Co-deleted Oligodendrogliomas Research Articles

1237 The Mutational Landscape of Molecularly Defined Oligodendrogliomas

INTRODUCTION: Oligodendrogliomas are molecularly defined by IDH1/2 mutation and codeletion of chromosome arms 1p/19q. Prior studies identified capicua transcriptional repressor (CIC), far upstream binding protein (FUBP1), and the promoter region of telomerase reverse transcriptase (TERTp) as commonly mutated in oligodendrogliomas. However, prognostically relevant molecular signatures have yet to be identified. METHODS: A retrospective single-center study evaluated adults with pathologically confirmed IDH-mutant and 1p/19q co-deleted oligodendrogliomas that underwent surgery between 2005 and 2021. Genetic data from formalin-fixed, paraffin-embedded specimens were analyzed with the NGS Solid Tumor Panel at the Johns Hopkins Medical Laboratories, which tested over 400 genes. Kaplan-Meier curves and log-rank tests were used to compare progression-free survival (PFS) and overall survival (OS). Chi-squared tests compared clinical characteristics between mutation status in the ten most frequently mutated genes. RESULTS: From 277 patients with IDH-mutated, 1p/19q co-deleted oligodendrogliomas, 95 patients with NGS were included. Ten genes had 9 or more patients with a mutation, with CIC and FUBP1 being the most frequently mutated genes (n = 60 and n = 23, respectively). Kaplan-Meier curves showed that most genes were not associated with differences in PFS or OS. CIC conferred a reduction in PFS in patients with a PFS <100 months (p = 0.038), though this significance was lost when including all PFS durations (p = 0.52). While no biomarkers had sufficient statistical power, our analysis showed trends in shortened survival in patients with TP53 (p = 0.01) and PIK3CA (p = 0.03) mutations. CONCLUSIONS: Oligodendrogliomas harbor frequent mutations in CIC, FUBP1, and TERTp, but most patients typically have minimal additional alterations. As NGS becomes routine, understanding these mutations may inform therapeutic and prognostic recommendations or the development of novel targeted therapies. Additional molecular assays beyond mutation analysis with NGS may reveal prognostically relevant biologic subgroups of oligodendrogliomas.

Neurologic Events and Outcomes in Patients Receiving Proton and Photon Reirradiation for High Grade Non-Codeleted Gliomas

Patients undergoing reirradiation (ReRT) for high grade glioma are at risk for tumor progression, pseudoprogression, and radiation necrosis. We investigated factors associated with neurologic events and disease control after re-irradiation with protons and photons at a single academic center. We reviewed records and MRIs of patients receiving scanning beam proton (since center opening in 2016) and photon (since 2015) reirradiation in ≥10 fractions for grade 3 anaplastic astrocytoma (AA) and grade 4 glioblastoma (GBM), excluding 1p19q co-deleted oligodendrogliomas and extensive multifocal/leptomeningeal disease. The primary endpoint was time from ReRT to ≥ grade 2 pseudoprogression or radiation necrosis (PsP/RN, grade 2: moderate symptoms requiring outpatient steroids/bevacizumab, grade 3: severe symptoms leading to admission or surgical intervention). Dose was converted to EQD2 using a/b = 3. Cox proportional hazards model was used to calculate survival and time to PsP/RN. A total of 53 patients were included (26 protons, 27 photons, median KPS 80). Patients receiving protons had more favorable features. Compared to the photons, the proton group was younger (48 vs. 58) and more likely to have AA (46% vs. 22%) and resection within 3 months (42% vs 26%). The proton group also had a longer interval from prior RT (57 vs. 39 months) and were less likely to receive bevacizumab at reRT (15% vs. 59%). CTV was 130 cc for protons vs 99 cc for photons, and most had active disease at time of ReRT identified on planning MRI (76% protons, 85% photons). Median OS was 10.5 months (14.1 months protons, 8.1 months photons), with time from initial RT the only significant factor on multivariate analysis. Median PFS was 9.4 months (9.8 months protons, 6.2 months photons). 9 patients (18%) had ≥ grade 3 PsP/RN (8 proton, 1 photon) and 21 patients (41%) had ≥ grade 2 PsP/RN (16 proton, 5 photon). Grade 3 events included 1 seizure (photon group), 1 hemorrhage, 1 thalamic stroke, 1 shunt placement, 1 re-resection, and PSP4 4 PsP/RN requiring admission. Protons were associated shorter time to ≥ grade 2 PsP/RN (4 months vs. not reached, p = 0.027). When accounting for bevacizumab use at time of reRT, the association between protons and PsP/RN lost significance but there remained a trend (grade 2, p = 0.095, HR 2.4; grade 3, p = 0.105, HR 5.8). CTV, MGMT status, EQD2, and interval from prior RT were not associated with PsP/RN. High grade neurologic events were common in patients with predominantly active, unresected high grade gliomas receiving ReRT. Though ascertainment and survival bias are significant limitations, pseudoprogression and necrosis appeared to be more prominent in patients receiving protons. These results contribute to ongoing efforts to both optimize ReRT for high grade glioma and investigate biologic effects of proton therapy.

A Multigene Signature Associated with Progression-Free Survival after Treatment for IDH Mutant and 1p/19q Codeleted Oligodendrogliomas

Background. IDH mutant and 1p/19q codeleted oligodendrogliomas are the gliomas associated with the best prognosis. However, despite their sensitivity to treatment, patient survival remains heterogeneous. We aimed to identify gene expressions associated with response to treatment from a national cohort of patients with oligodendrogliomas, all treated with radiotherapy +/− chemotherapy. Methods. We extracted total RNA from frozen tumor samples and investigated enriched pathways using KEGG and Reactome databases. We applied a stability selection approach based on subsampling combined with the lasso-pcvl algorithm to identify genes associated with progression-free survival and calculate a risk score. Results. We included 68 patients with oligodendrogliomas treated with radiotherapy +/− chemotherapy. After filtering, 1697 genes were obtained, including 134 associated with progression-free survival: 35 with a better prognosis and 99 with a poorer one. Eight genes (ST3GAL6, QPCT, NQO1, EPHX1, CST3, S100A8, CHI3L1, and OSBPL3) whose risk score remained statistically significant after adjustment for prognostic factors in multivariate analysis were selected in more than 60% of cases were associated with shorter progression-free survival. Conclusions. We found an eight-gene signature associated with a higher risk of rapid relapse after treatment in patients with oligodendrogliomas. This finding could help clinicians identify patients who need more intensive treatment.

NCOG-10. RADIATION THERAPY CAN BE SAFELY DEFERRED IN OLIGODENDROGLIOMAS

Abstract Deferring multimodal aggressive therapies in young patients to delay treatment-induced toxicity without jeopardizing long-term outcome would be of great benefit to our patients. After IRB approval, we retrospectively reviewed 80 confirmed IDH mutant and 1p19q codeleted oligodendrogliomas treated at one institution between 2005 and 2020. Median follow-up was 5 (range 1-26) years. All patients underwent maximal safe resection, followed by observation with routine imaging (n=28), chemotherapy alone (n=27), or radiation with chemotherapy (n=25) as initial upfront therapy. Median progression free survival was 36 (range 1-203), 54 (range 1-306), and 57 (range 4-281) months, respectively. Median overall survival was not reached, with 85% (67/80) alive, 8 on treatment and 59 stable off therapy. Among 35 patients who died or were followed for 10 years, median PFS was 12, 15, and 10 years for observation (n=9), chemotherapy (n=11) and chemoradiotherapy (n=15), with deaths or KPS below 50 in 3, 6, and 8, respectively. Three deaths in the observation group occurred 12, 12 and 17 years after diagnosis; one at 95 years old and another tumor-unrelated. Among 44 patients eventually receiving radiation, 15 suffered toxicity, including pathologically proven necrosis (n=6), cognitive decline with KPS< 50 (n=5), memory loss with KPS > 50 (n=3), and optic neuropathy (n=1). Myelosuppression from PCV was more pronounced after chemoradiation than in the upfront setting. Temozolomide after PCV chemotherapy was well tolerated. Long term follow-up of oligodendroglioma patients is challenging, but essential in determining late toxicities and treatment efficacy. Long-term results of European and North American multicenter cooperative group trials contradicted earlier publications reporting no benefit from early chemotherapy. Some management practice guidelines established a half-century ago persist (i.e., administer radiation therapy early), despite potentially crippling late effects. Deferring upfront radiation therapy is safe, less toxic, and equally efficacious in codeleted oligodendrogliomas.

T2-FLAIR mismatch sign for diagnosis of 1p19q non-codeleted or ATRX mutant astrocytoma

Abstract Aims The World Health Organisation (WHO) classification of adult gliomas has undergone significant revision in recent years, with current emphasis on the role of the molecular biomarkers IDH, 1p19q, ATRX, and p53 for classification of glioblastoma, astrocytoma, and oligodendroglioma. When correctly applied the T2-FLAIR mismatch sign is reported to have 100% specificity for WHO grade II or III IDH mutant 1p19q non-codeleted astrocytoma. We sought to verify this classic imaging-molecular correlate in our cohort at a single tertiary level neurosurgical referral centre in the United Kingdom. Method Data were gathered by searching the histopathology database for cases between 2014 and 2019 containing the keywords ‘IDH Mutant’ AND ‘Astrocytoma’ or ‘Glioblastoma’ or ‘Oligodendroglioma’ in the report. Inclusion criteria: Biopsy/resection proven IDH mutant tumours in adults (age >17). A strict application of the T2-FLAIR mismatch sign was used when evaluating MRI. Native T2 signal was required to be homogenous or near homogenous, with hypointense signal on T2 weighted FLAIR except for a hyperintense peripheral rim. In addition, the T2-FLAIR mismatch sign was not applied to tumours showing any unequivocal contrast enhancement or macrocystic change. Results 66/185 cases were excluded for reasons of insufficient imaging, duplication, 1p19q partial deletion/unknown + ATRX wild type/unknown, IDH wild type/negative, Grade IV histology. 119 cases fit the inclusion criteria, all IDH positive. Group 1 comprised 49 (39%) 1p19q codeleted tumours, or oligodendrogliomas. ATRX was wild type (78%), unknown (18%), or mutated (<1%). Group 2 comprised 37 (29%) 1p19q non-codeleted tumours, or astrocytomas. ATRX was mutated (70%), unknown (22%), wild type (5%), or equivocal (3%). Group 3 comprised 41 (32%) 1p19q unknown tumours, all ATRX mutated, p53 expressed (83%). When p53 status was unaltered/equivocal, microscopy was convincingly astrocytic. Groups 2 and 3 comprised the astrocytomas (61%). T2-FLAIR mismatch was positive in 5 1p19q non-codeleted astrocytomas, 5 1p19q unknown ATRX mutant astrocytomas, and no 1p19q co-deleted oligodendrogliomas. Test sensitivity and specificity was 14% and 100% for 1p19q non-codeletion, 13% and 100% for ATRX mutation. Conclusion Although relatively uncommon, when present and correctly applied we confirm 100% specificity of the T2-FLAIR mismatch sign for IDH mutant 1p19q non-codeleted astrocytoma. However, if 1p19q status is unknown, clear astrocytic histology and ATRX mutation and/or p53 overexpression is also considered sufficient to diagnose astrocytoma. When 1p19q status is unavailable we also report 100% specificity of T2-FLAIR mismatch for ATRX mutated astrocytomas. T2-FLAIR mismatch was not observed in any 1p19q codeleted oligodendrogliomas or ATRX wild type tumours. More accurate methods of non-invasive glioma diagnosis will help improve neurohistopathological correlation, prognostication, and guide the tempo of the pre-operative planning phase.

TGF-β promotes microtube formation in glioblastoma through thrombospondin 1.

BackgroundMicrotubes (MTs), cytoplasmic extensions of glioma cells, are important cell communication structures promoting invasion and treatment resistance through network formation. MTs are abundant in chemoresistant gliomas, in particular, glioblastomas (GBMs), while they are uncommon in chemosensitive IDH-mutant and 1p/19q co-deleted oligodendrogliomas. The aim of this study was to identify potential signaling pathways involved in MT formation.MethodsBioinformatics analysis of TCGA was performed to analyze differences between GBM and oligodendroglioma. Patient-derived GBM stem cell lines were used to investigate MT formation under transforming growth factor-beta (TGF-β) stimulation and inhibition in vitro and in vivo in an orthotopic xenograft model. RNA sequencing and proteomics were performed to detect commonalities and differences between GBM cell lines stimulated with TGF-β.ResultsAnalysis of TCGA data showed that the TGF-β pathway is highly activated in GBMs compared to oligodendroglial tumors. We demonstrated that TGF-β1 stimulation of GBM cell lines promotes enhanced MT formation and communication via calcium signaling. Inhibition of the TGF-β pathway significantly reduced MT formation and its associated invasion in vitro and in vivo. Downstream of TGF-β, we identified thrombospondin 1 (TSP1) as a potential mediator of MT formation in GBM through SMAD activation. TSP1 was upregulated upon TGF-β stimulation and enhanced MT formation, which was inhibited by TSP1 shRNAs in vitro and in vivo.ConclusionTGF-β and its downstream mediator TSP1 are important mediators of the MT network in GBM and blocking this pathway could potentially help to break the complex MT-driven invasion/resistance network.

OTME-14. TGF-beta signaling in microtube formation of glioblastoma

Microtubes (MTs) are cytoplasmic extensions of glioma cells serving as important cell communication structures while also promoting invasion and treatment resistance through network formation. MTs are abundant in chemoresistant gliomas, in particular glioblastomas, while they are uncommon in chemosensitive IDH mutated and 1p/19q co-deleted oligodendrogliomas.By performing a bioinformatics analysis on data from The Cancer Genome Atlas (TCGA) we identified the TGF-b pathway as being distinctly upregulated in glioblastomas compared to oligodendrogliomas, making this a signaling pathway potentially involved in MT formation. Based on patient-derived GBM stem cell line models we demonstrated that stimulation of TGF-b increased MT formation, while inhibition of TGF-b reduced MT formation. MT formation was verified by expression of GAP43 and nestin, which have previously been shown to be important structural proteins of MTs.Interestingly, we also observed a responder/non-responder relationship between GBM cell lines P3 and GG16/ GG6 regarding MT formation upon TGF-b stimulation. To determine downstream signaling mediators of the TGF-b pathway crucial for MT formation, we subsequently performed RNA sequencing of these cell lines. From the 34 initial candidates common to responders, but absent in non-responders, only 3 genes were left after filtering through TCGA data and in vivo RNA sequencing data of a GBM xenograft model derived from P3.Thrombospondin 1 (TSP1) emerged as the most interesting candidate as we have previously shown that transcription of this gene is activated by TGF-b/SMAD signaling and TSP1 also promotes invasiveness of GBM. TSP1 was upregulated by TGFB1 stimulation in responder cells and promoted MT formation. Transcriptional activation of TSP1 was absent in the non-responder cell line GG6 and could be reversed in the responder cell line P3 by TSP1 shRNAs in vitro and in vivo. Thus, TSP1 was experimentally verified as an important mediator of microtube formation downstream of TGF-b signaling.

Static 18F-FET PET and DSC-PWI based on hybrid PET/MR for the prediction of gliomas defined by IDH and 1p/19q status.

To investigate the predictive value of static O-(2-18F-fluoroethyl)-L-tyrosine positron emission tomography (18F-FET PET) and cerebral blood volume (CBV) for glioma grading and determining isocitrate dehydrogenase (IDH) mutation and 1p/19q codeletion status. Fifty-two patients with newly diagnosed gliomas who underwent simultaneous 18F-FET PET and dynamic susceptibility contrast perfusion-weighted imaging (DSC-PWI) examinations on hybrid PET/MR were retrospectively enrolled. The mean and max tumor-to-brain ratio (TBR) and normalized CBV (nCBV) were calculated based on whole tumor volume segmentations with reference to PET/MR images. The predictive efficacy of FET PET and CBV in glioma according to the 2016 World Health Organization (WHO) classification was evaluated by receiver operating characteristic curve analyses with the area under the curve (AUC). TBRmean, TBRmax, nCBVmean, and nCBVmax differed between low- and high-grade gliomas, with the highest AUC of nCBVmean (0.920). TBRmax and nCBVmean showed significant differences between gliomas with and without IDH mutation (p = 0.032 and 0.010, respectively). Furthermore, TBRmean, TBRmax, and nCBVmean discriminated between IDH-wildtype glioblastomas and IDH-mutated astrocytomas (p = 0.049, 0.034 and 0.029, respectively). The combination of TBRmax and nCBVmean showed the best predictive performance (AUC, 0.903). Only nCBVmean differentiated IDH-mutated with 1p/19q codeletion oligodendrogliomas from IDH-wildtype glioblastomas (p < 0.001) (AUC, 0.829), but none of the parameters discriminated between oligodendrogliomas and astrocytomas. Both FET PET and DSC-PWI might be non-invasive predictors for glioma grades and IDH mutation status. FET PET combined with CBV could improve the differentiation of IDH-mutated astrocytomas and IDH-wildtype glioblastomas. However, FET PET and CBV might be limited for identifying oligodendrogliomas. • Static 18F-FET PET and DSC-PWI parameters differed between low- and high-grade gliomas, with the highest AUC of the mean value of normalized CBV. • Static 18F-FET PET and DSC-PWI parameters based on hybrid PET/MR showed predictive value in identifying glioma IDH mutation subtypes, which have gained importance for both determining the diagnosis and prognosis of gliomas according to the 2016 WHO classification. • Static 18F-FET PET and DSC-PWI parameters have limited potential in differentiating IDH-mutated with 1p/19q codeletion oligodendrogliomas from IDH-wildtype glioblastomas or IDH-mutated astrocytomas.

Narrowing down the Common Cytogenetic Deletion 14q to a 5.6-Mb Critical Region in 1p/19q Codeletion Oligodendroglioma-Relapsed Patients Points to Two Potential Relapse-Related Genes: SEL1L and STON2

Based on a literature review and our database, we report on the smallest 14q deletion identified in a brain tumor characterized by 1p/19q codeletion low-grade oligodendroglioma. In 2013, array-comparative genomic hybridization of the brain tumor revealed 1p/19q codeletion as a sole abnormality. In 2019, the patient relapsed showing additional abnormalities including a 14q deletion of 16.5 Mb at 14q24.2q31.3. This region overlaps with 2 previously identified minimal regions, 14q21.2q24.3 and 14q31.3q32.1, based on 142 cases of glioma. The authors reported no correlation between these 2 regions and survival. By extracting these 2 regions from our patient's deletion and comparing it to 12 other cases of 1p/19q codeletion oligodendrogliomas reported in the literature, we narrowed down the 14q loss possible critical region to 5.6 Mb mapping at 14q31.1q31.2. This region contains 2 potential relapse-related genes: SEL1L and STON2.

GENE-29. INCREASED COPY NUMBER BURDEN (CNB) IS ASSOCIATED WITH GRADE IN IDH-MUTANT, 1p/19q-CODELETED OLIGODENDROGLIOMAS.

Abstract BACKGROUND Oligodendrogliomas are classified as either WHO grade II or III depending on histologic features. Grade often influences treatment decisions. However, there is variability in patient outcome within tumors of similar grade. We hypothesized that copy number burden (CNB) and specific copy number variants (CNV) might be associated with oligodendroglioma grade and prognosis. METHODS Copy number array analyses were performed on 285 molecular oligodendrogliomas (IDH-mutant, 1p/19q-whole arm-codeleted) from the Mayo Clinic internal and consult neuropathology practice and 167 TCGA molecular oligodendrogliomas. CNB was defined as the total number of copy number alterations. The association of CNB and CNV with grade and overall survival (when available) was assessed. All Mayo and TCGA data were evaluated using the ChAS software suite (Thermo- Fisher) and blindly reviewed by a clinical cytogeneticist (RBJ). RESULTS The mean CNB was 5.0 and 10.4 in the Mayo WHO grade II and III oligodendrogliomas, respectively (p = 5.4 x 10–17). Among the TCGA WHO grade II and III oligodendrogliomas the mean CNB was 4.4 and 5.3, respectively (p = 0.034). Common CNVs (occurring in at least 5% of cases) were -4/4q-, +8/8q+, -9/9p-/cnLOH 9p, +11/11q+, -14/14q-, -15 and -18/18q-. Of these, -9/9p-/cnLOH 9p was significantly associated with higher grade in both the Mayo and TCGA cohorts (p = 8.3 x 10-10 and 0.018, respectively). In the TCGA cohort the presence of &gt;10 CNVs or +11/11q+ was associated with a poorer survival (p = 0.016 and 0.006, respectively). CONCLUSIONS CNB is significantly associated with WHO grade in IDH-mutant, 1p/19q co-deleted oligodendrogliomas. The presence of a significantly elevated CNB in some WHO grade II tumors may be suspicious for the presence of unappreciated grade III histologic features. Longer follow-up will be necessary to determine if CNB or single CNVs are associated with survival.

OS9.7 Telomere length, TERTp mutation and ALT status in adult diffuse gliomas

Abstract BACKGROUND The current classification of adult diffuse gliomas integrates two alternative telomere maintenance mechanisms: reactivation of telomerase activity by TERT promoter (TERTp) mutations or ATRX mutations associated with alternative length telomere (ALT). We investigated here the relation between these two mechanisms, telomere length, and outcome in a large series of diffuse gliomas. MATERIAL AND METHODS We performed C-circle assay (CCA) to determine ALT status, determined telomere length in tumor (RTLt) and leukocyte (RTLl) in a cohort of 354 adult diffuse gliomas, and sequenced ATRX gene. We calculated an age-adjusted telomere score considering tumor and leukocyte (blood) telomere length and corrected by age. This score was used in univariate and multivariate survival analyses to evaluate the potential impact of telomere length on the prognosis of gliomas. We used the TCGA LGG-GBM dataset to validate our findings in an independent cohort. RESULTS RTLl and RTLt were associated with ATRX mutation and ALT phenotype, and negatively associated with age and TERTp mutations. ATRX mutations (found in 52% (64/123) of samples) were mostly transitions (C&gt;T or T&gt;C), and were associated with ALT phenotype. None of 1p/19q co-deleted oligodendrogliomas harbored an ALT phenotype. No patients with TERTp mutations had ALT phenotype except for a very small subgroup of patients (3/87, 3.4%) suggesting that multiple ways of telomere maintenance, may co-exist in a single tumor, probably expressed in different clones. Telomere age-adjusted score was independently associated with better outcome (HR= 0.73 [95% CI 0.56–0.97], p-value 0.03 adjusted for age, TERTp mutation, IDH mutation, 1p/19q co-deletion and WHO grade). These results were validated using the LGG-GBM TCGA dataset. CONCLUSION We unravel the relation between RTLl and RTLt, TERTp mutation and ALT phenotype and describe a novel telomere age-adjusted score independently associated with better prognosis in adult diffuse gliomas.

Eighty percent survival rate at 15years for 1p/19q co-deleted oligodendroglioma treated with upfront chemotherapy irrespective of tumor grade.

Chromosomes 1p/19q co-deletion is a robust molecular marker for the diagnosis of oligodendroglial tumors, and has been included in the 2016 WHO modified classification. Although treatment for oligodendroglioma is controversial, upfront chemotherapy is regarded as one of the treatment option for low-grade tumor. We have treated all the 1p/19q co-deleted oligodendrogliomas, both grades II and III, with upfront chemotherapy without conventional radiotherapy for 20years. The clinical experience from this trial may be suggestive for understanding of the biological features of oligodendroglioma with 1p/19q co-deletion toward precision medicine. This is a long-term retrospective data of the non-selected patients with 1p/19q co-deleted oligodendrogliomas uniformly treated with up-front chemotherapy. Seventy consecutive patients (48 with grade II and 22 with grade III tumors) were included. The median follow-up period was 13years. The 5-, 10-, and 15-year progression-free survival (PFS) rates were 85.7%, 54.8%, and 31.5%, respectively, and the median PFS was 146months. In most cases, tumor recurrence was remained local and could be controlled by salvage surgery and/or chemotherapy. The 5-, 10-, and 15-year overall survival (OS) rates were 96.8%, 88.7%, and 80.0%, respectively, and the median OS was not reached. These survival data compared favorably with previous large clinical studies employing radiotherapy. Tumor grades based on World Health Organization classification, extent of surgery, and age affected neither PFS nor OS. Most patients were able to return to their premorbid social life. The long-term results drawn from 20-years of single institution experience show that the patients with 1p/19q co-deleted oligodendrogliomas can be successfully treated with up-front chemotherapy alone without compromising OS.

Radiographic assessment of contrast enhancement and T2/FLAIR mismatch sign in lower grade gliomas: correlation with molecular groups.

With the updated World Health Organization (WHO) 2016 neuropathological diagnostic criteria, radiographic prognostic associations in lower-grade gliomas (LGG, WHO grade II and III) are undergoing re-evaluation. We identified 316 LGG patients (151 grade II and 165 grade III) for a combined cohort from three independent databases. We analyzed the preoperative axial FLAIR, axial T2-weighted and post-gadolinium volumetric T1-weighted MR images. The molecular data collected included the status of IDH1/2, TP53, TERT promoter and ATRX mutations, in addition to 1p/19q co-deletions. In a subset of cases (n = 133), we assessed the "T2-FLAIR mismatch" sign. Gliomas were assigned to one of the three molecular groups: Group O (IDH-mutant, 1p/19q co-deleted oligodendrogliomas, n = 95), Group A (IDH-mutant, ATRX inactivated astrocytomas, n = 175) and Group G (IDH wild-type, GBM-like, n = 46). A contrast-enhancing tumor was seen in 98 patients (31%), most frequently in Group G (n = 28/45, 57%), when compared to Group A (n = 49/175, 28%) and Group O (n = 24/95, 25.3%) tumors (p = 0.008 and p = 0.0011, respectively). Consistent with previous reports, T2-FLAIR mismatch was preferentially found in Group A tumors (73.1%, 60 of 82), although its presence was not associated with survival, after controlling for molecular group. False positive mismatch sign was noted in 28.5% (12/42) Group O tumors, but none of the tumors in Group G. A combination of all three factors: age under 40years at first diagnosis, a tumor size larger than 6cm and T2-FLAIR mismatch was highly specific for IDH mutant astrocytoma (Group A). We identify radiographic correlates of molecular groups in lower-grade gliomas, which join clinical demographic features in defining the characteristic presentation of these tumors. Radiographic correlates of prognosis in LGG require re-evaluation within molecular group.

GENE-11. SMALL TERMINAL ALTERATIONS AND ALTERNATIVE LENGTHENING OF TELOMERES ARE A FEATURE OF IDH-MUTANT, 1p/19q NON-CODELETED GLIOMAS

Gliomas are typified by genetic variability and instability. The full potential of molecular genetics to classify tumors has not been realized. We previously proposed a novel glioma classification system that increases the sensitivity and specificity of diagnosis and improve prognostication. We have completed copy number array mutational analyses and a targeted next-generation sequencing 50-gene glioma panel on 148 Mayo Clinic formalin-fixed paraffin-embedded gliomas with subsequent data validation performed on 419 gliomas from the TCGA. Median age at resection was 49 years (range: 17–80; 95% 46.5–51.6 years). There were 36 (24.3%) IDH-mutant, 1p/19q codeleted oligodendrogliomas; 46 (31.1%) IDH-mutant, 1p/19q non-codeleted astrocytomas and 66 (44.6%) IDH-wildtype gliomas. Small terminal alterations (STAs) defined as copy number variations (CNVs) IDH-mutant, 1p/19q non-codeleted tumors. Acquisition of 32 STAs was observed in 47% IDH-mutant, 1p/19q non-codeleted versus 27% IDH-wildtype tumors (P=1.8x10-5). In the TCGA dataset, these were seen in 67% versus 26% respectively (P=2.8x10-16). STAs were glioma subclass-specific and did not correlate with overall genetic instability as determined manually or with a computational method. ATRX loss was observed in 27 of 41 (65.9%) tumors with an ATRX mutation versus 20 of 106 (18.9%) ATRX-wildtype tumors (P=1.3x10-7). ATRX loss also correlated with the alternative lengthening of telomeres (ALT) phenotype and was seen in 25 of 31 (80.6%) ALT-positive versus 7 of 55 (12.7%) ALT-negative tumors (P=1.5x10-9). STAs were present in 19 of 32 (59.4%) ALT-positive cases and 8 of 35 (22.9%) ALT-negative cases (P=0.0061). IDH-mutant, 1p/19q non-codeleted astrocytomas have a high prevalence of STAs. This is associated with ATRX loss and the ALT. These alterations do not appear to have de novo implications for survival but may provide novel diagnostic tools and therapeutic targets.

Clinical Outcomes of Reirradiation in IDH-Mutant Astrocytomas and 1p/19q Codeleted Oligodendrogliomas

Recent data has demonstrated that IDH-mutant gliomas (IMGs) have a favorable prognosis as compared to IDH wild type gliomas. While primary fractionated radiation therapy (RT) is part of standard of care for IMGs, clinical outcomes and optimal technique of reirradiation for relapsed IMGs after primary RT are not well defined. This study aims to analyze the clinical outcomes and toxicity of reirradiation for recurrent IMGs. Recurrent IMG patients including IDH-mutant astrocytomas and 1p/19q codeleted oligodendrogliomas who received reirradiation at our institution were retrospectively reviewed. Reirradiation techniques included stereotactic radiosurgery (SRS) or external beam RT (EBRT). Local control (LC), progression-free survival (PFS), and overall survival (OS) were calculated from start of reirradiation and compared using Kaplan-Meier analysis. Biologically equivalent dose in 2Gy fractions (EQD2) for brain were estimated for each course of RT using the linear-quadratic model and α/β of 3. Radiation necrosis (RN) was evaluated based on all available clinical, radiographic and pathological data. From 2001-2017, 23 recurrent IMGs were reirradiated (74% oligodendrogliomas, 26% astrocytomas). All tumors were initially diagnosed as grade II (65%) or III (35%) before primary RT. In 21 patients who had surgery for relapsed disease, 62% had increased tumor grade. Median follow up after reirradiation was 20 months (range 1 - 105). Median time between RT courses was 13.2 years (0.4 – 26.2). Fifteen patients (65%) were treated with EBRT (53% Intensity-modulated RT, 47% proton therapy); 8 patients (35%) were treated with SRS (87% single-fraction, 13% multi-fraction). Median EQD2 of reirradiation was 51.8 Gy (25.2 – 92), and cumulative EQD2 of combined RT courses was 102.5 Gy (85 – 148). Sixteen (70%) patients received concurrent or adjuvant chemotherapy.For the entire cohort, 2-year LC was 79%, 2-year PFS was 58%, and 2-year OS was 65%. LC, PFS, and OS were not significantly different between oligodendrogliomas and astrocytomas (all P > 0.05). Two-year LC for EBRT and SRS were 80% for both groups (P= 0.35), and 2-year PFS for EBRT and SRS were 60% and 57%, respectively (P=0.60). Radiation necrosis occurred in 5 patients (22%). Reirradiation appears to show promising activity for radiation-relapsed IMGs with moderate risk of RN. Future investigation with longer follow-up and larger cohort is warranted.

PATH-38. COMPREHENSIVE GENOMIC PROFILING OF OLIGODENDROGLIOMAS REFINES TUMOR DIAGNOSES AND IDENTIFIES PATIENTS FOR TARGETED THERAPIES AND IMMUNE CHECKPOINT INHIBITORS

Oligodendrogliomas (ODG) are diffusely infiltrating gliomas characterized by IDH mutations and 1p/19q co-deletion. Distinguishing between diffuse gliomas can be challenging based solely on microscopic features and lead to misclassification of glioma lineage. Genomic profiling of oligodendrogliomas is critical to ensuring diagnostic accuracy and identifying therapeutic options for patients with progressive and/or malignant tumors. DESIGN: Comprehensive genomic profiling (CGP) was performed on FFPE material acquired from 200 consecutive submitted cases of locally diagnosed ODG. CGP identifies tumor mutational burden, microsatellite instability status (MSI) and all classes of genomic alterations in 315 cancer-associated genes including a validated novel algorithm that accurately determines 1p/19q co-deletion status. Among the 202 ODG samples, 1p/19q co-deletion was identified in 152 (75.2%) of cases and in these tumors, the most frequently altered genes were TERT, IDH1/2, CIC, FUBP1, PIK3CA/PIK3R1 and NOTCH1/2. Notably in these tumors activating alterations were frequently detected in PI3K pathway genes including PIK3CA (19.5%), PIK3R1 (7.5%) and PTEN (1.3%). Of the 50 (24.8%) ODG negative for 1p/19q co-deletion (24.8%), the genomic profiles supported astrocytic lineage gliomas (IDH1, TP53, ATRX, TERT, CDKN2A/B and PTEN mutations) warranting tumor reclassification. Among the 1p/19q co-deleted ODG, the median TMB was 2.7 mutations/Mb (range <1 to 818 mutations/Mb) with 8.6% (n=13) of tumors demonstrating hypermutation (≥20 mutations/Mb). MSI-High status was not detected in any ODG. By characterizing 1p/19q co-deletion and genomic profiles of diffuse gliomas, CGP ensures diagnostic accuracy by distinguishing between oligodendroglial and astrocytic lineage tumors. CGP identified pathways for therapeutic intervention in 1p/19q positive ODG including IDH, PI3K pathway and NOTCH1/2 inhibitors. We also report that a subpopulation of oligodendrogliomas with high TMB may benefit from immune checkpoint inhibitors.

Static and dynamic 18F-FET PET for the characterization of gliomas defined by IDH and 1p/19q status.

The molecular features isocitrate dehydrogenase (IDH) mutation and 1p/19q co-deletion have gained major importance for both glioma typing and prognosis and have, therefore, been integrated in the World Health Organization (WHO) classification in 2016. The aim of this study was to characterize static and dynamic O-(2-18F-fluoroethyl)-L-tyrosine (18F-FET) PET parameters in gliomas with or without IDH mutation or 1p/19q co-deletion. Ninety patients with newly diagnosed and untreated gliomas with a static and dynamic 18F-FET PET scan prior to evaluation of tumor tissue according to the 2016 WHO classification were identified retrospectively. Mean and maximum tumor-to-brain ratios (TBRmean/max), as well as dynamic parameters (time-to-peak and slope) of 18F-FET uptake were calculated. Sixteen (18%) oligodendrogliomas (IDH mutated, 1p/19q co-deleted), 27 (30%) astrocytomas (IDH mutated only), and 47 (52%) glioblastomas (IDH wild type only) were identified. TBRmean, TBRmax, TTP and slope discriminated between IDH mutated astrocytomas and IDH wild type glioblastomas (P<0.01). TBRmean showed the best diagnostic performance (cut-off 1.95; sensitivity, 89%; specificity, 67%; accuracy, 81%). None of the parameters discriminated between oligodendrogliomas (IDH mutated, 1p/19q co-deleted) and glioblastomas or astrocytomas. Furthermore, TBRmean, TBRmax, TTP, and slope discriminated between gliomas with and without IDH mutation (p<0.01). The best diagnostic performance was obtained for the combination of TTP with TBRmax or slope (accuracy, 73%). Data suggest that static and dynamic 18F-FET PET parameters may allow determining non-invasively the IDH mutation status. However, IDH mutated and 1p/19q co-deleted oligodendrogliomas cannot be differentiated from glioblastomas and astrocytomas by 18F-FET PET.

IDH mutant and 1p/19q co-deleted oligodendrogliomas: tumor grade stratification using diffusion-, susceptibility-, and perfusion-weighted MRI

PurposeCurrently, isocitrate dehydrogenase (IDH) mutation and 1p/19q co-deletion are proven diagnostic biomarkers for both grade II and III oligodendrogliomas (ODs). Non-invasive diffusion-weighted imaging (DWI), susceptibility-weighted imaging (SWI), and dynamic susceptibility contrast perfusion-weighted imaging (DSC-PWI) are widely used to provide physiological information (cellularity, hemorrhage, calcifications, and angiogenesis) of neoplastic histology and tumor grade. However, it is unclear whether DWI, SWI, and DSC-PWI are able to stratify grades of IDH-mutant and 1p/19q co-deleted ODs.MethodsWe retrospectively reviewed the conventional MRI (cMRI), DWI, SWI, and DSC-PWI obtained on 33 patients with IDH-mutated and 1p/19q co-deleted ODs. Features of cMRI, normalized ADC (nADC), intratumoral susceptibility signals (ITSSs), normalized maxim CBV (nCBV), and normalized maximum CBF (nCBF) were compared between low-grade ODs (LGOs) and high-grade ODs (HGOs). Receiver operating characteristic curve and logistic regression were applied to determine diagnostic performances.ResultsHGOs tended to present with prominent edema and enhancement. nADC, ITSSs, nCBV, and nCBF were significantly different between groups (all P < 0.05). The combination of SWI and DSC-PWI for grading resulted in sensitivity and specificity of 100.00 and 93.33%, respectively.ConclusionsIDH-mutant and 1p/19q co-deleted ODs can be stratified by grades using cMRI and advanced magnetic resonance imaging techniques including DWI, SWI, and DSC-PWI. Combined ITSSs with nCBV appear to be a promising option for grading molecularly defined ODs in clinical practice.

OS11.2 Risk-adjusted survival outcomes for and features of 1p/19q codeletion oligodendrogliomas

Background: Oligodendrogliomas (OGs) are diffuse gliomas defined by IDH mutation and 1p/19q codeletion, in which response to treatment and survival are dictated not by histology, but by molecular subtypes. Methods: The US NCDB was queried for OG patients newly-diagnosed from 2004–2014. Patient and tumor factors were compared by Chi2 or t test. Overall survival (OS) was assessed by Cox proportional hazards and Kaplan-Meier methods, stratified by histology, grade, and codeletion status, and risk adjusted for age, sex, race, Charlson’s comorbidity index, insurance, facility location, chemoradiotherapy, and tumor location, laterality, and size. Results: 14,948 patients with gliomas with OG histology remained after exclusion, 67% (n=10,075) were WHO gr2, 33% were WHO gr3 (i.e. anaplastic), and 36% displayed mixed oligoastrocytoma histology. Complete 1p/19q data were available in 20% (n=2,920). Compared to gr2 non-codeleted cases, codeleted OGs presented at an older median age of 43 yrs (IQR: 25–52; vs. 38 yrs, IQR: 25–51, p<0.0001). Notably, 67% were MGMT methylated (vs. 38%, p<0.001) and 75% arose in the frontal lobe (vs. 56%, p<0.001), and 12% in the temporal lobe (vs. 30%). For treatment, 41% of gr2 codeleted OGs received chemotherapy (vs. 36%, p<0.01), 28% received radiotherapy (vs. 41%, p<0.001), 86% underwent surgery, 55% of which were GTR. In risk-adjusted analysis of gr2 OGs, codeletion was associated with significantly improved OS (HR 0.44, 95%CI: 0.27–0.72, p=0.001), with 2-yr and 5-yr OS rates of 96% (95%CI; 94–97) and 87% (95%CI: 84–90), respectively; vs. 87% (95%CI: 84–90) and 70% (95%CI: 63–76) in non-codeleted OG. Mixed histology was not significant (HR 1.49, 95%CI; 0.92–2.44, p=0.11). Compared to gr3 non-codeleted cases, codeleted anaplastic OGs presented at a median age of 46 yrs (IQR: 37–56; vs. 43 yrs, IQR: 40–46, p=0.066). 75% were MGMT methylated (vs. 46%, p<0.001) and a majority arose in frontal lobes (78% vs. 62%, p<0.001); involving temporal lobes in 9% (vs. 23%). For treatment, 84% of gr3 codeleted OGs received chemotherapy, 70% received radiotherapy, and 96% underwent surgery, 52% of which were GTR. In risk-adjusted analysis of gr3 OGs, codeletion was associated with significantly improved OS (HR 0.36, 95%CI: 0.22–0.59, p<0.001), with 2-yr and 5-yr OS rates of 90% (95%CI; 87–93) and 72% (95%CI: 64–77), respectively; vs. non-codeleted OGs’ 73% (95%CI: 68–78) and 47% (95%CI: 37–56). Mixed histology portends a worse OS (HR 1.72, 95%CI; 1.08–2.74, p=0.02). Conclusion: Although previously referred to as OGs, grade 2 and 3 diffuse gliomas without 1p/19q codeletion are markedly different from molecularly-defined OGs; particularly demonstrating reduced rates of MGMT methylation and significantly worse OS. In cases where a high grade OG is suspected histologically but 1p/19q are not codeleted, careful evaluation and management for IDH-wildtype GBM should be considered.

P06.19 TERT promoter mutation is an independent prognostic factor in 1p/19q co-deleted oligodendrogliomas: a POLA network study

P06.19 TERT promoter mutation is an independent prognostic factor in 1p/19q co-deleted oligodendrogliomas: a POLA network study