2026 Background: There is a critical need for more specific and less invasive diagnostic and pharmacodynamic biomarkers in glioblastoma (GBM) patients (pts). Previously, we detected TERT promoter hotspot mutations (C228T and C250T) in the ctDNA of IDH wildtype ( IDHwt) TERT promoter mutant GBM pts with 100% specificity using mutation-specific droplet digital PCR (ddPCR) assays. Here, we explored the dynamics and clinical associations of mutant TERT ctDNA levels in GBM pts undergoing therapy. Methods: We examined 14 pts with suspected IDHwt GBM based on preoperative MRI. Plasma was isolated and frozen from ~15 mL whole blood samples collected pre- and post-op, at end of radiation (RT), and 1, 3, and 6 m after end of RT. TERT promoter mutations were identified in FFPE tumor samples using ddPCR assays for C228T/C250T. Plasma samples were analyzed using ddPCR assays specific for the corresponding tumor mutation. The validated thresholds for positive detection were 1.5 (C228T) and 1.7 copies/mL (C250T). Results: 13/14 (92.9%) IDHwt tumors had TERT mutations (7 C228T and 6 C250T). Six of these 13 (46%) pts had positive plasma TERT ctDNA preop (4 C228T, 2 C250T). The mean cross sectional area of enhancing disease at presentation for positive or negative preop mutant ctDNA was similar. All 4 pts with multiple contrast enhancing lesions had positive preop mutant ctDNA. 2 pts who were negative initially developed detectable mutant ctDNA preceding progression. 3/4 pts with equivocal radiographic pseudoprogression had ctDNA dynamics that correlated with eventual clinical outcome. One patient with unresectable GBM had declining mutant ctDNA in later collections during clinical stability. Conclusions: We detected plasma TERT ctDNA in 46% of TERT mutant GBM pts before surgery, and in 100% of pts with multiple contrast enhancing lesions. TERT mutant ctDNA levels correlated with pseudoprogression or true disease progression and predicted progression before MRI. These data suggest that larger studies to test circulating cell-free TERT mutation as a diagnostic and pharmacodynamic biomarker in GBM are warranted.
Introduction: Liquid biopsies, especially plasma cell-free circulating tumor DNA (ctDNA), provide a potential opportunity to be a noninvasive biomarker for the diagnosis and monitoring of glioblastoma (GBM) patients. Previously, we detected TERT promoter hotspot mutations (C228T and C250T) in ctDNA of IDH wild-type (IDHwt) TERT promoter mutant GBM patients with 100% specificity using mutation-specific droplet digital PCR (ddPCR) assays. Here, we examine the association between mutant TERT ctDNA levels and clinical outcomes in newly diagnosed GBM patients undergoing chemoradiation. Methods: We analyzed 76 serially collected plasma samples from 17 patients with suspected IDHwt GBM based on MRI before surgery. Twenty mL of whole blood was collected in EDTA tubes at predetermined times: pre- and postoperatively, at the end of chemoradiation, and 1, 3, and 6 months from the end of chemoradiation. TERT promoter mutations C228T or C250T were identified in FFPE tumor samples using ddPCR assays specific for these mutations. Plasma samples were analyzed for the patient’s tumor TERT mutation using the ddPCR assays. The analytically validated thresholds for positive ctDNA detection were 1.5 and 1.7 copies/mL for C228T and C250T, respectively. Results: Sixteen of 17 (94%) IDHwt tumors had TERT mutations (10 C228T, 6 C250T) with MGMT methylated, unmethylated, or unknown status in 10, 5, and 1, respectively. Fourteen of the 16 patients (87.5%) had detectable mutant ctDNA at one or more time points (range 1.66 to 22.13 copies/mL). Of the 2 patients with undetectable ctDNA, one had diffuse and non-avidly enhancing disease and the other only had pre/postop plasma samples collected. Six patients had detectable ctDNA preop, and most had a dominant rim-enhancing mass with additional nonenhancing or enhancing lesion(s). Ten patients had detectable ctDNA up to 4 days postop, half of whom had undergone gross total resection. For 3 of 5 patients for whom there was a question of pseudoprogression versus true progression, ctDNA kinetics matched the clinical outcome. One patient with MGMT unmethylated multifocal GBM achieved ctDNA zeroconversion at 6 months post radiation (RT), and did not progress for another five months. Another patient was negative at all time points until their 3-month post RT follow-up, at which time they developed a recurrence. Another patient achieved zeroconversion at the end of RT but developed a borderline positive ctDNA at 6 months after RT, 2 months before documented radiographic progression. Conclusions: In this pilot, prospective ctDNA monitoring study of IDHwt GBM, TERT mutant ctDNA was detected at one or more time points in the majority of patients. ctDNA kinetics were associated with clinical outcomes for some patients. These data suggest that additional, larger studies could refine how ctDNA monitoring may be used to enhance the clinical management of IDHwt GBM patients. Citation Format: Christine Cordova, Mahrukh M. Syeda, Broderick Corless, Jennifer M. Wiggins, Amie Patel, Sylvia C. Kurz, Malcolm Delara, Zacharia Sawaged, Minerva Utate, Dimitris Placantonakis, John Golfinos, Jessica Schafrick, Joshua S. Silverman, Rajan Jain, Matija Snuderl, David Zagzag, George Karlin-Neumann, David Polsky, Andrew S. Chi. Longitudinal detection of TERT-mutant plasma cell-free circulating tumor DNA in newly diagnosed glioblastoma patients [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr A65.
Objective This study was undertaken to identify molecular mechanisms in brain tissue of Rasmussen encephalitis (RE) when compared to people with non‐RE epilepsy (PWE) and control cases using whole exome sequencing (WES), RNAseq, and proteomics. Methods Frozen brain tissue (ages = 2–19 years) was obtained from control autopsy (n = 14), surgical PWE (n = 10), and surgical RE cases (n = 27). We evaluated WES variants in RE associated with epilepsy, seizures, RE, and human leukocyte antigens (HLAs). Differential expression was evaluated by RNAseq (adjusted p < .05) and label‐free quantitative mass spectrometry (false discovery rate < 5%) in the three groups. Results WES revealed no common pathogenic variants in RE, but several rare and likely deleterious variants of unknown significance (VUS; ANGPTL7/MTOR, SCN1A, FCGR3B, MTOR) and more common HLA VUS in >25% of RE cases (HLA‐DRB1, HLA‐DQA2), all with allele frequency < 5% in the general population. RNAseq in RE versus PWE (1516 altered transcripts) revealed significant activation of crosstalk between dendritic and natural killer cells (p = 7.94 × 10−6, z = 2.65), in RE versus control (7466 transcripts) neuroinflammation signaling activation (p = 6.31 × 10−13, z = 5.07), and in PWE versus control (945 transcripts) phagosome formation activation (p = 2.00 × 10−13, z = 5.61). Proteomics detected fewer altered targets. Significance In RE, we identified activated immune signaling pathways and immune cell type annotation enrichment that suggest roles of the innate and adaptive immune responses, as well as HLA variants that may increase vulnerability to RE. Follow‐up studies could evaluate cell type density and subregional localization associated with top targets, clinical history (neuropathology, disease duration), and whether modulating crosstalk between dendritic and natural killer cells may limit disease progression.
BACKGROUND Meningiomas are the most common primary intracranial neoplasm. Once surgical and radiotherapeutic options are exhausted, there are no effective medical treatments available. A majority of meningiomas express somatostatin receptor 2 (SSTR2), representing a promising treatment target. 177Lu-DOTATATE is a SSTR2-targeting radionuclide that has been successful in SSTR2-expressing neuroendocrine tumors. Here we hypothesize that 177Lu-DOTATATE is effective in treating progressive intracranial meningiomas. METHODS In this ongoing phase II study (NCT03971461), adults with advanced intracranial meningiomas received 177Lu-DOTATATE 7.4 GBq (200 mCi) every 8 weeks for 4 doses. 68Ga-DOTATATE PET-MRI was obtained before and at the end of treatment (EOT). The primary endpoint was progression-free survival at 6 months (PFS-6). Correlative studies evaluated the association of PFS-6, objective response rate, progression-free survival, overall survival with radiographic tumor measurements, 68Ga-DOTATATE uptake on PET-MRI, SSTR2 expression in tumor, and meningioma methylation subclass. RESULTS Nine patients (F = 7, M = 2) with progressive meningiomas (WHO I = 2, II = 6, III = 1) have been enrolled. Median age was 63 (range 49–78) years. All patients previously underwent tumor resection and at least one course of radiation. Treatment with 177Lu-DOTATATE was well tolerated, although CTCAE grade 3/4 electrolyte derangements and cytopenias were observed. Six patients reached PFS-6, three patients experienced progressive disease. Four patients had EOT 68Ga-DOTATATE PET-MRI evaluations in which anatomic measurements and 68Ga-DOTATATE standardized uptake values (SUV) pre- and post-treatment were assessed: one patient had reduced SUV measurements in all target lesions indicating altered SSTR2 expression and functional treatment response, one patient had stable disease, one patient had a mixed treatment response, and one patient experienced progressive disease. CONCLUSIONS SSTR2-targeting 177Lu-DOTATATE represents a promising treatment option for patients with progressive intracranial meningiomas. Treatment is well tolerated and can lead to functional alteration of tumoral SSTR2 expression by 68Ga-DOTATATE PET-MR imaging.
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