2. MEDULLOBLASTOMA
• Most common malignant CNS
tumor in children (age 3 - 8)
• Also rarely seen in adults
• 15-20% of all pediatric brain
tumors
• In children up to 15 years of age
the incidence is 0.5 per 100,000
• 80% of children, in the region of
the fourth ventricle
4. Risk stratification
Extent of CNS disease at diagnosis.
Age at diagnosis.
Amount of residual disease after definitive surgery.
Tumor histopathology.
Biological/molecular tumor cell characteristics
8. Molecular subgroups of Medulloblastoma
Taylor et al Acta Neuropathol (2012) 123:465–472
5 yr OS ~95% ~75% ~ 50% ~ 75%
9. Study Hypothesis
“a biomarker is prognostic across all medulloblastomas, but the
prognostic impact is driven by a single subgroup”
10. Study Design
• Biomarker discovery study design:--
Discovery:potential biomarkers were identified among a large set of
miRNAs by micro array assay
Assay Development,: most relevant biomarkers were selected
Validation: diagnostic protocol was tested on blinded independent
cohorts by qPCR/iFISH
• multicenter, 43 sites in the North America and Europe.
• The main sponsor of the study was Canadian Institutes of Health
Research.
11. discovery cohort :N: 673 medulloblastomas MAGIC (Medulloblastoma
Advanced Genomics International Consortium
Clinical data with follow up: max 10 year
subgroup-specific copy-number aberration by Affymetrix SNP6
platform
Validation cohort: N:453
GLI2,MYC, chr11, chr14,17p, and 17q by iFISH on a FFPE
12. Metastasis status
not prognostic for patients with WNT tumors
macroscopic metastasis (M2/M3) was consistently associated with poor survival in all non-WNT subgroups
13. Age at diagnosis
SHH tumors, there were significantly better outcomes among adult patients as compared with children or infants
Group 4 tumors had infants has significantly worse outcomes than children or adults
21. DISCUSSION
• Clinical heterogeneity within these core molecular subgroups
• Incorporating subgroup status with conventional clinical parameters
for risk stratification, the accuracy of survival prediction can be
dramatically improved.
• Study demonstrate the utility of incorporating tumor biology into
clinical decision making and offer a novel perspective on risk
stratification using FISH.
• Heterogeneity of treatment of discovery cohorts could have affected
our results.
• Approaches such as array comparative genomic hybridization could
also be used to determine the copy-number status of the six markers
22. CONCLUSION
The combination of clinical variables, subgroup affiliation, and six
cytogenetic markers can achieve an unprecedented level of prognostic
prediction for patients that is practical, reliable, and reproducible even in
the context of heterogeneous clinical therapies.
The prognostic significance of most molecular biomarkers is restricted to a
specific subgroup.
The panel of cytogenetic biomarkers that reliably identifies very high-risk
and very low-risk groups of patients, making it an excellent tool for
selecting patients for therapy intensification and therapy de-escalation
Notes de l'éditeur
Five- and 10-year event-free survivals were 81 ± 2% and 75.8 ± 2.3%; overall survivals were 87 ± 1.8% and 81.3 ± 2.1%. Event-free survival was not impacted by chemotherapeutic regimen, sex, race, age at diagnosis, or gender.