Cytogenetics prognostic model of Medulloblastoma

1. J Clin Oncol. 2014 Mar 20;32(9):886-96

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

3. Management of Medulloblastoma
Surgery
Gross total or
sub total
rescection
RT
CSI+Posterior
fossa boost
Chemotherapy
CDDP+VCR+
CCNU/CYCLO

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

5. Management of Medulloblastoma
Gajjar et. al., Lancet Oncology, 2006 Parker et al COG-A9961 Trial Neuro Oncol. 2013 Jan;15(1):97-103

6. Post treatment complications
20-25% have neurologic dysfunction
- Ataxia
- Posterior fossa-mutism syndrome
- dysmetria
- weakness
10-20% have neurosensory dysfunction
- visual problems
- dizziness
- tinnitus

7. Molecular prognostic markers

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

14. Wnt Subgroup analysis

15. SHH subgroup analysis

16. SHH group

17. Group 3 subgroup analysis

18. Group 3

19. Group 4 subgroup analysis

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