Cell-free DNA employed to identify measurable residual disease

Researchers from the St. Jude Children’s Research Hospital demonstrated that cell-free DNA from cerebrospinal fluid (CSF) could be employed to examine measurable residual disease (MRD) in children treated for the brain tumor medulloblastoma.

Cell-free DNA employed to identify measurable residual disease
From left: Amar Gajjar MD, Pediatric Medicine chair; Paul Northcott PhD, Developmental Neurobiology; Kyle Smith PhD, Developmental Neurobiology; and Giles Robinson MD, Oncology, developed a test to detect MRD, and thus the risk of relapse, earlier than a recurrent tumor would be identified using a traditional imaging scan (photo follows CDC guidelines at the time). Image Credit: St. Jude Children’s Research Hospital.

The scientists created a test to identify MRD, and thus the risk of relapse, faster than a recurrent tumor will be discovered employing conventional imaging scan. The results were published on October 21st, 2021, in the Cancer Cell journal.

One of the common malignant pediatric brain tumors is medulloblastoma. Imaging at the end of therapy is useful to examine for the absence of bulky disease. However, until today, there is no definitive test to affirm a patient free of disease. Clinicians also cannot determine who will relapse or who is cured; however, they are certain that around one-third of patients might relapse.

MRD indicates tumor cells present during or after cancer treatment. Identifying these tumor cells, or their markers like cell-free DNA is important for identifying early risk of relapse and possibly heading this off before it establishes.

We scan patients frequently for the first couple of years when they come off therapy, but unfortunately, by the time we see a recurrence on a scan there is already a lot of disease. Relapsed medulloblastoma harbors an incredibly poor prognosis and for many, it is too late to cure. As a result, we sought a better way to determine whether a child is truly clear of disease at the time they come off therapy.”

Giles Robinson, MD, Study Co-Senior Author, Department of Oncology, St. Jude Children’s Research Hospital

With this test, we now know that if there is medulloblastoma cell-free DNA in the CSF at the end of therapy, then that patient is very likely to relapse. That gives us something we can act on, an opportunity to truly eradicate the disease before it has had a chance to relapse or re-emerge,” added Robinson.

The right test to answer the right question

Children usually undergo serial spinal taps to identify the disease as part of the conventional treatment for medulloblastoma, specifically for the treatment of pediatric brain tumors—which likely spreads through CSF.

Cell-free DNA is seen floating in CSF or plasma rather than being bound by the membrane of a cell. Scientists employed CSF samples from patients treated for medulloblastoma on the SJMB03 research to identify cell-free DNA that shows the presence of MRD. The trial samples were gathered as part of necessary care.

There’s a lot of interest in the concept of liquid biopsy for cancer, but the technology hadn’t been optimized for pediatric brain tumors. Through careful scientific trial and error and optimization at the lab bench, we found a protocol that can reliably identify the genomic variations characteristic of medulloblastoma.”

Paul Northcott, PhD, Study Corresponding and Co-Senior Author, Department of Developmental Neurobiology, St. Jude Children’s Research Hospital

Northcott and his group depended on a methodology named low-coverage whole-genome sequencing that sums up genome-wide copy number variation (changes in the genetic code). Medulloblastoma genomes mostly entertain these changes which are easily identified with this approach.

The findings revealed that this technique of identifying MRD can warn clinicians of the risk of relapse. But before incorporating it into clinical trials, a certified clinical lab will have to adopt the test (instead of a research lab).

Source:
Journal reference:

Liu, A. P. Y., et al. (2021) Serial assessment of measurable residual disease in medulloblastoma liquid biopsies. Cancer Cell. doi.org/10.1016/j.ccell.2021.09.012.

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