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

Autor:	Yu Y; Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York, USA., Villanueva-Meyer J; Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, California, USA., Grimmer MR; Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA., Hilz S; Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA., Solomon DA; Division of Neuropathology, Department of Pathology, University of California, San Francisco, San Francisco, California, USA., Choi S; Department of Radiation Oncology, University Hospitals Cleveland Medical Center, Cleveland, Ohio, USA., Wahl M; Department of Radiation Oncology, St. Charles Cancer Center, Bend, Oregon, USA., Mazor T; Department of Computational Biology, Dana-Farber/Harvard Cancer Center, Boston, Massachusetts, USA., Hong C; Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA., Shai A; Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA., 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., Wainer BH; Franklin County Coroner, Columbus, Ohio, USA., McDermott M; Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA.; Department of Neurosurgery, Baptist Health South Florida, Florida, USA., Haas-Kogan D; Department of Radiation Oncology, Dana-Farber/Harvard Cancer Center, Boston, Massachusetts, USA., 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., Butowski N; Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA., 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., Berger MS; Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA., Molinaro AM; Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA., Chang SM; Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA., Costello JF; Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA., 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.
Jazyk:	angličtina
Zdroj:	Neuro-oncology [Neuro Oncol] 2021 Nov 02; Vol. 23 (11), pp. 1872-1884.
DOI:	10.1093/neuonc/noab081
Abstrakt:	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. (© 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.)
Databáze:	MEDLINE
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