The 2016 revision of brain tumour classifications from the World Health Organisation (WHO) included the four consensus subgroups for medulloblastoma (WNT-activated, SHH-activated, Group 3 and Group 4).
These subgroups have been acknowledged by clinical and academic brain tumour researchers since 2012, but following the inclusion in the 2016 WHO revision they are now considered an essential diagnostic, prognostic and treatment indicator.
Two children’s medulloblastoma clinical trials in North America (called ACNS0331 and ACNS0332) have been running for so long that these subgroups were not incorporated in the design, effectively making all the data they have collected to date obsolete. This research grant will mean that all the stored tumour samples (from about 800 children) collected during these trials will be analysed in the lab and assigned one of the four consensus subgroups. The results of the clinical trials will then be reassessed, incorporating the new subgroup information.
To date, medulloblastomas in Groups 3 and 4 have been notoriously difficult to treat because they have many different and unpredictable responses to treatment. Some researchers think this is because Groups 3 and 4 include more than two different types of tumour. To investigate this possibility, information about the Group 3 and Group 4 samples from ACNS0331 and ACNS0332 will be combined with the data from the same subgroups in two other North American clinical trials, namely SJMP03 and SJYC07 (Group 3 and Group 4 analysis already complete).
Dr Northcott’s team will use sophisticated statistical analysis, on over 1,200 samples, to determine if there are further subtypes within these subgroups.
Without this work, the information collected about treatment response from children on ACNS0331 and ACNS0332 will not be brought up to the current standard and any results from the trials will be confounded by the lack of subgroups. It could mean that important treatment responses in one subgroup are lost in the ‘noise’ of the other subgroups.
Having this vital information on these older trials will mean that the next trials that are designed for children with medulloblastoma have the best possible starting point and that better treatments can be given to children sooner.
The second part of the study (further subdividing Groups 3 and 4) will lead to better understanding of the tumours within these subgroups. Better understanding will mean that dedicated time and effort can be given to each subtype of tumour and that development of new targeted treatments will be possible.
This study will help all children diagnosed with medulloblastoma in the future.
The most immediate impact will be that the clinical trials ACNS0331 and ACNS0332 will be able to report more meaningful results, because of the inclusion of the four subgroups in their analysis. Publication of the results of these large trials will mean that clinicians treating children with a medulloblastoma, even if they’re not on a trial, will have the most up-to-date information to inform their care.
A longer-term impact is that the results of these trials will help shape the next generation of clinical trials in North America. They’ll also influence the next European trials by linking with trial data from existing trials, like PNET5, to make sure the field is moving forward and not duplicating work.
Aim 2, discovering more subtypes of medulloblastoma within Groups 3 and 4, will give hope for better treatments for children with these subgroups of tumour. Better understanding of the tumours will make it easier to test more tailored treatments, with the ultimate aim of defeating them with minimal detriment to quality of life.
The results of these studies will have a direct impact on the design of forthcoming clinical trials and lead to better treatment outcomes for medulloblastoma patients in the future.
Years 1 and 2: The first milestone the group is working towards is assigning one of the four consensus subgroups to each tumour sample from the clinical trials ACNS0331 and ACNS0332.
Years 3 and 4: They will then combine the Group 3 and Group 4 samples from ACNS0331 and ACNS0332 with those from additional clinical trials (SJMP03 and SJYC07) and determine if there are any further subtypes within the subgroups.
Research is the only way we will discover kinder, more effective treatments and, ultimately, stamp out brain tumours – for good! However, brain tumours are complex and research in to them takes a great deal of time and money.
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