Biomarker-driven stratification of medulloblastoma therapy through international clinical trials
Medulloblastoma is the most common malignant paediatric brain tumour and accounts for ~10% of childhood cancer deaths. Currently, overall survival rates of around 70% are achieved, but improvements have plateaued and the majority of survivors suffer life-long therapy-associated late-effects. The delivery of individualised therapies based on disease-risk is therefore a major goal; intensified treatment for poor-risk disease, whilst reducing therapy for favourable-risk patients, with the overall aim of maximising survival whilst minimising late-effects. However, disease outcome remains difficult to predict using current clinical indices.
Recent years have witnessed major breakthroughs in our understanding of the biological basis of medulloblastoma. Through integrated collaborative biological studies conducted alongside recent international Phase III clinical trials, we have identified and validated a series of molecular and histopathological prognostic biomarkers, which allow more accurate prediction of disease outcome (e.g. β-catenin status as a favourable-risk marker, MYC gene amplification and large-cell histology as high-risk markers).
Based on these findings, two groundbreaking pan-European Phase II/III clinical trials will, for the first time, stratify paediatric brain tumour patients into treatment groups based on their molecular risk-status. Commencing in late-2011, PNET5 MB will test whether treatment can be reduced for a favourable-risk medulloblastoma sub-group, with the aim of maintaining survival rates while reducing late-effects, while PNET6 MB will aim to improve survival rates in the standard-risk group. Furthermore, these trials together provide unique opportunities for further biological investigations, aimed at the discovery of novel disease biomarkers and therapeutic targets.
These major initiatives present important new logistical challenges in clinical practice, focussed on the upfront collection of fresh-frozen tumour material and delivery of centralised biomarker analysis and histopathological review, prior to therapy selection. Feasibility studies are currently underwayto establish such systems, which will provide a framework to support the delivery of individualised therapies in paediatric neuro-oncology across Europe.