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Long-term survival in patients with IDH-wildtype glioblastoma: clinical and molecular characteristics

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Abstract

Backg round

Glioblastoma is an aggressive tumor that has a dismal prognosis even with multimodal treatment. However, some patients survive longer than expected. The objective of this study was to revisit patients diagnosed with glioblastoma according to the 2021 WHO classification and analyze clinical and molecular characteristics associated with long-term survival (LTS).

Methods

We retrospectively analyzed 120 IDH-wildtype glioblastomas operated on at our institution between 2013 and 2018. We divided them into LTS patients, surviving more than 3 years, and non-LTS patients, and then compared their features. Additionally, we performed DNA methylation-based brain tumor classification in LTS patients.

Results

Sixteen patients were long-term survivors. Age < 70 years, MGMT promoter methylation, extent of resection ≥ 95%, and administration of radiochemotherapy were associated with LTS (P = 0.005, P < 0.001, P = 0.048, and P = 0.008, respectively). In addition, when these factors were combined, the probability of LTS was 74% (95% CI: 62–-84). The methylome analysis confirmed the diagnosis of glioblastoma in the majority of the tested LTS patients. Regarding subtypes, 29% of cases were mesenchymal (MES), 43% were RTK1, and 29% were RTK2. Interestingly, RTK1 and RTK2 cases tended to have longer overall survival than MES cases (P = 0.057). Moreover, the only tested LTS patient with an unmethylated MGMT promoter had an “adult-type diffuse high-grade glioma, IDH-wildtype, subtype E” rather than a glioblastoma. This tumor was characterized by multinucleated giant cells and a somatic mutation in POLE.

Conclusions

We suggest that glioblastoma patients with a combination of favorable prognostic factors can achieve LTS in 74% of cases. In addition, methylome analysis is important to ascertain the type of glioma in LTS patients, especially when the MGMT promoter is unmethylated.

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Abbreviations

GBM:

Glioblastoma

OS:

Overall survival

MGMT :

O(6)-methylguanine-DNA methyltransferase

IDH:

Isocitrate dehydrogenase

WHO:

World Health Organization

CNS:

Central nervous system

LTS:

Long-term survival

TERT :

Telomerase reverse transcriptase

EGFR :

Epidermal growth factor receptor

KPS:

Karnofsky performance status

MRI:

Magnetic resonance imaging

GTR:

Gross total resection

NTR:

Near-total resection

STR:

Subtotal resection

PR:

Partial resection

MNP:

Molecular neuropathology

VAF:

Variant allele frequency

CI:

Confidence interval

MES:

Mesenchymal

RTK:

Receptor tyrosine kinase

POLE :

DNA polymerase epsilon, catalytic subunit

TP53 :

Tumor protein p53

TEK :

TEK receptor tyrosine kinase

PTEN :

Phosphatase and tensin homolog

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Acknowledgements

The authors wish to thank Anne-France Dekairelle, Salma El Mere, Isabelle Lambermont, Mila Jhamai, Gaby Van Dijk, and Michael Verbiest for the technical support, and Aurélie Bertrand for her help with the statistical analysis, and the molecular tumor board at Saint-Luc University Hospital for the advisory support.

Funding

This research was supported by the following grants: FNRS PDR T00075.15, FNRS PDR T0236.20, FNRS-FWO EOS 30913351, Fondation Médicale Reine Elisabeth, and Fondation JED-Belgique. GC is research fellow at the Belgian Fund for Scientific Research (FNRS) and laureate of the Helaers research prize for neurosurgery.

Author information

Author notes

  1. Julie Lelotte

    Present address: Department of Neuropathology, Institut de Pathologie et de Génétique, Charleroi, Belgium

Authors and Affiliations

  1. Department of Neurosurgery, Saint-Luc University Hospital, Université Catholique de Louvain, 10 Hippocrate Av, 1St Floor, Woluwe-Saint-Lambert, 1200, Brussels, Belgium

    Georges Chehade, Tévi Morel Lawson & Christian Raftopoulos

  2. Developmental Neurobiology, Institute of Neuroscience, Université Catholique de Louvain, Brussels, Belgium

    Georges Chehade & Fadel Tissir

  3. Department of Neuropathology, Saint-Luc University Hospital, Université Catholique de Louvain, Brussels, Belgium

    Julie Lelotte & Lina Daoud

  4. Department of Radiotherapy, Saint-Luc University Hospital, Université Catholique de Louvain, Brussels, Belgium

    Dario Di Perri

  5. Department of Oncology, Saint-Luc University Hospital, Université Catholique de Louvain, Brussels, Belgium

    Nicolas Whenham

  6. Department of Radiology, Saint-Luc University Hospital, Université Catholique de Louvain, Brussels, Belgium

    Thierry Duprez

  7. Cell Physiology, Institute of Neuroscience, Université Catholique de Louvain, Brussels, Belgium

    Nicolas Tajeddine

  8. College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar

    Fadel Tissir

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Contributions

G.C., T.M.L., N.T., F.T., and C.R. designed the study. G.C., T.M.L., D.D.P., N.W., T.D., and N.T. collected and analyzed clinical data. G.C., J.L., and L.D. prepared material and analyzed histological and molecular data. G.C., F.T., and C.R. wrote the initial version of the manuscript. All the authors edited the manuscript and approved its final version.

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Correspondence to Christian Raftopoulos.

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This study was approved by the institutional review board “Comité d'Ethique Hospitalo-Facultaire Saint-Luc – UCL” under agreement 2018/27NOV/450, in accordance with all applicable laws, regulations, guidelines and approvals, including, without limitation, the Declaration of Helsinki. Given the retrospective nature of the study, specific patient informed consent was waived.

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Chehade, G., Lawson, T.M., Lelotte, J. et al. Long-term survival in patients with IDH-wildtype glioblastoma: clinical and molecular characteristics. Acta Neurochir 165, 1075–1085 (2023). https://doi.org/10.1007/s00701-023-05544-3

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