Temozolomide-induced hypermutation is associated with distant recurrence and reduced survival after high-grade transformation of low-grade IDH-mutant gliomas.

Brain Brain Neoplasms / drug therapy Glioma / drug therapy Humans Mutation / drug effects Neoplasm Recurrence, Local / genetics Temozolomide / adverse effects
IDH-mutant hypermutation low-grade glioma temozolomide tumor mutational burden

Journal

Neuro-oncology
ISSN: 1523-5866
Titre abrégé: Neuro Oncol
Pays: England
ID NLM: 100887420

Informations de publication

Date de publication:
02 11 2021
Historique:
pubmed: 7 4 2021
medline: 6 11 2021
entrez: 6 4 2021
Statut: ppublish

Résumé

Chemotherapy improves overall survival after surgery and radiotherapy for newly diagnosed high-risk IDH-mutant low-grade gliomas (LGGs), but a proportion of patients treated with temozolomide (TMZ) will develop recurrent tumors with TMZ-induced hypermutation. We aimed to determine the prevalence of TMZ-induced hypermutation at recurrence and prognostic implications. We sequenced recurrent tumors from 82 patients with initially low-grade IDH-mutant gliomas who underwent reoperation and correlated hypermutation status with grade at recurrence and subsequent clinical outcomes. Hypermutation was associated with high-grade disease at the time of reoperation (OR 12.0 95% CI 2.5-115.5, P = .002) and was identified at transformation in 57% of recurrent LGGs previously exposed to TMZ. After anaplastic (grade III) transformation, hypermutation was associated with shorter survival on univariate and multivariate analysis (HR 3.4, 95% CI 1.2-9.9, P = .024), controlling for tumor grade, subtype, age, and prior radiotherapy. The effect of hypermutation on survival after transformation was validated in an independent, published dataset. Hypermutated (HM) tumors were more likely to develop discontiguous foci of disease in the brain and spine (P = .003). To estimate the overall incidence of high-grade transformation among low-grade IDH-mutant tumors, data from a phase II trial of TMZ for LGG were analyzed. Eight-year transformation-free survival was 53.8% (95% CI 42.8-69.2), and 61% of analyzed transformed cases were HM. TMZ-induced hypermutation is a common event in transformed LGG previously treated with TMZ and is associated with worse prognosis and development of discontiguous disease after recurrence. These findings impact tumor classification at recurrence, prognostication, and clinical trial design.

Sections du résumé

BACKGROUND
Chemotherapy improves overall survival after surgery and radiotherapy for newly diagnosed high-risk IDH-mutant low-grade gliomas (LGGs), but a proportion of patients treated with temozolomide (TMZ) will develop recurrent tumors with TMZ-induced hypermutation. We aimed to determine the prevalence of TMZ-induced hypermutation at recurrence and prognostic implications.
METHODS
We sequenced recurrent tumors from 82 patients with initially low-grade IDH-mutant gliomas who underwent reoperation and correlated hypermutation status with grade at recurrence and subsequent clinical outcomes.
RESULTS
Hypermutation was associated with high-grade disease at the time of reoperation (OR 12.0 95% CI 2.5-115.5, P = .002) and was identified at transformation in 57% of recurrent LGGs previously exposed to TMZ. After anaplastic (grade III) transformation, hypermutation was associated with shorter survival on univariate and multivariate analysis (HR 3.4, 95% CI 1.2-9.9, P = .024), controlling for tumor grade, subtype, age, and prior radiotherapy. The effect of hypermutation on survival after transformation was validated in an independent, published dataset. Hypermutated (HM) tumors were more likely to develop discontiguous foci of disease in the brain and spine (P = .003). To estimate the overall incidence of high-grade transformation among low-grade IDH-mutant tumors, data from a phase II trial of TMZ for LGG were analyzed. Eight-year transformation-free survival was 53.8% (95% CI 42.8-69.2), and 61% of analyzed transformed cases were HM.
CONCLUSIONS
TMZ-induced hypermutation is a common event in transformed LGG previously treated with TMZ and is associated with worse prognosis and development of discontiguous disease after recurrence. These findings impact tumor classification at recurrence, prognostication, and clinical trial design.

Identifiants

DOI: 10.1093/neuonc/noab081 PMID: 33823014 PMC: PMC8563321
pubmed: 33823014
pii: 6211336
doi: 10.1093/neuonc/noab081
pmc: PMC8563321
doi:

Substances chimiques

Temozolomide YF1K15M17Y

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

1872-1884

Subventions

Organisme : NCI NIH HHS
ID : R01 CA244838
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA151022
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA097257
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA169316
Pays : United States
Organisme : NCI NIH HHS
ID : K12 CA076917
Pays : United States

Commentaires et corrections

Type : CommentIn

Informations de copyright

© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

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Auteurs

Yao Yu (Y)

Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

Javier Villanueva-Meyer (J)

Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, California, USA.

Matthew R Grimmer (MR)

Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA.

Stephanie Hilz (S)

Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA.

David A Solomon (DA)

Division of Neuropathology, Department of Pathology, University of California, San Francisco, San Francisco, California, USA.

Serah Choi (S)

Department of Radiation Oncology, University Hospitals Cleveland Medical Center, Cleveland, Ohio, USA.

Michael Wahl (M)

Department of Radiation Oncology, St. Charles Cancer Center, Bend, Oregon, USA.

Tali Mazor (T)

Department of Computational Biology, Dana-Farber/Harvard Cancer Center, Boston, Massachusetts, USA.

Chibo Hong (C)

Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA.

Anny Shai (A)

Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA.

Joanna J Phillips (JJ)

Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA.
Division of Neuropathology, Department of Pathology, University of California, San Francisco, San Francisco, California, USA.

Bruce H Wainer (BH)

Franklin County Coroner, Columbus, Ohio, USA.

Michael McDermott (M)

Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA.
Department of Neurosurgery, Baptist Health South Florida, Florida, USA.
ORCID: 0000-0002-7635-5268

Daphne Haas-Kogan (D)

Department of Radiation Oncology, Dana-Farber/Harvard Cancer Center, Boston, Massachusetts, USA.

Jennie W Taylor (JW)

Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA.
Department of Neurology, University of California, San Francisco, San Francisco, California, USA.

Nicholas Butowski (N)

Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA.

Jennifer L Clarke (JL)

Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA.
Department of Neurology, University of California, San Francisco, San Francisco, California, USA.

Mitchel S Berger (MS)

Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA.
ORCID: 0000-0003-1983-4892

Annette M Molinaro (AM)

Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA.

Susan M Chang (SM)

Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA.

Joseph F Costello (JF)

Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA.

Nancy Ann Oberheim Bush (NA)

Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA.
Department of Neurology, University of California, San Francisco, San Francisco, California, USA.

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Classifications MeSH

questionsmedicales.fr › Système nerveux › Système nerveux central › Encéphale › Temozolomide-induced hypermutation is...
questionsmedicales.fr › Maladies du système nerveux › Tumeurs du système nerveux › Tumeurs du système nerveux central › Tumeurs du cerveau › Temozolomide-induced hypermutation is...
questionsmedicales.fr › Tumeurs › Tumeurs par type histologique › Tumeurs du tissu nerveux › Tumeurs neuroectodermiques › Tumeurs neuroépitheliales › Gliome › Temozolomide-induced hypermutation is...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Temozolomide-induced hypermutation is...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Mutation › Temozolomide-induced hypermutation is...
questionsmedicales.fr › États, signes et symptômes pathologiques › Processus pathologiques › Processus néoplasiques › Récidive tumorale locale › Temozolomide-induced hypermutation is...
questionsmedicales.fr › Composés hétérocycliques › Composés hétéromonocycliques › Azoles › Imidazoles › Dacarbazine › Témozolomide › Temozolomide-induced hypermutation is...