Genomic Correlates of Disease Progression and Treatment Response in Prospectively Characterized Gliomas

Abstract

Purpose: The genomic landscape of gliomas has been characterized and now contributes to disease classification, yet the relationship between molecular profile and disease progression and treatment response remain poorly understood. Experimental Design: We integrated prospective clinical sequencing of 1,004 primary and recurrent tumors from 923 glioma patients with clinical and treatment phenotypes. Results: Thirteen percent of glioma patients harbored a pathogenic germline variant, including a subset associated with heritable genetic syndromes and variants mediating DNA repair dysfunctions (29% of the total) that were associated with somatic biallelic inactivation and mechanism-specific somatic phenotypes. In astrocytomas, genomic alterations in effectors of cell-cycle progression correlated with aggressive disease independent of IDH mutation status, arose preferentially in enhancing tumors (44% vs. 8%, P < 0.001), were associated with rapid disease progression following tumor recurrence (HR ¼ 2.6, P ¼ 0.02), and likely preceded the acquisition of alkylating therapyassociated somatic hypermutation. Thirty-two percent of patients harbored a potentially therapeutically actionable lesion, of whom 11% received targeted therapies. In BRAFmutant gliomas, response to agents targeting the RAF/MEK/ ERK signaling axis was influenced by the type of mutation, its clonality, and its cellular and genomic context. Conclusions: These data reveal genomic correlates of disease progression and treatment response in diverse types of glioma and highlight the potential utility of incorporating genomic information into the clinical decision-making for patients with glioma.

Lower Grade Gliomas

“…Other poor prognostic factors have also been reported, including a rapid growth rate of more than 8 mm/year and a poor initial performance status [27]. More recent studies have reported that homozygous loss of chromosome 9p21 with loss of CDKN2A, a common phenomenon in higher WHO grade gliomas, is also associated with a worse outcome in IDH-mutant astrocytomas and oligodendrogliomas [28][29][30].…”

“…The immune checkpoint inhibitor avelumab, which targets the programmed death-ligand 1 (PD-L1) is being investigated in combination with hypofractionated radiation for patients with IDH-mutant gliomas that have transformed to grade IV following prior chemotherapy treatment (NCT02968940). A significant proportion of IDH-mutant gliomas that have previously been treated with alkylating chemotherapy develop a hypermutant phenotype [11,12,29], which could theoretically lead to increased neoantigen load in the tumor.…”

EGFRvIII expression and isocitrate dehydrogenase mutations in patients with glioma

“…IDH1 and EGFR are most recurrently mutated cancer driver genes in GBM_TCGA dataset ( ). Poor prognostic markers included genetic changes in the EGFR mutations in this group ( 65 ), and among most driver genes, IDH mutations are good prognostic factor in diffuse gliomas ( 66 , 67 ).…”

Prognostic and radiographic correlates of a prospectively collected molecularly profiled cohort of IDH1/2‐wildtype astrocytomas

“…A retrospective waiver was obtained from the Memorial Sloan Kettering Cancer Center Institutional Review Board (IRB) to integrate tumor sequencing and clinical data, including detailed demographic, pathologic, radiographic and treatment information. This collection of histologic grade II and III IDH1/2-WT astrocytomas expands upon a previously reported cohort, which includes the collection of glioblastoma, IDH1/2-WT used in this data analysis, in that it includes additional cases, more mature survival data and additional radiographic and histologic annotation (14).…”