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01-11-2019 | Glioblastoma | Clinical Study

Negative prognostic impact of epidermal growth factor receptor copy number gain in young adults with isocitrate dehydrogenase wild-type glioblastoma

Authors: Daniel I. Hoffman, Kalil G. Abdullah, Makayla McCoskey, Zev A. Binder, Donald M. O’Rourke, Arati S. Desai, MacLean P. Nasrallah, Ashkan Bigdeli, Jennifer J. D. Morrissette, Steven Brem, Stephen J. Bagley

Published in: Journal of Neuro-Oncology | Issue 2/2019

Abstract

Purpose

Young adults with isocitrate-dehydrogenase wild-type (IDH-WT) glioblastoma (GBM) represent a rare, understudied population compared to pediatric high-grade glioma, IDH-mutant GBM, or IDH-WT GBM in older patients. We aimed to explore the prognostic impact of epidermal growth factor receptor copy number gain (EGFR CN gain), one of the most common genetic alterations in IDH-WT glioma, in young adults with IDH-WT GBM.

Methods

We performed a retrospective cohort study of patients 18–45 years old with newly diagnosed, IDH-WT GBM whose tumors underwent next-generation sequencing at our institution between 2014 and 2018. The impact of EGFR CN gain on time to tumor progression (TTP) and overall survival (OS) was assessed. A validation cohort of patients 18–45 years old with IDH-WT GBM was analyzed from The Cancer Genome Atlas (TCGA).

Results

Ten of 28 patients (36%) from our institution had EGFR CN gain, which was associated with shorter TTP (median 6.5 vs. 11.9 months; p = 0.06) and OS (median 16.3 vs. 23.5 months; p = 0.047). The negative prognostic impact of EGFR CN gain on OS persisted in a multivariate model (HR 6.40, 95% CI 1.3–31.0, p = 0.02). In the TCGA cohort (N = 43), EGFR CN gain was associated with shorter TTP and worse OS, although these did not reach statistical significance (TTP, median 11.5 vs. 14.4 months, p = 0.18; OS, median 23.6 vs. 27.8 months; p = 0.18).

Conclusions

EGFR CN gain may be associated with inferior outcomes in young adults with newly diagnosed, IDH-WT GBM, suggesting a potential role for targeting EGFR in this population.

Ostrom QT, Gittleman H, Liao P et al (2017) CBTRUS Statistical Report: primary brain and other central nervous system tumors diagnosed in the United States in 2010–2014. Neuro Oncol 19(suppl_5):v1–v88. https://doi.org/10.1093/neuonc/nox158 CrossRefPubMedPubMedCentral

Ohgaki H, Kleihues P (2007) Genetic pathways to primary and secondary glioblastoma. Am J Pathol 170(5):1445–1453. https://doi.org/10.2353/ajpath.2007.070011 CrossRefPubMedPubMedCentral

Ohgaki H, Dessen P, Jourde B et al (2004) Genetic pathways to glioblastoma. Cancer Res 64(19):6892–6899. https://doi.org/10.1158/0008-5472.CAN-04-1337 CrossRefPubMed

Sanson M, Marie Y, Paris S et al (2009) Isocitrate dehydrogenase 1 codon 132 mutation is an important prognostic biomarker in gliomas. J Clin Oncol 27(25):4150–4154. https://doi.org/10.1200/JCO.2009.21.9832 CrossRefPubMed

Hamisch C, Ruge M, Kellermann S et al (2017) Impact of treatment on survival of patients with secondary glioblastoma. J Neurooncol 133(2):309–313. https://doi.org/10.1007/s11060-017-2415-y CrossRefPubMed

Popov S, Jury A, Laxton R et al (2013) IDH1-associated primary glioblastoma in young adults displays differential patterns of tumour and vascular morphology. PLoS ONE 8(2):e56328. https://doi.org/10.1371/journal.pone.0056328 CrossRefPubMedPubMedCentral

Jha P, Suri V, Singh G et al (2011) Characterization of molecular genetic alterations in GBMs highlights a distinctive molecular profile in young adults. Diagnostic Mol Pathol 20(4):225–232. https://doi.org/10.1097/PDM.0b013e31821c30bc CrossRef

Kiesel S, Pezzutto A, Haas R, Moldenhauer G, Dörken B (1988) Functional evaluation of CD19- and CD22-negative variants of B-lymphoid cell lines. Immunology 64(3):445–450PubMedPubMedCentral

Vadgaonkar R, Epari S, Chinnaswamy G et al (2018) Distinct demographic profile and molecular markers of primary CNS tumor in 1873 adolescent and young adult patient population. Child’s Nerv Syst 34(8):1489–1495. https://doi.org/10.1007/s00381-018-3785-y CrossRef

10.

Flavahan WA, Drier Y, Liau BB et al (2016) Insulator dysfunction and oncogene activation in IDH mutant gliomas. Nature 529(7584):110–114. https://doi.org/10.1038/nature16490 CrossRefPubMed

11.

Parsons DW, Jones S, Zhang X et al (2008) An integrated genomic analysis of human glioblastoma multiforme. Science (80-) 321(5897):1807–1812. https://doi.org/10.1126/science.1164382 CrossRef

12.

Louis DN, Perry A, Reifenberger G et al (2016) The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol 131(6):803–820. https://doi.org/10.1007/s00401-016-1545-1 CrossRefPubMed

13.

Figueroa ME, Abdel-Wahab O, Lu C et al (2010) Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell 18(6):553–567. https://doi.org/10.1016/j.ccr.2010.11.015 CrossRefPubMedPubMedCentral

14.

Waitkus MS, Diplas BH, Yan H (2016) Isocitrate dehydrogenase mutations in gliomas. Neuro Oncol 18(1):16–26. https://doi.org/10.1093/neuonc/nov136 CrossRefPubMed

15.

Jones C, Karajannis MA, Jones DTW et al (2016) Pediatric high-grade glioma: biologically and clinically in need of new thinking. Neuro Oncol 19(2):now101. https://doi.org/10.1093/neuonc/now101 CrossRef

16.

Wick W, van den Bent MJ (2018) First results on the DCVax phase III trial: raising more questions than providing answers. Neuro Oncol 20(10):1283–1284. https://doi.org/10.1093/neuonc/noy125 CrossRefPubMedPubMedCentral

17.

Ferguson SD, Xiu J, Weathers S-P et al (2016) GBM-associated mutations and altered protein expression are more common in young patients. Oncotarget 7(43):69466–69478. https://doi.org/10.18632/oncotarget.11617 CrossRefPubMedPubMedCentral

18.

Zhang R, Shi Z, Chen H et al (2016) Biomarker-based prognostic stratification of young adult glioblastoma. Oncotarget 7(4):5030–5041. https://doi.org/10.18632/oncotarget.5456 CrossRefPubMed

19.

Brennan CW, Verhaak RGW, McKenna A et al (2013) The somatic genomic landscape of glioblastoma. Cell 155(2):462–477. https://doi.org/10.1016/j.cell.2013.09.034 CrossRefPubMedPubMedCentral

20.

Binder ZA, Thorne AH, Bakas S et al (2018) Epidermal growth factor receptor extracellular domain mutations in glioblastoma present opportunities for clinical imaging and therapeutic development. Cancer Cell 34(1):163–177.e7. https://doi.org/10.1016/j.ccell.2018.06.006 CrossRefPubMedPubMedCentral

21.

Thompson JC, Yee SS, Troxel AB et al (2016) Detection of therapeutically targetable driver and resistance mutations in lung cancer patients by next-generation sequencing of cell-free circulating tumor DNA. Clin Cancer Res 22(23):5772–5782. https://doi.org/10.1158/1078-0432.CCR-16-1231 CrossRefPubMedPubMedCentral

22.

Talevich E, Shain AH, Botton T, Bastian BC (2016) CNVkit: genome-wide copy number detection and visualization from targeted DNA sequencing. PLoS Comput Biol 12(4):e1004873. https://doi.org/10.1371/journal.pcbi.1004873 CrossRefPubMedPubMedCentral

23.

Liu J, Lichtenberg T, Hoadley KA et al (2018) An integrated TCGA pan-cancer clinical data resource to drive high-quality survival outcome analytics. Cell 173(2):400–416.e11. https://doi.org/10.1016/j.cell.2018.02.052 CrossRefPubMedPubMedCentral

24.

Chen J-R, Xu H-Z, Yao Y, Qin Z-Y (2015) Prognostic value of epidermal growth factor receptor amplification and EGFRvIII in glioblastoma: meta-analysis. Acta Neurol Scand 132(5):310–322. https://doi.org/10.1111/ane.12401 CrossRefPubMed

25.

Smith JS, Tachibana I, Passe SM et al (2001) PTEN mutation, EGFR amplification, and outcome in patients with anaplastic astrocytoma and glioblastoma multiforme. J Natl Cancer Inst 93(16):1246–1256CrossRefPubMed

26.

Shinojima N, Tada K, Shiraishi S et al (2003) Prognostic value of epidermal growth factor receptor in patients with glioblastoma multiforme. Cancer Res 63(20):6962–6970PubMed

27.

Brodbelt A, Greenberg D, Winters T et al (2015) Glioblastoma in England: 2007–2011. Eur J Cancer 51(4):533–542. https://doi.org/10.1016/j.ejca.2014.12.014 CrossRefPubMed

28.

Curran WJ, Scott CB, Horton J et al (1993) Recursive partitioning analysis of prognostic factors in three Radiation Therapy Oncology Group malignant glioma trials. J Natl Cancer Inst 85(9):704–710CrossRefPubMed

29.

Yan H, Parsons DW, Jin G et al (2009) IDH1 and IDH2 mutations in gliomas. N Engl J Med 360(8):765–773. https://doi.org/10.1056/NEJMoa0808710 CrossRefPubMedPubMedCentral

30.

Yang P, Zhang W, Wang Y et al (2015) IDH mutation and MGMT promoter methylation in glioblastoma: results of a prospective registry. Oncotarget 6(38):40896–40906. https://doi.org/10.18632/oncotarget.5683 CrossRefPubMedPubMedCentral

31.

Hartmann C, Hentschel B, Simon M et al (2013) Long-term survival in primary glioblastoma with versus without isocitrate dehydrogenase mutations. Clin Cancer Res 19(18):5146–5157. https://doi.org/10.1158/1078-0432.CCR-13-0017 CrossRefPubMed

32.

Molenaar RJ, Verbaan D, Lamba S et al (2014) The combination of IDH1 mutations and MGMT methylation status predicts survival in glioblastoma better than either IDH1 or MGMT alone. Neuro Oncol 16(9):1263–1273. https://doi.org/10.1093/neuonc/nou005 CrossRefPubMedPubMedCentral

33.

Ohgaki H, Kleihues P (2013) The definition of primary and secondary glioblastoma. Clin Cancer Res 19(4):764–772. https://doi.org/10.1158/1078-0432.CCR-12-3002 CrossRefPubMed

34.

Miller JJ, Shih HA, Andronesi OC, Cahill DP (2017) Isocitrate dehydrogenase-mutant glioma: evolving clinical and therapeutic implications. Cancer 123(23):4535–4546. https://doi.org/10.1002/cncr.31039 CrossRefPubMed

35.

Berghoff AS, Kiesel B, Widhalm G et al (2017) Correlation of immune phenotype with IDH mutation in diffuse glioma. Neuro Oncol 19(11):1460–1468. https://doi.org/10.1093/neuonc/nox054 CrossRefPubMedPubMedCentral

36.

Turcan S, Rohle D, Goenka A et al (2012) IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature 483(7390):479–483. https://doi.org/10.1038/nature10866 CrossRefPubMedPubMedCentral

37.

Karpel-Massler G, Ishida CT, Bianchetti E et al (2017) Induction of synthetic lethality in IDH1-mutated gliomas through inhibition of Bcl-xL. Nat Commun 8(1):1067. https://doi.org/10.1038/s41467-017-00984-9 CrossRefPubMedPubMedCentral

38.

Molenaar RJ, Botman D, Smits MA et al (2015) Radioprotection of IDH1-mutated cancer cells by the IDH1-mutant inhibitor AGI-5198. Cancer Res 75(22):4790–4802. https://doi.org/10.1158/0008-5472.CAN-14-3603 CrossRefPubMed

39.

Sulkowski PL, Corso CD, Robinson ND et al (2017) 2-Hydroxyglutarate produced by neomorphic IDH mutations suppresses homologous recombination and induces PARP inhibitor sensitivity. Sci Transl Med 9(375):eaal2463. https://doi.org/10.1126/scitranslmed.aal2463 CrossRefPubMedPubMedCentral

40.

Dang L, Yen K, Attar EC (2016) IDH mutations in cancer and progress toward development of targeted therapeutics. Ann Oncol 27(4):599–608. https://doi.org/10.1093/annonc/mdw013 CrossRefPubMed

41.

Leibetseder A, Ackerl M, Flechl B et al (2013) Outcome and molecular characteristics of adolescent and young adult patients with newly diagnosed primary glioblastoma: a study of the Society of Austrian Neurooncology (SANO). Neuro Oncol 15(1):112–121. https://doi.org/10.1093/neuonc/nos283 CrossRefPubMed

42.

Kleinschmidt-DeMasters BK, Meltesen L, McGavran L, Lillehei KO (2006) Characterization of glioblastomas in young adults. Brain Pathol 16(4):273–286. https://doi.org/10.1111/j.1750-3639.2006.00029.x CrossRefPubMedPubMedCentral

43.

Korshunov A, Sycheva R, Golanov A (2005) The prognostic relevance of molecular alterations in glioblastomas for patients age %3c 50 years. Cancer 104(4):825–832. https://doi.org/10.1002/cncr.21221 CrossRefPubMed

44.

Zou P, Xu H, Chen P et al (2013) IDH1/IDH2 mutations define the prognosis and molecular profiles of patients with gliomas: a meta-analysis. PLoS ONE 8(7):e68782. https://doi.org/10.1371/journal.pone.0068782 CrossRefPubMedPubMedCentral

45.

Lassman AB, Roberts-Rapp L, Sokolova I et al (2019) Comparison of biomarker assays for EGFR: implications for precision medicine in patients with glioblastoma. Clin Cancer Res 25(11):3259–3265. https://doi.org/10.1158/1078-0432.CCR-18-3034 CrossRefPubMedPubMedCentral

46.

Lassman AB, van den Bent MJ, Gan HK et al (2019) Safety and efficacy of depatuxizumab mafodotin + temozolomide in patients with EGFR -amplified, recurrent glioblastoma: results from an international phase I multicenter trial. Neuro Oncol 21(1):106–114. https://doi.org/10.1093/neuonc/noy091 CrossRefPubMed

47.

Zhao J, Chen AX, Gartrell RD et al (2019) Immune and genomic correlates of response to anti-PD-1 immunotherapy in glioblastoma. Nat Med. https://doi.org/10.1038/s41591-019-0349-y CrossRefPubMedPubMedCentral

Title: Negative prognostic impact of epidermal growth factor receptor copy number gain in young adults with isocitrate dehydrogenase wild-type glioblastoma
Authors: Daniel I. Hoffman
Kalil G. Abdullah
Makayla McCoskey
Zev A. Binder
Donald M. O’Rourke
Arati S. Desai
MacLean P. Nasrallah
Ashkan Bigdeli
Jennifer J. D. Morrissette
Steven Brem
Stephen J. Bagley
Publication date: 01-11-2019
Publisher: Springer US
Keywords: Glioblastoma
Glioblastoma
Glioblastoma
Published in: Journal of Neuro-Oncology / Issue 2/2019
Print ISSN: 0167-594X
Electronic ISSN: 1573-7373
DOI: https://doi.org/10.1007/s11060-019-03298-6

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Negative prognostic impact of epidermal growth factor receptor copy number gain in young adults with isocitrate dehydrogenase wild-type glioblastoma

Abstract

Purpose

Methods

Results

Conclusions

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusions

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