Investigation of leptomeningeal disease in high grade glioma and characterization of molecular alterations.
Authors: Shoaf Madison L. , Glantz Michael J. , Tuohy Kyle J. , Chow Frances Elaine , Xiu Joanne , Aulakh Sonikpreet , Ashley David M. , Lipp Eric S. , López Giselle Y. , Sumrall Ashley Love , Walker Phillip , Spetzler David , Nicolaides Theodore , Ahluwalia Manmeet Singh , Peters Katherine B. 
Published: June 2023

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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.