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Presentation 4 3/1/2019
Advances in the Treatment
of Brain Tumors
Patricia Bruns MSN, APRN, CNS
Allina Health – Givens Brain Tumor Center
Abbott Northwestern Hospital
March 1, 2019
DISCLOSURE
No disclosures or conflicts of interest to report
OBJECTIVES
• Describe two treatment options for a patient with a brain tumor
• Explain how molecular testing can influence brain tumor diagnosis
• Examine an advance in treating tumors based on the use of molecular
testing through a case study
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More than any other cancer, brain tumors can
have lasting and life-altering physical,
cognitive, and psychological impacts on a
patient’s life.
Case study: AZ, 42-year-old female
• Presented with seizures and mental status changes
• Right occipital lobe lesion measuring 1.6 x 1.3 x 1.6 cm
• Underwent gross total resection in February 2018
The Basics
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Brain Tumors and Cancer
• Cancer - disease caused by uncontrolled division of abnormal cells in a part of the body
• Cancerous tumors are malignant, which means they can spread into, or invade, nearby
tissues
• Although called brain tumors, it is appropriate to consider them to be cancers
• MRI is the diagnostic tool of choice
• Primary brain tumor - tumor that starts in the brain
• Metastatic brain tumor - also called secondary brain tumor - occurs when cancer
spreads to the brain from another part of the body (often referred to as brain mets)
Statistics
• 86,970 will be diagnosed with a primary brain tumor in 2019
• 26,170 will be malignant
• 16,830 people will die from malignant brain tumors in 2019
• 5-year survival for glioblastoma = 5.6%
Pathology
• Brain tumor pathology first described by Virchow in 1865 as low-grade and
high-grade gliomas
• 1926 - first modern classification of glioblastoma by Bailey and Cushing
• Names based on cell from which tumor arises
• Tumors are graded, not staged
• 2016 - new WHO classification system
• More precise definitions based on molecular testing
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Neuroglial Cells
Central Nervous System
• Astrocytes
• Oligodendrocytes
• Ependymal cells
• Microglia
• Supportive
• Abundant
• Mitotic
Tumor Types - >130 types with many subtypes
• Meningioma (grade I), Atypical Meningioma (grade II), or
Anaplastic Meningioma (grade III)
• Oligodendroglioma (grade II) or Anaplastic Oligodendroglioma (grade III)
• Diffuse Glioma (grade II) or Anaplastic Diffuse Glioma (grade III)
• Astrocytoma (grade II) or Anaplastic Astrocytoma (grade III or IV)
• Glioblastoma or Gliosarcoma (grade IV)
• Features of high-grade tumors: hypercellular with abnormal mitoses, necrosis, and
microvascular proliferation
Case study, cont.
• Mother passed away from an anaplastic astrocytoma in 2002
• Has no known syndromes or conditions associated with a greater risk for
brain tumor development such as neurofibromatosis, Von Hippel-Lindau, Li
Fraumeni syndrome, or tuberous sclerosis
• Pathology: WHO grade IV Glioblastoma
• IDH1 negative, p53 variable, ATRX preserved
• Recommendation made for concurrent chemoradiation followed by
adjuvant chemotherapy with temozolomide
• Molecular testing – Foundation One
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Where have we been?
Timeline, through 1999
• 1958 – Dexamethasone developed – treats cerebral edema
• 1973 – CT scanning provides first clear images of brain tumor
• 1974 – First promising chemotherapy for glioma – carmustine (BCNU) – able to cross the blood-
brain barrier and directly attack glioma cells
• 1977 – Radiation established as standard treatment for glioblastoma - extended median survival
from ~ 3 months to ~ 9 months
• 1983 – MRI greatly improves ability to diagnose and monitor brain tumors
• 1990’s – 2005 – Procarbazine, Vincristine, and CCNU (lomustine) standard of care for
chemotherapeutic treatment - average life expectancy: 44 weeks
• 1999 – Temozolomide received accelerated approval
Timeline, 2000 - present
• 2003 – Carmustine (BCNU) chemotherapy wafers – delay tumor growth
• 2005 – Temozolomide approval for use in combination with radiation – 25% survival benefit -
increased survival to ~ 55 weeks
• Researchers begin mapping the genome of glioblastoma
• Patients with tumors carrying specific alteration in MGMT benefit from temozolomide therapy
• 2006 – Molecular sub-classification of high-grade gliomas predicts prognosis
• Genetic mutations (1p and 19q) affect survival in oligodendroglioma
• 2007 – FDA approves bevacizumab to treat glioblastoma – increased survival ~ 4 months
• 2009 – Gene mutations linked to tumor aggressiveness
• 2011 – Optune (Tumor Treating Fields) was approved for use in recurrent glioblastoma
• 2015 – Optune approved for newly diagnosed glioblastoma – increased survival from 15.6 to 20.5 mo
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Where
are
we
now?
Surgery
• Biopsy • Goal:
• Partial resection • Establish definitive diagnosis
• Gross total resection • Remove tumor
• Prolong survival
• Laser ablation
After surgery, anxiety over having to wait for final pathology
• What will treatment involve
• Where can treatment take place
• Clinical trial participation
Image from: http://seniorcitylocal.com/wp-content/uploads/2016/10/stroke-brain-regions.jpg
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Radiation
• Conventional
• 3 or 6 week course
• Concurrent chemotherapy
• Stereotactic Radiosurgery
• Proton Beam
• Gamma Knife
• Cyberknife
• Metastatic tumors – whole brain
Chemotherapy
• Cytotoxic agents - interfere with cell division, damage DNA, do not
discriminate between normal and cancer cells
• Temozolomide
• Carboplatin
• Etoposide
• Cyclophosphamide
• Methotrexate
• Can be given orally, IV, or IA
• Side effects include cytopenias, nausea, vomiting, and fatigue
• Adherence to oral medications
Tumor Treating Fields (TTF)
• Low voltage
electrical impulses
delivered in
alternating fields to
interrupt cell division,
resulting in cell death
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Standard of Care for Treatment of Glioblastoma
Maximal surgical resection followed by radiation with concurrent
temozolomide followed by adjuvant temozolomide and
alternating electric field therapy
Bevacizumab
• Anti-angiogenic drug
• Interferes with the development of blood vessels that tumors need to grow
and spread by blocking a protein called vascular endothelial growth
factor (VEGF)
• Normal cells make VEGF but some cancer cells make too much
• Blocking VEGF may prevent the growth of new blood vessels, inhibiting
growth of the tumor
• Used in the setting of disease recurrence/progression, radiation necrosis,
and pseudoprogression
Case study, cont.
• AZ underwent standard of care treatment with a 6-week course of
radiation with concurrent oral temozolomide as recommended
• Well-tolerated with only modest fatigue and constipation
• Started on adjuvant temozolomide at standard dose taking 5 days of drug
followed by 23 days off
• Molecular testing completed showing the patient was hypermutated
meaning there were many abnormal markers found in the tumor tissue
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Case Study: Molecular Testing Results
Usual findings AZ findings
4 mutations found 47 mutations found
The
Trouble
with
Brain
Tumors
Brain Protection
• Meninges – covers and protects the brain itself
• CSF – filters blood and waste in the CNS
• Blood-brain barrier – prevents most blood-borne toxins from entering the brain
• Estimated that 98% of FDA approved drugs do not cross the BBB
• Therefore, when there is a tumor in the brain, it is difficult to get agents such as
chemotherapy into the brain to treat the cancer
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Cost
• Has the highest per-patient initial cost of care for any cancer group, with
an annualized cost almost $150,000
• Also has the highest cost for the last-year-of-life care relative to other
cancers at $135,000 - $210,000 per-patient
• These costs do not take into account the personal cost due to cognitive
and functional disabilities, socioeconomic ramifications, or the out of
pocket dollars not covered by insurance
• Only four FDA approved drugs and one device have been approved to
treat brain tumors in the past 30 years
Where Do We Go From Here?
Research
• Through research, unique biological features that appear to influence a
tumor’s behavior and response to certain therapies are found. The findings
pave the way for future research that may help personalize therapy for
each tumor and patient, ensuring better outcomes and avoiding
unnecessary side-effects
• Between 1998 and 2014, there were 78 investigational brain tumor drugs
that entered the clinical trial evaluation process
• Of those 78 investigational drugs…
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75 Failed!!!
Clinical Trials
• Immunotherapy
• Vaccines
• Autologous – derived from one’s own tumor cells
• Allogeneic – developed in a lab from someone else's tumor
• Vaccines such as the polio vaccine
• Agents used in other tumor types
• Surgical interventions
• Radiation interventions
• Basket trials – target a specific gene alteration or molecular signature
rather than a specific tumor type
Personalized Medicine
• Patients desire a treatment plan geared toward their specific tumor and it’s
molecular/genetic make-up
• There is a gold-standard of treatment which must often be met before patients
branch out into clinical trials or other treatment regimens
• “Routine” molecular testing currently being done based on tumor type to identify
robust predictive biomarkers
• Genomic testing can identify mutations which can lead researchers to specific
drugs currently being used in other tumor types
• Cost can be astronomical. Who is going to pay for the treatment?
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Molecular Biomarkers
• MGMT • BRAF V600E • NF-2
• IDH1 • ATRX • CDK-6
• IDH2 • TERT • NTRK
• 1p • Tumor Mutational • Notch 2
Burden
• 19q • PD-L1
• Ki67 • Microsatellite Status • EGFR
• NF-1
• P53 • Many, many more
Molecular Testing
• 1p / 19q – codeletion is seen in Oligodendrogliomas
• Consistent with better response to chemotherapy and improved survival
• IDH 1 and 2 – Isocitrate dehydrogenase – positivity consistent with a lower-grade tumor
• Associated with a more favorable prognosis
• Located on a pathway that governs the metabolic function of cells and mutations to these genes may
enable abnormal, or cancerous, cells to form
• TP53 - plays a role in apoptosis and suppresses the cell cycle
• Involved in triggering the development and spread of glioblastoma
• MGMT - O6-methylguanine methyltransferase - involved in repairing DNA damage in cancer cells
• Tumors with a genetic alteration that silence this gene are unable to repair the damage caused by
temozolomide and therefore are more susceptible to the drug
• Tumors without this gene alteration are more resistant to the drug
• Tumor Mutational Burden – refers to the total amount of cancer tissue in the body
• found in < 3% of glioblastoma patients
Molecular Markers
• ATRX - plays a key role in gene expression regulation
• BRAF V600E – rarely found in high-grade gliomas. Common in pediatric population
• TERT – telomerase reverse transcriptase
• When mutated, allows for unlimited proliferative activation. Poor prognosis/survival noted
• PD-1/PD-L1 – programmed cell death protein 1 and PD-ligand 1
• Limited data to show consistent benefit
• Pembrolizumab and Nivolumab
• EGFR – epidermal growth factor receptor
• Found in many cancers (glioblastoma) which now have targeted drugs (tyrosine kinase
inhibitors) to use as treatment
• High EGFR expression associated with a poor prognosis
• Ki-67 – a protein in cells which increases when a cell is preparing to divide
• May be predictive of poor prognosis when it is overexpressed
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Case Study, cont.
• Based on the molecular testing, temozolomide was contraindicated and
stopped as there was evidence that in patients who are hypermutated,
chemotherapy such as temozolomide could actually cause tumor growth
• Pembrolizumab was started based on the molecular testing
• Thyroid problems occurred requiring Endocrinology involvement
• Chose to pursue a vaccine in Germany (vaccine cost > $100,000)
• All expenses were out of pocket for vaccine development, travel, extended
stays in Germany.
Of ~ 50 patients with molecular testing completed, this is the ONLY case
found to have significant abnormalities altering the treatment plan
Summary
• Brain tumors carry dismal statistics with regard to survival and cost
• Over the past 20 years, we have seen relatively small gains in survival
(glioblastoma: 44w to 65w) and treatment options compared to other
tumor types
• Research and clinical trials, especially in the area of immunotherapy, are
absolutely necessary to further impact survival with molecular testing
being at the forefront
• Survival isn’t enough! We need to identify how to protect the brain from
the long-term effects of treatment which often results in significant
cognitive impairment and decreased quality of life
REFERENCES
• Aquilanti, E., Miller, J., Santagata, S. Cahill, D. P., & Brastianos, P. K. (2018). Updates in prognostic markers for
gliomas. Neuro-Oncology, 20(S7), 17-26. doi: 10:1093/neuonc/noy158
• Cominelli, M., Grisanti, S., Mzaaoleni, S., Branca, C., Buttolo, L., Furlan, D.,…Poliani, P. L. (2015). EGFR amplified
and overexpressing glioblastomas and association with better response to adjuvant metronomic
temozolomide. Journal of the National Cancer Institute, 107(5), djv041. doi: 10.1093/jnci/djv041
• Eckel-Passow, J. E., Lachance, D. H., Molinaro, A. M., Walsh, K. M., Decker, P. A., Sicotte, H.,…Jenkins, R. B.
(2015). Glioma groups based on 1p/19q, IDH, and TERT promoter mutations in tumors. The New England
Journal of Medicine, 372(26), 1-10. doi: 10.1056/NEJMoa1407279
• Gittleman, H., Boscia, A., Ostrom, Q. T., Truitt, G. T., Fritz, Yi., Kruchko, C., Barnholtz-Sloan, J. S. (2018), Survivorship
in adults with malignant brain and other central nervous system tumor from 2000-2014. Neuro-Oncology,
20(S7), 6-16. doi: 10.1093/neuonc/nay090
• Hegi, M. E., Diserens, A., Gorlia, T., Hamou, M., de Tribolet, N., Weller, M.,…Stupp, R. (2005). MGMT gene
silencing and benefit from temozolomide in glioblastoma. The New England Journal of Medicine, 352(10), 997-
1003. Retrieved nejm.org
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• Horbinski, C. (2013). To BRAF or not to BRAF: is that even a question anymore? Journal of Neuropathology
and Experimental Neurology 72(1), 2-7. doi: 10.1097/NEN.0b013e318279f3db
• Louis, D. N., Perry, A., Reifenberger, G., von Deimling, A., Figarella-Branger, D., Cavenee, W. K., … Ellison, D.
W. (2016). The 2016 world health organization classification of tumor of the central nervous system: a
summary. Acta Neuropathologica, 131, 803-820. doi:10/1007/s00401-016-1545-1
• National Brain Tumor Society. http://braintumor.org/brain-tumor-information/brain-tumor-facts/
• National Cancer Institute. https://seer.cancer.gov/statfacts/html/brain.html#risk
• Parsons, D. W., Jones, S., Zhang, X., Cheng-Ho Lin, J., Leary, R.J., Angenendt, P., … Kinzler, K. W. (2008). An
integrated genomic analysis of human glioblastoma multiforme. Science: 321: 1807-1812. Retrieved from
http://science.sciencemag.org/
• The Cancer Genome Atlas Research Network. (2015). Comprehensive, integrative genomic analysis of
diffuse lower-grade gliomas. The New England Journal of Medicine, 372(26), 2481-2498. doi:
10.1056/NEJMoa1402121
• Yan, H., Parsons, D. W., Jin, G., McLendon, R., Rasheed, B., A., Yuan, W.,…Bigner, D. D. (2009). IDH1 and
IDH2 mutations in gliomas. The New England Journal of Medicine, 360(8), 765-773. Retrieved nejm.org
TO CONTACT ME
• Patti Bruns MSN, APRN, CNS
• Givens Brain Tumor Center
• Abbott Northwestern Hospital
• Piper building, suite 304
• Patricia.Bruns@Allina.com
• 612.863.3732
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