Infant medulloblastoma can be stratified into molecular subtypes that vary widely in prognosis, paving the way for more targeted and less toxic therapies, new research has shown.
One study identified DNA methylation-based subgroups of non-WNT/non-sonic hedgehog (SHH) medulloblastoma, with five-year progression-free survival (PFS) ranging from 64% to 0%.
Another paper by the same group showed that infants with SHH medulloblastoma could experience similar PFS outcomes from upfront chemotherapy, but with far fewer adverse effects than with craniospinal irradiation.
Prof Steve Clifford (Source: Newcastle University)
While infant medulloblastoma is generally treated with a ‘one-size-fits-all’ approach, the research brings hope for more precise risk-stratified therapies, according to Professor Steve Clifford, Chair of Molecular Paediatric Oncology at Newcastle University, UK, and senior author on both papers.
“The next steps will involve looking towards treatment reductions where appropriate,” he told the limbus.
“The other side is that we are now looking to develop all new therapies for these very high-risk patients, and we have a lot of very interesting biological clues as to targets that we could potentially exploit,” he added.
The first study, published in The Lancet Child & Adolescent Health [link here], analysed outcomes from a pooled non-trial cohort of 375 infants with medulloblastoma classified as non-WNT/non-SHH medulloblastoma group 3 (MBGroup3, n=246) or group 4 (MBGroup4, n=129).
Using DNA methylation data, the researchers defined various molecular subgroups among MBGroup3 tumours, with subgroups 4 (40%), 2 (30%), and 3 (19%) most common.
Patients with MBGroup3 subgroup 4 tumours (n=14) appeared to be particularly sensitive to chemotherapy, with five-year PFS of 64% following upfront high-dose chemotherapy only.
In contrast, Patients with MBGroup3 subgroup 2 or 3 with MYC amplification (n=10) had 5-year PFS and overall survival (OS) rates of 0% when given the same treatment, while the same groups without MYC amplification (n=10) had 5-year PFS and OS rates of 30% and 58%, respectively.
Prof Clifford said a planned pan-European trial will look to identify new treatments for the patients with the worst prognosis and determine how to reduce the harmful impacts of treatments in the lower risk patients.
“For the first time we can now start to understand the biology and start to think about delivering treatment accordingly,”he told the limbus.
Another paper, published in eClinical Medicine [link here], analysed real-world outcomes within an international pooled cohort of 267 infants with SHH medulloblastoma.
Patients with non-metastatic disease showed similarly favourable five-year PFS from upfront chemotherapy with intraventricular methotrexate (73%) or high-dose chemotherapy (73%), as seen with craniospinal irradiation (74.0%).
Based on the findings, the team are planning another clinical trial which will look at the quality of survival in these patients, rather than just survival outcomes.
“We’ve essentially got two treatments that look like they’re doing the same – they’re both producing great survival rates – so we can now move our trials to asking which of those treatments is going to produce least side effects,” said Prof Clifford.