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Biological and therapeutic implications of multisector sequencing in newly diagnosed glioblastoma.

ABSTRACT: Background:Diagnostic workflows for glioblastoma (GBM) patients increasingly include DNA sequencing-based analysis of a single tumor site following biopsy or resection. We hypothesized that sequencing of multiple sectors within a given tumor would provide a more comprehensive representation of the molecular landscape and potentially inform therapeutic strategies. Methods:Ten newly diagnosed, isocitrate dehydrogenase 1 (IDH1) wildtype GBM tumor samples were obtained from 2 (n = 9) or 4 (n = 1) spatially distinct tumor regions. Tumor and matched blood DNA samples underwent whole-exome sequencing. Results:Across all 10 tumors, 51% of mutations were clonal and 3% were subclonal and shared in different sectors, whereas 46% of mutations were subclonal and private. Two of the 10 tumors exhibited a regional hypermutator state despite being treatment naïve, and remarkably, the high mutational load was predominantly limited to one sector in each tumor. Among the canonical cancer-associated genes, only telomerase reverse transcriptase (TERT) promoter mutations were observed in the founding clone in all tumors. Reconstruction of the clonal architecture in different sectors revealed regionally divergent evolution, and integration of data from 2 sectors increased the resolution of inferred clonal architecture in a given tumor. Predicted therapeutic mutations differed in presence and frequency between tumor regions. Similarly, different sectors exhibited significant divergence in the predicted neoantigen landscape. Conclusions:The substantial spatial heterogeneity observed in different GBM tumor sectors, especially in spatially restricted hypermutator cases, raises important caveats to our current dependence on single-sector molecular information to guide either targeted or immune-based treatments.

SUBMITTER: Mahlokozera T

PROVIDER: S-EPMC5909635 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Biological and therapeutic implications of multisector sequencing in newly diagnosed glioblastoma.

Mahlokozera Tatenda T Vellimana Ananth K AK Li Tiandao T Mao Diane D DD Zohny Zohny S ZS Kim David H DH Tran David D DD Marcus Daniel S DS Fouke Sarah J SJ Campian Jian L JL Dunn Gavin P GP Miller Christopher A CA Kim Albert H AH

Neuro-oncology 20180301 4

<h4>Background</h4>Diagnostic workflows for glioblastoma (GBM) patients increasingly include DNA sequencing-based analysis of a single tumor site following biopsy or resection. We hypothesized that sequencing of multiple sectors within a given tumor would provide a more comprehensive representation of the molecular landscape and potentially inform therapeutic strategies.<h4>Methods</h4>Ten newly diagnosed, isocitrate dehydrogenase 1 (IDH1) wildtype GBM tumor samples were obtained from 2 (n = 9) ...[more]

PMID: 29244145

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Project description:BackgroundThe impact of prolonging temozolomide (TMZ) maintenance beyond six cycles in newly diagnosed glioblastoma (GBM) remains a topic of discussion. We investigated the effects of prolonged TMZ maintenance on progression-free survival (PFS) and overall survival (OS).Patients and methodsIn this retrospective single-center cohort study, we included patients with GBM who were treated with radiation therapy with concomitant and adjuvant TMZ. For analysis, patients were considered who either completed six TMZ maintenance cycles (group B), continued with TMZ therapy beyond six cycles (group C), or stopped TMZ maintenance therapy within the first six cycles (group A). Patients with progression during the first six TMZ maintenance cycles were excluded.ResultsClinical data from 107 patients were included for Kaplan-Meier analyses and 102 for Cox regressions. Median PFS times were 8.1 months (95% confidence interval [CI] 6.1-12.4) in group A, 13.7 months (95% CI 10.6-17.5) in group B, and 20.9 months (95% CI 15.2-43.5) in group C. At first progression, response rates of TMZ/lomustine rechallenge were 47% in group B and 13% in group C. Median OS times were 12.7 months (95% CI 10.3-16.8) in group A, 25.2 months (95% CI 17.7-55.5) in group B, and 28.6 months (95% CI 24.4-open) in group C. Nevertheless, multivariate Cox regression for patients in group C compared with group B that accounted for imbalances of other risk factors showed no different relative risk (RR) for OS (RR 0.77, p = .46).ConclusionOur data do not support a general extension of TMZ maintenance therapy beyond six cycles. The Oncologist 2017;22:570-575 IMPLICATIONS FOR PRACTICE: Radiation therapy with concomitant and adjuvant temozolomide (TMZ) maintenance therapy is still the standard of care in patients below the age of 65 years in newly diagnosed glioblastoma. However, in clinical practice, many centers continue TMZ maintenance therapy beyond six cycles. The impact of this continuation is controversial and has not yet been addressed in prospective randomized clinical trials. We compared the effect of more than six cycles of TMZ in comparison with exactly six cycles on overall survival (OS) and progression-free survival (PFS) by multivariate analysis and found a benefit in PFS but not OS. Thus, our data do not suggest prolonging TMZ maintenance therapy beyond six cycles, which should be considered in neurooncological practice.

Dataset Information

Biological and therapeutic implications of multisector sequencing in newly diagnosed glioblastoma.

Publications

Biological and therapeutic implications of multisector sequencing in newly diagnosed glioblastoma.

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