Patient 1 Presentation Jennie W Taylor, MD 02/15/2019 A 34 year old right handed woman presents in 07/2015 with 9 years of stereotyped spells of olfactory change, nausea, and altered awareness. Imaging reveals diffuse, nonenhancing mass in the right insula. She underwent a biopsy with pathology revealing low grade glioma: diffuse astrocytoma, grade 2, IDH1 R132H mutant, 1p19q intact by FISH. Given her age, burden of disease, and toxicity of radiation, she was treated with 2 years of the alkylating agent, temozolomide. Her MRI in 08/2017 demonstrated marked reduction in FLAIR consistent with partial response to treatment. She developed worsening seizures in 06/2018 (~1 year off treatment) with MRI demonstrating increased FLAIR and new enhancement in left insula. She underwent extensive subtotal resection with preliminary pathology consistent with glioblastoma, IDH mutant. However, sequencing of her tumor revealed presence of 1p19q co deletion and confirmed IDH mutation. By the 2016 WHO classification, this characterizes her tumor as an anaplastic oligodendroglioma. Sequencing also revealed a hypermutated phenotype with > 50 non synomymous somatic mutations in the tumor, all harboring the C>T/G>A mutations seen in temozolomide induced mutagenesis. She was subsequently treated with radiation and immunotherapy with checkpoint inhibition, given data that tumors with high mutation burden have improved response rates to immunotherapy. In 11/2018, she had a favorable response to treatment with decreased FLAIR and improved seizures. References: 1. Pignatti F, et al, J Clin Oncol, 2002 2. van den Bent MJ, et al, Lancet, 2005 3. Buckner J, et al, NEJM, 2016 4. Louis D, et al, Acta Neuropathologica, 2016 5. Johnson B, Science, 2014 6. Yarchoan M, NEJM, 2017 7. Cuzzubbo S, Eur J Cancer, 2017
Patient 2 Presentation Jennie W Taylor, MD 02/15/2019 57 year old right handed woman presented with acute onset of slurred speech 08/2014. Her imaging revealed enhancing mass deep in the left frontal lobe with significant surrounding FLAIR consistent with edema. She underwent biopsy at an outside institution with pathology consistent with glioblastoma, IDH wildtype, MGMT unmethylated. She was subsequently treated with standard of care with fractioned radiation and concurrent temozolomide. She received 4 cycles of adjuvant temozolomide when imaging revealed increased enhancement and FLAIR around the left frontal biopsy site. Clinically, she had worsened right sided weakness, expressive aphasia, and developed cushingoid features from chronic dexamethasone use. She underwent additional extensive subtotal resection as part of a clinical trial of generating treatment recommendation based on genetic sequencing. Her pathology was consistent with 90% treatment effect and 10% recurrent/residual glioblastoma. Whole exome sequencing identified several actionable mutations, including PALB2, NF1, and EGFR. A molecular tumor board, consisting of pharmacologists and several neuro oncologists, recommended combination treatment of carboplatin and PARP inhibition to target the PALB2 mutation, and MEK inhibitor to target the NF1 mutation. She completed 10 months of combination therapy followed by another 12 months of MEK inhibitor monotherapy until there was evidence of progressive nonenhancing disease and seizures. Given the timing since completion of radiation and that disease was diffuse and nonsurgical, the recommendation for treatment was hypofractionated radiation. Within a few months, she developed worsening symptoms and increased enhancement. She went on to receive treatment with bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF) that sequesters VEGF in the vasculature decreasing vascular permeability and, therefore, cerebral edema. She has continued to intermittently receive bevacizumab and is doing well 4.5 years after her initial diagnosis. References 1. Stupp R, Mason WP, van den Bent MJ, et al. N Engl J Med 2005;352:987 96. 2. Sanai N 1, Polley MY, McDermott MW, et al. J Neurosurg. 2011 Jul;115(1):3 8. 3. Fogh SE 1, Andrews DW, Glass J, et al. J Clin Oncol. 2010 Jun 20;28(18):3048 53. 4. Fink J, Born D, Chamberlain MC. Curr Treat Options Oncol 12:240 252, 2011. 5. Brandes AA, Franceschi E, Tosoni A, et al. J Clin Oncol 26:2192 2197, 2008. 6. Hegi ME, Diserens AC, Gorlia T, et al. N Engl J Med 2005;352:997 1003.
NEUROLOGY AND NEUROLOGICAL SURGERY Recent Advances in Neurology Neuro-Oncology Case Presentation Jennie W Taylor, MD, MPH Assistant Professor Division of Neuro-oncology February 15, 2019 Disclosures Clinical trials research funding support from: Bristol-Meyer Squibb Agios Abbvie 1
Case 1: 34 year old woman with panic attacks 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 3 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 Underwent biopsy with pathology revealing diffuse astrocytoma, grade 2, IDH1 R132H mutant, 1p19q intact by FISH 4 2
Q2 next steps in treatment? A. Chemotherapy alone B. Chemotherapy with radiation C. Radiation alone D. Observation 5 Stratification of grade 2 gliomas Construction set EORTC 22844 and 22845 Prognostic index for lowgrade glioma: Age 40 High risk Tumor diameter 6 cm Tumor crossing midline Astrocytic histology Pre-operative deficit Low risk = < 2 factors High risk mos ~ 7 years High risk = 3 factors mos ~ 3 years Pignatti et al, J Clin Oncol 2002 Overall survival Overall survival Low risk Validation set Low risk 3
Radiation in low-grade glioma EORTC 22845 Upfront RT versus RT at recurrence 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%) Progression Free Survival Overall Survival No early radiotherapy No early radiotherapy Early radiotherapy Early radiotherapy van den Bent et al, Lancet, 2005 Radiation and chemotherapy in low-grade glioma RTOG 9802 Upfront RT versus RT + 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) Overall Survival Progression Free Survival Buckner NEJM 2016 4
Q2 next steps in treatment? A. Chemotherapy alone B. Chemotherapy with radiation C. Radiation alone D. Observation Temozolomide for 23 months (08/2017) 9 06/2018 progressive disease MRI revealed increased mass-like FLAIR and new enhancement with necrosis Clinically with increased fatigue, headaches, inattention, and word finding difficulties 10 5
06/2018 post-op Underwent extensive resection of enhancing disease with residual FLAIR Pathology: glioblastoma, IDH mutated 11 Q3 next steps in treatment? A. Chemotherapy alone B. Chemotherapy with radiation C. Radiation alone D. Immunotherapy with either radiation and/or chemotherapy 12 6
UCSF500: Targeted Sequencing Pathology consistent with anaplastic oligodendroglioma > 50 nonsynonymous somatic mutations Virtually all mutations are C>T/G>A No germ line alternations These findings are indicative of hypermutated phenotype from temozolomide 13 Temozolomide-induced hypermutation Defined C>T/G>A transitions predominantly occur- ring at CpC and CpT dinucleotides, which is a signature of TMZinduced mutagenesis distinct from nonhypermutated tumors Implicated is some malignant transformation Unclear how common Johnson B, Science, 2014 14 7
Q3.5 next steps in treatment? A. Chemotherapy alone B. Chemotherapy with radiation C. Radiation alone D. Immunotherapy with either radiation and/or chemotherapy Immunotherapy with either radiation 15 Mutational burden predictive of response to immunotherapy with checkpoint inhibition Correlation between tumor mutational burden and objective response rate with anti PD-1 or anti PD- L1 therapy Yarchoan M, NEJM, 2017 16 8
Just a word on neurologic complications of checkpoint inhibitors Outcome of naes showed a partial or complete neurological recovery in 73% of cases (20/27), with a median delay of 4 weeks. Cuzzubbo S, Eur J Cancer, 2017 17 11/2018 18 9
Case 2: 57 year old woman with acute onset 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 19 Case 2: 57 year old woman with acute onset of slurred speech 08/2014 20 10
Case 2: 57 year old woman with acute onset of slurred speech 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 21 Q1 Next steps? A. Consider surgery for high suspicion of recurrent disease B. Continue adjuvant temozolomide C. Repeat radiation D. Start bevacizumab 22 11
Extent of resection (EOR) improves outcomes 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 Underwent extensive resection Path: 10% recurrent glioblastoma and 90% treatment effect 24 12
Treatment recommendation To target the PALB2 mutation started carboplatin AUC of 4 q4 weeks and PARP inhibitor, oliparib 200 BID To target the NF1 mtuation started MEK inhibitor, trametinib 2mg daily Olaparib was stopped secondary to myelosuppression Treated with carboplatin for 10 cycles with stable disease 25 Treatment recommendation Continued on trametinib 2mg daily for additional year Developed new seizures and increased mass-like FLAIR concerning for progressive disease 26 13
Q2 Next steps? A. Consider surgery for high suspicion of recurrent disease B. Restart temozolomide C. Repeat radiation D. Start bevacizumab 27 Treated with re-irradiation 28 14
29 Q3 - What are radiologic changes most consistent with? Tumor progression Pseudoprogression 30 15
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 31 Response to bevacizumab Started bevacizumab with favorable radiologic and clinical response Has remained on intermittent bevacizumab for last year with stable findings 32 16
01/2019 33 Prognostic value of MGMT Some patients with MGMT methylation do well Hegi M, NEJM, 2005 34 17
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 Susan Chang, MD Nicholas Butowski, MD Jennifer Clarke, MD http://neurosurgery.ucsf.edu/index.php/brain_tumor_center.html Jennie Taylor, MD Mitchel Berger, MD Michael McDermott, MD Philip Theodosopoulos, MD Manish Aghi, MD, PhD Shawn Hervey- Jumper, MD Nancy Ann Oberheim- Bush MD, PhD 35 Questions? 18
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 of Dr Alberico (has completed six infusions to date last on 11/28/18) 37 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 occurs 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 38 19
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 oligodendroglioma, IDH1 R132H mutant, focal MIB 80% 39 04/2016 40 20
06/2017 41 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 42 21
2016 WHO classification of gliomas Incorporates integrated phenotypic and genotypic diagnosis Emphasis on more objective molecular results versus subjective H&E Louis et al, Acta Neuropathol 2017 43 Molecular algorithm Louis et al, Acta Neuropathol 2017 22