yazmin odia, md ms - cme.baptisthealth.net 1 yazmin odia, md ms lead physician of medical...
TRANSCRIPT
11/21/2016
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YAZMIN ODIA, MD MSLEAD PHYSICIAN OF MEDICAL NEURO-
ONCOLOGY
Molecular Profiling of Molecular Profiling of Molecular Profiling of Molecular Profiling of
GliomasGliomasGliomasGliomas
Implications for Prognosis and Treatment
DISCLOSURES
➤ Novocure: Advisory Board for Optune in Glioblastoma
➤ No other financial conflicts of interest
Glioma OVERVIEW
➤ GLIOMAS
➤ Overview
➤ Molecular subtypes
➤ Treatment Modalities
http://www.medicallibraryonline.com
Glioma OVERVIEW
➤ INFILTRATIVE, MALIGNANT, PRIMARY BRAIN TUMOR
➤ Not resectable
➤ Not curable
➤ CNS-born
➤ Rarely metastasize
http://www.medicallibraryonline.com
Glioma CLASSIFICATION
➤ GRADE not STAGE
➤ No T-N-M staging
➤ WHO Grade II (infiltrative), III (anaplastic), and IV
(glioblastoma)
➤ I = SEGA and pilocytic astrocytoma (benign, childhood)
Glioma imaging
➤ MRI FINDINGS – WHO Grade II-III Gliomas
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Glioma imaging
➤ MRI FINDINGS – WHO Grade IV Glioblastomas
Glioma PROGNOSIS
➤ PROGNOSIS by Age and Grade
IV
III
II
RTOG
Oligoastrocytomas
Glioma CLASSIFICATION
➤ MORPHOLOGYOligoastrocytomas
Glioma prognosis
➤ Prognosis better for Oligodendrogliomas
➤ Explained by 1p/19q co-deletion
Boots-Sprenger SHE, Modern Pathology, 2013
Reifenberger J, AJP 1994
➤ PARADIGM SHIFT from Morphologic to Molecular Classification
Glioma CLASSIFICATION
Glioma CLASSIFICATION
Yan H, NEJM 2009; Cancer Res 2009
➤ Mutations in Isocitrate Dehydrogenases linked to Gliomagenesis
➤ Expressed in ~70% of WHO II-III gliomas, <5% of glioblastomas
➤ Diffusely expressed in neoplastic cells
IDH1-R132H Mutant IDH1 Wild Type
IDH1 R132H Immunohistochemistry
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gliomas
➤ Mutations in Isocitrate Dehydrogenases linked to Gliomagenesis
➤ Prognosis predicted by mutations in IDH1 (and IDH2)
Boots-Sprenger SHE, Modern Pathology, 2013
Epigenetic Changes: Hypermethylation
Altered Fatty Acid Profile
gliomas
➤ Oncometabolism in Gliomas and other Neoplasms
TCA cycle
IDH2, IDH3
Citrate
TCA Cycle Reversed in Neoplastic Cells
Glucose
Pyruvate
AcetylCoA
Citrate
Isocitrate
Malate
In Normal Cells, TCA Cycle is supplied via G6PD pathway
Mitochondrion Cytosol
TCA cycle
Fatty Acid Synthesis
Isocitrate
aKG
IDH1
IDH1-R132
aKG
2HG
Glutamine
Glutamate
Glutamate DehydrogenaseGlutaminase
aKGaKG cMYC promotes expression of enzymes in Glutamine metabolism
Altered Fatty Acid Profile
Glutamate
gliomas
➤ Oncometabolism
MRS optimized to detect 2-hydroxygluterate (2HG)
Andronesi OC, Sci Transl Med (2012)
➤ PARADIGM SHIFT from Morphologic to Molecular Classification
Glioma CLASSIFICATION
gliomas
➤ PARADIGM SHIFT from Morphologic to Molecular Classification
Infiltrative Glioma
IDH1/2 Mutant Infiltrative Glioma
1p/19q Co-Deletion: Oligodendroglioma
(WHO II-III)
ATRX loss, p53 mutation
Astrocytoma
(WHO II-III)
IDH-Mutant, Secondary
Glioblastoma
(WHO IV)
IDH 1/2 Wild Type (WT) Infiltrative Astrocytoma
IDH-WT Astrocytoma “Pre-Glioblastoma”
(WHO II-III)
IDH-WT, Secondary
Glioblastoma
(WHO IV)
Primary Glioblastoma
(WHO IV)
Infiltrative Glioma
IDH1/2 Mutant Infiltrative Glioma
1p/19q Co-Deletion: Oligodendroglioma
(WHO II-III)
ATRX loss, p53 mutation
Astrocytoma
(WHO II-III)
IDH-Mutant, Secondary
Glioblastoma
(WHO IV)
IDH 1/2 Wild Type (WT) Infiltrative Astrocytoma
IDH-WT Astrocytoma “Pre-Glioblastoma”
(WHO II-III)
IDH-WT, Secondary
Glioblastoma
(WHO IV)
Primary Glioblastoma
(WHO IV)
gliomas
➤ WHO 2016 GLIOMA CLASSIFICATION
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Infiltrative Glioma
IDH1/2 Mutant Infiltrative Glioma
Oligodendroglioma
(WHO II-III)
Astrocytoma Glioblastoma
IDH 1/2 Wild Type (WT) Infiltrative Astrocytoma
IDH-WT Astrocytoma “Pre-Glioblastoma Glioblastoma
Primary Glioblastoma
gliomas
➤ WHO 2016 GLIOMA CLASSIFICATION
➤ IDH 1/2 mutations in gliomagenesis
Infiltrative Glioma
IDH1/2 Mutant Infiltrative Glioma
Glioblastoma
IDH 1/2 Wild Type (WT) Infiltrative Astrocytoma
IDH-WT Astrocytoma “Pre-Glioblastoma”
(WHO II-III)
IDH-WT, Secondary
Glioblastoma
(WHO IV)
Primary Glioblastoma
(WHO IV)
gliomas
➤ WHO 2016 GLIOMA CLASSIFICATION
➤ EGFR amplification, EGFRvIII mutation, PTEN loss, VEGF expression
Infiltrative Glioma
IDH1/2 Mutant Infiltrative Glioma
1p/19q Co-Deletion: Oligodendroglioma
(WHO II-III)
ATRX loss, p53 mutation
Astrocytoma
(WHO II-III)
IDH-Mutant, Secondary
Glioblastoma
(WHO IV)
IDH 1/2 Wild Type (WT) Infiltrative Astrocytoma
Glioblastoma
Primary Glioblastoma
gliomas
➤ WHO 2016 GLIOMA CLASSIFICATION
➤ 1p/19q co-deletion vs. ATRX and/or p53 mutations
gliomas
➤ WHO 2016 GLIOMA CLASSIFICATION
Infiltrative Glioma
IDH1/2 Mutant Infiltrative Glioma
1p/19q Co-Deletion: Oligodendroglioma
(WHO II-III)
ATRX loss, p53 mutation
Astrocytoma
(WHO II-III)
IDH-Mutant, Secondary
Glioblastoma
(WHO IV)
IDH 1/2 Wild Type (WT) Infiltrative Astrocytoma
IDH-WT Astrocytoma “Pre-Glioblastoma”
(WHO II-III)
IDH-Mutant, Secondary
Glioblastoma
(WHO IV)
Primary Glioblastoma
(WHO IV)
Worse PrognosisWHO Grade
Molecular Profile
Infiltrative Glioma
IDH1/2 Mutant Infiltrative Glioma
1p/19q Co-Deletion: Oligodendroglioma
(WHO II-III)
ATRX loss, p53 mutation
Astrocytoma
(WHO II-III)
IDH-Mutant, Secondary
Glioblastoma
(WHO IV)
IDH 1/2 Wild Type (WT) Infiltrative Astrocytoma
IDH-WT Astrocytoma “Pre-Glioblastoma”
(WHO II-III)
IDH-Mutant, Secondary
Glioblastoma
(WHO IV)
Primary Glioblastoma
(WHO IV)
gliomas
➤ TREATMENT: Implications of Molecular Profile
Infiltrative Glioma
IDH1/2 Mutant Infiltrative Glioma
Oligodendroglioma
Glioblastoma
IDH 1/2 Wild Type (WT) Infiltrative Astrocytoma
IDH-WT Astrocytoma “Pre-Glioblastoma”
(WHO II-III)
IDH-WT, Secondary
Glioblastoma
(WHO IV)
Primary Glioblastoma
(WHO IV)
gliomas
➤ TREATMENT: IDH-WT WHO Grade III-IV Astrocytomas
➤ Surgery + radiation + concurrent/adjuvant temozolomide
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gliomas
➤ TREATMENT: Glioblastomas
➤ Surgery + radiation + concurrent/adjuvant temozolomide
Stupp R, NEJM 2005
gliomas
➤ TREATMENT: Glioblastomas
➤ MGMT promoter methylation status predicts response
Hegi ME, NEJM 2005
gliomas
➤ TREATMENT: Glioblastomas
➤ MGMT promoter methylation status predicts response
➤ O6-methylguanine methyltransferase (MGMT) – DNA repair gene
➤ MGMT promoter hypermethylation leads to gene silencing
➤ Predicts response to alkylating chemotherapy, like temozolomide and nitrosoureas
➤ Predicts response to oxidizing radiation
gliomas
➤ TREATMENT: Glioblastomas
➤ Tumor Treating Fields (TTF) at recurrence (2010) and upfront (2016)
gliomas
➤ TREATMENT: Glioblastomas
➤ Surgery + radiation + concurrent/adjuvant temozolomide + TTF
Median OS increased by 3-5 months
2-Year Survival rates increased by ~15%
Low Compliance
Stupp R, JAMA 2016
gliomas
➤ TREATMENT: Glioblastomas
➤ Surgery + radiation + concurrent/adjuvant temozolomide + TTF
MEDIANOVERALL SURVIVAL 2-YEAR SURVIVAL
Surgery 6 mos <5%
Radiation 12 mos 10-12%
Radiation + Temozolomide 15-16 mos 21-29%
Radiation + TMZ + TTF 19-20 mos 43%Stupp R, NEJM 2005 and JAMA 2016
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Infiltrative Glioma
IDH1/2 Mutant Infiltrative Glioma
Glioblastoma
IDH 1/2 Wild Type (WT) Infiltrative Astrocytoma
IDH-WT Astrocytoma “Pre-Glioblastoma”
(WHO II-III)
IDH-WT, Secondary
Glioblastoma
(WHO IV)
Primary Glioblastoma
(WHO IV)
gliomas
➤ TREATMENT: Extrapolated to WHO II-III, IDH-WT Astrocytomas
➤ Surgery + radiation + concurrent/adjuvant temozolomide + TTF(?)
gliomas
➤ TREATMENT: Extrapolated to WHO II-III, IDH-WT Astrocytomas
➤ TTF trials pending for WHO III
➤ Patient compliance and physician acceptance remain low
➤ Unclear benefit in WHO II
➤ Unclear benefit in elderly and/or frail patients
➤ Hypofractionated (shortened) radiation course
➤ Temozolomide alone for MGMT hypermethylated tumors
Infiltrative Glioma
IDH1/2 Mutant Infiltrative Glioma
1p/19q Co-Deletion: Oligodendroglioma
(WHO II-III)
ATRX loss, p53 mutation
Astrocytoma
(WHO II-III)
IDH-Mutant, Secondary
Glioblastoma
(WHO IV)
IDH 1/2 Wild Type (WT) Infiltrative Astrocytoma
IDH-WT Astrocytoma “Pre-Glioblastoma”
(WHO II-III)
IDH-Mutant, Secondary
Glioblastoma
(WHO IV)
Primary Glioblastoma
(WHO IV)
gliomas
➤ TREATMENT: Implications of Molecular Profile
Infiltrative Glioma
IDH1/2 Mutant Infiltrative Glioma
1p/19q Co-Deletion: Oligodendroglioma
(WHO II-III)
ATRX loss, p53 mutation
Astrocytoma
(WHO II-III)
IDH-Mutant, Secondary
Glioblastoma
(WHO IV)
IDH 1/2 Wild Type (WT) Infiltrative Astrocytoma
Pre-Glioblastoma” Glioblastoma
(WHO IV)
Primary Glioblastoma
gliomas
➤ TREATMENT: IDH-mutant Gliomas
Infiltrative Glioma
IDH1/2 Mutant Infiltrative Glioma
1p/19q Co-Deletion: Oligodendroglioma
(WHO II-III)
ATRX loss, p53 mutation
Astrocytoma
(WHO II-III)
IDH-Mutant, Secondary
Glioblastoma
(WHO IV)
IDH 1/2 Wild Type (WT) Infiltrative Astrocytoma
Pre-Glioblastoma”
(WHO II-III)
Glioblastoma
Glioblastoma
gliomas
➤ TREATMENT: IDH-mutant, 1p/19q co-deleted Oligodendrogliomas
Infiltrative Glioma
IDH1/2 Mutant Infiltrative Glioma
1p/19q Co-Deletion: Oligodendroglioma
(WHO II-III)
➤ TREATMENT: IDH-mutant, 1p/19q co-deleted Oligodendrogliomas
➤ Surgery + Radiation + Procarbazine, CCNU, Vincristine (PCV)
gliomas
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gliomas
➤ TREATMENT: IDH-mutant, 1p/19q co-deleted Oligodendrogliomas
1p/19q Intact Astrocytomas
1p/19q Co-deleted Oligodendrogliomas
van den Bent MJ, JCO 2013 – EORTC 26951
gliomas
Cairncross G, JCO 2013 – RTOG 9402
➤ TREATMENT: IDH-mutant, 1p/19q co-deleted Oligodendrogliomas
1p/19q Intact Astrocytomas
1p/19q Co-deleted Oligodendrogliomas
gliomas
➤ TREATMENT: IDH-mutant, 1p/19q co-deleted Oligodendrogliomas
➤ Procarbazine, CCNU, Vincristine (PCV)
➤ WHO grade III
➤ Surgery + PCV + radiation
➤ WHO grade II
➤ Observe: LOW RISK (age <40 years, unilateral, gross total resection)
➤ PCV + radiation: HIGH RISK (age >40, bilateral, subtotal resection)
gliomas
➤ TREATMENT: IDH-mutant, 1p/19q co-deleted Oligodendrogliomas
➤ PCV superior to temozolomide, but more toxic
TOXICITY vs. CONTROL PCV TEMOZOLOMIDE
Toxicity 10-40% <10%
Noncompliance/Refusal 5-10% <5%
Response Rate 90-100% 35-80%
Median Time to Progression 7.2 years 3.2 years
Median Overall Survival 10.5 years 7.6 years
Lassman AB, CNS Onc 2015
gliomas
➤ TREATMENT: IDH-mutant, 1p/19q co-deleted Oligodendrogliomas
➤ Balancing Toxicity vs. Control
➤ PCV vs. TMZ?
➤ Radiation upfront or deferred to recurrence?
➤ Radiation-induced cognitive deficits
Infiltrative Glioma
IDH1/2 Mutant Infiltrative Glioma
1p/19q Co-Deletion: Oligodendroglioma
(WHO II-III)
ATRX loss, p53 mutation
Astrocytoma
(WHO II-III)
IDH-Mutant, Secondary
Glioblastoma
(WHO IV)
IDH 1/2 Wild Type (WT) Infiltrative Astrocytoma
Pre-Glioblastoma Glioblastoma
Primary Glioblastoma
gliomas
➤ TREATMENT: IDH-mutant Astrocytomas
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gliomas
➤ TREATMENT: IDH-mutant Astrocytomas
➤ Surgery + radiation + concurrent/adjuvant temozolomide?
➤ Surgery + PCV + radiation?
Cairncross JCO 2014 – RTOG9402
PCV + RT RT only
gliomas
➤ TREATMENT: IDH-mutant Astrocytomas
➤ Surgery + radiation + concurrent/adjuvant temozolomide?
➤ Surgery + PCV + radiation?
➤ Additive benefit of molecular profiles
➤ 1p/19q co-deletion > IDH1 mutations > MGMT hypermethylation
➤ Toxicity vs. Control
➤ Timing
➤ Chemotherapy alone for WHO grade II?
➤ TREATMENT: Multimodal Approach
gliomas
Cutting-Edge,
Evidence-
BasedTherapy
Chemotherapy
Tumor Treating Fields
Biologics
Immunotherapy
Surgery
Radiation
➤ TREATMENT: Multimodal Approach
gliomas
Cutting-Edge,
Evidence-
BasedTherapy
Chemotherapy
Tumor Treating Fields
Biologics
Immunotherapy
Surgery
Radiation
➤ TREATMENT: Multimodal Approach
gliomas
Cutting-Edge,
Evidence-
BasedTherapy
Chemotherapy
Tumor Treating Fields
Biologics
Immunotherapy
Surgery
Radiation
Genomics & Molecular Profiling
Cutting-Edge,
Evidence-
BasedTherapy
Chemotherapy
Tumor Treating Fields
Biologics
Immunotherapy
Surgery
Radiation
gliomas
➤ TREATMENT: Biologics
➤ Bevacizumab (VGEF) inhibits angiogenesis
➤ Initial promising results:
➤ Progression-free but not overall survival benefit
➤ Dramatic MRI response due to steroid-like effect
➤ Increasing concern for more invasive phenotype after exposure
➤ Palliative benefit only
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Cutting-Edge,
Evidence-
BasedTherapy
Chemotherapy
Tumor Treating Fields
Biologics
Immunotherapy
Surgery
Radiation
gliomas
➤ TREATMENT: Biologics
➤ EGFR amplification and/or EGFRvIII mutation
Cutting-Edge,
Evidence-
BasedTherapy
Chemotherapy
Tumor Treating Fields
Biologics
Immunotherapy
Surgery
Radiation
gliomas
➤ TREATMENT: Biologics
➤ EGFR amplification and/or EGFRvIII mutation
➤ EGFR inhibitors poor CNS penetrance
Cutting-Edge,
Evidence-
BasedTherapy
Chemotherapy
Tumor Treating Fields
Biologics
Immunotherapy
Surgery
Radiation
gliomas
➤ TREATMENT: Biologics
➤ EGFR amplification and/or EGFRvIII mutation
➤ EGFR inhibitors poor CNS penetrance � pulse dosing?
Cutting-Edge,
Evidence-
BasedTherapy
Chemotherapy
Tumor Treating Fields
Biologics
Immunotherapy
Surgery
Radiation
gliomas
➤ TREATMENT: Biologics
➤ EGFR amplification and/or EGFRvIII mutation
➤ EGFR inhibitors poor CNS penetrance � pulse dosing?
➤ Rindopepimut vaccine targeted EGFRvIII
Cutting-Edge,
Evidence-
BasedTherapy
Chemotherapy
Tumor Treating Fields
Biologics
Immunotherapy
Surgery
Radiation
gliomas
➤ TREATMENT: Biologics
➤ EGFR amplification and/or EGFRvIII mutation
➤ EGFR inhibitors poor CNS penetrance � pulse dosing?
➤ Rindopepimut vaccine targeted EGFRvIII � negative!
Cutting-Edge,
Evidence-
BasedTherapy
Chemotherapy
Tumor Treating Fields
Biologics
Immunotherapy
Surgery
Radiation
gliomas
➤ TREATMENT: Biologics
➤ EGFR amplification and/or EGFRvIII mutation
➤ EGFR inhibitors poor CNS penetrance � pulse dosing?
➤ Rindopepimut vaccine targeted EGFRvIII � negative!
➤ ABT414 antibody drug conjugate (ADC)
➤ Anti-EGFR antibody + cytotoxic Monomethyl Auristatin F or MMAF
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Cutting-Edge,
Evidence-
BasedTherapy
Chemotherapy
Tumor Treating Fields
Biologics
Immunotherapy
Surgery
Radiation
gliomas
➤ TREATMENT: Biologics
➤ EGFR amplification and/or EGFRvIII mutation
➤ EGFR inhibitors poor CNS penetrance � pulse dosing?
➤ Rindopepimut vaccine targeted EGFRvIII � negative!
➤ ABT414 antibody drug conjugate (ADC)
➤ Anti-EGFR antibody + cytotoxic Monomethyl Auristatin F or MMAF
➤ Promising early response, now in Phase III trial
Cutting-Edge,
Evidence-
BasedTherapy
Chemotherapy
Tumor Treating Fields
Biologics
Immunotherapy
Surgery
Radiation
gliomas
➤ TREATMENT: Biologics
➤ EGFR amplification and/or EGFRvIII mutation
➤ EGFR inhibitors poor CNS penetrance � pulse dosing?
➤ Rindopepimut vaccine targeted EGFRvIII � negative!
➤ ABT414 antibody drug conjugate (ADC)
➤ Anti-EGFR antibody + cytotoxic Monomethyl Auristatin F or MMAF
➤ Promising early response, now in Phase III trial
…OPENING AT MCI SOON!
➤ TREATMENT: Immunotherapy
gliomas
Cutting-Edge,
Evidence-
BasedTherapy
Chemotherapy
Tumor Treating Fields
Biologics
Immunotherapy
Surgery
Radiation
➤ TREATMENT
gliomas
Cutting-Edge,
Evidence-
BasedTherapy
Chemotherapy
Tumor Treating Fields
Biologics
Immunotherapy
Surgery
Radiation
Cutting-Edge,
Evidence-
BasedTherapy
Chemotherapy
Tumor Treating Fields
Biologics
Immunotherapy
Surgery
Radiation
➤ TREATMENT: Immunotherapy
➤ Vaccines
➤ CTLA-4 and OX40 Inhibitors
➤ Checkpoint Inhibitors
gliomas
Cutting-Edge,
Evidence-
BasedTherapy
Chemotherapy
Tumor Treating Fields
Biologics
Immunotherapy
Surgery
Radiation
➤ TREATMENT: Immunotherapy
➤ Vaccines – Negative or In Development
➤ Rindopepimut; Polio, Heat Shock (HSPPC-96), Toca511/FC
➤ CTLA-4 Inhibitors
➤ Checkpoint Inhibitors
gliomas
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Cutting-Edge,
Evidence-
BasedTherapy
Chemotherapy
Tumor Treating Fields
Biologics
Immunotherapy
Surgery
Radiation
➤ TREATMENT: Immunotherapy
➤ Vaccines – Negative or In Development
➤ CTLA-4 Inhibitors in development
➤ Ipilimumab – combination therapy, reduced dose
➤ Checkpoint Inhibitors
gliomas
Cutting-Edge,
Evidence-
BasedTherapy
Chemotherapy
Tumor Treating Fields
Biologics
Immunotherapy
Surgery
Radiation
➤ TREATMENT: Immunotherapy
➤ Vaccines – Negative or In Development
➤ CTLA-4 Inhibitors
➤ Checkpoint Inhibitors
➤ Nivolumab and Pembrolizumab in trials for gliomas
gliomas
Cutting-Edge,
Evidence-
BasedTherapy
Chemotherapy
Tumor Treating Fields
Biologics
Immunotherapy
Surgery
Radiation
➤ TREATMENT: Immunotherapy
➤ Vaccines – Negative or In Development
➤ CTLA-4 Inhibitors
➤ Checkpoint Inhibitors
➤ Response linked to high mutational load
gliomas
➤ TREATMENT: Multimodal
gliomas
Multimodal
Therapy
Chemotherapy
Tumor Treating Fields
Biologics
Immunotherapy
Surgery
Radiation
Cutting-Edge,
Evidence-
BasedTherapy
Chemotherapy
Tumor Treating Fields
Biologics
Immunotherapy
Surgery
Radiation
➤ TREATMENT: Evolving
➤ Guided by Genomic and Molecular Profiles
➤ Advanced by Clinical Trials
➤ Highly Variable and Unpredictable Course
Gliomas - SUMMARY
Quality of Life & Patient
Preferences
Genomics &
Molecular Targets
GLIOMAS - SUMMARY
➤ TREATMENT: Personalized
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12
QUESTIONS? CONTACT US
NEURO-ONCOLOGY
Office: 305-271-6159
Appointment: 305-595-2141
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