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Oligodendroglioma with 1p/19q co-deletion: What is (are) the

next question(s)?Marc Sanson

Service de Neurologie Mazarin, Institut du Cerveau et de la Moelle, Hôpital de la Salpêtrière,

Université Pierre et Marie Curie

EANO-EORTC meeting Istanbul 27-

28 march 2015

Grade Astrocytic Mixed Oligodendroglial Survival

Grade I Pilocytic Astro >20 y

Grade II Low grade Astro Low grade Oligoastro Low grade Oligo 5-20 y

Grade III Anaplastic Astro Anaplastic Oligoastro Anaplastic Oligo 2-15 y

Grade IV Glioblastoma 1-2 y

BRAFBRAFBRAFBRAFIDHIDHIDHIDH

Gene amplifications Gene amplifications Gene amplifications Gene amplifications (EGFR)(EGFR)(EGFR)(EGFR)

Classification of gliomas

1p19q1p19q1p19q1p19qcodeletioncodeletioncodeletioncodeletion

EANO Marseille 6-9 october

anaplastic oligodendroglioma with 1p19q

codeletion: response to chemotherapy

2 cycles2 cycles2 cycles2 cycleschemotherapychemotherapychemotherapychemotherapy

Chr 1p lossChr 1p lossChr 1p lossChr 1p lossChr 19q lossChr 19q lossChr 19q lossChr 19q loss

Jenkins, 2006Jenkins, 2006Jenkins, 2006Jenkins, 2006

0 1000 2000 3000 4000 5000 6000 7000 8000 9000 10 000

0

10

20

30

40

50

60

70

80

90

(days)

MT

D (

mm

)

A No 1p19q deletion = 5.9 mm/yearNo 1p19q deletion = 5.9 mm/yearNo 1p19q deletion = 5.9 mm/yearNo 1p19q deletion = 5.9 mm/year

1p19q deletion = 3.4 mm/year1p19q deletion = 3.4 mm/year1p19q deletion = 3.4 mm/year1p19q deletion = 3.4 mm/year

Ricard et al, 2007

Natural history:1p19q codeleted LGG grow

slower

All the 1p19q codeleted gliomas are IDH mutatedAll the 1p19q codeleted gliomas are IDH mutatedAll the 1p19q codeleted gliomas are IDH mutatedAll the 1p19q codeleted gliomas are IDH mutatedisocitrate

α-ketoglutarate

NADP

NADPH

IDH1

nal

+

D-2-H glutarate↑↑

NADP+

NADPH

IDH1

mut

Reshape cell epigenome

• DNA hypermethylation (CIMP)

• Histone methylation

++++

----

O

Dang et al, Nature 2010; van den Bent et al, Clin Cancer Res 2011; Turcan et al, Nature 2012; Lu et al, Nature 2012

Gène MGMT

Promoter

Unmethylated

Promoter

methylated

Gène MGMT

1p19q codeletion and IDH mutation

Only IDH mutation

None of these alterations

All gliomas with 1p19q codeletion are IDH mutated

Months

Grade III

0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

1

0 50 100 150 200 250

Grade II

Months

0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

1

0 50 100 150 200

Survival %

0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

1

0 50 100 150 200

Grade IV

Months

Labussière 2010, 2014

Prognostic classification based on IDH and 1p19q status

IDH Mutated Non mutated

Telomere maintenance

hTERTpromotermutation

ATRX mutationALT (alternative

lenghteningtelomeres)

hTERT promoter mutation

Other frequent

alterations

1p19q codeletion

TP53 mut Gene amplif (EGFR), loss 10q..

Predominant histology

Oligo Astro GBM

MedianSurvival

>14 y 4-7 y 1.5 y

1p19q codeletion predictspredictspredictspredictsthe benefit of adjuvant

PCV chemotherapy

Cairncross 2013-2014, RTOG 9402Van den Bent 2013, EORTC 26951

IDH mutation IDH mutation IDH mutation IDH mutation no 1p19 codeletionno 1p19 codeletionno 1p19 codeletionno 1p19 codeletion

No IDH mutationNo IDH mutationNo IDH mutationNo IDH mutationno 1p19 codeletionno 1p19 codeletionno 1p19 codeletionno 1p19 codeletion

IDH mutation IDH mutation IDH mutation IDH mutation 1p19 codeletion1p19 codeletion1p19 codeletion1p19 codeletion

• Molecular oligodendrogliomas

• Tertp-mut, IDH-mut, proneural

expression profile (Alpha-internexine

expression)

• OS=14 years « LGG like »

• Standard: RT-PCV (>RT alone)

• Concern: long term toxicity

IDHmut

with 1p19q

codeletion

1p19q codeleted (oligodendro)gliomas:

next questions

• Can we consider to delay the radiotherapy

in grade III 1p19q codeleted glioma?

• Should we separate grade II and III?

• Which chemotherapy TMZ? PCV?

• New molecular markers

• New therapies


28 march 2015EANO-EORTC meeting Istanbul 27-

28 march 2015

EANO-EORTC meeting Istanbul 27-28

march 2015

Can we consider to delay the radiotherapy

in grade III 1p19q?

• Risk of radiation-induced cognitive dysfunction:

– Among 32 long-term progression-free survivors treated within the EORTC

26951 trial: 74% cognitively impaired (30% severely) (Habets 2014).

• In LLG, deferring RT until tumor progression did not impair OS as

compared to early RT (Van den Bent 2005)

• Chemotherapy alone not inferior to RT alone (Wick 2009)

• No difference of chemotherapy alone (10.5 years) vs RT plus

chemotherapy (8.4 years) (Lassman 2011)

• Survey of treatment recommendation, 42% of neuro-oncologists

deferred radiotherapy (Abrey 2007)



28 march 2015


march 2015

POLCA TrialMulticentric study comparing chemotherapy with PCV alone vs radiotherapy

followed by PCV as post operative treatment of anaplastic oligodendroglial

tumors with 1p/19q codeletion

Lassman et al, Neuro-Oncology 2011 13:649–659; Cairncross et al, J clin Oncol 2012;31:337-43; Ducray, PHRC 2013

RT

280 patients

PCV 6 adjuvant cycles

R

PCV 6 cycles

RT

74% cognitive impairment (30% severe)

POLCA trial (1p-19q codeleted)

Primary objective: survival

without cognitive deterioration

Secondary objectives:

PFS, OS, QoL,…


current questions

• Can we consider to delay the radiotherapy in

grade III 1p19q codeleted glioma?




• New therapies



28 march 2015


march 2015

Overall survival grade II and III gliomas

0 100 2000

50

100

Codel IICodel III

IDHmut non-codel II

IDHmut non-codel III

IDHwt II

IDHwt III

p=0.13

*** p<0.001

*** p<0.001

OS (month)

Perc

en

t su

rviv

al

n=89n=96

n=208

n=166

n=81

n=169

Relevance of grade according to molecular subtype

Trial on grade II (RTOG 9802) reachs the

same conclusion than Trials for 1p19q

codeleted grade III

RT-PCV>RT alone

OS: 13.3 vs. 7.8 years, p=0.03; HR=0.59)

PFS (10.4 vs. 4.0 years, p=0.002; HR=0.50)

Codel Trial

Inclusion of grade II (54 Gy) and

III (59 gy)

235 pts RT→PCV

235 pts RT-TMZ→TMZ

50 pts TMZ→ → → RT-PCV


28 march 2015


current questions






• New therapies



28 march 2015


march 2015

- Longer TTP compared to TMZ (Lassman 2011)

- Sustained effect of PCV chemotherapy

Peyre 2010

Why PCV (and not TMZ) ?Why PCV (and not TMZ) ?Why PCV (and not TMZ) ?Why PCV (and not TMZ) ?


28 march 2015

Peyre 2010

Case 1 Case 2Start PCVStart PCVStart PCVStart PCV Start PCVStart PCVStart PCVStart PCV

End PCVEnd PCVEnd PCVEnd PCV End PCVEnd PCVEnd PCVEnd PCVBest RespBest RespBest RespBest Resp Best RespBest RespBest RespBest Resp


28 march 2015


current questions





• New molecular markers: Tertp, IDHmut,

CIC, FUBP1, Notch pathway

• New therapies



28 march 2015


march 2015

Gleize 2015

CIC mutations

• CIC(capicua homologue) on

19q13.2 is a transcriptional

repressor

• 50-60% of 1p19q codeleted

gliomas (60/109)

• Specific to 1p19q codeleted

gliomas

• Inactivated by mutation

• CIC inactivating mutation

are associated with poorer

outcome

• CIC mutated LGG grow

faster

• CIC inactivation results in

resistance to TMZ

Gleize 2015

Clinical impact of CIC mutations


current questions






• New therapies



28 march 2015


march 2015

Future therapies: IDH mutated gliomas

isocitrate

α-ketoglutarate

NADP

NADPH

IDH1

nal

+

D-2-H glutarate↑↑

NADP+

NADPH

IDH1

mut

Reshape cell epigenome

• DNA hypermethylation (CIMP)

• Histone methylation

++++

----

• Demethylating agents (5-Aza)

• Specific inhibitor of IDHmut enzyme

O

AG120

In acute myeloid leukemia (AML):

• 14 relapsed and/or refractory AML

• 7 Responses (4 CR)

• Reduced plasmatic D-2HG

• Re-differenciation


28 march 2015

Pollyea et al 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics Barcelona, 2014

Still on evaluation in gliomas (phase 1)

Conclusion

• Molecular signature (ie1p19q codeletion) more

important than grade

• Predictive marker

• Two goals for the treatment

– To maintain (increase) long survival (oncological

endpoint)

– To preserve cognitive function and QOL (neurological

endpoint)

• Futures perspectives

– To « reprogramme » and to differentiate IDH-mut tumor

– New targets specific to 1p19q codeleted gliomas

Department of Neurology

Experimental Neuro-oncology

Université Pierre et Marie Curie

• Jean-Yves Delattre

• Khe Hoang-Xuan

• Ahmed Idbaih

• Agusti Alentorn

• Vincent Gleize

• Marianne Labussière

• Amithys Rahimian

• Karima Mokhtari (neuropath)

• Laurent Capelle (neurosurgery)

• Matthieu Peyre (neurosurgery)

• François Ducray (HopitalNeurologique, Lyon)

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