Vorasidenib in IDH1- or IDH2-Mutant Low-Grade Glioma

Mellinghoff, Ingo K.; Bent, Martin J. van den; Blumenthal, Deborah T.; Touat, Mehdi; Peters, Katherine B.; Clarke, Jennifer; Mendez, Joe; Yust‐Katz, Shlomit; Welsh, Liam; Mason, Warren P.; Ducray, François; Umemura, Yoshie; Nabors, Burt; Holdhoff, Matthias; Hottinger, Andreas F.; Arakawa, Yoshiki; Sepúlveda, Juan Manuel; Wick, Wolfgang; Soffietti, Riccardo; Perry, James; Giglio, Pierre; Fuente, Macarena De La; Maher, Elizabeth A.; Schoenfeld, Steven; Zhao, Dan; Pandya, Shuchi S.; Steelman, Lori; Hassan, Islam; Wen, Patrick Y.; Cloughesy, Timothy F.

doi:10.1056/nejmoa2304194

Cited by 182 publications

(72 citation statements)

References 41 publications

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“…This example is illustrative because it highlights the limitations of conventional gene panels for cancer diagnostics, which provide binary calls for the presence or absence of common oncogenic mutations. In this case, such panels would indicate the presence of IDH1 R132H and recommend treatment that targets this mutation 60 . However, with knowledge of this tumor’s clonal phylogeny, we can see that such treatment will be entirely ineffective for one-fifth of malignant cells, since the mutated IDH1 protein is no longer there.…”

Section: Discussionmentioning

confidence: 99%

Deconstructing intratumoral heterogeneity through multiomic and multiscale analysis of serial sections

Schupp

Shelton

Brody

et al. 2023

Preprint

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Understanding the transcriptional consequences of oncogenic mutations is an important goal that may reveal new therapeutic targets for diverse cancers. Although single-cell methods hold promise for this task, it remains non-trivial to isolate and sequence DNA and RNA from the same cell at scale. Here we present a statistically motivated strategy that utilizes multiscale and multiomic analysis of individual human tumor specimens to deconstruct intra-tumoral heterogeneity by clarifying clonal populations of malignant cells and their transcriptional profiles. By combining deep, multiscale sampling of IDH-mutant astrocytomas with integrative, multiomic analysis, we reconstruct and validate the phylogenies, spatial distributions, and transcriptional profiles of distinct malignant clones. We identify a core set of genes that is consistently expressed by the truncal clone, including AKR1C3, whose expression is associated with poor outcomes in several types of cancer. Some derived clones exhibit significant enrichment with gene sets representing glioblastoma subtypes and nonmalignant cell types, including ependymal cells. Importantly, by genotyping nuclei for truncal mutations, we show that existing strategies for inferring malignancy from gene expression profiles of single cells may be inaccurate. Furthermore, we find that transcriptional phenotypes of malignancy persist despite loss of the mutant IDH1 protein following chr2q deletion in a subset of malignant cells. In summary, our study provides a generalizable strategy for precisely deconstructing intra-tumoral heterogeneity and clarifying the molecular profiles of malignant clones in any kind of solid tumor.

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Section: Discussionmentioning

confidence: 99%

Deconstructing intratumoral heterogeneity through multiomic and multiscale analysis of serial sections

Schupp

Shelton

Brody

et al. 2023

Preprint

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show abstract

“…The successful identification of genetic alterations in specific subsets of CNS tumors has led to the development of innovative therapeutic strategies, such as temozolomide for MGMT methylated gliomas and IDH inhibitors for IDH-mutant gliomas. [125][126][127][128][129] As a result, morphomolecular characterization was incorporated into the integrated diagnosis. Because the integration of DNA methylome analysis has emerged as an essential component of the diagnostic process, novel therapeutic strategies will drive the implementation of DNA methylome-based classification.…”

Section: Challenges In Clinical Applicationmentioning

confidence: 99%

Decoding the DNA methylome of central nervous system tumors: An emerging modality for integrated diagnosis

Satomi,

Ichimura,

Shibahara

2024

Pathology International

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The definitive diagnosis and classification of individual cancers are crucial for patient care and cancer research. To achieve a robust diagnosis of central nervous system (CNS) tumors, a genotype‐phenotype integrated diagnostic approach was introduced in recent versions of the World Health Organization classification, followed by the incorporation of a genome‐wide DNA methylome‐based classification. Microarray‐based platforms are widely used to obtain DNA methylome data, and the German Cancer Research Center (Deutsches Krebsforschungszentrum [DKFZ]) has a webtool for a DNA methylation‐based classifier (DKFZ classifier). Integration of DNA methylome will further enhance the precision of CNS tumor classification, especially in diagnostically challenging cases. However, in the clinical application of DNA methylome‐based classification, challenges related to data interpretation persist, in addition to technical caveats, regulations, and limited accessibility. Dimensionality reduction (DMR) can complement integrated diagnosis by visualizing a profile and comparing it with other known samples. Therefore, DNA methylome‐based classification is a highly useful research tool for auxiliary analysis in challenging diagnostic and rare disease cases, and for establishing novel tumor concepts. Decoding the DNA methylome, especially by DMR in addition to DKFZ classifier, emphasizes the capability of grasping the fundamental biological principles that provide new perspectives on CNS tumors.

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“…21 A recently published study on vorasidenib, an IDH mutant inhibitor, in participants with residual or recurrent grade 2 IDH-mutant glioma provided evidence supporting an alternative approach of delaying the radiation therapy and its side effects. 22 However, the long-term effects of vorasidenib on the biology of the IDH-mutant glioma and the OS are unknown.…”

Section: Gliomasmentioning

confidence: 99%

“…50 A phase III clinical trial of vorasidenib in IDH-mutant LGGs allowed the enrollment of AYA patients. 22 However, among the 331 randomly assigned participants, only one fell into the age group of 12-18 years, highlighting the need for better clinical trial access in AYA patients with CNS tumors. To address this issue, community outreach to primary care providers can play a vital role in encouraging specialty care referral for AYA patients with CNS tumors.…”

Section: Special Consideration Of Increasing Enrollment On Clinical T...mentioning

confidence: 99%

Adolescents and Young Adults With Cancer: CNS Tumors

Wu,

Heidelberg,

Gajjar

2024

JCO

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Tumors of CNS are common in adolescents and young adults (AYAs). As the second leading cause of cancer-related death, CNS tumors in AYAs require improved clinical management. In this review, we discussed the current diagnostic approaches and recommended management strategies for malignant tumors in adult-type (IDH-mutant gliomas) and pediatric-type gliomas (pediatric high-grade gliomas), ependymoma and medulloblastoma, which commonly occur in AYAs. The impact of advanced molecular diagnostic approaches on the understanding of tumor biology of AYA CNS tumors is emphasized. To enhance participation in clinical trials, which poses a unique challenge in AYAs with CNS tumors, we propose encouraging referrals to neuro-oncology specialty care and improving collaboration between oncologists who care for both pediatric and adult patients. This will ensure better representation of AYA patients in research studies. Finally, we discussed the importance of considering neurocognitive and psychological function in AYAs with CNS tumor.

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Vorasidenib in IDH1- or IDH2-Mutant Low-Grade Glioma

Cited by 182 publications

References 41 publications

Deconstructing intratumoral heterogeneity through multiomic and multiscale analysis of serial sections

Deconstructing intratumoral heterogeneity through multiomic and multiscale analysis of serial sections

Decoding the DNA methylome of central nervous system tumors: An emerging modality for integrated diagnosis

Adolescents and Young Adults With Cancer: CNS Tumors

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