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

Author:

Yu Yao1,Villanueva-Meyer Javier2,Grimmer Matthew R3,Hilz Stephanie3,Solomon David A4,Choi Serah5,Wahl Michael6,Mazor Tali7,Hong Chibo3,Shai Anny3,Phillips Joanna J34,Wainer Bruce H8,McDermott Michael39ORCID,Haas-Kogan Daphne10,Taylor Jennie W311,Butowski Nicholas3,Clarke Jennifer L311,Berger Mitchel S3ORCID,Molinaro Annette M3,Chang Susan M3,Costello Joseph F3,Oberheim Bush Nancy Ann311

Affiliation:

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

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

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

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

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

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

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

8. Franklin County Coroner, Columbus, Ohio, USA

9. Department of Neurosurgery, Baptist Health South Florida, Florida, USA

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

11. Department of Neurology, University of California, San Francisco, San Francisco, California, USA

Abstract

Abstract 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.

Funder

NCI

NIH

UCSF Brain Tumor Center SPORE Biorepository and Pathology Core

Publisher

Oxford University Press (OUP)

Subject

Cancer Research,Neurology (clinical),Oncology

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