Working Committee 1 concluded that histologic grade II and III IDH-wildtype diffuse astrocytic gliomas that contain high-level EGFR amplification, the combination of whole chromosome 7 gain and whole chromosome 10 loss (+7/−10), or TERT promoter mutations, correspond to WHO grade IV and should be referred to as diffuse astrocytic glioma, IDH-wildtype, with molecular features of glioblastoma, WHO grade IV. Assessment of classification by DNA methylation profiling and additional +7/−10 signatures appear to be promising as well and could be considered in the future following additional experience and validation. We also concluded that specific molecular signatures in subsets of IDH-wildtype diffuse astrocytic gliomas are associated with better clinical outcomes and should not lead to a high-grade designation, including, but not limited to, those gliomas with MYB/MYBL or BRAF alterations as individual drivers.

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cIMPACT-NOW Update 3: Recommended diagnostic criteria for “Diffuse astrocytic glioma, IDH-wildtype, with molecular features of glioblastoma, WHO grade IV”

Effective treatments are needed to improve outcomes for high-grade glioma and low-grade glioma. The activity and safety of dabrafenib plus trametinib were evaluated in adult patients with recurrent or progressive BRAFV600E mutation-positive high-grade glioma and low-grade glioma.This study is part of an ongoing open-label, single-arm, phase 2 Rare Oncology Agnostic Research (ROAR) basket trial at 27 community and academic cancer centres in 13 countries (Austria, Belgium, Canada, France, Germany, Italy, Japan, the Netherlands, Norway, South Korea, Spain, Sweden, and the USA). The study enrolled patients aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0, 1, or 2. Patients with BRAFV600E mutation-positive high-grade glioma and low-grade glioma received dabrafenib 150 mg twice daily plus trametinib 2 mg once daily orally until unacceptable toxicity, disease progression, or death. In the high-grade glioma cohort, patients were required to have measurable disease at baseline using the Response Assessment in Neuro-Oncology high-grade glioma response criteria and have been treated previously with radiotherapy and first-line chemotherapy or concurrent chemoradiotherapy. Patients with low-grade glioma were required to have measurable non-enhancing disease (except pilocytic astrocytoma) at baseline using the Response Assessment in Neuro-Oncology low-grade glioma criteria. The primary endpoint, in the evaluable intention-to-treat population, was investigator-assessed objective response rate (complete response plus partial response for high-grade glioma and complete response plus partial response plus minor response for low-grade glioma). This trial is ongoing, but is closed for enrolment, NCT02034110.Between April 17, 2014, and July 25, 2018, 45 patients (31 with glioblastoma) were enrolled into the high-grade glioma cohort and 13 patients were enrolled into the low-grade glioma cohort. The results presented here are based on interim analysis 16 (data cutoff Sept 14, 2020). In the high-grade glioma cohort, median follow-up was 12·7 months (IQR 5·4-32·3) and 15 (33%; 95% CI 20-49) of 45 patients had an objective response by investigator assessment, including three complete responses and 12 partial responses. In the low-grade glioma cohort, median follow-up was 32·2 months (IQR 25·1-47·8). Nine (69%; 95% CI 39-91) of 13 patients had an objective response by investigator assessment, including one complete response, six partial responses, and two minor responses. Grade 3 or worse adverse events were reported in 31 (53%) patients, the most common being fatigue (five [9%]), decreased neutrophil count (five [9%]), headache (three [5%]), and neutropenia (three [5%]).Dabrafenib plus trametinib showed clinically meaningful activity in patients with BRAFV600E mutation-positive recurrent or refractory high-grade glioma and low-grade glioma, with a safety profile consistent with that in other indications. BRAFV600E testing could potentially be adopted in clinical practice for patients with glioma.Novartis. 

Dabrafenib plus trametinib in patients with BRAFV600E-mutant low-grade and high-grade glioma (ROAR): a multicentre, open-label, single-arm, phase 2, basket trial

Mutations in the telomerase reverse transcriptase gene promoter (TERTp) are common in glioblastomas (GBMs) and oligodendrogliomas (ODGs), and therefore, have a key role in tumorigenesis and may be of prognostic value. However, the extent of their prognostic importance in various gliomas is controversial. We studied 168 patients separated into five groups: Group 1: 65 patients with ODG carrying an IDH1 or IDH2 mutation (IDH-mutant) and 1p/19q–codeletion, Group 2: 23 patients with anaplastic astrocytoma (AA), IDH-mutant, Group 3: 13 patients with GBM, IDH-mutant, Group 4: 15 patients with AA, IDH-wildtype (WT), and Group 5: 52 patients with GBM, IDH-WT. TERTp mutations were found in 96.9%, 4.4%, 76.9%, 20.0%, and 84.6% of patients in Groups 1, 2, 3, 4, and 5, respectively. The R132H mutation in IDH1 was found in 60.5% (23/38) of patients in the AA cohort (Groups 2 and 4) and 20.0% (13/65) of patients from our GBM cohort (Groups 3 and 5), whereas all patients with ODG (Group 1) had a mutation either in IDH1 (n = 62) or IDH2 (n = 3). Using Kaplan Meier survival analysis, we found that the TERTp mutation was correlated with poor overall survival (OS) in Groups 2 and 4 combined (P = 0.001) and in Group 4 (P = 0.113), and in multivariate analysis, the TERTp mutant group was associated with significantly poor survival in Group 5 (P = 0.045). However, IDH mutation, MGMT methylation, and younger patient age (<55 years old) were significantly correlated with favorable OS (all P < 0.05) in our cohort of astrocytic and ODGs. In patients with ODG (Group 1), mutant IDH and TERTp did not have prognostic value because these mutations were universally present. Based on the revised 2016 WHO classification of gliomas, we found that TERTp mutation was frequently present in patients with GBM or ODG and because it was strongly correlated with poor survival outcome in patients with IDH-WT GBM in multivariate analysis, it may be of prognostic value in this subgroup of patients with gliomas.

The frequency and prognostic effect of TERT promoter mutation in diffuse gliomas

have been suggested. However, as this is not a well-defined separate entity, the question remains whether IDHwt DLGG classified according to current WHO classification qualifies as a single entity, with sufficient information to estimate prognosis adequately, and therefore, guide treatment, or if the assessment of additional markers is necessary and if so which. A recent study by Aibaidula et al. showed that IDHwt DLGG are prognostically heterogeneous and that markers like TERTp, EGFR amplification and H3F3A mutation could be of additional value [1]. The prognostic role of + 7/− 10q and its relationship with TERTp mutations were not reported, however. In this study, we report on the impact of additional molecular markers, including + 7/− 10q and TERTp, on overall survival in adult IDHwt DLGG. In our institute targeted next-generation sequencing is part of routine diagnostics for DLGG. We assess copy number changes of chromosome 1, 7 (including EGFR amplification), 9p, 10, 12, 19, and mutational status of genes IDH1/2, TP53, ATRX, CIC, FUBP1, EGFR, PIK3CA, CDKN2A, PTEN, H3F3A, BRAF, NOTCH1, TERTp. In our routine diagnostics, we use gain of whole chromosome 7 and loss of whole chromosomal arm 10q as criterion for + 7/− 10q status. Our sequencing protocol has been described previously [3, 4]. Between January 2003 and January 2017, we sequenced a total of 639 tumors as part of daily diagnostic routine (samples since 2013) and as part of a project on extent of resection in DLGG (samples since 2003) [8]. Of these, 510 tumors were histologically classified as DLGG and on sequencing 74 were IDHwt. We collected Karnofsky Performance Status (KPS) at diagnosis, age, gender and overall survival which were defined as time between date of diagnostic imaging and date of death. Patients that were alive at the time of analysis were censored. Further stratification of these IDHwt DLGG showed a molecularly heterogeneous group of tumors. Only 52.7% of With the 2016 revision of the World Health Organization classification of tumors of the central nervous system (WHO 2016) testing for the presence of mutations in isocitrate dehydrogenase 1 and 2 (IDH) and chromosome 1p/19q status is the cornerstone of glioma classification [5]. Approximately 80% of diffuse low-grade (grades II and III) gliomas (DLGG) are IDH mutated and have a relatively favorable prognosis compared to their IDH wild-type (IDHwt) counterparts [2]. The prognosis of IDHwt DLGG is almost similar to primary glioblastoma and genetic aberrations that are seen in primary glioblastoma are also reported in IDHwt DLGG: the combination of trisomy of whole chromosome 7 and loss of chromosomal arm 10q (+ 7/− 10q), and telomerase reverse transcriptase gene promoter (TERTp) mutations [2, 6, 7]. However, + 7/− 10q or TERTp mutations are not part of the WHO 2016 criteria and not all IDHwt DLGG have these specific molecular aberrations [2, 5]. Although clinical trials have not been performed, in view of their poor prognosis, aggressive treatment regimens for IDHwt DLGG

Molecular and clinical heterogeneity of adult diffuse low-grade IDH wild-type gliomas: assessment of TERT promoter mutation and chromosome 7 and 10 copy number status allows superior prognostic stratification

In the 2016, WHO classification of tumors of the central nervous system, isocitrate dehydrogenase (IDH) mutation is a main classifier for lower grade astrocytomas and IDH-mutated astrocytomas is now regarded as a single group with longer survival. However, the molecular and clinical heterogeneity among IDH mutant lower grade (WHO Grades II/III) astrocytomas have only rarely been investigated. In this study, we recruited 160 IDH mutant lower grade (WHO Grades II/III) astrocytomas, and examined PDGFRA amplification, CDKN2A deletion and CDK4 amplification by FISH analysis, TERT promoter mutation by Sanger sequencing and ATRX loss and p53 expression by immunohistochemistry. We identified PDGFRA amplification, CDKN2A homozygous deletion and CDK4 amplification in 18.8%, 15.0% and 18.1% of our cohort respectively, and these alterations occurred in a mutually exclusive fashion. PDGFRA amplification was associated with shorter PFS (P = 0.0003) and OS (P < 0.0001). In tumors without PDGFRA amplification, CDKN2A homozygous deletion or CDK4 amplification was associated with a shorter OS (P = 0.035). Tumors were divided into three risk groups based on the presence of molecular alterations: high risk (PDGFRA amplification), intermediate risk (CDKN2A deletion or CDK4 amplification) and low risk (neither CDKN2A deletion and CDK4 amplification nor PDGFRA amplification). These three risk groups were significantly different in overall survival with mean survivals of 40.5, 62.9 and 71.5 months. The high-risk group also demonstrated a shorter PFS compared to intermediate- (P = 0.036) and low-risk (P < 0.0001) groups. One limitation of this study is the relatively short follow-up period, a common confounding factor for studies on low-grade tumors. Our data illustrate that IDH mutant lower grade astrocytomas is not a homogeneous group and should be molecularly stratified for risk.

IDH mutant lower grade (WHO Grades II/III) astrocytomas can be stratified for risk by CDKN2A, CDK4 and PDGFRA copy number alterations

Background Astrocytoma of the isocitrate dehydrogenase (IDH) wild-type gene is described as a provisional entity within the new World Health Organization (WHO) classification. Some groups believe that IDH wild-type lower-grade gliomas, when interrogated for other biomarkers, will mostly turn out to be glioblastoma. We hypothesize that not all IDH wild-type lower-grade gliomas have very poor outcomes and the group could be substratified prognostically. Methods Seven hundred and eighteen adult WHO grades II and III patients with gliomas from our hospitals were re-reviewed and tested for IDH1/2 mutations. One hundred and sixty-six patients with IDH wild-type cases were identified for further studies, and EGFR and MYB amplifications, mutations of histone H3F3A, TERT promoter (TERTp), and BRAF were examined. Results EGFR amplification, BRAF, and H3F3A mutations were observed in 13.8%, 6.9%, and 9.5% of patients, respectively, in a mutually exclusive pattern in IDH wild-type lower-grade gliomas. TERTp mutations were detected in 26.8% of cases. Favorable outcome was observed in patients with young age, oligodendroglial phenotype, and grade II histology. Independent adverse prognostic values of older age, nontotal resection, grade III histology, EGFR amplification, and H3F3A mutation were confirmed by multivariable analysis. Tumors were further classified into "molecularly" high grade (harboring EGFR, H3F3A, or TERTp) (median overall survival = 1.23 y) and lower grade (lacking all of the 3) (median overall survival = 7.63 y) with independent prognostic relevance. The most favorable survival was noted in molecularly lower-grade gliomas with MYB amplification. Conclusion Adult IDH wild-type lower-grade gliomas are prognostically heterogeneous and do not have uniformly poor prognosis. Clinical information and additional markers, including MYB, EGFR, TERTp, and H3F3A, should be examined to delineate discrete favorable and unfavorable prognostic groups.

Adult IDH wild-type lower-grade gliomas should be further stratified.

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Rui-qi Zhang

Papers

Adult IDH wild-type lower-grade gliomas should be further stratified.

Glioma groups classified by IDH and TERT promoter mutations remain stable among primary and recurrent gliomas.