What yield in the last decade about Molecular Diagnostics in Neuro

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1 What yield in the last decade about Molecular Diagnostics in Neuro Oncology? Raphael Salles S.Medeiros Neuropathologist at HC FMUSP Clinical Research Project Manager at Oncology department at Hospital Santa Marcelina TA Pi Principles i and Practices of Clinical i l Research at Harvard Medical School III Congresso Internacional de Neuro Oncologia III Congresso Internacional de Neuro Oncologia 23/05/2014

2 Big data 2

3 Generation Advances Explore Molecular data Animal models Integrate Knowledge 3

4 Good judgment is the result of experience; experience is the result of bad judgment. In other words, the system that we currently use has arisen from many trials and errors, and from a good aliquot of subjectivity infused with the convictions of our famous men. Louis, D. Acta Neuropathol (2012) 124:

5 NationalCancer Institute TCGA The Cancer Genome Atlas NationalHuman Genome Research Institute 5

6 The challenge of the decade Genomics Transcriptomics Proteomics Metabolomics Thousands of promising biomarkers Basic Research Translational Research New targeted t ddrugs (phase I, II and III) Clinical Research 6

7 Current status: few biomarkers proved to be useful for clinical neuropathology 1p/19q IDH1/2 P53 EGFR BRAF 7

8 1p/19q codelection Non balanced bl translocation between chr 1 e chr 19 loss of der (1,19) 19) (p10,q10). Chr. 1 Chr. 19 Diagnostic i feature of oligodendroglioma Evidence of association with btt better therapeutic ti response and outcome. 8

9 Lack of evidence of the loss of 1p or 19q as prognostic relevance for GBM variable hazard ratio 95% CI P age</= 45 0,43 0,30-0,61 < 0,00001 resection vs. Biopsy 0,45 0,35-0,57 < 0,00001 TMZ vs. No TMZ 0,37 0,29-0,47 < 0,00001 any 1p LOH 1,15 0,88-1,50 0,32 any 19q LOH 0,94 0,73-1,22 0,64 N= 378 1p/19q testing has no significance in the workup of glioblastomas. Clark KH, Villano JL, Nikiforova MN, Hamilton RL, Horbinski C. Neuropathol Appl Neurobiol Jan 31. doi: /nan [Epub ahead of print] 9

10 N Engl J Med 2009;360:

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13 IDH1/2 13

14 Variable Hazard Ratio 95% CI P IDH1 mutation to Grade to Grade to p19q codeletion to EGFR amplification to MGMT methylation to Age > 48 years to Surgery v biopsy py to Radiotherapy to Chemotherapy to

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16 TP53 Mutated in 60 80% of WHO grade II and III astrocytomas Related to secondary GBM Mutually exclusive with ih1 1p/19q codelection dl and EGFR amplification Co expressed with IDH1/2 Useful lto discriminate i i from oligodendroglioma 16

17 EGFR amplification i is diagnostic i for primary GBM GBM: 98,8% AA: 5.6% A2: 0,6% 1p/19q codelection and EGFR amplification i are mutually exclusive. Horbinski et al., Sem Diagn Pathol 27,

18 IHC EGFR/EGFRvIII may be reliable as initial screening for EGFR amplification status Horbinski et al AJP 179(4),

19 MGMT promoter methylation Great interest among neuro oncologists 30 40% of GBM and more than 50% of low grade gliomas. Although there is strong association with IDH1/2 mutation, they are not mutually inclusive. Betterresponse response to alkylating chemotherapy and radiotherapy. Putative marker for global methylation status of tumor genoma. 19

20 Assessment methods for MGMT Acta Neuropathol (2010) 120:

21 A amplificação/duplicação do gen BRAF forma uma fusãogênica com atividade iidd kinase desregulada d RTK Kinase Domain RAS Binding Domain Ras GDP Ras GTP C Term BRAF N Term Exons Neurofibromin KIAA BRAF PI3K Predictedtelomeric telomeric endof 7q34 gain MEK ERK Akt mtor BRAF V600E mutation SRGAP3:RAF1 Cyclin D1 Translation Growth Cell Cycle 21

22 42 of 64 PXA (66%) 14 of 77 Ganglioglioma (18%) 9 of 97 Pilocytic Astrocytoma (9%, mostly outside cerebellum) 22

23 Louis D. et al. 23

24 Lessons from the last decade 24

25 Arch Pathol Lab Med Vol 135, May 2011 Acta Neuropathol (2010) 120:

26 Molecular markers with diagnostic relevance 26

27 The challenge of the new decade Genômica Transcriptomica Proteômica Metabolômica Hundreds of promising biomarkers Basic Research Incorporation of Biomarker Assessment in Novel Clinical Trial Designs: Personalizing Brain Tumor Treatments Translational Research New targeted drugs on clinical practice Clinical Research 27

28 GBM heterogeneity and molecular classification C/EBP beta and STAT3 master regulator that could control the transition into a prognosticallyunfavorable gene expression Drug resistance mechanisms MSH6, MSH2 and PMS2: lower expression in recurred GBM 28

29 G CIMP Promotermethylation methylation silences critical genes that mediates glioblastoma agressiveness and therapeutic resistance, including MGMT promoter methylated profile. G CIMP+ GBM have better prognosis than G CIMP GBM. Oligodendrogliomas are more likely to exhibit the G CIMP phenotype relative to low grade astrocytoma. Observation that Oligodendroglioma g are more likely to harbor the G CIMP phenotype is largely consistent with the more favorable prognosis of this LGG relative to low grade astrocytic tumors. Neurosurg Focus / Volume 36 / April

30 The role of mirnas Relative to Oligodendroglioma, low grade astrocytoma exhibit a higher expression of genes related to mitosis, replication and inflammation. Low grade astrocytic tumor harbor mirna profiles similar to those previously described for GBM. Notably such mirna profiles were not observed din oligodendrogliomas. Manyof the mirnasdownregulated in astrocytoma relative to oligodendroglioma have been shown to be required in maintaining astrocytic differentiation (mirna 124 and mirna 128). Neurosurg Focus / Volume 36 / April

31 the question of whether we will see a shift from classification based on famous men to one based on famous molecules. Louis, D. At Acta Neuropathol l(2012) 124:

32 Further decade and beyond 32

33 Acta Neuropathol (2013) 126:

34 Obrigado! 34