Brain Cancer

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Glioblastoma accounts for over 46% of all primary malignant brain and CNS tumors.1

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Only 5% of patients survive 5 years past diagnosis.1

Incidence & Mortality

Glioblastoma (GBM) is the most common form of malignant brain and CNS tumors.1

  • Over 12,000 persons are diagnosed with malignant GBM each year in the US.1,2
  • Approximately 94% of new GBM cases are diagnosed in persons over the age of 40 years; ~50% are in persons aged over 65 years.1
  • Median age at diagnosis is 64 years.1
  • GBM is 1.6 times more common in males; incidence is about 2 times higher among whites than blacks.1

GBM is a highly lethal cancer.

  • Relative overall 1-, 5-, and 10-year survival rates are 37.2%, 5.1%, and 2.6%, respectively.1
  • These rates drop to 34.9%, 3.7%, and 1.7% in adults ≥40 years at diagnosis.1

GBM is a difficult-to-treat brain tumor marked by an extremely rapid cell-division rate and extensive brain infiltration.3

The cause of GBM is unknown. An increased risk of developing GBMhas been associated with4:

  • Exposure to ionizing irradiation
  • Rare hereditary syndromes (ie, Cowden-, Turcot-, Lynch-, and Li-Fraumeni syndromes and neurofibromatosis type 1)

Genetic and epigenetic changes contribute to the intratumor heterogeneity of GBM, and have detrimental effects on treatment resistance and residual disease. Significant genetic variance is observed between samples from the same tumor mass.5

Alterations affecting established signal transduction and tumor suppressor pathways have been identified.5

  • Amplification and subsequent overexpression of the receptor tyrosine kinases EGFR, PDGFRA, MET and FGFR, PIK3 and CDK4 are detected, as are deletions and mutations of PTEN, TP53 and CDKN2A/B.5
  • The most common genetic alterations in GBM are those of the EGFR gene, occurring in approximately 60% of tumors.6,7
    • Amplification occurs in up to 50% of GBM tumors and usually remains unchanged at the time of tumor recurrence.6,7
    • EGFRvIII is the most common mutation in GBM, producing a receptor with a truncated extracellular domain and ligand-independent constitutive activity.7,8
    • About 50% of GBMs with EGFR amplification also harbor the EGFRvIII deletion variant (i.e., ~25% of all GBM).7,8

Brain tumors usually are detected by computed tomography (CT) or magnetic resonance imaging (MRI) after patients present with symptoms, but the final diagnosis of type or grade is not made until after the tumor is surgically removed and pathologically examined.4,9

Symptoms include9:

  • Headaches
  • Seizures
  • Neurological deficits (ie, loss of vision, language or sensation)
  • Personality and behavioral changes
  • Memory loss

In the past, brain tumors were classified based on their histology (putative cell of origin and level of differentiation). The 2016 World Health Organization (WHO) classification of central nervous system tumors still uses histology to define tumor entities, but does so in conjunction with molecular parameters and genetic characteristics.10

Glioblastoma are grade IV diffuse astrocytic or oligodendroglial tumors and are delineated as either IDH-wild type (~90% of cases) or IDH-mutant.10

  • WHO II (low-grade) and WHO III (anaplastic) diffuse gliomas can follow protracted clinical courses lasting years or even decades.11
  • WHO IV glioblastoma demonstrate median survival of approximately 15 months.11

There are 2 types of GBM10,12:

  • GBM, IDH-wildtype or primary GBM (~90% of cases) develop rapidly de novo without clinical or histologic evidence of a lower-grade glioma.
    • Predominates in patients >55 years of age
  • GBM, IDH-mutant or secondary GBM (~10% of cases) progress from lower-grade gliomas and carry a significantly better prognosis.
    • Preferentially arise in younger patients

Current standard of care for newly diagnosed patients4:

  • Surgery for tumor debulking and obtaining tissue for evaluation
  • Followed by chemotherapy and radiotherapy

IDH-wild type tumors often show a similar molecular profile to primary glioblastomas, with enrichment for EGFR amplification, PTEN loss, and PI3K/AKT pathway activation, as well as unfavorable outcomes regardless of grade.11

  • Grade III histology and EGFR amplification are independent adverse prognostic indicators of IDH-wild type astrocytoma.13

IDH-mutant tumors often exhibit TP53 mutations and platelet-derived growth factor receptor (PDGFRA) overexpression, and correlate with a benefit to survival, even after WHO grade stratification.11

Unfortunately, most patients will have a recurrence of GBM within 2 years of their original diagnosis.14,15

Available targeted agents affecting growth factor signaling pathways have demonstrated limited-to-no therapeutic efficacy.4

Treatment options are limited and offer only modest survival benefits for newly-diagnosed patients. Overcoming the systemic toxicity of conventional agents via tumor-specific carriers with targeted drug delivery may improve outcomes for these patients.

Glioblastoma has a high rate of recurrence, and median survival is less than 7 months in the recurrent setting.16

  • For recurrent GBM, reoperation may have only a modest benefit
    • In one study, median survival after reoperation was 36 weeks versus 23 weeks for patients who did not undergo reoperation.14
  • There are few treatment options to offer patients at disease recurrence. Targeted drug-delivery may provide a benefit for these patients.

Relevant Biomarker Pathways

  1. Ostrom QT, Gittleman H, Fulop J, et al. CBTRUS Statistical Report: Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2008-2012. Neuro Oncol. 2015;17 Suppl 4:iv1-iv62.
  2. Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2017. CA Cancer J Clin. 2017;67(1):7-30.
  3. Korshunov A, Sycheva R, Golanov A. The prognostic relevance of molecular alterations in glioblastomas for patients <50. Cancer. 2005;104(4):825-832.
  4. Stupp R, Brada M, van den Bent MJ, et al. High-grade glioma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2014;25(3):iii93-iii101.
  5. Ellis HP, Greenslade M, Powell B, et al. Current challenges in glioblastoma: intratumour heterogeneity, residual disease, and models to predict disease recurrence. Front Oncol. 2015;5:1-8.
  6. van den Bent MJ, Gao Y, Kerkhof M, et al. Changes in the EGFR amplification and EGFRvIII expression between paired primary and recurrent glioblastomas. Neuro Oncol. 2015;17(7):935-941.
  7. Gan HK, Cvrljevic AN, Johns TG. The epidermal growth factor receptor variant III (EGFRvIII): where wild things are altered. FEBS J. 2013;280:5350-5370.
  8. Zhao LI, Xu KI, Wang SW, et al. Pathological significance of epidermal growth factor receptor expression and amplification in human gliomas. Histopathology. 2012;61:726-736.
  9. Young RM, Jamshidi A, Davis G, Sherman JH. Current trends in the surgical management and treatment of adult glioblastoma. Ann Transl Med. 2015;3(9):121.
  10. Louis DN, Perry A, Reifenberger G, et al. The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol. 2016;131(6):803-820.
  11. Groovets D, Kannan K, Shen R, et al. IDH mutation and neuroglial developmental features define clinically distinct subclasses of lower grade diffuse astrocytic glioma. Clin Cancer Res. 2012;18(9):2490-2501.
  12. Ohgaki H, Kleihues P. The definition of primary and secondary glioblastoma. Clin Cancer Res. 2012;19(4):764-772.
  13. Aibaidula A, Chan AK, Shi Z, et al. Adult IDH wild-type lower-grade gliomas should be further stratified. Neuro Oncol. 2017;19(10):1327-1337.
  14. Barker FG, Chang SM, Gutin PH, Survival and functional status after resection of recurrent glioblastoma multiforme. Neurosurgery. 1998;42(4):709-720.
  15. Weller M, Cloughesy, Perry JR, Wick W. Standards of care for treatment of recurrent glioblastoma-are we there yet? Neuro Oncol. 2013;15(1):4-27.
  16. Wong ET, Hess KR, Gleason MJ, et al. Outcomes and prognostic factors in recurrent glioma patients enrolled onto phase II clinical trials. J Clin Oncol. 1999;17(8):2572-2758.
  17. Phillips AC, Boghaert ER, Vaidya KS, et al. ABT-414, an antibody-drug conjugate targeting a tumor-selective EGFR epitope. Mol Cancer Ther. 2016 Apr;15(4):661-669.

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