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2/15/2019 1

Recent Advances in Neurology

Neuro-Oncology Case Presentation

Jennie W Taylor, MD, MPH Assistant Professor Division of Neuro-oncology

February 15, 2019

NEUROLOGY AND NEUROLOGICAL SURGERY

Disclosures

Clinical trials research funding support from:

• Bristol-Meyer Squibb
• Agios
• Abbvie

Case 1: 34 year old woman with panic attacks

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In 07/2015 patient presented to academic medical center with 9 years of escalating spells described as a "weird smell" followed by "fuzzing out", nausea and a panicky sense with deja vu

Q1 – next steps for work-up?

• A. EEG for evaluation of seizures
• B. Biopsy/resection for possible low grade

glioma

• C. Biopsy/resection for possible high grade

glioma

• D. Lumbar puncture and empiric acyclovir for

presumed HSV

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Underwent biopsy with pathology revealing diffuse astrocytoma, grade 2, IDH1 R132H mutant, 1p19q intact by FISH

E E G f

• r

e v a l u a t i

• n
• f

s e i . . . B i

• p

s y / r e s e c t i

• n

f

• r

p

• s

s . . . B i

• p

s y / r e s e c t i

• n

f

• r

p

• s

s . . . L u m b a r p u n c t u r e a n d e m . . .

23% 11% 18% 48%

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Q2 – next steps in treatment?

• A. Chemotherapy alone
• B. Chemotherapy with radiation
• C. Radiation alone
• D. Observation

5 C h e m

• t

h e r a p y a l

• n

e C h e m

• t

h e r a p y w i t h r a d . . . R a d i a t i

• n

a l

• n

e O b s e r v a t i

• n

22% 10% 22% 46%

Risk stratification of grade 2 gliomas

• EORTC 22844 and 22845
• Prognostic index for low-

grade glioma: – Age ≥ 40 – Tumor diameter ≥ 6 cm – Tumor crossing midline – Astrocytic histology – Pre-operative deficit

• Low risk = < 2 factors

– mOS ~ 7 years

• High risk = ≥ 3 factors

– mOS ~ 3 years

Pignatti et al, J Clin Oncol 2002

Construction set Validation set Overall survival Overall survival

Low risk High risk Low risk High risk

Radiation alone does not improve survival in low-grade gliomas

• EORTC 22845

Upfront radiation versus radiation at progression in low-grade gliomas

• Improvement in

progression free survival (5.3 v 3.4 years; HR 0.59)

• No improvement in overall

survival (7.4 v 7.2 years; HR 0.97)

• Improves seizure control

at one year (41% v 25%)

van den Bent et al, Lancet, 2005

Progression Free Survival Overall Survival

Early radiation Early radiation Radiation at progression Radiation at progression

Overall Survival Progression Free Survival

Radiation and chemotherapy improve

• utcomes in low-grade glioma
• RTOG 9802

– Upfront radiation versus radiation + chemotherapy (PCV) in newly diagnosed high risk patients

• Improvement in

progression free survival (10.4 v 4.0 years; HR 0.50)

• Improvement in overall

survival (13.3 v 7.8 years; HR 0.59)

Buckner NEJM 2016

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Q2 – next steps in treatment?

• A. Chemotherapy alone
• B. Chemotherapy with

radiation

• C. Radiation alone
• D. Observation

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Temozolomide for 23 months (08/2017)

06/2018 – Progressive disease

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• MRI revealed increased

mass-like FLAIR and new enhancement with necrosis

• Clinically with increased

fatigue, headaches, inattention, and word finding difficulties

• Recommended to undergo

resection

• Subtotal resection with

pathology revealing glioblastoma, IDH mutated

Q3 – next steps in treatment?

• A. Chemotherapy alone
• B. Chemotherapy with radiation
• C. Radiation alone
• D. Immunotherapy with either radiation

and/or chemotherapy

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Chemotherapy alone Chemotherapy with radi... Radiation alone Immunotherapy with eit...

3% 80% 2% 15%

UCSF500: Targeted sequencing

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• Pathology consistent

with anaplastic

• ligodendroglioma
• > 50 non-

synonymous somatic mutations

• Virtually all

mutations are C>T/G>A

• No germ line

alternations

• These findings are

indicative of hypermutated phenotype from temozolomide

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Temozolomide-induced hypermutation

• Defined as C>T/G>A

transitions predominantly

• ccurring at CpC and CpT

dinucleotides, which is a distinct signature of TMZ- induced mutagenesis not seen in other tumors tumors

• Implicated is some cases
• f malignant

transformation

• True incidence is not

known

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Johnson B, Science, 2014

Q3.5 – next steps in treatment?

• A. Chemotherapy alone
• B. Chemotherapy with radiation
• C. Radiation alone
• D. Immunotherapy with either radiation

and/or chemotherapy

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Immunotherapy with either radiation or chemotherapy

C h e m

• t

h e r a p y a l

• n

e C h e m

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h e r a p y w i t h r a d i . . . R a d i a t i

• n

a l

• n

e I m m u n

• t

h e r a p y w i t h e i t . . .

0% 100% 0% 0%

High mutational burden is predictive of response to immunotherapy checkpoint inhibition

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Yarchoan M, NEJM, 2017

Just a word on neurologic complications

• f checkpoint inhibitors...

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Outcome of neurological adverse events correlated with a partial

• r complete neurological recovery in 73% of cases (20/27), with a

median delay of 4 weeks.

Cuzzubbo S, Eur J Cancer, 2017

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11/2018 – post-radiation and immunotherapy

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• MRI revealed

favorable response to treatment

• Expected post

surgical changes

• Decreased mass-

like FLAIR

• Clinically stable

with improved seizure control

• MRI revealed enhancing mass with

significant surrounding edema

• Past medical history notable for

lupus, eczema, and thyroid disease

• Exam notable for dysarthria and

right arm weakness

Case 2: 57 year old woman with acute

• nset of slurred speech

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• She underwent biopsy of left frontal
• mass. Pathology: glioblastoma, IDH

wildtype, MGMT unmethylated

• Completed standard of care with

fractionated radiation and temozolomide

• 4 cycles of adjuvant temozolomide
• MRI with increased enhancement

and neurologic worsening expressive aphasia and right sided weakness

Case 2: 57 year old woman with acute

• nset of slurred speech

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Q1 – Next steps?

• A. Consider surgery for high suspicion of recurrent

disease

• B. Continue adjuvant temozolomide
• C. Repeat radiation
• D. Start bevacizumab

20 Consider surgery for high... Continue adjuvant temo... Repeat radiation Start bevacizumab

37% 53% 3% 7%

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Extent of resection (EOR) improves

• utcomes for newly diagnosed GBM
• Retrospective review of

500 patients with newly diagnosed GBM

• EOR evaluated by 48 hour

post-op MRI

• EOR was an independent

predictor of outcome when adjusting for age and KPS

• Improvement in OS was

seen with incremental increase in EOR, starting at 78%

Sanai, J Neurosurg, 2011

Pathology revealed 10% recurrent glioblastoma and 90% treatment effect MGMT unmethylated

Underwent extensive resection with sequencing 05/2015 (9 months from diagnosis)

Genomic Alteration Drug EGFR (V292L) Afatinib Erlotinib Ibrutinib Lapatinib Propranolol Vandetanib NF1 (T956fs) Trametinib PALB2 (S700fs) Carboplatin Cisplatin Mitomycin Olaparib Oxaliplatin TLK1 (K433N) Perphenazine Thioridazine Trifluoperazine

Treatment recommendation by molecular tumor board

• PALB2 mutation

– Carboplatin: alkylating agent impairs DNA synthesis – Olaparib: PARP inhibitor further damages DNA in platinum sensitive tumors

• NF1 mutation

– Trametinib: MEK inhibitor blocks MAPK/ERK pathway of dysregulated cell growth

• Stable disease after 10 months of

carboplatin/trametinib from 06/2015 - 03/2016 (19 months from diagnosis)

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Treatment recommendation by molecular tumor board

• Continued on trametinib monotherapy from 03/2016

– 06/2017 (34 months from diagnosis)

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03/2016 06/2017

• Developed new seizures and increased mass-like

FLAIR concerning for progressive disease

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Q2 – Next steps?

• A. Consider surgery for high suspicion of recurrent

disease

• B. Restart temozolomide
• C. Repeat radiation
• D. Start bevacizumab

25 C

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s i d e r s u r g e r y f

• r

h i g h . . . R e s t a r t t e m

• z
• l
• m

i d e R e p e a t r a d i a t i

• n

S t a r t b e v a c i z u m a b

37% 52% 11% 0%

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Re-irradiation to 35 Gy in 10 fractions Q3 - What are radiologic changes most consistent with?

• A. Tumor progression
• B. Pseudoprogression

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Tumor progression Pseudoprogression

90% 10%

Subacute radiation

• CNS complications of radiation occur in 3 clinical phases

– Acute (during treatment) – Subacute (within 6 months of treatment) – Delayed (within years of treatment)

• Subacute effects (i.e. pseudoprogression) felt to be

exaggerated response to radiation

• Radiographically appears similar to tumor progression

with increased enhancement at the site of maximum radiation, increased edema, and mass effect. Often without significant diffusion restriction

• Treatment includes steroids though anti-angiogenic

therapy (i.e. bevacizumab) may be needed

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2/15/2019 8

• Started on bevacizumab

(monoclonal antibody to VEGFA) used to treat pseudoprogression and glioblastoma

• Favorable radiologic and clinical

response

• Has remained on intermittent

bevacizumab for with stable findings through 01/2019 (52 months, or 4.2 years, from diagnosis)

Started on bevacizumab

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• Initially diagnosed with biopsy
• MGMT unmethylated tumor
• Undergoing additional surgery within a year of

diagnosis

• Treated with unique combination of medications
• Multiple recurrences
• There is hope!!

> 4 year survivor despite...

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Clinical Neuro-Oncology Program and Brain Tumor Research Center

Jennie W. Taylor, MD, MPH (Jennie.Taylor@ucsf.edu) 400 Parnassus Avenue A808|San Francisco, CA 94143 Phone: (415) 353-2966 Fax: (415) 353-2167 http://neurosurgery.ucsf.edu/index.php/brain_tumor_center.html

31 Nicholas Butowski, MD Susan Chang, MD Jennifer Clarke, MD Manish Aghi, MD, PhD Philip Theodosopoulos, MD Michael McDermott, MD Mitchel Berger, MD Jennie Taylor, MD Nancy Ann Oberheim- Bush MD, PhD Shawn Hervey- Jumper, MD

Questions?

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Prognostic value of MGMT

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Hegi M, NEJM, 2005

Case 2: 57 year old woman with acute

• nset of slurred speech
• 6. 05/15/15: Re-resection of left frontal tumor under ALA guidance by Dr. Mitchel Berger at UCSF.

Pathology: residual/recurrent glioblastoma with treatment effect per TGEN protocol

• 7. 06/22/2015: carboplatin AUC of 4, oliparib 200 BID, trametinib 2mg daily
• 8. 09/01/2015: Admitted to Redding Memorial with concern for cellulitis and subsequent course

complicated by pancytopenia with platelet nadir of 12K, hemoglobin down to 6, ANC nadir of 0.4, requiring transfusions and growth factor support

• 9. 09/21/2015 - 03/30/2016: 10 cycles of carboplatin, dose reduced by 25%, and trametinib 2mg

daily

• 10. 03/2016 - 06/2017: Trametinib monotherapy (held from 09/2016 - 11/2016 for cataract surgery

and perionychia of right toe). Decreased to 1mg as of 03/2017

• 11. 07/10/2017 - 07/21/2017: Re-irradiation to 35 Gy in 10 fractions by Dr. Steven Braunstein

12: 07/2017- 04/2018: 6 cycles of CCNU 90 mg/m2 and intermittent bevacizumab (last 03/23/2018)

• 13. 06/30/2018: Fall and pubic bone fracture managed conservatively
• 14. 09/2018 - present: Bevacizumab 10mg/kg q2 weeks

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01/2019

35

Case 1: 34 year old woman with panic attacks

• 6/2015: Presented with a 9 year history of subtle spells described as a "weird

smell" followed by "fuzzing out", nausea and a panicky sense with deja

• vu. This prompted a brain MRI which showed a right frontotemporal
• mass. She was started on Keppra initially, but did not tolerate this well and

was switched to Zonegran. 7/16/2015: Established care with UVA neuro-oncology 7/28/2015: She underwent stereotactic biopsy by Dr. Mark Shaffrey, pathology showed diffuse astrocytoma 10/5/2015 - 8/17/2017: Completed 23 cycles of adjuvant Temodar 21/7 8/3/2017: Diagnosed with shingles in right truncal region. 8/19/2017: Admitted locally for headaches and was treated for

• meningitis. Superficial blood clot in my left arm near axillary vein was

diagnosed and did not require anti-coagulation. 8/25/17: Required blood patch for spinal headaches following lumbar puncture. 5/3/18: Concern for radiographic progression of disease; clinically some worsening with fatigue, headaches, inattention, and word finding difficulties. 6/13/18: Underwent resection with Dr. Berger at UCSF; pathology revealed

• GBM. Reports she obtained a platelet transfusion during this time.

7/17/18 - 8/28/18: Completed RT 60Gy in 30 fractions under the direction of Dr. Crandley 7/27/18 - Current: Pembrolizumab infusions every 3 weeks under the direction

• f Dr. Alberico (has completed six infusions to date - last on 11/28/18).

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2/15/2019 10

• Tumor type: Diffuse astrocytoma, IDH mutated, 1p19q

intact, ATRX intact, MGMT unmethylated. Pathology from 2018 consistent with anaplastic oligodendroglioma UCSF500 (06/2018): Hypermutation with >300 somatic nonsynonymous mutations that are virtually all C>T/G>A transitions corresponding to Mutational Signature 11 that

• ccurs after alkylating chemotherapy;

Chromosomes 1p and 19q co-deletion Mutations in AKT1, AKT3, BORL1, CIC, DNMT3A, IDH R132H, PIK3CA, RB1, SMARCB1, TERT, TET2, TP53 Location: Right frontotemporal Age at diagnosis: 34 year-old right-handed female

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• 1. 2009: Presented with several years of spells. Imaging

revealed right frontotemporal mass

• 2. 7/28/2015: Stereotactic biopsy of right frontotemporal

mass by Dr. Mark Shaffrey at University of Virginia. Pathology: diffuse astrocytoma

• 3. 10/05/2015 - 08/17/2017: 23 cycles of temozolomide

under the direction of Dr. David Schiff at UVA

• 4. 08/2017: Diagnosed with shingles and meningitis
• 5. 06/13/2018: Extensive subtotal resection of right

frontal mass by Dr. Mitchel Berger. Pathology: anaplastic

• ligodendroglioma, IDH1 R132H mutant, focal MIB 80%

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04/2016

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06/2017

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• This recurrent high grade glioma that has recurred/progressed from a lower-grade diffuse glioma

demonstrates a very high mutation burden with greater than 300

• somatic nonsynonymous mutations identified in the 480 genes targeted for sequencing on this
• panel. There are approximately 250 somatic mutations per Mb
• based on this sequencing assay, which is consistent with “hypermutation”. Virtually all of these are

C>T/G>A transitions that corresponds with Mutational

• Signature 11, a signature predominantly seen in recurrent gliomas following adjuvant

chemotherapy with the alkylating agent temozolomide [ref. 1 and COSMIC

• Signatures of Mutational Processes in Human Cancer database].
• Only 23 of the 1,037 assessed microsatellites (<3%) demonstrate instability, consistent with a

microsatellite stable tumor.

• Chromosomal copy number changes in the tumor are limited to losses of chromosomes 1p and
• 19q. This co-deletion of 1p and 19q involves the entire arms of
• these chromosomes.
• Somatic mutations seen in the tumor include the p.R132H hotspot mutation in the IDH1 oncogene,

a hotspot mutation in the promoter region of the TERT gene,

• and a nonsense mutation in the CIC gene. In addition to the 1p/19q-codeletion, these genetic

features support the diagnosis of an oligodendroglial neoplasm, IDHmutant

• and 1p/19q-codeleted. Oligodendrogliomas and anaplastic oligodendrogliomas within the cerebral

hemispheres of adults are genetically defined by the

• combination of IDH mutation, 1p/19q-codeletion, and TERT promoter mutation, and very

frequently have additional CIC or FUBP1 mutations as seen in this tumor

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2016 WHO classification of gliomas

• Incorporates “integrated”

phenotypic and genotypic diagnosis

• Emphasis on more
• bjective molecular

results versus subjective H&E

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Louis et al, Acta Neuropathol 2017

Molecular algorithm

Louis et al, Acta Neuropathol 2017