yazmin odia, md ms - cme.baptisthealth.net 1 yazmin odia, md ms lead physician of medical...

11/21/2016

1

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

11/21/2016

2

Glioma imaging

➤ MRI FINDINGS – WHO Grade IV Glioblastomas

Glioma PROGNOSIS

➤ PROGNOSIS by Age and Grade

IV

III

II

RTOG

Oligoastrocytomas


➤ 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



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

11/21/2016

3

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)



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

IDH-WT Astrocytoma “Pre-Glioblastoma”

(WHO II-III)

IDH-WT, Secondary

Glioblastoma

(WHO IV)

Primary Glioblastoma

(WHO IV)

Infiltrative Glioma



(WHO II-III)


Astrocytoma

(WHO II-III)


Glioblastoma

(WHO IV)



(WHO II-III)

IDH-WT, Secondary

Glioblastoma

(WHO IV)


(WHO IV)

gliomas

➤ WHO 2016 GLIOMA CLASSIFICATION

11/21/2016

4

Infiltrative Glioma


Oligodendroglioma

(WHO II-III)

Astrocytoma Glioblastoma


IDH-WT Astrocytoma “Pre-Glioblastoma Glioblastoma


gliomas


➤ IDH 1/2 mutations in gliomagenesis

Infiltrative Glioma


Glioblastoma



(WHO II-III)

IDH-WT, Secondary

Glioblastoma

(WHO IV)


(WHO IV)

gliomas


➤ EGFR amplification, EGFRvIII mutation, PTEN loss, VEGF expression

Infiltrative Glioma



(WHO II-III)


Astrocytoma

(WHO II-III)


Glioblastoma

(WHO IV)


Glioblastoma


gliomas


➤ 1p/19q co-deletion vs. ATRX and/or p53 mutations

gliomas


Infiltrative Glioma



(WHO II-III)


Astrocytoma

(WHO II-III)


Glioblastoma

(WHO IV)



(WHO II-III)


Glioblastoma

(WHO IV)


(WHO IV)

Worse PrognosisWHO Grade

Molecular Profile

Infiltrative Glioma



(WHO II-III)


Astrocytoma

(WHO II-III)


Glioblastoma

(WHO IV)



(WHO II-III)


Glioblastoma

(WHO IV)


(WHO IV)

gliomas

➤ TREATMENT: Implications of Molecular Profile

Infiltrative Glioma


Oligodendroglioma

Glioblastoma



(WHO II-III)

IDH-WT, Secondary

Glioblastoma

(WHO IV)


(WHO IV)

gliomas

➤ TREATMENT: IDH-WT WHO Grade III-IV Astrocytomas

➤ Surgery + radiation + concurrent/adjuvant temozolomide

11/21/2016

5

gliomas

➤ TREATMENT: Glioblastomas

➤ Surgery + radiation + concurrent/adjuvant temozolomide

Stupp R, NEJM 2005

gliomas


➤ MGMT promoter methylation status predicts response

Hegi ME, NEJM 2005

gliomas


➤ 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


➤ Tumor Treating Fields (TTF) at recurrence (2010) and upfront (2016)

gliomas


➤ 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


➤ 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

11/21/2016

6

Infiltrative Glioma


Glioblastoma



(WHO II-III)

IDH-WT, Secondary

Glioblastoma

(WHO IV)


(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



(WHO II-III)


Astrocytoma

(WHO II-III)


Glioblastoma

(WHO IV)



(WHO II-III)


Glioblastoma

(WHO IV)


(WHO IV)

gliomas

➤ TREATMENT: Implications of Molecular Profile

Infiltrative Glioma



(WHO II-III)


Astrocytoma

(WHO II-III)


Glioblastoma

(WHO IV)


Pre-Glioblastoma” Glioblastoma

(WHO IV)


gliomas

➤ TREATMENT: IDH-mutant Gliomas

Infiltrative Glioma



(WHO II-III)


Astrocytoma

(WHO II-III)


Glioblastoma

(WHO IV)


Pre-Glioblastoma”

(WHO II-III)

Glioblastoma

Glioblastoma

gliomas

➤ TREATMENT: IDH-mutant, 1p/19q co-deleted Oligodendrogliomas

Infiltrative Glioma



(WHO II-III)


➤ Surgery + Radiation + Procarbazine, CCNU, Vincristine (PCV)

gliomas

11/21/2016

7

gliomas


1p/19q Intact Astrocytomas

1p/19q Co-deleted Oligodendrogliomas

van den Bent MJ, JCO 2013 – EORTC 26951

gliomas

Cairncross G, JCO 2013 – RTOG 9402


1p/19q Intact Astrocytomas

1p/19q Co-deleted Oligodendrogliomas

gliomas


➤ 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


➤ 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


➤ Balancing Toxicity vs. Control

➤ PCV vs. TMZ?

➤ Radiation upfront or deferred to recurrence?

➤ Radiation-induced cognitive deficits

Infiltrative Glioma



(WHO II-III)


Astrocytoma

(WHO II-III)


Glioblastoma

(WHO IV)


Pre-Glioblastoma Glioblastoma


gliomas

➤ TREATMENT: IDH-mutant Astrocytomas

11/21/2016

8

gliomas


➤ Surgery + radiation + concurrent/adjuvant temozolomide?

➤ Surgery + PCV + radiation?

Cairncross JCO 2014 – RTOG9402

PCV + RT RT only

gliomas


➤ 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


gliomas

Cutting-Edge,

Evidence-

BasedTherapy

Chemotherapy


Biologics

Immunotherapy

Surgery

Radiation


gliomas

Cutting-Edge,

Evidence-

BasedTherapy

Chemotherapy


Biologics

Immunotherapy

Surgery

Radiation

Genomics & Molecular Profiling

Cutting-Edge,

Evidence-

BasedTherapy

Chemotherapy


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

11/21/2016

9

Cutting-Edge,

Evidence-

BasedTherapy

Chemotherapy


Biologics

Immunotherapy

Surgery

Radiation

gliomas


➤ EGFR amplification and/or EGFRvIII mutation

Cutting-Edge,

Evidence-

BasedTherapy

Chemotherapy


Biologics

Immunotherapy

Surgery

Radiation

gliomas



➤ EGFR inhibitors poor CNS penetrance

Cutting-Edge,

Evidence-

BasedTherapy

Chemotherapy


Biologics

Immunotherapy

Surgery

Radiation

gliomas



➤ EGFR inhibitors poor CNS penetrance � pulse dosing?

Cutting-Edge,

Evidence-

BasedTherapy

Chemotherapy


Biologics

Immunotherapy

Surgery

Radiation

gliomas




➤ Rindopepimut vaccine targeted EGFRvIII

Cutting-Edge,

Evidence-

BasedTherapy

Chemotherapy


Biologics

Immunotherapy

Surgery

Radiation

gliomas




➤ Rindopepimut vaccine targeted EGFRvIII � negative!

Cutting-Edge,

Evidence-

BasedTherapy

Chemotherapy


Biologics

Immunotherapy

Surgery

Radiation

gliomas





➤ ABT414 antibody drug conjugate (ADC)

➤ Anti-EGFR antibody + cytotoxic Monomethyl Auristatin F or MMAF

11/21/2016

10

Cutting-Edge,

Evidence-

BasedTherapy

Chemotherapy


Biologics

Immunotherapy

Surgery

Radiation

gliomas







➤ Promising early response, now in Phase III trial

Cutting-Edge,

Evidence-

BasedTherapy

Chemotherapy


Biologics

Immunotherapy

Surgery

Radiation

gliomas







➤ Promising early response, now in Phase III trial

…OPENING AT MCI SOON!

➤ TREATMENT: Immunotherapy

gliomas

Cutting-Edge,

Evidence-

BasedTherapy

Chemotherapy


Biologics

Immunotherapy

Surgery

Radiation

➤ TREATMENT

gliomas

Cutting-Edge,

Evidence-

BasedTherapy

Chemotherapy


Biologics

Immunotherapy

Surgery

Radiation

Cutting-Edge,

Evidence-

BasedTherapy

Chemotherapy


Biologics

Immunotherapy

Surgery

Radiation


➤ Vaccines

➤ CTLA-4 and OX40 Inhibitors

➤ Checkpoint Inhibitors

gliomas

Cutting-Edge,

Evidence-

BasedTherapy

Chemotherapy


Biologics

Immunotherapy

Surgery

Radiation


➤ Vaccines – Negative or In Development

➤ Rindopepimut; Polio, Heat Shock (HSPPC-96), Toca511/FC

➤ CTLA-4 Inhibitors


gliomas

11/21/2016

11

Cutting-Edge,

Evidence-

BasedTherapy

Chemotherapy


Biologics

Immunotherapy

Surgery

Radiation



➤ CTLA-4 Inhibitors in development

➤ Ipilimumab – combination therapy, reduced dose


gliomas

Cutting-Edge,

Evidence-

BasedTherapy

Chemotherapy


Biologics

Immunotherapy

Surgery

Radiation





➤ Nivolumab and Pembrolizumab in trials for gliomas

gliomas

Cutting-Edge,

Evidence-

BasedTherapy

Chemotherapy


Biologics

Immunotherapy

Surgery

Radiation





➤ Response linked to high mutational load

gliomas

➤ TREATMENT: Multimodal

gliomas

Multimodal

Therapy

Chemotherapy


Biologics

Immunotherapy

Surgery

Radiation

Cutting-Edge,

Evidence-

BasedTherapy

Chemotherapy


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

11/21/2016

12

QUESTIONS? CONTACT US

NEURO-ONCOLOGY

Office: 305-271-6159

Appointment: 305-595-2141

baptisthealth.net

11/21/2016

13

CONTACT US

NEURO-ONCOLOGY

Office: 305-271-6159

Appointment: 305-595-2141

baptisthealth.net

yazmin odia, md ms - cme.baptisthealth.net 1 yazmin odia, md ms lead physician of medical...

Documents