Molecular Correlates of Long Survival in IDH-Wildtype Glioblastoma Cohorts

Abstract IDH-wildtype glioblastoma is a relatively common malignant brain tumor in adults. These patients generally have dismal prognoses, although outliers with long survival have been noted in the literature. Recently, it has been reported that many histologically lower-grade IDH-wildtype astrocytomas have a similar clinical outcome to grade IV tumors, suggesting they may represent early or undersampled glioblastomas. cIMPACT-NOW 3 guidelines now recommend upgrading IDH-wildtype astrocytomas with certain molecular criteria (EGFR amplifications, chromosome 7 gain/10 loss, and/or TERT promoter mutations), establishing the concept of a “molecular grade IV” astrocytoma. In this report, we apply these cIMPACT-NOW 3 criteria to 2 independent glioblastoma cohorts, totaling 393 public database and institutional glioblastoma cases: 89 cases without any of the cIMPACT-NOW 3 criteria (GBM-C0) and 304 cases with one or more criteria (GBM-C1-3). In the GBM-C0 groups, there was a trend toward longer recurrence-free survival (median 12–17 vs 6–10 months), significantly longer overall survival (median 32–41 vs 15–18 months), younger age at initial diagnosis, and lower overall mutation burden compared to the GBM-C1-3 cohorts. These data suggest that while histologic features may not be ideal indicators of patient survival in IDH-wildtype astrocytomas, these 3 molecular features may also be important prognostic factors in IDH-wildtype glioblastoma.

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OS10.1 Survival analysis of IDH wildtype astrocytomas with molecular features of glioblastoma, WHO grade IV

Neuro-Oncology ◽

10.1093/neuonc/noz126.067 ◽

2019 ◽

Vol 21 (Supplement_3) ◽

pp. iii20-iii20 ◽

Cited By ~ 2

Author(s):

C M S Tesileanu ◽

J A F Koekkoek ◽

L Dirven ◽

H J Dubbink ◽

J M Kros ◽

...

Keyword(s):

Molecular Data ◽

Lower Grade ◽

Who Grade ◽

Historical Cohort ◽

Molecular Features ◽

Tert Promoter ◽

Significant Difference ◽

Tert Promoter Mutations ◽

Grade Ii ◽

Promoter Mutations

Abstract BACKGROUND Recently, isocitrate dehydrogenase wildtype (IDHwt) lower grade gliomas (LGGs) that have a telomerase reverse transcriptase (TERT) promoter mutation and/or gain of chromosome 7 combined with loss of chromosome 10 and/or epidermal growth factor receptor amplification have been reclassified as IDHwt astrocytomas with molecular features of glioblastoma, WHO grade IV (‘astrocytomas IDHwt, WHO IV’). Survival of these tumors meeting the criteria of these tumors is less well studied. The objective of this study is to compare the overall survival (OS) between the IDHwt astrocytomas, WHO IV and histological glioblastomas (GBMs). MATERIAL AND METHODS In this retrospective multicenter cohort study, all adult patients with a newly diagnosed IDHwt LGG (histologically WHO grade II or III) and with molecular data available were selected from the Erasmus MC and the LUMC from October 2002 to April 2019. LGG patients showing contrast enhancement with necrosis on the MRI at the time of histological diagnosis were excluded. Molecular data were determined using a diagnostic NGS panel. A historical cohort of 195 patients with IDHwt GBMs with molecular data available was used to compare OS. OS was measured from the date of the first diagnostic MR scan. RESULTS 79 IDHwt LGG patients were identified of which 62 patients had molecular features of glioblastoma (‘astrocytomas IDHwt, WHO IV’), 11 patients did not have these molecular features (‘astrocytomas IDHwt, WHO II & III’). In the remaining 6 patients the molecular data were not conclusive (astrocytomas IDHwt, WHO NOS). Patients with astrocytomas IDHwt, WHO IV were slightly older at diagnosis (median age = 57 years) than patients with GBMs IDHwt in the reference cohort or astrocytomas IDHwt, WHO II & III (respectively: median age 55 years, p=0.032 and 47 years, p=0.035). The relatively young age of our GBM IDHwt cohort reflects more extensive molecular testing in younger patients and histologically lower grade tumors. The median OS of astrocytomas IDHwt, WHO IV (23.8 months) was similar to the median OS of GBMs (19.2 months, log-rank test p=0.37). The median OS in 19 patients with only TERT promoter mutations was 16.8 months, similar to GBMs (p=0.94). CONCLUSION There is no statistically significant difference between the OS of IDHwt astrocytomas with molecular features of glioblastoma and the OS of true glioblastomas. Grade II and III IDHwt astrocytoma with molecular features of glioblastoma should be designated WHO grade IV. The presence of TERT promoter mutations alone in this histological context also qualifies for this designation.

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214 The effect of Anti-PD-1 therapy on median overall survival and progression free survival in glioblastoma multiforme patients with certain tumor markers

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0214 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A233-A233

Author(s):

Awais Paracha ◽

Jian Campian

Keyword(s):

Tumor Markers ◽

Treatment Options ◽

Progression Free Survival ◽

Free Survival ◽

Tumor Mutation Burden ◽

Tert Promoter ◽

Mutation Burden ◽

Idh Mutations ◽

Tert Promoter Mutations ◽

Promoter Mutations

BackgroundAlmost 1 in 6 malignant brain cancers are Glioblastoma Multiforme, relative to most other brain cancers it is the most aggressive and prevalent by the numbers.1 Even with the best treatment options median Overall Survival(OS) remains morbid at 14.6 months and Progression Free Survival(PFS) remains 6.9 months.2 Telomerase Reverse Transcriptase promoter mutations,3 Isocitrate Dehydrogenase(IDH) mutations,4 and Tumor Mutation Burden(TMB)5 are three prominent tumor markers that are known to be associated with better PFS and OS; markers like these in the presence of new therapies maybe prove crucial to the development of novel therapies. Immunotherapy has been dubbed a ‘game changer’ in certain hematological and solid malignancies. Specifically, PD1 is a glycoprotein that is a strong negative regulator of the immune system, by blocking this glycoprotein Anti-PD-1 agents harness a strong response by the immune system to fight a malignancy6. In conjunction with these new found tumor markers, Anti-PD-1 agents maybe the solution that could dramatically improve OS and PFS in these patients.MethodsThe goal of this study was to retrospectively analyze patients‘ charts who had received Anti-PD-1 therapy and had TERT promoter mutations, IDH mutations, different TMBs, and other markers and to compare their OS and PFS outcomes with conventional therapies and their response to immunotherapy.ResultsUpon analyzing the data the presence of a TERT promoter 124C>T mutation, IDH wildtype, and lower TMB gave much better OS and PFS after treatment in patients on Anti-PD1 therapy.ConclusionsAlthough this was a small study, these results certainly can be used to examine larger subsets of patients with these markers receiving immunotherapy because they had definitively better outcomes as compared to status quo treatment options.Ethics ApprovalThe study was approved by Washington University Ethics Board, approval number 201111001.ReferencesDavis, M.E., Glioblastoma: overview of disease and treatment. Clinical journal of oncology nursing, 2016;20(5 Suppl): p. S2–S8.Stupp R, et al., Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. New England Journal of Medicine 2005;352(10): p. 987–996.Mosrati MA, et al., TERT promoter mutations and polymorphisms as prognostic factors in primary glioblastoma. Oncotarget 2015;6(18): p. 16663–16673.Chen J-R., et al., Isocitrate Dehydrogenase (IDH)1/2 Mutations as Prognostic Markers in Patients With Glioblastomas. Medicine, 2016;95(9): p. e2583–e2583.Wu Y, et al. The predictive value of tumor mutation burden on efficacy of immune checkpoint inhibitors in cancers: a systematic review and meta-analysis. Frontiers in Oncology 2019;9:p. 1161–1161.Almåsbak H, Aarvak T, and Vemuri MC, CAR T. Cell Therapy: a game changer in cancer treatment. Journal of Immunology Research 2016;2016:p. 5474602–5474602.

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Radiological Characteristics and Natural History of Adult IDH-Wildtype Astrocytomas with TERT Promoter Mutations

Neurosurgery ◽

10.1093/neuros/nyy513 ◽

2018 ◽

Vol 85 (3) ◽

pp. E448-E456 ◽

Cited By ~ 4

Author(s):

Cristina Izquierdo ◽

Marc Barritault ◽

Delphine Poncet ◽

Stéphanie Cartalat ◽

Bastien Joubert ◽

...

Keyword(s):

Natural History ◽

Contrast Enhancement ◽

Slow Growth ◽

Gliomatosis Cerebri ◽

Lower Grade ◽

Tert Promoter ◽

Anaplastic Transformation ◽

Tert Promoter Mutations ◽

History Of ◽

Promoter Mutations

Abstract BACKGROUND Adult IDH-wildtype astrocytomas with TERT promoter mutations (TERTp) are associated with a poor prognosis. OBJECTIVE To analyze the radiological presentation and natural history of adult IDH-wildtype astrocytomas with TERTp. METHODS We retrospectively reviewed the characteristics of 40 IDH-wildtype TERTp-mutant astrocytomas (grade II n = 19, grade III n = 21) and compared them to those of 114 IDH-mutant lower grade gliomas (LGG), of 92 IDH-wildtype TERTp-mutant glioblastomas, and of 15 IDH-wildtype TERTp-wildtype astrocytomas. RESULTS Most cases of IDH-wildtype TERTp-mutant astrocytomas occurred in patients aged >50 yr (88%) and presented as infiltrative lesions without contrast enhancement (73%) that were localized in the temporal and/or insular lobes (37.5%) or corresponded to a gliomatosis cerebri (43%). Thalamic involvement (33%) and extension to the brainstem (27%) were frequently observed, as was gyriform infiltration (33%). This radiological presentation was different from that of IDH-mutant LGG, IDH-wildtype TERTp-mutant glioblastomas, and IDH-wildtype TERTp-wildtype astrocytomas. Tumor evolution before treatment initiation was assessable in 17 cases. Ten cases demonstrated a rapid growth characterized by the apparition of a ring-like contrast enhancement and/or a median velocity of diametric expansion (VDE) ≥8 mm/yr but 7 cases displayed a slow growth (VDE <8 mm/yr) that could last several years before anaplastic transformation. Median overall survival of IDH-wildtype TERTp-mutant astrocytomas was 27 mo. CONCLUSION IDH-wildtype TERTp-mutant astrocytomas typically present as nonenhancing temporo-insular infiltrative lesions or as gliomatosis cerebri in patients aged >50 yr. In the absence of treatment, although rapid tumor growth is frequent, an initial falsely reassuring, slow growth can be observed.

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PATH-41. POLYMORPHOUS LOW-GRADE NEUROEPITHELIAL TUMOR OF THE YOUNG WITH FGFR3-TACC3 FUSION MIMICKING HIGH-GRADE GLIOMA: CASE REPORT AND SERIES OF HIGH-GRADE CORRELATES

Neuro-Oncology ◽

10.1093/neuonc/noab196.493 ◽

2021 ◽

Vol 23 (Supplement_6) ◽

pp. vi124-vi124

Author(s):

Danielle Golub ◽

Peter C Pan ◽

Benjamin Liechty ◽

Cheyanne Slocum ◽

Tejus Bale ◽

...

Keyword(s):

Progression Free Survival ◽

High Grade Glioma ◽

Proliferation Index ◽

Molecular Profile ◽

Low Grade ◽

High Grade ◽

Molecular Features ◽

Tert Promoter ◽

Tert Promoter Mutations ◽

Promoter Mutations

Abstract BACKGROUND Polymorphous low-grade neuroepithelial tumor of the young (PLNTY) is a recently-described entity that can occasionally histologically and molecularly mimic high-grade glioma. The histologic and molecular features that predict aggressive behavior in FGFR3-TACC3 altered tumors are unclear. CASES We present a rare case of an indolent neuroepithelial neoplasm in a 59-year-old female with imaging initially suggestive of high-grade glioma and analyze common molecular features between this case and a series of high-grade gliomas. After total resection, pathology of the case patient revealed predominantly low-grade cytomorphology, abundant microcalcifications, unusual neovascularization, and a low proliferation index. The lesion was diffusely CD34 immunoreactive and harbored both an FGFR3-TACC3 fusion and a TERT promoter mutation. Based on the overall histologic and molecular profile, a diagnosis of PLNTY was favored. The patient was thereafter observed without adjuvant therapy with no evidence of progression at 15-month follow-up. In contrast, a series of eight adult patients with glioblastomas harboring FGFR3-TACC3 fusions and correspondingly aggressive clinical courses are also presented. Common molecular findings included IDH-wildtype status, absence of 1p19q codeletion, and CDKN2A loss. TERT promoter mutations and lack of MGMT promoter methylation were also frequently observed. These patients demonstrated a median 15-month overall survival and a 6-month progression-free survival. CONCLUSIONS PLNTY is a rare low-grade entity that can display characteristics of high-grade glioma, particularly in adults. The potential for a unique entity mimicking PLNTY which may act as a precursor lesion for a more malignant phenotype should be considered in cases with FGFR3-TACC3 fusions and other high-grade features.

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TERT promoter mutations in progressive treatment-resistant meningiomas.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.2047 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 2047-2047 ◽

Cited By ~ 2

Author(s):

Tareq A. Juratli ◽

Christian Thiede ◽

Dietmar Krex ◽

Priscilla Kaliopi Brastianos ◽

Hiroaki Wakimoto ◽

...

Keyword(s):

Initial Diagnosis ◽

Lower Grade ◽

Treatment Resistant ◽

Mutation Status ◽

Tert Promoter ◽

Tert Promoter Mutations ◽

Promoter Gene ◽

History Of ◽

Promoter Mutations

2047 Background: Recurrent meningiomas often undergo a grade-progression to become atypical or malignant upon recurrence. Detailed study of progressive meningioma has been hampered by the lack of available paired specimens. Here, we sequenced the TERT promoter ( TERTp) in a large series of patients with treatment-resistant meningiomas at initial diagnosis as well as their sequential recurrences. Methods: We scored 77 meningiomas from 36 patients for TERTp mutations. All patients in this study developed recurrences during the median follow-up of 13.3 years (range 6.4 - 25.5 years) and underwent three surgeries on average (range 2-8). Additionally, we screened geographically distinct sites of all TERTp-mutant meningiomas to interrogate intratumoral heterogeneity. Results: TERTp mutations were detected in 18 tumor samples (18/77 = 23.3%) from 12 patients, but not in any of the matched blood sample DNAs, excluding germline mutations. Notably, the TERTp mutations were absent in the initial lower-grade tumor and were present in the subsequent recurrent tumors. Moreover, we observe emergent spatial heterogeneity in the form of mixed populations of recurrent tumor cells containing different mutation status of the TERT promoter gene in three cases. Patients with emergence of TERTp -mutant meningiomas had a significantly shorter overall survival than their TERTp wild-type counterparts, when measured from the time of initial diagnosis (2.4 vs 11.1 years, 95% CI 0.25-4.54 vs 9.3- 16.8 years p = 0.007). Conclusions: Our data confirm the high frequency of TERTp mutations and the emergence of TERT promoter mutation in recurrent progressive meningiomas, strongly indicating the presence of ongoing evolution impacting the natural history of these tumors. TERTp mutations are mostly associated with poor outcome. Finally, our study provides important insight into the complexity of tumor heterogeneity and has important implications for targeted therapy in treatment-resistant meningiomas.

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Analysis of TERT promoter mutations, polymorphisms, clinicopathologic features and recurrence-free survival in primary melanoma.

Journal of Clinical Oncology ◽

10.1200/jco.2016.34.15_suppl.e21065 ◽

2016 ◽

Vol 34 (15_suppl) ◽

pp. e21065-e21065

Author(s):

Gregory Chang ◽

Eric Michael Robinson ◽

Jyothirmayee S. Tadepalli ◽

Christine Salvaggio ◽

Yilong Zhang ◽

...

Keyword(s):

Primary Melanoma ◽

Recurrence Free Survival ◽

Clinicopathologic Features ◽

Free Survival ◽

Tert Promoter ◽

Tert Promoter Mutations ◽

Promoter Mutations

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151 TERT Promoter Mutations in Progressive Treatment-resistant Meningiomas

Neurosurgery ◽

10.1093/neuros/nyx417.151 ◽

2017 ◽

Vol 64 (CN_suppl_1) ◽

pp. 236-237

Author(s):

Tareq A Juratli ◽

Ganesh Shankar ◽

Mara Koerner ◽

Shilpa Tummala ◽

Hiroaki Wakimoto ◽

...

Keyword(s):

Initial Diagnosis ◽

Lower Grade ◽

Treatment Resistant ◽

Mutation Status ◽

Tert Promoter ◽

Tert Promoter Mutations ◽

Promoter Gene ◽

History Of ◽

Promoter Mutations

Abstract INTRODUCTION Recurrent meningiomas often undergo a grade-progression to become atypical or malignant upon recurrence. Detailed study of progressive meningioma has been hampered by the lack of available paired specimens. Here, we sequenced the TERT promoter (TERTp) in a large series of patients with treatment-resistant meningiomas at initial diagnosis as well as their sequential recurrences. METHODS We scored 77 meningiomas from 36 patients for TERTp mutations. All patients in this study developed recurrences during the median follow-up of 13.3 years (range 6.4-25.5 years) and underwent three surgeries on average (range 2–8). Additionally, we screened geographically distinct sites of all TERTp-mutant meningiomas to interrogate intratumoral heterogeneity. RESULTS >TERTp mutations were detected in 18 tumor samples (18/77 = 23.3%) from 12 patients, but not in any of the matched blood sample DNAs, excluding germline mutations. Notably, the TERTp mutations were absent in the initial lower-grade tumor and were present in the subsequent recurrent tumors. Moreover, we observe emergent spatial heterogeneity in the form of mixed populations of recurrent tumor cells containing different mutation status of the TERT promoter gene in three cases. Patients with emergence of TERTp-mutant meningiomas had a significantly shorter overall survival than their TERTp wild-type counterparts, when measured from the time of initial diagnosis (2.4 vs 11.1 years, 95% CI 0.25-4.54 vs 9.3- 16.8 years P = 0.007). CONCLUSION Our data confirm the high frequency of TERTp mutations and the emergence of TERT promoter mutation in recurrent progressive meningiomas, strongly indicating the presence of ongoing evolution impacting the natural history of these tumors. TERTp mutations are mostly associated with poor outcome. Finally, our study provides important insight into the complexity of tumor heterogeneity and has important implications for targeted therapy in treatment-resistant meningiomas.

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TERT PROMOTER MUTATIONS CONTRIBUTE TO PROGNOSTIC SUBGROUPS OF LOWER GRADE ASTROCYTOMAS

Neuro-Oncology ◽

10.1093/neuonc/nou209.12 ◽

2014 ◽

Vol 16 (suppl 3) ◽

pp. iii45-iii45

Author(s):

H. K. Ng ◽

A. Chan ◽

Y. Yao ◽

D. Chan

Keyword(s):

Lower Grade ◽

Tert Promoter ◽

Tert Promoter Mutations ◽

Promoter Mutations

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IDH-wildtype lower grade diffuse gliomas: the importance of histological grade and molecular assessment for prognostic stratification

Neuro-Oncology ◽

10.1093/neuonc/noaa258 ◽

2020 ◽

Author(s):

Giulia Berzero ◽

Anna Luisa Di Stefano ◽

Susanna Ronchi ◽

Franck Bielle ◽

Chiara Villa ◽

...

Keyword(s):

Histological Grade ◽

Lower Grade ◽

Who Grade ◽

Tert Promoter ◽

Tert Promoter Mutations ◽

Prognostic Stratification ◽

Grade Ii ◽

Definition Of ◽

Promoter Mutations ◽

Grade Iii

Abstract Background IDH-wildtype (IDHwt) grade II gliomas are a rare and heterogeneous entity. Survival and prognostic factors are poorly defined. Methods We searched retrospectively all patients diagnosed with diffuse WHO grade II and III gliomas at our center (1989-2020). Results Out of 517 grade II gliomas, 47 were “diffuse astrocytomas, IDHwt”. Tumors frequently had fronto-temporo-insular location (28/47, 60%) and infiltrative behavior. We found TERT promoter mutations (23/45, 51%), whole chromosome 7 gains (10/37, 27%), whole chromosome 10 losses (10/41, 24%), and EGFR amplifications (4/43, 9%) but no TP53 mutations (0/22, 0%). Median overall survival (OS) was 59 months (vs. 19 months for IDHwt grade III gliomas (p< 0.0001). Twenty-nine patients (29/43, 67%) met the definition of molecular glioblastoma according to cIMPACT-NOW update3. Median OS in this subset was 42 months, which was shorter compared to patients with IDHwt grade II gliomas not meeting this definition (median OS: 57 months), but substantially longer compared to IDHwt grade III gliomas meeting the definition for molecular glioblastoma (median OS: 17 months, p<0.0001). Most patients with IDHwt grade II gliomas met cIMPACT criteria because of isolated TERT promoter mutations (16/26, 62%), which were not predictive of poor outcome (median OS: 88 months). Actionable targets, including 5 gene fusions involving FGFR3, were found in 7 patients (24%). Conclusions Our findings highlight the importance of histological grading and molecular profiling for the prognostic stratification of IDHwt gliomas and suggest some caution when assimilating IDHwt grade II gliomas to molecular glioblastomas, especially those with isolated TERT promoter mutation.

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