predictive and prognostic diagnosis of gliomas

1. JOURNAL CLUB
By - DR ABHILASH MENON
MODERATOR - DR ASHUTOSH MUKHERJI

2. INTRODUCTION
• What is the importance of this article?
• For the first time, the WHO classification of CNS tumors
2016 uses molecular parameters in addition to histology to
define many tumor entities, thus formulating a concept for
how CNS tumor diagnoses should be structured in the
molecular era.
• In this review,the current prognostic biomarkers validated
for clinical use or with future clinical validity for gliomas.
Accurate prognostication is crucial for managing patients as
treatments may be associated with high morbidity and the
benefits of high risk interventions must be judged by the
treating clinicians

3. • Prognostic biomarker is a tumor-specific trait
that predicts clinical outcome regardless of
treatment given
• Predictive biomarker predicts clinical response
to a specific treatment or drug class

5. GLIOMAGENESIS

7. IDH 1&2 MUTATIONS
• IDH 3 is involved in Krebs cycle
• IDH1 in cytosol,IDH2 in mitochondria to
generate NADPH from NADP,by oxidative
decarboxylation of isocitrate to alpha
ketogluterate
• IDH maintain cellular redox state
• Mutant IDH will cause conversion of alpha KG
to 2-hydroxygluterate
• IDH also important in hypoxic pathway

8. Pathways of GLIOMAGENESIS

9. MGMT PROMOTER METHYLATION
The MGMT gene is located at chromosome
10q26 and codes for a ubiquitously expressed
suicide DNA repair enzyme that removes alkyl
adducts from the O6-position of guanine
O6-alkylated guanine leads to double-strand
breaks and base mispairing, thereby inducing
apoptosis and cell death, MGMT protects
normal cells from carcinogens.

10. • It also protects tumor cells from normally lethal
effects of chemotherapy with alkylating agents such
as temozolomide
• Methylation of the MGMT promoter is found in 35%–
45% of malignant gliomas (WHO grades III and IV)
and in about 80% of WHO grade II gliomas

11. 1p19q codeletion
Complete deletion of both the short arm of
chromosome 1 (1p) and the long arm of
chromosome 19 (19q) (1p/19q co-deletion) is
the molecular genetic signature of
oligodendroglioma
The biologic effect of 1p/19q co-deletion
remains unclear.

12. • The presence of 1p/19q co-deletion is a strong
independent prognostic biomarker associated
with improved survival in both diffuse low-
grade and anaplastic tumours,among all
diffuse gliomas, patients with 1p/19q-co-
deletion have the most favourable prognosis
• 1p/19q-co-deletion has predictive value for
response to chemotherapy in anaplastic
oligodendrogliomas

13. EGFR MUTATION

14. • EGFR is a receptor tyrosine kinase. Ligand binding by
EGF promotes receptor dimerization and
autophosphorylation of the cytoplasmic domain
• Such EGFR activation is thought to promote cellular
proliferation via activation of the MAPK and PI3K-Akt
pathways.
• It is well known up to 65% of so-called primary
glioblastomas showepidermal growth factor receptor
(7p12) amplification,over- expression, and/or
mutations of this pathway. Such glioblas-tomas are
part of the “classic” expression subtype occurring
mutually exclusively with IDH-mutated secondary GBM

15. • The majority of GBMs with EGFR amplification
also contain the mutant EGFR gene, EGFRvIII ,
which is typically expressed in about 30% of
newly diagnosed GBM patients.
• The EGFRvIII is characterized by the deletion
of exons 2 – 7, resulting in a sense mutation
that has a truncated extracellular domain with
ligand-independent constitutive activity

16. PTEN MUTATION
• Phosphatase and tensin homolog (PTEN), located
on chromosome 10q23.3, is one of the most
commonly lost or downregulated genes
implicated in brain, breast cancer, and prostate
tumors
• PTEN is a tumor suppressor gene, playing
important roles in the regulation of cell
proliferation, adhesion and invasion, apoptosis,
and DNA damage repair.
• Pten has independently been shown to play roles
in both neurogenesis and gliogenesis

17. • Pten loss results in disrupted regulation of cell
size or cell number in the brain
• The loss of PTEN expression has been
indicated to be an early event in glioma, with
mutations occurring in between 5% and 40%
of glioma cases
• Studies have suggested that PTEN gene
mutations in glioma are associated with poor
survival

18. PDGFRA
• Discovered as a serum growth factor for fibroblasts,
smooth muscle cells, and glial cells, the PDGF family
has become one of the most extensively studied
growth factor families
• Ligands binds to the receptors, homo- and
heterodimerization of the receptors occur. This in turn
leads to transphosphorylation of the intracellular
domains and receptor activation. Once activated,
intracellular mediators dock to phosphotyrosine
residues in the receptor, which leads to downstream
activation of intracellular signaling pathways

19. • In GBM, platelet-derived growth factor receptor
alpha (PDGFRA) is the most commonly altered
receptor tyrosine kinase after EGFR
• GBM with amplified PDGFRA have been shown to
be associated with either amplified EGFR or
amplified MET (the hepatocyte growth factor
receptor)
• PDGFRA amplification has recently been shown
to be associated with a poor prognosis in IDH1
mutant GBM and have a negative prognostic
value in Grade III gliomas

21. PEDIATRIC GLIOMAS
• TP53 and PIK3CA mutations occur in all high
grade gliomas,<10% of childhood GBM harbor
EGFR amplifications or PTEN mutations.
• IDH mutations are found in <5% of pediatric GBM
although become more common in adolescents
• K27M mutations have been shown to occur in
over 70% of pediatric diffuse intrinsic pontine
gliomas (DIPG) and confer a worse OS when
compared to patients with wild type H3.3.

22. • A tandem duplication at 7q34 is seen in a high
proportion of pilocytic astrocytomas. This
rearrangement creates a fusion gene
(KIAA1549:BRAF) with constitutive BRAF kinase
activity and putative abnormal activation of
MAPK/ERK pathway
• KIAA1549:BRAF fusion was an independent
prognostic marker for significantly improved 5
year PFS for pilocytic astrocytomas as well as
Grade II diffuse and pilomyxoid astrocytomas

23. IMPORTANT TRIALS
• Codeletion of 1p19q-RTOG9402
• IDH1 mutation-RTOG 9802
• MGMT promoter methylation-NOA-08,EORTC-
NCIC
• EGFR mutation-RTOG 0825
• EGFRviii mutation targeted vaccine-
ACTIVATE,ACT2,ACT3. 2 ongoing trials-
ACT4,ReACT

24. RTOG9402

28. RTOG 9802

31. NOA-08 TRIAL

34. EORTC -NCIC TRIAL

36. RTOG 0825
• Phase III double-blind placebo-controlled trial
evaluating bevacizumab (Bev) in patients (Pts)
with newly diagnosed glioblastoma (GBM).
• The addition of Bev for newly diagnosed GBM did
not improve OS, did improve PFS but did not
reach the significance criterion.
• MGMT and 9 gene profile did not identify
selective benefit, but risk subset results
suggested strongly against the upfront use of Bev
in the best prognosis pts.

37. ACTIVATE TRIAL

39. ACT III STUDY

40. ACTIVATE,ACT II,ACT III TRIALS

41. ONGOING TRIALS
• Results from the ACT III, ACT II, and ACTIVATE
studies are encouraging but are small, open-label,
single-arm studies.
• A pivotal,double-blind, phase III trial (“ACT IV”),
randomizing patients with resected, EGFRvIII+
glioblastoma to receive either rindopepimutor a
control injection of KLH, is under way.
• Rindopepimut is also under evaluation in
recurrent glioblastoma (the“ReACT” study) and
pediatric pontine glioma.

42. SUMMARY
• Only IDH mutation status (prognostic)
andMGMTmethylation status and 1p/19q co-
deletion (predictive) are currently routinely used
for evaluation of glioma patients by clinicians
• Gliomas with mutated IDH1 and IDH2 have
improved prognosis compared to gliomas with
wild-type IDH.
• IDH1 mutations often occur with a TP53 mutation
in astrocytic tumors, and these tumors rarely
demonstrate loss of chromosomes 1p and 19q.

43. • IDH mutation is seen in virtually all
oligodendrogliomas with 1p/19q co-deletion, and
these tumors rarely demonstrate p53 mutation
• MGMT promoter methylation not only predict an
improved response to temozolomide, but may
represent a surrogate marker of a more
treatment-responsive tumor in general.
• Among all diffuse gliomas, patients with 1p/19q-
co-deletion have the most favourable prognosis

44. • PTEN gene mutations in glioma are associated
with poor survival
• The ongoing development of targeted
therapies as mono and combination
treatments necessitates the discovery of
optimal molecular predictive biomarkers

45. THANK YOU