Test Detects Early Signs of Remaining Cancer in Kids

Treated for Medulloblastoma

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December 8, 2021,
by NCI Staff

In up to one-third of children treated for a common and

fast-growing type of brain tumor called medulloblastoma,
the tumor will come back. But by the time doctors discover
the cancer has returned—through magnetic resonance
imaging (MRI) or a spinal tap—it is often at such an
advanced stage that it is difficult to treat. Almost all children
whose cancer returns after treatment ultimately die from
the disease.

Now, researchers have developed a test that detects

specific changes in DNA fragments, or cell-free DNA, shed
from medulloblastoma tumor cells into the fluid
surrounding the brain and spinal cord, known as the
cerebrospinal fluid. Based on their findings from a recent
study, the researchers believe this test could potentially be
MRI of a medulloblastoma in the
used to identify children who, shortly after completing
brain.
treatment, still have evidence of cancer—known as residual
Credit: NCI-CONNECT Staff
disease—who are at high risk of relapse.

The findings appeared October 21 in Cancer Cell.

Being able to identify residual disease sooner than is possible with other methods could be very important
for children with medulloblastoma, the researchers who led the study believe, giving doctors precious time
to treat these patients with more aggressive therapy.

“Parents will tell you that once they reach the end of therapy, they get incredibly nervous because they’re
just waiting and observing” to see if their child’s cancer comes back, said Giles W. Robinson, M.D., of St.
Jude Children’s Research Hospital, one of the study’s leaders.

“If you have a test that can say you’re truly free of the disease at the end of treatment, that adds a huge
amount of reassurance,” he said. But if the test shows you have evidence of residual disease, “then maybe
that shouldn't be the end of therapy.”

In the new study, researchers analyzed samples of cerebrospinal fluid collected at various points during and
after treatment from children with medulloblastoma. Patients whose cancer came back, they found, were
much more likely to have cell-free DNA with cancer-related characteristics in the fluid samples than those
who remained cancer free.
“This study is groundbreaking,” said Marta Penas-Prado, M.D., of the Neuro-Oncology Branch in NCI’s Center
for Cancer Research, who was not involved with the study. “It opens the door to a highly sensitive method of
confirming the presence of tumor cells when imaging scans or conventional spinal taps aren’t conclusive.”

Dr. Robinson noted that more studies are needed to validate the test in additional groups of patients before
we can determine how it might be used to direct treatment.

Improving Residual Disease Detection

Medulloblastoma typically forms in the cerebellum region of the brain and is very fast growing, with tumors
spreading to other areas of brain and spinal cord through the cerebrospinal fluid. Depending on the age at
diagnosis and whether the disease has spread, approximately 70% of kids with medulloblastoma will survive
at least 5 years.

Doctors currently treat medulloblastomas with surgery, followed by radiation and chemotherapy. But in up
to one-third of children with medulloblastoma, the cancer comes back after treatment.

MRI scans can help doctors see when a tumor has come back, but imaging cannot detect small amounts of
remaining tumor cells—known as measurable residual disease, or minimal residual disease—that can
indicate that treatment has not eliminated the cancer entirely. Also, imaging can be difficult to interpret,
especially in patients who have undergone previous surgeries and radiation.

“There are things like scar tissue from surgery and from radiation that can look exactly the same as a
tumor,” said Dr. Penas-Prado.

As a result, during the period of treatment after surgery, repeated spinal taps—in which a needle is inserted
between vertebrae (under anesthesia) to collect samples of cerebrospinal fluid for analysis—are typically
performed to look for any cancer cells that remain.

“The cerebrospinal fluid is currently used to identify metastatic tumor cells under the microscope,” said one
of the study’s lead researchers, Paul Northcott, Ph.D., also of St. Jude. “But even in patients who have active
disease, we often fail to detect tumor cells in the cerebrospinal fluid. It's not a very sensitive test.”  

Many studies have investigated whether identifying cancer-related changes in bits of genetic material in the
blood or other body fluids can help to detect cancer recurrences sooner than other methods. The St. Jude
team wanted to see if this approach could be used as a marker of measurable residual disease in
cerebrospinal fluid from kids with medulloblastoma. 

“What we have seen in diseases like leukemia is that, if you can detect signs of residual disease really early
on, then you can make some treatment adjustments and actually improve the prognosis of those patients
and potentially prevent relapse,” said Dr. Robinson.

“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,” said Dr. Northcott. “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.”

Genetic Analysis of Cerebrospinal Fluid Looks Promising

In the new study, the researchers analyzed available
cerebrospinal fluid samples that had been collected from
123 children ages 6 to 11 years who were newly diagnosed
with medulloblastoma and participating in a clinical trial.
Using a technique called low-coverage whole-genome
sequencing, they looked for cell-free DNA that had specific
genomic changes, called copy number variations, that are
characteristic of medulloblastoma.

In the samples collected from children after surgery but

before the start of treatment, the new test detected these
tumor-specific copy number variations—the marker for
measurable residual disease—in 85% of children with Lumbar puncture. A patient lies in a
disease that spread beyond the cerebellum (metastatic curled position on a table. After a
disease) and in 54% of children whose cancer had not small area on the lower back is
spread. This suggested to the researchers that this test numbed, a spinal needle (a long, thin
could identify disease when it was present in small needle) is inserted into the lower
quantities.  part of the spinal column to remove
cerebrospinal fluid (CSF, shown in
However, in samples collected after therapy had begun
blue). The fluid may be sent to a
from 25 children within 3 months of their cancer returning,
laboratory for testing.
measurable residual disease was found in nearly all of
Credit: National Cancer Institute
them: 24 out of 25. In comparison, the test did not detect
any measurable residual disease in 92% (193 out of 209) of
cerebrospinal fluid samples from children whose cancer did
not return.

What’s more, in 32 children whose MRIs showed no signs of cancer after radiation therapy but whose
disease eventually returned, the test found measurable residual disease in half of these patients at least 3
months, and up to 2 years, earlier than imaging did.

“We could see that the disease was starting to re-emerge in that fluid well before we could see it on an MRI,”
Dr. Robinson said. “This offers us an opportunity to intervene earlier than ever before.”

Spotting the return of disease this early also has scientific potential, Dr. Northcott said. With further
improvements in technology and as researchers gain more experience in analyzing cell-free DNA, he
continued, “we believe we will be able to make more molecular discoveries [that can explain] why the
disease has not gone away.”

Still Work to Do before Test Can Be Used for Kids with

Medulloblastoma
Dr. Robinson noted that it may take years before such a test is incorporated as part of standard care for
children with medulloblastoma. Additional studies are needed to validate their results, he explained.
However, it may not be long before this test is included in future medulloblastoma clinical trials “so we can
better understand how to tailor therapy around detection of measurable residual disease,” he said.
 Dr. Penas-Prado also cautioned that this test has only been studied in children and may not apply to adults
with medulloblastoma. This brain cancer is now commonly grouped into four subtypes, based on the
cancer’s genetic makeup. The majority of adults have a subtype of medulloblastoma called Sonic Hedgehog.
This subtype is less common among children.

“It turns out in this study that the tumors with the Sonic Hedgehog molecular subtype were less likely to
shed DNA into the cerebrospinal fluid,” she said. “That means this [test] may be less applicable for adults
with medulloblastoma than for children.”

In an accompanying editorial, John R. Prensner, M.D., Ph.D., and Scott L. Pomeroy, M.D., Ph.D., of the Broad
Institute of Massachusetts Institute of Technology and Harvard University noted that analyzing cerebrospinal
fluid may be less practical for patients not being treated as part of a clinical trial where cerebrospinal fluid is
collected at different time points.

Although further research is needed, they continued, “the lessons gained from this work will inevitably
catalyze important conversations regarding the development and standardization of measurable residual
disease assays for patients with medulloblastoma.”

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