Using an analysis of nearly 900 cases of childhood medulloblastoma, researchers at St. Jude Children’s Research Hospital have designed a new approach to treatment that could safely reduce radiation and chemotherapy exposure for many young patients. Their work, which combines clinical and molecular data from three major clinical trials, offers a data-driven method to guide therapy intensity and limit long-term treatment toxicities.
“We found data to support that 40% of patients with medulloblastoma can receive lower doses of craniospinal radiation therapy and almost all can receive less chemotherapy than they received in the clinical trials we analyzed and maintain the same or better survival,” said Giles Robinson, MD, director of neuro-oncology at St. Jude and St. Jude Division co-senior author of the study published in Cancer Research.
To develop the new method, the researchers analyzed genomic, molecular, and survival data from 898 patients enrolled in the ACNS0331, ACNS0332, and SJMB03 clinical trials. They compared a number of factors including the outcomes data between the three trials, taking into account differences in the molecular and methylation profiles of the patients.
Using this information, the researchers identified new risk factors and predictors of treatment outcomes and stratified patients into one of four actionable treatment recommendation groups from low to high intensity. This method, which has also been launched as an easy-to-use web portal, provides a guide which could lead to many patients receiving lower-intensity treatments, while identify the relatively few who need high-intensity approaches.
“Medulloblastoma is highly variable and can be divided into many different subcategories, so it has been unclear which factors are the most crucial for classifying patients into different treatment groups,” Robinson said. “Our results provide a blueprint to better risk-stratify therapy so that not everyone receives such toxic treatment and only the most aggressive tumors receive the most aggressive therapy.”
Medulloblastoma is a malignant pediatric brain tumor typically treated with craniospinal radiation and chemotherapy. These therapies can cause developmental and neurological side effects that affect survivors throughout life. By using molecular data to refine risk assessment, the St. Jude team found opportunities to preserve survival rates while reducing treatment burden.
Patients whose tumors fall into the two most common molecular subgroups, known as group 3 (G3) and group 4 (G4), could be further classified based on specific chromosomal gains and losses, methylation patterns, and amplification of the MYC oncogene. The result is a protocol that guides therapy intensity to the biology of each tumor rather than relying on broad diagnostic categories.
To make the data accessible to clinicians, the team developed the Medulloblastoma Meta-Analysis (MB-meta) Portal. Built using the ProteinPaint visualization framework, the portal allows physicians and scientists to explore patient cohorts using demographic, clinical, and molecular features to view predicted survival outcomes or test how other variables affect a patient’s prognosis.
“We created the portal so anyone can perform a simple point-and-click, choosing variables to generate predicted survival curves for patients with medulloblastoma,” said co-senior author Xin Zhou, PhD, of St. Jude’s department of computational biology. “The survival curves tell the expected differences of survivors’ outcome, based on the way the cohort is stratified.”
One challenge for clinicians treating medulloblastoma has been the need to interpret complicated genomic data without advanced computational training. The MB-meta portal was designed to bridge that gap by visualizing molecular and clinical variables side by side, allowing physicians to match individual patients with similar profiles and predicted outcomes.
As a proof of principle, the St. Jude team used the portal to study mutations in the gene KBTBD4, identifying two distinct mutation clusters that could help inform disease classification. The researchers wrote that these findings “demonstrate the importance of integrating multiomics data to better understand the genetic underpinnings of medulloblastoma disease.”
Robinson noted their intent to launch new clinical trials based on these findings, using the portal to guide enrollment and therapy decisions. “By making this data available through the portal,” he said, “we hope that others will explore and make findings, like ours, that may have a dramatic impact on quality of life, greatly improving it for future survivors of medulloblastoma.”
The researchers also plan to append the portal with additional data, including MRI imaging and cerebrospinal fluid analysis.
