patients we’re performing it more often, including in surveillance. We want to see if we can detect relapse at a much earlier stage—before it shows up on MRI.
Just a few weeks ago, we also diagnosed our first patient based solely on liquid biopsy. That child had a rare central nervous system tumor called diffuse leptomeningeal glioneuronal tumor (DLGNT). We had a suspicion this was the case, but this tumor is quite challenging to biopsy in a traditional way. Because DLGNT has a specific genetic alteration, we were able to diagnose it with a liquid biopsy—sparing the child an invasive brain surgery.
Are the results influencing treatment decisions?
In some cases, yes. That said, the liquid biopsy test is one factor, in combination with many other factors, that we use in our shared decision-making with families.
For example, we had one patient who had a metastatic tumor at diagnosis and because of side effects was not able to receive all planned therapy. The patient then had a positive liquid biopsy at the end of treatment. Because of those risk factors, along with some concerning MRI findings, we decided to continue treatment with a different regimen. Once the child had several negative liquid biopsies, we stopped therapy.
It has now been over a year, and the patient has continued to test negative and is back at school and doing well. Would we have made the same decisions without the liquid biopsy? Maybe not. The liquid biopsy particularly helped us know when to stop that additional therapy.
What does your data show so far?
To date we have sent 81 liquid biopsies from 35 patients, ranging in age from less than 1 year to 20 years. Out of those, 20 liquid biopsies have found additional DNA alterations when compared with the tissue biopsy. In other words, it’s possible the liquid biopsy may provide a more comprehensive assessment. A tissue biopsy only reflects the tumor in one location, and we know that tumors are not uniform.
We’ve also found that most patients with persistently positive liquid biopsies ultimately experienced progression or relapse, indicating that the test seems to be predictive of recurrence.
In addition, in 16 cases of serial liquid biopsies, we saw changes over time, including new alterations consistent with tumor evolution. This is exciting because we know tumors evolve, and this is part of how they become resistant to therapy. Liquid biopsy allows us to watch this genomic evolution in almost real time.
Can physicians from other institutions order this liquid biopsy?
Yes. It is CAP-certified and CLIA-certified, and we generate a formal pathology report that we share with the outside provider and patient. It typically takes two to three weeks to get results, which is similar to pathology results taken from actual tumor biopsies.
How do you think this test will impact patient care in the future?
It’s going to help us better tailor care to each patient. My hope is that liquid biopsy monitoring could eventually allow us to de-escalate therapy and reduce toxicities for children who are responding well—and intensify therapy for those who are not responding.
Liquid biopsy findings could also help us understand more about how these tumors evolve to evade treatment. This may lead to new therapies that could also be tailored to each patient. If a tumor begins to develop X changes, we give Y therapy.
That is years down the road. But for the first time, we can monitor the genetic evolution of these tumors in close to real time, in a minimally invasive way. It’s already helping us diagnose patients and assess their response to therapy. That is immensely exciting, and it points to a future where treatment can truly be personalized to improve outcomes for each child.