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  • 1
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    Molecular features of gliomas with high tumor mutational burden.
    American Society of Clinical Oncology (ASCO) ; 2020
    In:  Journal of Clinical Oncology Vol. 38, No. 15_suppl ( 2020-05-20), p. 2549-2549
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 38, No. 15_suppl ( 2020-05-20), p. 2549-2549
    Abstract: 2549 Background: TMB-H in gliomas is caused by molecular alterations or alkylator treatment- induced genomic changes characterized by a large number of G:C 〉 A:T transitions. Our study describes the molecular features of TMB-H gliomas. Methods: Gliomas were tested with NextGen sequencing (592 genes), MGMT promoter methylation (MGMT-m) fragment analysis and IHC at Caris Life Sciences. Microsatellite instability (MSI) was test by NGS, FA/IHC. The GC:AT transition rate was calculated as the prevalence of G:A and C:T changes seen in each tumor and 〉 80% was regarded as high transition(TR-H). TMB values were compared using Wilcoxon Rank Sum. TMB-H was defined as the top quartile of all TMB values (TMB 〉 9). Results: TMB in the 3129 gliomas ranged from 0 to 372 mutations/MB (mean: 8.5, median: 6). TMB-H was observed in 31% of glioblastomas, 16% of astrocytomas (astro) (22% of grade III, 7% of grade I/II) and 22% of oligodendrogliomas (oligo) (32% of grade III and 15% of grade I/II). MGMT-m (58% vs. 47%; p=0.0001), pathogenic (p) or likely p (lp) EGFR (14% vs 10%, p=0.004) and PIK3CA mutations (13% vs. 9%, p=0.002), as well as p/lp in 30 other genes were more prevalent in TMB-H cases (p 〈 0.01). In the 613 TMB-H tumors, TR-H was seen in 12% (73) and was strongly associated with increased TMB (median TMB 52 in TR-H vs. 9 in TR-L,) and MSI-H (7.3% vs. 1.1%), both p 〈 0.0001. Tumors with both TR-H and MSI-H had a mTMB of 114 vs. 49 in TR-H /MSS tumors. MSI-H and TR-L tumors had an mTMB of 23 vs. 9 in MSS /TR-L tumors (p 〈 0.0001). All 5 POLE-MT tumors had TMB of 〉 100 (median 264) and TR-L; 4 of the 5 were also MSI-H. PDL1 IHC had no correlation with TMB, MSI or transition rates. In 89 paired samples taken 〉 150 days apart (regardless of intervening treatment), acquisition of TMB-H was seen in 11 pairs: 8 glioblastomas, 2 grade II/III astro and 2 oligo. In the paired tumors that acquired TMB-H status compared to those that did not, a significantly higher prevalence of MGMT-m (82% vs. 37%, p=0.008) and IDH mutation (64% vs. 19%, p=0.004) were seen. 10 of the 11 recurrent tumors with acquisition of TMB-H had TR-H while none in the other 78 pairs. Conclusions: TMB varies significantly in gliomas and associates with POLE, TR-H and MSI-H, but not with an increase of PD-L1. POLE-mutated tumors had the highest TMB levels. TR-H, an indicator of alkylator-induced phenotype, is associated with a higher TMB than MSI-H, however, TR-H may synergize with MSI-H to further increase TMB. Tumors with an IDH mutation and MGMT-m are more prevalent in tumors with high TMB gain. Further understanding of molecular and immune profile of the TMB-H may facilitate more individualized treatment planning.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2020.38.15_suppl.2549
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    XA 52760
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2020
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  • 2
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    The impact of socioeconomic factors and survivorship on radiation induced hypothyroidism in a single institution cohort study.
    American Society of Clinical Oncology (ASCO) ; 2020
    In:  Journal of Clinical Oncology Vol. 38, No. 15_suppl ( 2020-05-20), p. e24065-e24065
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 38, No. 15_suppl ( 2020-05-20), p. e24065-e24065
    Abstract: e24065 Background: To determine factors associated with the development of post-treatment hypothyroidism (HY) in the head and neck (HN) population as well as evaluate the impact of socio-economic factors and survivorship program. Methods: We collected demographics, insurance coverage, disease staging, treatment characteristics, and details of thyroid function measurement as well as supplementation for all HN oncology patients (n = 608) who presented between January 2011 and January 2019 at Levine Cancer Institute, Charlotte, North Carolina. Insurance was categorized as Government (Medicaid or Medicare), Private, or Uninsured. Patient malignancies were grouped as oropharynx, oral cavity, larynx/hypopharynx, nasopharynx, nasal cavity/sinus, or primary salivary gland. Thyroid function was evaluated by use of laboratory thyroid stimulating hormone (TSH) values. Timing of thyroid supplementation was standardized to start of treatment. Details of thyroid hormone supplementation was collected. Data was analyzed with Chi-square and ANOVA methods, using SAS 9.4 (Cary, NC). Results: 483 patients (79%) had post treatment surveillance with TSH. The patients (n = 125, 21%) with no identifiable thyroid surveillance did not have any racial or socioeconomic disparities identified. Caucasian and African American thyroid surveillance rates were similar at 79% and 81%, respectively. There was no difference based on insurance: Government 81%, Uninsured 81%, and Private 76%. Of patients with thyroid surveillance, 203 (42%) developed post-treatment HY. The mean and median time frame until HY identification was 544 days and 450 days, respectively. A mean and median dose of thyroid hormone supplementation of 75 mcg of levothyroxine. Most patients had lower rates of thyroid dysfunction with TSH levels between 5-10. Fewer African Americans (24%) developed HY than Caucasians (47%). Patients with laryngeal cancer were at greatest risk to develop HY (57%), followed by oropharynx (40%) and oral cavity (40%). Staging did not demonstrate a significant difference between development of HY. Conclusions: This study is the largest cohort of HN patients to be evaluated for post HN treatment induced HY. Oncology team providers and primary care physicians should be aware of the significant rates of HY. In our institution we identified a consistency of care provided regardless of socioeconomic and racial factors.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2020.38.15_suppl.e24065
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    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2020
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  • 3
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    Investigation of leptomeningeal disease in high grade glioma and characterization of molecular alterations.
    American Society of Clinical Oncology (ASCO) ; 2023
    In:  Journal of Clinical Oncology Vol. 41, No. 16_suppl ( 2023-06-01), p. 2070-2070
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 16_suppl ( 2023-06-01), p. 2070-2070
    Abstract: 2070 Background: Leptomeningeal disease (LMD) is a challenging complication of high grade glioma (HGG) and questions remain regarding risk factors, molecular associations, and optimal treatment. Here we report updated results on a larger cohort from our previously reported multicenter study (Shoaf 2022, Neuro-Oncology). Methods: Patients with molecularly-profiled HGG (Caris Life Sciences; Phoenix, AZ) with LMD at 3 institutions were included. NextGen Sequencing of DNA (592 gene or whole exome) and RNA (whole transcriptome) were tested. Medical records were reviewed for clinicopathologic characteristics and outcome. Kaplan-Meier estimates of survival were performed using Cox’s proportional hazard model. Mann-Whitney U or Chi-square tests were applied for molecular comparison as appropriate and adjusted for multiple comparisons. Results: Seventy-two patients (female: 20, male: 52; median age: 54.5y) were identified, comprising 65 grade 4 tumors (glioblastoma [GBM]: 62; gliosarcoma: 2; H3K27M diffuse midline glioma: 1), 5 grade 3 tumors (astrocytoma: 4; pleomorphic xanthoastrocytoma: 1), and 1 astrocytoma NOS. LMD diagnosed at glioma diagnosis (n=23) vs. recurrence (n=44) was associated with longer post-LMD survival [pLMD-OS: 16.9m vs. 5.5m, p 〈 0.0001] but similar overall survival [mOS: 16.9m vs. 20.9m; p=0.36] . Pathology-diagnosed LMD (n=15) vs. MRI-diagnosed LMD (n=54) was associated with longer post-LMD survival [pLMD-OS: 15.2m vs. 6.2m, p=0.0002] but similar overall survival [mOS: 16.9m vs. 20.9m; p=0.72] . Post-LMD survival [pLMD-OS: 8.7m vs. 6.8m, p=0.33] and overall survival [mOS: 21.1m vs. 20.9m, p=0.20] were similar for supratentorial (n=45) vs. infratentorial/spinal (n=10) locations, and post-LMD survival did not significantly differ for symptomatic (n=40) vs. asymptomatic (n=22) patients [pLMD-OS: 6.6m vs. 10.5m, p=0.13). pTERT mutation (73%), MGMT methylation (38%), EGFR amplification (31%), and PTEN mutation (28%) were the most prevalent molecular alterations in this group. Comparison of grade 4 LMD tumors with an independent GBM cohort (n=5431) suggested a male predominance (73.4% vs. 58.5%, p=0.016) and a trend towards more frequent mutations in RB1 (25% vs. 9.2%, p=0.002) and MDM4 (12.7% vs. 4.3%, p=0.01) and amplification of WIF1 (6.1% vs. 0.3%, p=0.006), CHIC2 (17.0% vs. 5.2%, p=0.002), and LGR5 (5.9% vs. 0.4%, p=0.012). The expression of immune checkpoint-related genes was similar, although a trend towards immunologically “colder” tumors in the LMD cohort was observed. However, these effects were not significant after correcting for multiple comparisons. Conclusions: LMD is more common in male patients and may be associated with various genomic alterations and tumor microenvironment differences. Overall survival does not differ from patients without LMD, but these differences may provide clues to the pathogenesis and treatment resistance of GBM.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2023.41.16_suppl.2070
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
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  • 4
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    PATH-22. CLINICAL FEATURES AND MOLECULAR CHARACTERIZATION OF LEPTOMENINGEAL DISEASE IN PATIENTS WITH HIGH GRADE GLIOMA
    Oxford University Press (OUP) ; 2022
    In:  Neuro-Oncology Vol. 24, No. Supplement_7 ( 2022-11-14), p. vii154-vii155
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    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 24, No. Supplement_7 ( 2022-11-14), p. vii154-vii155
    Abstract: Leptomeningeal disease (LMD) is a challenging complication of high grade glioma (HGG) and critical questions remain unanswered regarding clinicopathologic risk factors, molecular associations, and optimal treatment. METHODS Patients with molecularly-profiled HGG (Caris Life Sciences; Phoenix, AZ) with LMD at two institutions were included. Medical records were reviewed for clinicopathological characteristics, treatment, and outcome. Kaplan-Meier estimates of patient survival were performed on censored data using Cox’s proportional hazard model. RESULTS 43 patients (male: 33, female: 10; median age: 56 years) were identified, comprising 41 grade 4 (glioblastoma: 38; gliosarcoma: 2; H3K27M diffuse midline glioma: 1) and 2 grade 3 tumors (astrocytoma: 1; pleomorphic xanthoastrocytoma: 1). LMD diagnosed at HGG diagnosis (n=18) versus recurrence (n=22) was associated with longer post-LMD survival [pLMD-OS: 15.3m vs. 4.8m, HR: 0.07, 95% CI: 0.02-0.29, p=0.0004] but similar overall survival [mOS: 15.3m vs. 12.3m; HR: 0.82; 95% CI: 0.36-1.85; p=0.63] . Pathology-diagnosed LMD (n=15) versus MRI-diagnosed LMD (n=26) was associated with longer post-LMD survival [pLMD-OS: 15.4m vs. 5.2m, HR: 14.9, 95% CI: 0.01-0.30, p=0.0004] but similar overall survival [mOS: 17.1m vs. 12.3m; HR: 0.66; 95% CI: 0.3-1.58; p=0.38] . Post-LMD survival was significantly prolonged for supratentorial (n=28) versus infratentorial/spinal (n=4) locations regardless of the diagnostic modality [pLMD-OS: 2.6m vs. 11.3m, HR: 14.4, 95% CI: 2.73-75.7, p=0.0017], and did not significantly differ between symptomatic (n=20) and asymptomatic (n=23) patients [pLMD-OS: 4.8m vs. 11.2m, HR: 1.75, 95% CI: 0.82-3.77, p=0.15). pTERT mutation (81%), EGFR amplification (43%), and MGMT methylation (33%) were prevalent but IDH1 mutation was rare (2.8%). Comparison with a separate glioblastoma cohort (n=1400) suggested more frequent amplification of CHIC2, MDM4, and KDR, higher mutation rates of RUNX1, APC, and RAD51C, colder tumor microenvironment (TME), and lower expression of immune checkpoint-related genes. CONCLUSIONS Clinicopathological characteristics affect post-LMD survival, and cohort comparison suggests molecular and TME differences in LMD-HGG tumors.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noac209.595
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
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  • 5
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    BIOM-17. DIFFERENCES IN THE IMMUNE MICROENVIRONMENT OF GLIOMAS HARBORING IDH2 VERSUS IDH1 MUTATIONS
    Oxford University Press (OUP) ; 2021
    In:  Neuro-Oncology Vol. 23, No. Supplement_6 ( 2021-11-12), p. vi13-vi14
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 23, No. Supplement_6 ( 2021-11-12), p. vi13-vi14
    Abstract: IDH mutations are a defining feature of lower-grade glioma and secondary glioblastoma. Approximately 95% of glioma-associated IDH mutations are in codon 132 of IDH1, but a small proportion are in IDH2. IDH mutations produce the oncometabolite 2-hydroxyglutarate, which induces global DNA hypermethylation and is associated with an immunosuppressive tumor microenvironment. IDH1 is localized in the cytosol while IDH2 is found in the mitochondrial matrix, and mutations in these genes may have differing effects on the tumor microenvironment. METHODS Formalin-fixed, paraffin-embedded tissue from 633 IDH-mutant gliomas (615 IDH1-mutant, 18 IDH2-mutant) underwent whole-exome and whole-transcriptome sequencing at Caris Life Sciences (236 grade 2/3 astrocytoma, 158 grade 2/3 oligodendroglioma, 202 IDH-mutant glioblastoma, 37 glioma, NOS). QuantiSEQ was used to infer tumor-infiltrating immune cell populations from RNAseq data, and gene-set enrichment analyses (GSEA) were performed using Wikipathway. RESULTS IDH1-mutant gliomas had higher levels of pro-inflammatory M1 macrophages (P=0.04), modestly higher levels of monocytes (P=0.08), and lower levels of neutrophils (P=0.04) – typically considered immunosuppressive – compared with IDH2-mutant gliomas. No differences were observed in levels of B cells, dendritic cells, NK cells, or T cell subsets (Treg, CD4+, CD8+). IDH2-mutant gliomas were enriched for hallmark oligodendroglioma mutations (TERT promoter, CIC, FUBP1), while IDH1-mutant gliomas were enriched for hallmark astrocytoma mutations (ATRX, TP53). However, associations with tumor-infiltrating immune cells persisted after excluding 1p/19q co-deleted oligodendroglioma from analyses. GSEA revealed upregulation of the microglial TYROBP signaling pathway, the microglial phagocytic pathway, and of Type II Interferon signaling in IDH1-mutant gliomas versus IDH2-mutant gliomas. CONCLUSIONS Although IDH2 mutations are generally thought to function similarly to IDH1 mutations, we observe differences in tumor-infiltrating immune cells across groups. IDH2-mutant gliomas appeared to have a more immunosuppressive tumor microenvironment than their IDH1-mutant counterparts. Early-phase immunotherapy trials should consider covariate-adaptive randomization approaches to equally allocate IDH2-mutant gliomas across treatment arms.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noab196.048
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
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  • 6
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    BIOM-43. THE GENOMIC, TRANSCRIPTOMIC, AND EPIGENOMIC LANDSCAPE OF ISOCITRATE DEHYDROGENASE WILD TYPE GLIOBLASTOMA ACROSS THE AGE CONTINUUM
    Oxford University Press (OUP) ; 2022
    In:  Neuro-Oncology Vol. 24, No. Supplement_7 ( 2022-11-14), p. vii13-vii14
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 24, No. Supplement_7 ( 2022-11-14), p. vii13-vii14
    Abstract: Older age is a poor prognostic factor for glioblastoma (GBM) patients. We tested whether the intrinsic molecular landscape of the tumor may contribute to this poor prognosis. METHODS In accordance with the 2021 WHO classification scheme, we included only isocitrate dehydrogenase (IDH) wild type GBM. Based on published literature, we defined older as age & gt; 65. RNA expression, gene amplification, tumor mutational burden (TMB) and mutational profiles were analyzed in three unique datasets: Tempus (n = 1,410), Caris (n = 1,432), and TCGA (n = 557). Comparison were made between & lt; 65 and ³ 65 year olds using Pearson’s Chi-squared tests, Fisher’s exact tests, or Wilcoxon rank-sum where appropriate. RESULTS From our evaluable gene sets, TERT promoter mutations were more prevalent in patients ³ 65 years old (Caris 82.64 vs 77.27%, p = 0.016; Tempus 58.0 vs 49.0%, p = 0.002). There were no significant differences in PDCD1, CD274, CD3E, TNFRSF18, CD40, CD8A, TNFRSF4, CTLA4, HAVCR2, TNFSF9, CD274, or CDKN2A; PDL-1 (by IHC); dMMR/MSI-H, TMB; CDK6 amplification, EGFR amplification, EGFR, EGFRvIII, EGFR fusions, MET fusions, PTEN, TP53, or NF-1. MGMT promoter methylation (Caris data) was more common in the older group (49.73 v 34.14%, p & lt; 0.001). TGCA data demonstrated that gene expression, TMB, and methylation did not change significantly with age. Additionally, PCOLCE2 and SLC10A4 were differentially methylated, and missense mutations, of any type, were more common in the older group (p=0.006). CONCLUSION Despite worse survival outcomes for older patients with IDHwt GBM as compared to younger counterparts, the molecular landscape is similar at the genomic, transcriptomic and epigenomic levels. The key exception is TERT promoter mutations that are more common in older GBM patients. Poorer survival is therefore not likely to be attributable solely to intratumoral factors.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noac209.053
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
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  • 7
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    BIOM-17. BRAF MUTATION IS AN EARLY EVENT IN THE EVOLUTION OF A SUBSET OF GLIOBLASTOMAS AND IS ASSOCIATED WITH INCREASED PD-L1 EXPRESSION
    Oxford University Press (OUP) ; 2020
    In:  Neuro-Oncology Vol. 22, No. Supplement_2 ( 2020-11-09), p. ii5-ii5
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 22, No. Supplement_2 ( 2020-11-09), p. ii5-ii5
    Abstract: BRAF is a RAF-family kinase that regulates MAPK/ERK signaling. Activating BRAF mutations, including V600E, are common in circumscribed low-grade gliomas of childhood and young adulthood, but are uncommon in infiltrative astrocytomas, including glioblastoma. Their role in glioblastoma initiation and progression requires analysis of large datasets given the low frequency (1.0%) in TCGA IDH-wild-type glioblastomas. METHODS Molecular profiling was done on 4679 FFPE gliomas by next-generation sequencing at Caris Life Sciences, of which 3170 underwent RNA-sequencing for gene fusion and 4603 DNA-sequencing for mutations. MGMT promoter methylation was tested by pyrosequencing and PD-L1 IHC was performed using the SP142 clone. RESULTS Excluding variants of uncertain significance, BRAF mutations/fusions were most common in pleomorphic xanthoastrocytoma (PXA; N=12/24, 50%), glioneuronal tumors (N=6/13, 46%), pilocytic astrocytoma (PA; N=15/48, 31%), and ganglioglioma (n=5/18, 28%). BRAF fusions were uncommon (N=17), most frequent in PA (N=8/31, 26%) where they were associated with older age at daignosis (P=0.043), and typically involved KIAA1549 as fusion partner (70%). BRAF-mutated/fused glioblastoma patients (N=59/3126, 2%) were younger than BRAF-wild-type glioblastoma patients (54 versus 59 years, P=3.5x10-3); more likely to be MGMT-unmethylated (75% versus 56%, P=5.0x10-3); and 3x more likely to express PD-L1 (55% versus 17%, P=2.1x10-10). In tumors harboring a V600E mutation, the variant allele frequency (VAF) was similar in glioblastoma as in PXA, PA, ganglioglioma, and glioneuronal tumors (median VAF=35%). CONCLUSIONS BRAF-mutated glioblastoma were 3x more likely to express PD-L1 than BRAF-wild-type glioblastoma. We observed no differences in BRAF V600E clonality in BRAF-mutated glioblastoma compared to BRAF-mutated PXA, PA, ganglioglioma, and glioneuronal tumors, suggesting BRAF mutation is an initiating event in the clonal evolution of a subset of glioblastoma. There is rationale to evaluate combined BRAF inhibition with checkpoint inhibition in BRAF-mutated glioblastoma, potentially synergizing the complete response profile of the former with the durable response profile of the latter.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noaa215.017
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2020
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  • 8
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    The mutational landscape of older patients with IDH wild-type glioblastoma (GBM).
    American Society of Clinical Oncology (ASCO) ; 2021
    In:  Journal of Clinical Oncology Vol. 39, No. 15_suppl ( 2021-05-20), p. e14033-e14033
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 39, No. 15_suppl ( 2021-05-20), p. e14033-e14033
    Abstract: e14033 Background: Advanced age is associated with poorer outcomes in GBM and current NCCN guidelines distinguish older GBM patients (≥70 years, oGBM) from their younger counterparts ( 〈 70 years, yGBM). We aim to characterize age-related comprehensive mutational profiles with the long-term goal of improving treatment strategies, outcomes, and rational clinical trial design. Specifically, we focused on IDH-wildtype (WT) oGBM, investigated if oGBM are more likely to acquire temozolomide-induced hypermutations, and finally, compared the frequency of high-tumor mutational burden (TMB) between oGBM vs. yGBM. Methods: Comprehensive molecular profiles of 1,657 adult IDH-WT GBM tumors tested at Caris Life Sciences (Phoenix, AZ) were queried. Tests included NGS of DNA (NextSeq, 592 Genes and NovaSEQ, WES) and RNA (NovaSeq) sequencing. SBS11 gene signature (i.e temozolomide-induced hypermutational profile) was queried using SigProfiler (Alexandrov 2020, Nature). Significance was determined by X 2 and Fisher-Exact and p adjusted for multiple comparisons ( q) was 〈 0.05. Results: We identified 1,657 patients (range 21-89 years old, median 61 years) with IDH-wildtype GBM, 22% (360) of whom were ≥ 70 years. There was a slight male predominance (60%) for all ages. The most prevalent alterations in oGBM were TERT promoter mutation (105/131,80%), MGMT promoter methylation (pMe) (175/346, 51%), and PTEN mutation (129/349, 37%). EGFR amplification was seen in 35% (125/356) and EGFRvIII in 23% (81/360); Overall, fusions were seen in 12% (44 of 360) oGBM; events 〉 1% included MET (3.6%), FGFR3 (3.1%), EGFR (2.6%) and ROS1 (1.4%). 17% (56/349) of oGBM had positive PD-L1 by IHC. High TMB ( 〉 10mt/Mb) tumors were rare (3.1%) and MSI-high tumors even rarer (0.8%) in oGBM. When compared to yGBM, MGMT pMe was more prevalent (51% vs 38%, risk ratio (RR) 1.35 [1.19-1.52], q 〈 0.05) and NF1 mutations were less frequent in oGBM (21% v 34%, RR 0.62 [0.50-0.77], q 〈 0.05). No significant differences were seen in other key markers examined. The prevalence of SBS11 gene signature across all ages (data available for 1,141 patients) was 1.2% and was comparable across the age spectrum; no significant difference seen in the MGMT pMe group when oGBM was compared to yGBM (3.9% vs. 1.8 %, p= 0.3). Conclusions: This study represents the largest comprehensive molecular characterization of older IDH-WT GBM patients. We show that molecular profiles of IDH-WT GBM are remarkably similar across the age spectrum, including immunotherapy-associated markers, gene fusion landscape, EGFR amplification, and TMB. The significantly higher prevalence of MGMT pMe and lower NF-1 mutation rate in the older population bear significant prognostic and therapeutic implications.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2021.39.15_suppl.e14033
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2021
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  • 9
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    Distinct molecular features and potential therapeutic strategies for spinal cord gliomas.
    American Society of Clinical Oncology (ASCO) ; 2023
    In:  Journal of Clinical Oncology Vol. 41, No. 16_suppl ( 2023-06-01), p. 2056-2056
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 16_suppl ( 2023-06-01), p. 2056-2056
    Abstract: 2056 Background: Spinal cord gliomas (SCG) are rare primary CNS tumors with varied prognosis. Standard treatment remains poorly defined, as no clear survival advantage exists with extensive resection, radiation, or chemotherapy. Mounting evidence suggests that tumors from different regions of the CNS harbor unique molecular signatures. In a retrospective study, we comprehensively characterized molecular alterations to identify potential therapeutic strategies in the largest cohort of SCG reported to date. Methods: We performed centralized pathology review and analyzed SCG with next-generation sequencing of DNA (592 gene NextSeq or WES, Novaseq), RNA (WTS, NovaSeq) and pyrosequencing (MGMT promoter methylation, MGMTme). We estimated tumor microenvironment cell infiltration by quanTIseq & Epithelial-Mesenchymal Transition (EMT) by RNAseq. We used X2/Fisher’s-exact/Mann-Whitney U tests for comparison & determined significance (p 〈 0.05), adjusting for multiple comparison by the Benjamini-Hochberg method (q 〈 0.05). Results: We analyzed 39 surgically accessible SCG (19 high grade, 17 low grade, 3 NOS); ependymomas were excluded. The most common alterations were mutations in H3F3A (31%), TP53 (25%), ATRX (21%), NF1 (18%) & BRAF fusion (19%). H3F3A mutations occurred exclusively in high grade SCG (63%, q 〈 0.05) while BRAF fusions occurred exclusively in low grade SCG (60%, p 〈 0.05). TP53 mutations were more prevalent in high grade SCG (50% vs. 8%, p 〈 0.05). Compared to intracranial gliomas (n = 6732), SCG harbor significantly more frequent H3F3A (31% vs. 1.6%), KRAS mutations (10% vs. 0.7%) & BRAF fusions (19% vs. 0.7%) but less frequent TERT (4.3% vs. 66%) & PTEN (0 vs. 27%) mutations or EGFR amplification (0 vs. 28%) (all q 〈 0.05). SCG rarely harbor the canonical intracranial alterations IDH1 (2.6% vs. 17%), EGFRvIII (0 vs. 17%) or MGMTme (19% vs. 47%) (p 〈 0.05). SCG have greater penetration of immune infiltrates of DCs (median cell fraction/MCF: 13% vs. 9%), T regs (positive percent: 47% vs. 26%) & B cells (MCF: 9% vs. 7%), with less penetration of monocytes (MCF: 0 vs. 2%) (q 〈 0.05). EMT score associates with high grade glioma in intracranial disease (q 〈 0.05) but does not recapitulate in SCG (p 〉 0.05). Conclusions: Clinical management of SCG is currently drawn from experience with intracranial gliomas. Our results identify unique molecular features of SCG suggesting an underlying biology distinct from intracranial gliomas. In SCG, H3F3A mutations are exclusive to high grade while BRAF fusions are exclusive to low grade; SCG rarely harbor canonical intracranial alterations such as IDH1, EGFR or MGMTme; and SCG have greater penetration of DCs with less penetration of monocytes. We provide a biological explanation for limited effectiveness of current therapies in SCG with potential implications for chemotherapy, targeted and immunotherapy. Our work underscores the need for investigations dedicated uniquely to SCG.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2023.41.16_suppl.2056
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
    detail.hit.zdb_id: 2005181-5
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    Online Resource
    Biological and prognostic relevance of epigenetic regulatory genes in high-grade gliomas (HGGs).
    American Society of Clinical Oncology (ASCO) ; 2022
    In:  Journal of Clinical Oncology Vol. 40, No. 16_suppl ( 2022-06-01), p. 2019-2019
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 16_suppl ( 2022-06-01), p. 2019-2019
    Abstract: 2019 Background: Gliomagenesis is regulated by dynamic epigenetic modifications of DNA methylation, deregulation of histones and alteration of the human Switch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complexes. These epigenetic genes are responsible for treatment resistance by inducing stemness of glioma cells and immune cells with in the tumor microenvironement (TME). We evaluated the key chromatin remodeling (CR) genes and their interactions with other regulatory genes that are of prognostic importance. Methods: 1856 HGGs underwent molecular profiling at Caris Life Sciences (Phoenix, AZ). Analyses included next-generation sequencing of DNA (592 Genes, NextSeq or WES, NovaSeq) and RNA (WTS, NovaSeq). Cell infiltration in the TME was estimated by quanTIseq. X 2 /Fisher’s-exact/Mann-Whitney U tests were used for comparison, and significance was determined as p-value adjusted for multiple comparison by the Benjamini-Hochberg method (q 〈 0.05). Overall survival (OS) was calculated from the start of temozolomide (TMZ) to last contact using insurance claims data. Results: In a cohort of 1856 HGGs, 181 (9.8%) displayed 〉 =1 mutation of 19 CR genes considered, including mutations (mt) of histone methyltransferases (HM) comprising SETD2 (62, 3.4%), KMT2D (18, 1.0%), KMT2C (11, 0.6%); SWI/SNF complexes (SSNF) including ARID1A (32, 1.74%), ARID2 (15, 0.82%), SMARCA4 (14, 0.76%) and ARID1B (12, 0.66%); and others including ( DNMT3A, 0.94%, ASLXL1: 13, 0.98%). When compared to CR-WT, CR-mt HGGs showed higher prevalence of Tumor Mutational Burden-High (TMB-H) (23% vs. 1.3%), MSI-H/dMMR (13% vs. 0.2%), gLOH (9.5% vs 4.3%), and mts in IDH1/2 (29% vs. 14%), TP53 (55% vs. 36%), MSH6 (8.8% vs. 0.6%), and PIK3CA (18.8% vs. 8.3%) (all q 〈 0.05). Investigation of CR-mt subgroups showed that SSNF mt had the highest MGMT-promoter methylation (68%) and IDH1/2 mt (46%), while HM and others showed similar prevalence. In IDH-WT and MSS HGGs, the CR association with TMB-H, MSH6, TP53 and PIK3CA persisted (q 〈 0.05). When studying the immune profile, CR-mt HGGs showed significantly lower expression of immune-related genes including PD-L1 (Fold change: 0.76), PD-L2 (0.72), IDO1 (0.65), TIM3 (0.76) and CD86 (0.77) and colder TME as manifested by lower infiltrations of M2 (0.87) and higher Treg (1.27, all q 〈 0.05); such effects were not observed in the subgroup of IDH WT/MSS tumors. Among TMZ-treated HGG tumors, CR mt was associated with improved OS (33 months vs 22m, HR: 0.713, 95% CI: 0.581-0.876, p =.001). In the IDH WT/MSS subgroup this effect was also observed (31.6m vs 19.2m, HR: 0.764, 95% CI: 0.59-0.99, p = 0.041). Conclusions: Nearly 10% of HGGs carry mts in CR genes. CR-mt HGGs possess significantly more favorable genetic alterations and colder TME compared to the CR-WT HGGs and showed better OS when treated with TMZ. Multivariate modeling and analysis of associations with specific targeted therapies is underway.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2022.40.16_suppl.2019
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
    detail.hit.zdb_id: 2005181-5
    Library Location Call Number Volume/Issue/Year Availability
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    Online Resource
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    Availability (electronic / print)
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