Genomic alterations predictive of response to radiosurgery in recurrent IDH-WT glioblastoma



Despite aggressive treatment, glioblastoma invariably recurs. The optimal treatment for recurrent glioblastoma (rGBM) is not well defined. Stereotactic radiosurgery (SRS) for rGBM has demonstrated favorable outcomes for selected patients; however, its efficacy in molecular GBM subtypes is unknown. We sought to identify genetic alterations that predict response/outcomes from SRS in rGBM-IDH-wild-type (IDH-WT).


rGBM-IDH-WT patients undergoing SRS at first recurrence and tested by next-generation sequencing (NGS) were reviewed (2009–2018). Demographic, clinical, and molecular characteristics were evaluated. NGS interrogating 205-genes was performed. Primary outcome was survival from GK-SRS assessed by Kaplan-Meier method and multivariable Cox proportional-hazards.


Sixty-three lesions (43-patients) were treated at 1st recurrence. Median age was 61-years. All patients were treated with resection and chemoradiotherapy. Median time from diagnosis to 1st recurrence was 8.7-months. Median cumulative volume was 2.895 cm3 and SRS median marginal dose was 18 Gy (median isodose-54%). Bevacizumab was administered in 81.4% patients. PFS from SRS was 12.9-months. Survival from SRS was 18.2-months. PTEN-mutant patients had a longer PFS (p = 0.049) and survival from SRS (p = 0.013) in multivariable analysis. Although no statistically significant PTEN-mutants patients had higher frequency of radiation necrosis (21.4% vs. 3.4%) and lower in-field recurrence (28.6% vs. 37.9%) compared to PTEN-WT patients.


SRS is a safe and effective treatment option for selected rGBM-IDH-WT patients following first recurrence. rGBM-IDH-WT harboring PTEN-mutation have improved survival with salvage SRS compared to PTEN-WT patients. PTEN may be used as a molecular biomarker to identify a subset of rGBM patients who may benefit the most from SRS.

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Availability of data and materials

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.


  1. 1.

    Ostrom QT, Cioffi G, Gittleman H et al (2019) CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2012–2016. Neuro-Oncology 21:v1–v100.

    Article  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Zhu P, Du XL, Zhu J-J, Esquenazi Y (2019) Improved survival of glioblastoma patients treated at academic and high-volume facilities: a hospital-based study from the National Cancer Database. J Neurosurg 132(2):491–502.

    Article  PubMed  Google Scholar 

  3. 3.

    Stupp R, Mason WP, van den Bent MJ et al (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996.

    CAS  Article  Google Scholar 

  4. 4.

    Reardon DA, Brandes AA, Omuro A, et al (2020) Effect of Nivolumab vs Bevacizumab in patients with recurrent glioblastoma the checkmate 143 phase 3 randomized clinical trial. 5450:1–8.

  5. 5.

    Suchorska B, Weller M, Tabatabai G et al (2016) Complete resection of contrast-enhancing tumor volume is associated with improved survival in recurrent glioblastoma—results from the DIRECTOR trial. Neuro-Oncology 18:549–556.

    Article  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Wen PY, Weller M, Lee EQ et al (2020) Glioblastoma in adults: a Society for Neuro-Oncology (SNO) and European Society of Neuro-Oncology (EANO) consensus review on current management and future directions. Neuro-Oncology 22(8):1073–1113.

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Tsien C, Pugh S, Dicker A et al (2019) ACTR-32. NRG oncology RTOG 1205: randomized phase II trial of concurrent Bevacizumab and Re-irradiation vs. Bevacizumab aone as treatment for recurrent glioblastoma. Neuro-Oncology 21:vi20.

    Article  PubMed Central  Google Scholar 

  8. 8.

    Niranjan A, Kano H, Iyer A et al (2015) Role of adjuvant or salvage radiosurgery in the management of unresected residual or progressive glioblastoma multiforme in the pre-bevacizumab era. J Neurosurg 122:757–765.

    Article  PubMed  Google Scholar 

  9. 9.

    Imber BS, Kanungo I, Braunstein S et al (2017) Indications and efficacy of gamma knife stereotactic radiosurgery for recurrent glioblastoma: 2 decades of institutional experience. Neurosurgery 80:129–139.

    Article  PubMed  Google Scholar 

  10. 10.

    Morris SAL, Zhu P, Rao M et al (2019) Gamma knife stereotactic radiosurgery in combination with Bevacizumab for recurrent glioblastoma. World Neurosurg 127:e523–e533.

    Article  PubMed  Google Scholar 

  11. 11.

    Sharma M, Schroeder JL, Elson P et al (2019) Outcomes and prognostic stratification of patients with recurrent glioblastoma treated with salvage stereotactic radiosurgery. J Neurosurg 131:489–499.

    Article  Google Scholar 

  12. 12.

    Elliott RE, Parker EC, Rush SC et al (2011) Efficacy of gamma knife radiosurgery for small-volume recurrent malignant gliomas after initial radical resection. World Neurosurg 76:128–140.

    Article  PubMed  Google Scholar 

  13. 13.

    Skeie BS, Enger PO, Brogger J et al (2012) Gamma knife surgery versus reoperation for recurrent glioblastoma multiforme. World Neurosurg 78:658–669.

    Article  PubMed  Google Scholar 

  14. 14.

    Kong DS, Lee JI, Park K et al (2008) Efficacy of stereotactic radiosurgery as a salvage treatment for recurrent malignant gliomas. Cancer 112:2046–2051.

    Article  PubMed  Google Scholar 

  15. 15.

    Pouratian N, Crowley RW, Sherman JH et al (2009) Gamma Knife radiosurgery after radiation therapy as an adjunctive treatment for glioblastoma. J Neuro-Oncol 94:409–418.

    CAS  Article  Google Scholar 

  16. 16.

    Hsieh PC, Chandler JP, Bhangoo S et al (2005) Adjuvant gamma knife stereotactic radiosurgery at the time of tumor progression potentially improves survival for patients with glioblastoma multiforme. Neurosurgery 57:684–692.

    Article  PubMed  Google Scholar 

  17. 17.

    McLendon R, Friedman A, Bigner D et al (2008) Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455:1061–1068.

    CAS  Article  Google Scholar 

  18. 18.

    Yan H, Parsons DW, Jin G et al (2009) IDH1 and IDH2 mutations in gliomas. N Engl J Med 360:765–773.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Eckel-Passow JE, Lachance DH, Molinaro AM et al (2015) Glioma groups based on 1p/19q, IDH, and TERT promoter mutations in tumors. N Engl J Med 372:2499–2508.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. 20.

    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 131:803–820.

    Article  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Harris PA, Taylor R, Minor BL et al (2019) The REDCap consortium: building an international community of software platform partners. J Biomed Inform 95:103208.

    Article  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Esquenazi Y, Friedman E, Liu Z et al (2017) The survival advantage of “supratotal” resection of glioblastoma using selective cortical mapping and the subpial technique. Neurosurgery 81:275–288.

    Article  PubMed  Google Scholar 

  23. 23.

    Arevalo OD, Soto C, Rabiei P et al (2019) Assessment of glioblastoma response in the era of bevacizumab: longstanding and emergent challenges in the imaging evaluation of pseudoresponse. Front Neurol 10:1–12.

    Article  Google Scholar 

  24. 24.

    Shaw E, Scott C, Souhami L et al (1996) Radiosurgery for the treatment of previously irradiated recurrent primary brain tumors and brain metastases: initial report of radiation therapy oncology group protocol 90-05. Int J Radiat Oncol Biol Phys 34:647–654.

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    Abbassy M, Missios S, Barnett GH et al (2018) Phase i trial of radiosurgery dose escalation plus bevacizumab in patientswith recurrent/progressive glioblastoma. Clin Neurosurg 83:385–392.

    Article  Google Scholar 

  26. 26.

    Wen PY, Macdonald DR, Reardon DA et al (2010) Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group. J Clin Oncol 28:1963–1972.

    Article  PubMed  Google Scholar 

  27. 27.

    Ene CI, Macomber MW, Barber JK et al (2019) Patterns of failure after stereotactic radiosurgery for recurrent high-grade glioma: a single institution experience of 10 years. Neurosurgery 85:E322–E331.

    Article  PubMed  Google Scholar 

  28. 28.

    Frampton GM, Fichtenholtz A, Otto GA et al (2013) Development and validation of a clinical cancer genomic profiling test based on massively parallel DNA sequencing. Nat Biotechnol 31:1023–1031.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Dono A, Wang E, Lopez V et al (2020) Molecular characteristics and clinical features of multifocal glioblastoma. J Neuro-Oncol 148(2):389–397.

    CAS  Article  Google Scholar 

  30. 30.

    Martinez R, Völter C, Behr R (2008) Parameters assessing neurological status in malignant glioma patients: prognostic value for survival and relapse-free time. Br J Neurosurg 22:557–562.

    CAS  Article  PubMed  Google Scholar 

  31. 31.

    Zehir A, Benayed R, Shah RH et al (2017) Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients. Nat Med 23:703–713.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Tate JG, Bamford S, Jubb HC et al (2019) COSMIC: the catalogue of somatic mutations in cancer. Nucleic Acids Res 47:D941–D947.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Souhami L, Seiferheld W, Brachman D et al (2004) Randomized comparison of stereotactic radiosurgery followed by conventional radiotherapy with carmustine to conventional radiotherapy with carmustine for patients with glioblastoma multiforme: report of radiation therapy oncology group 93-05 protocol. Int J Radiat Oncol Biol Phys 60:853–860.

    Article  PubMed  Google Scholar 

  34. 34.

    Bergman D, Modh A, Schultz L et al (2020) Randomized prospective trial of fractionated stereotactic radiosurgery with chemotherapy versus chemotherapy alone for bevacizumab – resistant high – grade glioma. J Neuro-Oncol 148(2):353–361.

    CAS  Article  Google Scholar 

  35. 35.

    Yan Y, Takayasu T, Hines G, et al (2020) Landscape of genomic alterations in IDH wild-type glioblastoma identifies PI3K as a favorable prognostic factor. 575–584

  36. 36.

    Cerami E, Gao J, Dogrusoz U et al (2012) The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov 2:401–404.

    Article  Google Scholar 

  37. 37.

    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 173:400.e1–416.e11.

    CAS  Article  Google Scholar 

  38. 38.

    Burford A, Little SE, Jury A et al (2013) Distinct phenotypic differences associated with differential amplification of receptor tyrosine kinase genes at 4q12 in glioblastoma. PLoS One 8(8):e71777.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Thakkar JP, Dolecek TA, Horbinski C et al (2014) Epidemiologic and molecular prognostic review of glioblastoma. Cancer Epidemiol Biomark Prev 23:1985–1996.

    CAS  Article  Google Scholar 

  40. 40.

    Mirimanoff RO, Gorlia T, Mason W et al (2006) Radiotherapy and temozolomide for newly diagnosed glioblastoma: Recursive partitioning analysis of the EORTC 26981/22981-NCIC CE3 phase III randomized trial. J Clin Oncol 24:2563–2569.

    CAS  Article  PubMed  Google Scholar 

  41. 41.

    Park KJ, Kano H, Iyer A et al (2012) Salvage gamma knife stereotactic radiosurgery followed by bevacizumab for recurrent glioblastoma multiforme: a case-control study. J Neuro-Oncol 107:323–333.

    CAS  Article  Google Scholar 

  42. 42.

    Ma J, Benitez JA, Li J et al (2019) Inhibition of nuclear PTEN tyrosine phosphorylation enhances glioma radiation sensitivity through attenuated DNA repair. Cancer Cell 35:504.e7–518.e7.

    CAS  Article  Google Scholar 

  43. 43.

    Hou SQ, Ouyang M, Brandmaier A et al (2017) PTEN in the maintenance of genome integrity: from DNA replication to chromosome segregation. BioEssays 39:1–9.

    CAS  Article  Google Scholar 

  44. 44.

    Milella M, Falcone I, Conciatori F et al (2015) PTEN: multiple functions in human malignant tumors. Front Oncol 5:1–14.

    Article  Google Scholar 

  45. 45.

    Stupp R, Wong ET, Kanner AA et al (2012) NovoTTF-100A versus physician’s choice chemotherapy in recurrent glioblastoma: a randomised phase III trial of a novel treatment modality. Eur J Cancer 48:2192–2202.

    Article  PubMed  Google Scholar 

  46. 46.

    Barthel FP, Johnson KC, Varn FS et al (2019) Longitudinal molecular trajectories of diffuse glioma in adults. Nature 576:112–120.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

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Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Number K08CA241651 (LYB). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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Study design: AD, YE. Data Recollection: AD, MA, MM, RHS, YE Data analysis: AD. Manuscript writing: AD, MA, RHS, YE. Manuscript revision and editing: AD, MA, RFR, JJZ, SH, DHK, NT, LYB, AIB, YE. Study Supervision: YE. Approved final manuscript: all authors.

Corresponding authors

Correspondence to Leomar Y. Ballester or Yoshua Esquenazi.

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This retrospective study was approved by the institutional review board of The University of Texas Health Science Center at Houston and Memorial Hermann Hospital, Houston, TX following the 1964 Helsinki Declaration and its later amendments.

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Dono, A., Amsbaugh, M., Martir, M. et al. Genomic alterations predictive of response to radiosurgery in recurrent IDH-WT glioblastoma. J Neurooncol 152, 153–162 (2021).

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  • Stereotactic radiosurgery
  • Gamma Knife
  • Recurrent glioblastoma
  • PTEN
  • Glioblastoma IDH wild-type
  • Biomarker