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

Abstract

Background Chemotherapy improves overall survival after surgery and radiotherapy for newly diagnosed high-risk IDH-mutant low-grade gliomas, 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 re-operation and correlated hypermutation status with grade at recurrence and subsequent clinical outcomes. Results Hypermutation was associated with high-grade disease at the time of re-operation (OR 12.0 95% CI 2.5-115.5, p=0.002) 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=0.024), 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=0.003). 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. 8-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.

Malignant Progression of Diffuse Low-grade Gliomas: A Systematic Review and Meta-analysis on Incidence and Related Factors

“…Recent studies have warned that temozolomide treatment of LGG induces hypermutation, which may drive malignant progression. 53 , 54 ) Tom et al 11 ) reported adjuvant temozolomide monotherapy as the only modifiable risk factor for malignant transformation among adult LGG cases. Aihara et al 55 ) indicated that malignancies are rarely promoted by additionally acquired mutations or genomic aberrations at recurrence of oligodendrogliomas.…”

RUNX1 (RUNX family transcription factor 1), a target of microRNA miR-128-3p, promotes temozolomide resistance in glioblastoma multiform by upregulating multidrug resistance-associated protein 1 (MRP1)

“…GBM is a progressive debilitating cancer in the central nervous system (CNS) and takes up over 50% of brain-related carcinomas in adults [ 36 ], which is associated with a very poor prognosis [ 29 , 37 ]. Despite the application of combined radiotherapy and chemotherapy with TMZ after optimal surgery, most patients eventually develop TMZ resistance and suffer from the malignant relapse of aggressive tumors [ 38–40 ].Recent studies revealed that RUNX1 and miRNAs are implicated in the development of resistant phenotype of TMZ in GBM [ 41–43 ]. Here, the present study identified miR-128-3p as a negative regulator of RUNX1 and validated their functional interaction in TMZ sensitivity of GBM cells, suggesting that miR-128-3p/RUNX1 axis could serve as a potential therapeutic target in TMZ-resistant GBM.…”

Spatial progression and molecular heterogeneity of IDH-mutant glioblastoma determined by DNA methylation-based mapping

“…This suggests that irradiation could have allowed for the evolution of MGMT -unmethylated tumor cells, which “escaped” and migrated to the other hemisphere, or perhaps that those cells had already infiltrated to the corpus callosum and out of the radiation field prior to the initial irradiation, providing an explanation for the development of temozolomide resistance seen at recurrence. It is also possible that the temozolomide treatment itself promoted extensive mutation, as recently demonstrated in IDH-mutant low-grade gliomas [ 44 ], promoting the escape of resistant clones toward the contralateral hemisphere. More importantly, our data also suggest that changing molecular features (including MGMT promoter methylation and other key markers of aggressiveness and treatment responsiveness in diffuse gliomas) may be missed in the routine analysis of single biopsy or resection samples and that whole-genome methylation profiling and copy number profiling in multiple samples may provide useful information in the case of tumor recurrence to identify potentially useful changing molecular milieu.…”