Leptomeningeal Metastases Research Articles

Clinical and molecular characteristics of patients with brain metastasis secondary to pancreatic ductal adenocarcinoma.

The prognosis for patients with pancreatic ductal adenocarcinoma (PDAC) is poor. Secondary brain metastasis (Br-M) occurs in less than 1% of patients. Clinical characteristics and molecular alterations have not been characterized in this rare patients' subset. The Foundry software platform was used to retrospectively query electronic health records for patients with Br-M secondary to PDAC from 2005 to 2023; clinical, molecular, and overall survival (OS) data were analyzed. Br-M was diagnosed in 44 patients with PDAC. Median follow-up was 78 months; median OS from initial PDAC diagnosis was 47 months. Median duration from PDAC diagnosis to Br-M detection was 24 months; median OS from Br-M diagnosis was 3 months. At Br-M diagnosis, 82% (n = 36) of patients had elevated CA19-9. Lung was the most common preexisting metastatic location (71%) with Br-M, followed by liver (66%). Br-M were most frequently observed in the frontal lobe (34%, n = 15), cerebellar region (23%, n = 10), and leptomeninges (18%, n = 8). KRAS mutations were detected in 94.1% (n = 16) of patients who had molecular data available (n = 17) with KRASG12V being the most frequent subtype 47% (n = 8); KRASG12D in 29% (n = 5); KRASG12R in 18% (n = 3). Patients who underwent Br-M surgical resection (n = 5) had median OS of 8.6 months, while median OS following stereotactic radiosurgery only (n = 11) or whole-brain radiation only (n = 20) was 3.3 and 2.8 months, respectively. Br-M is a late PDAC complication, resulting in an extremely poor prognosis especially in leptomeningeal disease. KRAS was mutated in 94.1% of the patients and the KRASG12V subtype was prevalent.

Identification of prognostic imaging biomarkers in H3 K27-altered diffuse midline gliomas in adults: impact of tumor oxygenation imaging biomarkers on survival.

To investigate prognostic markers for H3 K27-altered diffuse midline gliomas (DMGs) in adults with clinical, qualitative and quantitative imaging phenotypes, including tumor oxygenation characteristics. Retrospective chart and imaging reviews were conducted on 32 adults with H3 K27-altered DMGs between 2017 and 2023. Clinical and qualitative imaging characteristics were analyzed. Quantitative imaging assessment was performed from the tumor mask via automatic segmentation to calculate normalized cerebral blood volume (nCBV), capillary transit time heterogeneity (CTH), oxygen extraction fraction (OEF), relative cerebral metabolic rate of oxygen (rCMRO2), and mean ADC values. Leptomeningeal metastases (LM) was diagnosed with imaging. Cox analyses were conducted to determine predictors of overall survival (OS) in entire patients and a subgroup of patients with contrast-enhancing (CE) tumor. The median patient age was 40.5 years (range 19.9-75.7), with an OS of 30.3 months (interquartile range 11.3-32.3). In entire patients, the presence of LM was the only independent predictor of OS (hazard ratio [HR] = 6.01, P = 0.009). In the subgroup of 23 (71.9%) patients with CE tumors, rCMRO2 of CE tumor (HR = 1.08, P = 0.019) and the presence of LM (HR = 5.92, P = 0.043) were independent predictors of OS. The presence of LM was independently associated with poor prognosis in adult patients with H3 K27-altered DMG. In patients with CE tumors, higher rCMRO2 of CE tumor, which may reflect higher metabolic activity in the tumor oxygenation microenvironment, may be a useful imaging biomarker to predict poor prognosis.

Detection of cell-free tumor DNA in cerebrospinal fluid as a diagnostic biomarker for leptomeningeal melanoma metastasis: A case series.

Leptomeningeal melanoma metastases (LMM) are associated with poor survival. Diagnosis is based on clinical presentation, brain MRI and cerebrospinal fluid (CSF) analysis. Inconclusive findings at initial presentation can delay treatment. In this single-center case series, detection of BRAFV600- and NRASQ61-mutant cell-free tumor DNA (cfDNA) in CSF was evaluated as a complementary diagnostic biomarker. In 12 patients with clinical suspicion of LMM, a retrospective analysis of MRI, CSF cytology and cfDNA analysis on 1 mL of CSF using the Idylla® platform was carried out. Nine patients displayed MRI abnormalities suggesting LMM. CSF analysis identified malignant cells in three patients (including one without MRI abnormalities). BRAFV600- or NRASQ61-mutant cfDNA was detected in CSF of nine patients (eight with and one without MRI abnormalities; all patients with positive CSF cytology). Subsequent follow-up confirmed LMM in all patients with positive and in one patient with a negative CSF cfDNA analysis (sensitivity 81.8%; specificity 100%). Our findings suggest that analyzing BRAFV600- and NRASQ61-mutant cfDNA in CSF using the Idylla® platform holds promise as a sensitive and specific complementary diagnostic biomarker for LMM, particularly in case of inconsistency between imaging and CSF cytology. The 110-min analysis can facilitate urgent treatment decisions.

The postulated role of brain pulsations and arachnoid membranes in cerebrospinal fluid circulation, ventriculomegaly and related CSF disorders

Hydrocephalus can be obstructive or communicating. In cases of communicating hydrocephalus, patients will typically have enlarged brain ventricles. It has long been thought that the reason for this is obstruction to the outflow of cerebrospinal fluid from the subarachnoid space, which also results in raised intracranial pressure (ICP). However, there are several clinical and anatomic observations that are not well explained by this idea. These are for example, the conditions of Normal pressure hydrocephalus (NPH) which has normal ICP but ventriculomegaly, and idiopathic intracranial hypertension (IIH) which has raised ICP but normal sized ventricles. This hypothesis states that the mechanism for raised ICP and large ventricles seen in communicating hydrocephalus (ventriculomegaly) are different and seeks to explain the cause of ventriculomegaly using illustrative examples. It also suggests explanations for why ventriculomegaly occurs in NPH, infectious or carcinomatous meningitis, but is absent in IIH, or dural venous sinus thrombosis. Based on operative neurosurgical observations it states that the arachnoid membranes in the basal cisterns serve as part of a directional CSF flow mechanism consisting of fluid diodes, or “Tesla valves” of arachnoid membrane, containing CSF that is propelled by brain pulsations from the point of exit from the 4th ventricle to its points of absorption. This hypothesis suggests explanations for the physiologic appearance of a near uniform subarachnoid space, as well as the occurrence of the syndrome of the trephined and external hydrocephalus seen following a decompressive craniectomy. Also suggested are avenues of further research testing with MRI phase contrast CSF flow studies, classification of anatomic and peri-operative observations and rationale for creation of novel experiments to test the hypothesis, and aid diagnosis and treatment of a number of cranial CSF disorders.

Primary Meningeal Melanocytic Tumors of the Central Nervous System: A Review from the Ultra-Rare Brain Tumors Task Force of the European Network for Rare Cancers (EURACAN).

Primary meningeal melanocytic tumors are ultra-rare entities with distinct histological and molecular features compared with other melanocytic or pigmented lesions, such as brain and leptomeningeal metastases from metastatic melanoma. The European Network for Rare Cancers (EURACAN) Task Force on Ultra-Rare Brain Tumors (domain 10, subdomain 10) performed a literature review from January 1985 to December 2023 regarding the epidemiologic and clinical characteristics, histological and molecular features, radiological findings, and efficacy of local treatments (surgery and radiotherapy) and systemic treatments for these entities. Molecular analysis can detect specific mutations, including GNAQ, GNA11, SF3B1, EIF1AX, BAP1, that are typically found in circumscribed primary meningeal melanocytic tumors and not in other melanocytic lesions, whereas NRAS and BRAF mutations are typical for diffuse primary meningeal melanocytic tumors. The neuroimaging of the whole neuroaxis suggests a melanocytic nature of a lesion, depicts its circumscribed or diffuse nature, but cannot predict the tumor's aggressiveness. Gross-total resection is the first choice in the case of circumscribed meningeal melanocytoma and melanoma; conversely, meningeal biopsy may be reserved for patients with diffuse and multinodular leptomeningeal spread to achieve a definitive diagnosis. High-dose radiotherapy is rarely indicated in diffuse melanocytic tumors except as palliative treatment to alleviate symptoms. Last, a definitive advantage of a specific systemic treatment could not be concluded, as most of the data available derive from case reports or small cohorts. As primary meningeal melanocytic tumors are extremely rare, the correlations between the clinical characteristics, molecular profile, radiological findings at diagnosis and progression are weak, and poor evidence on the best therapeutic approach is available. There is a need to develop shared platforms and registries to capture more knowledge regarding these ultra-rare entities.

Combination of Cytologic Findings and Circulating Tumor DNA From Cerebrospinal Fluid Revealed SCLC Transformation in Patients With Leptomeningeal Metastases of Lung Adenocarcinoma

IntroductionTransformation to SCLC is a resistance mechanism to tyrosine kinase inhibitor in EGFR-mutated lung adenocarcinoma (LUAD). Nevertheless, the clinical and molecular features of SCLC transformation in LUAD with leptomeningeal metastases (LM) are scarce. MethodsWe retrospectively collected 237 patients with NSCLC who underwent lumbar puncture owing to suggestion of LM. All SCLC transformation in cerebrospinal fluid (CSF) was confirmed by two experienced pathologists using cytologic evaluation. CSF circulating tumor DNA (ctDNA) was tested by next-generation sequencing. ResultsTumor cells in CSF samples were found in 111 patients (111 of 237, 46.8%), and eight cases (eight of 111, 7.2%) were identified as having SCLC cells in CSF. Seven patients carried the EGFR mutation, including four patients with EGFR exon 19 deletion and three patients with EGFRexon21 L858R mutation. Another patient harbored ERBB2 insertion. Seven of these patients were resistant to targeted therapy. CSF ctDNA analysis reported that TP53 and RB1 mutations were common. The median time from the diagnosis of advanced NSCLC to SCLC transformation found in CSF was 9.7 months (95% confidence interval [CI]: 4.0–17.5 mo). The median overall survival since the initial diagnosis of metastatic NSCLC was 15.3 months (95% CI: 1.2–29.4 mo). The median overall survival after SCLC transformation detected in CSF was 5.0 months (95% CI: 4.0–5.9 mo). ConclusionsSCLC transformation may be revealed in CSF by both cytologic evaluation and ctDNA, not just in tissue that underwent rebiopsy. SCLC transformation of CSF is informative for resistance mechanism in patients with LUAD with LM on tyrosine kinase inhibitor progression, which was associated with poor survival.

AuNPs/DNAzyme/siRNA three-dimensional nanomotor for CEACAM6 RNA detection in cerebrospinal fluid and gene therapy of NSCLC

Non-small-cell lung cancer (NSCLC), with the most challenging problem of leptomeningeal metastasis (LM), is the most prevalent malignancy worldwide. Our previous research found that carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) serve as a potential biomarker in NSCLC-LM. Which is also a therapeutic target for NSCLC and related to cell migration, invasion, and metastasis. Herein, we first constructed a diagnostic and treatment-integrated Au NPs/DNAzyme/siRNA nanoplatform to detect the CEACAM6 RNA in cerebrospinal fluid and living cells, and inhibit tumor growth by gene therapy. The nanoprobe would be triggered by CEACAM6 RNA and the fluorescence signal would be amplified by DNAzyme cyclic reaction for in-situ imaging. The sensitivity and specificity of Au nanoprobe for the detection of CSF samples were 83.33% and 91.67%, respectively. The delivery of siRNA by Au NPs can enhance its uptake and accumulation by tumor cells, leading to a down-regulation of the CEACAM6 protein and ultimately inhibiting the invasion and migration of tumor cells. Furthermore, this nanoprobe have been effectively implemented for in-situ fluorescence imaging and tumor growth inhibition in mice models. It is undoubted that such a combination nanoplatform would be a promising diagnosis and treatment-integrated strategy for potential biomarker detection and cancer therapy.

The path to leptomeningeal metastasis.

The leptomeninges, the cerebrospinal-fluid-filled tissues surrounding the central nervous system, play host to various pathologies including infection, neuroinflammation and malignancy. Spread of systemic cancer into this space, termed leptomeningeal metastasis, occurs in 5-10% of patients with solid tumours and portends a bleak clinical prognosis. Previous, predominantly descriptive, clinical studies have provided few insights. Recent development of preclinical leptomeningeal metastasis models, alongside genomic, transcriptomic and proteomic sequencing efforts, has provided groundwork for mechanistic understanding and identification of long-needed therapeutic targets. Although previously understood as an anatomically isolated compartment, the leptomeninges are increasingly appreciated as a major conduit of communication between the systemic circulation and the central nervous system. Despite the unique nature of the leptomeningeal microenvironment, the general principles of metastasis hold true: cells metastasizing to the leptomeninges must gain access to the new environment, survive within the space and evade the immune system. The study of leptomeningeal metastasis has the potential to uncover novel site-specific metastatic principles and illuminate the physiology of the leptomeningeal space. In this Review, we provide a biology-focused overview of how metastatic cells reach the leptomeninges, thrive in this nutritionally sparse environment and evade the detection of the omnipresent immune system.

PP01.122 Inclusion of Patients with Brain Metastases and Leptomeningeal Disease in Phase 3 Lung Cancer Clinical Trials: Time for Action

PP01.122 Inclusion of Patients with Brain Metastases and Leptomeningeal Disease in Phase 3 Lung Cancer Clinical Trials: Time for Action

Intracranial management of HER-2 overexpression breast cancer with extensive volume or symptomatic brain metastases.

This study aimed to evaluate the impact of high intracranial burden and symptomatic presentation of brain metastases on treatment outcomes in patients with HER-2 positive breast cancer. Through a retrospective analysis, we explored the intracranial responses following the application of HER-2 targeted therapy alone or in combination with other modalities and further elucidated the relationship between treatment efficacy, intracranial progression-free survival (PFS), overall survival (OS), and the burden of intracranial lesions and symptomatic presentations. A retrospective analysis was conducted on cases of HER-2 overexpressing breast cancer patients with brain metastases. Clinical records were reviewed to extract patient demographics, treatment modalities, and intracranial disease characteristics. Intracranial tumor burden was quantified at diagnosis and post-initial treatment. High intracranial tumor burden was defined as either total metastatic volume >15 cc, or the largest lesion >3 cm. Responses were assessed using established criteria. The correlation between intracranial disease parameters and intracranial progression-free survival (PFS) and overall survival (OS) was determined. The study comprised 65 patients with HER-2 overexpression breast cancer and brain metastases. Symptomatic presentation was observed in 69.2% of patients at the diagnosis of brain metastases. Treatment with HER-2 target therapy alone or in combination with other modalities resulted in substantial intracranial responses, with 81.5% achieving at least a partial response at 3 months from therapy initiation. Median intracranial PFS and OS for patients with high intracranial burden were 9 and 22 months, respectively. Patients with high intracranial burden and symptomatic presentation at diagnosis demonstrated worse PFS and OS to those with lower burden and absence of symptoms (p < 0.05 for each). Her-2 overexpressing breast cancer and brain metastases face significant challenges, particularly those with high intracranial tumor burden, which correlates with poorer outcomes and higher incidence of leptomeningeal metastasis. Most patients responded positively to initial therapies, especially anti-HER-2 treatments combined with radiotherapy. Larger tumors necessitated more comprehensive treatment approaches, such as WBRT and SRS. Key factors influencing intracranial tumor control included the Ki-67 index, intracranial tumor burden, and continuous use of HER-2 targeted therapy post-diagnosis.

High-dose furmonertinib combined with intraventricular chemotherapy as salvage therapy for leptomeningeal metastasis from EGFR exon 20 insertion-mutated lung cancer.

The treatment of leptomeningeal metastasis (LM), a serious complication of advanced non-small cell lung cancer (NSCLC), presents challenges, particularly in patients with EGFR exon 20 insertion (ex20ins) mutations. This study retrospectively analyzed data from 10 EGFR ex20ins-mutated NSCLC patients with LM admitted at our institution from May 2011 to June 2023. Circulating tumor DNA (ctDNA) from cerebrospinal fluid (CSF) and matched plasma samples was analyzed using next-generation sequencing. All patients received high-dose furmonertinib combined with intraventricular chemotherapy (IVC) as salvage therapy. Data on patient demographics, treatment efficacy, and safety outcomes were collected. The most common insertion mutation identified in this study was p.A767_V769dup (n = 4, 40%), followed by D770-N771insY (n = 2, 20%). Nine patients had EGFR ex20ins occurring in the EGFR loop region following the C-helix, whereas only one patient had an EGFR ex20ins (A763_Y764insFQEA) occurring in the C-helix of the tyrosine kinase domain. LM response assessment using the RANO-LM criteria revealed that 6 patients (60%, 95% CI 26.2-87.8%) achieved a response, 3 had stable disease, and 1 had progressive disease. The median progression-free survival and overall survival were estimated to be 6.5 months and 8.8 months, respectively. The most commonly reported treatment-related adverse events were rash (n = 7) and diarrhea (n = 7), with no treatment-related deaths occurring. The current study demonstrated that high-dose furmonertinib plus IVC as salvage treatment for patients with LM harboring EGFR ex20ins mutations had promising clinical benefits and a manageable safety profile.

Leptomeningeal metastases from solid tumors: A Society for Neuro-Oncology and American Society of Clinical Oncology consensus review on clinical management and future directions.

Leptomeningeal metastases (LM) are increasingly becoming recognized as a treatable, yet generally incurable, complication of advanced cancer. As modern cancer therapeutics have prolonged the lives of patients with metastatic cancer, specifically in patients with parenchymal brain metastases, treatment options, and clinical research protocols for patients with LM from solid tumors have similarly evolved to improve survival within specific populations. Recent expansions in clinical investigation, early diagnosis, and drug development have given rise to new unanswered questions. These include leptomeningeal metastasis biology and preferred animal modeling, epidemiology in the modern cancer population, ensuring validation and accessibility of newer leptomeningeal metastasis diagnostics, best clinical practices with multimodality treatment options, clinical trial design and standardization of response assessments, and avenues worthy of further research. An international group of multi-disciplinary experts in the research and management of LM, supported by the Society for Neuro-Oncology and American Society of Clinical Oncology, were assembled to reach a consensus opinion on these pressing topics and provide a roadmap for future directions. Our hope is that these recommendations will accelerate collaboration and progress in the field of LM and serve as a platform for further discussion and patient advocacy.

Discontinuation of Palliative Brain Radiotherapy in Patients with Brain Metastases: A Case-Control Study.

Background: Discontinuation of radiotherapy is rarely discussed in the scientific literature. The goal of this study was, therefore, to estimate the frequency of and reasons for treatment discontinuations in patients receiving radiotherapy for brain metastases from solid tumors and to identify factors predicting said discontinuations. Methods: All patients treated for brain metastases from solid tumors between 2010 and 2020 at our institution were retrospectively reviewed. In addition to collecting relevant patient characteristics, the Recursive Partitioning Analysis (RPA) and disease-specific Graded Prognostic Assessment (GPA) groups for each patient were calculated to assess the performance of these scores in predicting treatment discontinuations. Results: Out of 468 patients who underwent cranial radiotherapy, 35 treatments (7.5%) were discontinued. The most frequent reason was clinical deterioration, which was documented in 26 (74.3%) of discontinued treatments. Patients whose radiotherapy was discontinued had, on average, more leptomeningeal disease (20.0% vs. 12.6%), worse ECOG performance status (mean ECOG performance status 1.86 vs. 1.39), and more uncontrolled extracranial metastases (85.3% vs. 70.8%). The frequencies of treatment discontinuation increased with worse prognosis and differed significantly across RPA groups (p = 0.037) but not across GPA groups (p = 0.612). Conclusions: Treatment discontinuation occurred in 7.5% of cases, mostly due to clinical deterioration. Poor performance status, as well as more advanced disease and, in turn, poor prognosis, were associated with higher discontinuation rates.

BIOM-14. UTILITY OF MIRNA-BASED LIQUID BIOPSY AND RADIOGRAPHIC IMAGING IN PEDIATRIC BRAIN TUMOR PATIENTS

Abstract BACKGROUND MRI is the current gold standard imaging technique for diagnostic evaluation and monitoring of pediatric CNS tumors; however, MRI measures can only provide inference into tumor biology and molecular stratification. miRNAs are an abundant and stable nucleic acid found circulating in blood and cerebrospinal fluid (CSF) and can be utilized as a tumor biomarker. METHODS We hypothesized that correlating miRNA biomarkers with radiological tumor measurements may provide improved diagnostic and monitoring for patients with pediatric brain tumors. Using a cohort of 54 pediatric brain tumors including low grade glioma, ependymoma, germ cell tumor, medulloblastoma, atypical teratoid rhabdoid tumor and high-grade glioma we attempted to combine MRI findings and circulating miRNA data. The miRNA expression was profiled in 33 CSF and 52 plasma samples using the HTG EdgeSeq platform. Clinically acquired, multi-parametric MRI scans at time-points close to liquid biopsy collection were collected retrospectively and used to generate volumetric tumor segmentations. Machine learning methods were implemented to evaluate combinatory features. RESULTS We identified unique miRNA targets that significantly correlated with MRI features, clinical findings, and patient outcomes. In both CSF and plasma, miRNA expression was found to correlate with diagnosis and clinical features including tumor grade and disease burden (p &amp;lt; 0.05). In CSF, miRNA expression was correlated with MRI features including cystic core presence, edema, leptomeningeal disease and tumor location (p &amp;lt;0.05). In plasma, differences in miRNA expression were related to MRI measurements including cystic core volume, location, and leptomeningeal disease (p &amp;lt; 0.05). Combination of miRNA targets for plasma or CSF with imaging-based features significantly improved histology specific multimodal diagnosis predictions. CONCLUSIONS These results demonstrate the potential utility of miRNAs as a pediatric brain tumor biomarker which when combined with imaging features can improve minimally and non-invasive diagnostics and the subsequent management of pediatric brain tumor patients.

LMIC-13. ENCOURAGING EXPERIENCE OF CONCURRENT CARBOPLATIN DURING CRANIOSPINAL IRRADIATION USING IMAGE GUIDED INTENSITY MODULATED PROTON BEAM (IMPT) IN HIGH-RISK EMBRYONAL TUMORS: FIRST REPORT FROM A LOW MIDDLE-INCOME COUNTRY

Abstract BACKGROUND Concurrent carboplatin during craniospinal irradiation (CSI) using photon radiotherapy in High risk (HR) embryonal tumors has been shown to improve the event free survival in select subgroup of patients. Experience of using concurrent carboplatin during CSI using proton therapy is limited. METHOD A retrospective audit was done in Children &amp;lt;18 years from January 2018 to December 2023 diagnosed with HR embryonal tumors who received image guided pencil beam intensity modulated proton beam therapy-based CSI (35Gy/21#) along with concurrent carboplatin 35mg/m2 at least for 15 fractions. The patient demographics, pathological diagnosis, treatment related toxicities and date of follow-up were recorded in predesigned proforma using electronic medical record. RESULTS Twenty children with HR embryonal tumors with median age at diagnosis 5 years (Range: 1-15 years) with M: F ratio of 3:1 were included in the study. Fifteen (75%) of the patients had HR medulloblastoma defined by spinal metastases or HR molecular subtype of which 5 patients had group 3 medulloblastoma (3- leptomeningeal disease at baseline, 2- MYC amplification) while rest had embryonal tumors (3-NOS, 1-Pinealoblastoma and 1-ETMR). Carboplatin was well tolerated, however 12 (60%) patients developed neutropenia requiring daily G-CSF for an average of 5 days. Average time to complete radiotherapy was 45 days with median interruption of 4 days (Range 1-7). Radiotherapy induced toxicities included Grade 3 skin toxicity in 6 (30%) and grade 2 weight loss in 3 (15%). At a median follow up of 14 months (Range: 4-58), the PFS was 80% in the whole cohort while in the Group 3 Medulloblastoma the PFS was only 20% which was statistically significant(p=0.004). CONCLUSIONS Carboplatin along with proton CSI is well tolerated in children with HR embryonal tumors without significant adversities. Experience is encouraging especially in non-group 3 medulloblastoma patients in our cohort of children with HR embryonal tumors.

MDB-69. RADIOLOGICAL PATTERNS OF RECURRENCE IN MEDULLOBLASTOMA SUBGROUPS AND CORRELATION WITH SURVIVAL

Abstract BACKGROUND Medulloblastomas can recur in up to one-third of the patients despite optimal therapy. The knowledge of the molecular group can provide clues to the possible pattern of relapse and the course of disease, with therapeutic implications. In the present study, we have identified anatomical locations and radiological patterns of relapse. METHODS AND MATERIALS Patients with a histopathological diagnosis and available subgroups of medulloblastoma with first relapse, treated in a single tertiary care center during 2005-2021 with available magnetic resonance imaging of brain and spine were included in the retrospective study. Statistical analysis was done using Pearson chi-square test and Fisher’s exact test. RESULTS 127 patients were included in the final analysis. Median age at diagnosis was 12 years and time to first recurrence was 21 months. Tumor bed relapse was seen in 49% cases, maximum in SHH subgroup, p&amp;lt;0.01. Involvement of the ventricular system (including cisterns and ventricles) was seen in 37% of cases, and was significantly associated (p:&amp;lt;0.01) with non-WNT, non-SHH tumours. Leptomeningeal metastasis was seen in 36% of cases, with significant association (p&amp;lt;0.01) in group 3 (75% of all group 3 cases) and group 4 tumors (50% of all group 4 cases). Disease in spine was most common in group 3 (65%) and group 4 tumours (71%), p&amp;lt;0.01. Hippocampus was involved in 19 cases (15%), mostly in non-WNT, non-SHH (14 cases). Significant difference in survival after recurrence was seen with ventricular, extraventricular metastases with one year survival 83% and 73% respectively, p=0.02. Hippocampal involvement showed significantly decreased survival, one year survival of 37%, p&amp;lt;0.01. CONCLUSIONS Leptomeningeal dissemination and diffuse disease were mostly seen in group 3 tumours, indicating their aggressive nature. The lower rates of ventricular relapse and around hippocampus in SHH medulloblastoma provide the opportunity to explore hippocampal avoidance-craniospinal irradiation.

METB-05. CSF LIQUID BIOPSY: PAVING THE WAY FOR MINIMALLY INVASIVE BRAIN TUMOR SURVEILLANCE USING LOW-PASS WHOLE GENOME SEQUENCING

Abstract OBJECTIVE We describe a clinical liquid biopsy platform for disease detection and surveillance in pediatric patients with primary central nervous system (CNS) tumors using low-pass whole genome sequencing (LP-WGS) on cell-free DNA (cfDNA) isolated from cerebrospinal fluid (CSF). METHODS CSF samples were collected during routine clinical procedures. cfDNA was extracted and LP-WGS performed using a validated Illumina NextSeq sequencing with a 37 bp paired-end read configuration. Sequencing results were compared to tumor molecular profiling performed by UW-Oncoplex™, a targeted DNA-based next-generation sequencing panel. RESULTS Sixty-one CSF specimens were collected from 29 individual patients with primary brain tumors across 7 institutions, with samples obtained at initial diagnosis or staging (n=17), during treatment (n=29), at therapy completion (n=4), or at disease recurrence (n=11). Patients with medulloblastoma (n=13), ATRT (n=3), high-grade glioma (n=3), low-grade glioma (n=6), ependymoma (n=1), and high-grade neuroepithelial tumor/ embryonal tumors (n=3) were included. Copy number variants consistent with tumor were detected in 24 samples from a median CSF volume of 2.5 mL (range: 1-8 mL) and 54.6 pg/ul of cfDNA (median, range: 1.3-5,220). 31/61 samples yielded enough DNA for LP-WGS while 30 were insufficient due to absence of tumor DNA (true negatives) or low DNA quantity (technical insufficiency). Among the 10 diagnostic samples collected from patients with MRI evidence of disease at initial staging, LP-WGS was positive in 8/10 (80%), compared to 2/10 (20%) positive by cytologic analysis for malignant cells. All 4 staging samples from patients with leptomeningeal metastasis were positive by LP-WGS. At recurrence, LP-WGS was positive for tumor in 6/8 (75%) of MRI-positive patients. CONCLUSIONS LP-WGS of CSF-derived cfDNA can identify clinically relevant somatic copy number variants, offering a minimally invasive liquid biopsy option for ongoing surveillance in pediatric CNS tumors. Further prospective analysis is needed to mitigate interpretation error and refine clinical applications.

Demographic and clinical characteristics of patients with metastatic breast cancer and leptomeningeal disease: a single center retrospective cohort study

PurposeLeptomeningeal disease (LMD) is a devastating complication of metastatic breast cancer (MBC). It is critical to better understand the risk factors, natural history, and treatment outcomes, including patients in a modern cohort.MethodsIn this single center retrospective cohort study, we identified patients with MBC and LMD who received care from 2000 to 2024 and abstracted key clinical, treatment, and survival data.ResultsWe identified 111 patients with MBC and LMD, including patients with the following subtypes: HR+/HER2− (n = 53, 47.7%), HER2+ (n = 30, 27.0%), and triple negative breast cancer (TNBC; n = 28, 25.2%). Median time from the diagnosis of MBC to LMD was 16.4 months (range 0–101.3 months). After the diagnosis of LMD, most patients received systemic therapy (n = 66, 59.5%) and/or central nervous system (CNS)-directed therapy (n = 94, 84.7%) including intrathecal therapy (n = 42, 37.8%) and/or CNS-directed radiation therapy (n = 70, 63.1%). In all patients, median overall survival (OS) from the diagnosis of LMD to death was 4.1 months (range 0.1–78.1 months) and varied by subtype, with HR+/HER2− or HER2+ MBC patients living longer than those with TNBC (4.2 and 6.8 months respectively vs. 2.0 months, p < 0.01, HR 2.15, 95% CI 1.36–3.39). Patients who received CNS-directed therapy lived longer than those who did not (4.2 vs. 1.3, p = 0.02 HR 0.54, 0.32–0.91). Patients diagnosed with LMD from 2015 to 2024 lived longer than those diagnosed from 2000 to 2014 (6.4 vs. 2.9 months, p = 0.04, HR 0.67, 95% CI 0.46–0.99). On multivariable analysis, having TNBC was associated with shorter OS from time of LMD to death (p = 0.004, HR 2.03, 95% CI 1.25–3.30).ConclusionThis is one of the largest case series of patients with MBC and LMD. Patients diagnosed with LMD from 2015 to 2024 lived longer than those diagnosed from 2000 to 2014, although median OS was short overall. Patients with TNBC and LMD had particularly short OS. Novel therapeutic strategies for LMD remain an area of unmet clinical need.

MDB-96. CEREBROSPINAL FLUID LEVELS OF THE MIR216B-5P AS A MINIMALLY INVASIVE MONITORING TOOL FOR MEDULLOBLASTOMA

Abstract BACKGROUND Current management of pediatric brain tumor patients relies on imaging as the only non-invasive tool available for monitoring therapeutic response and tumor progression. Results are often inconclusive and unable to capture biologically relevant changes that presage progression on imaging. Circulating miRNA provides an attractive non-invasive biomarker because miRNA has an essential role in regulating gene expression, stability in bio-fluids, selective over-expression in tumors, and is actively released from tumors into the extracellular environment. We aimed to establish the diagnostic and monitoring value of miRNA biomarkers for pediatric brain tumors in cerebrospinal fluid (CSF). METHODS We performed HTG EdgeSeq miRNA panel profiling (2100 targets) of CSF (n=33) samples across pediatric brain tumors from 5 histologies (low grade glioma, ependymoma, germ cell tumor, medulloblastoma, high-grade glioma). We utilized unsupervised consensus clustering, differential expression analysis, and machine learning approaches to investigate miRNA biomarkers. Results were validated using qPCR and ddPCR methods. RESULTS CSF miRNA signatures revealed a correlation with leptomeningeal disease and higher disease burden (p&amp;lt;0.05). Differentially expressed miRNA revealed histology-specific signatures for low grade glioma, medulloblastoma, and germinoma (p&amp;lt;0.05). miR216 expression was significantly elevated in medulloblastoma patients with active disease, indicating a potential novel biomarker for tumor monitoring. The miR216b-5p expression in CSF was confirmed using qPCR and ddPCR. The analysis of independent tumor tissue-based dataset confirmed miR216b-5p and its coding gene MIR217HG expression upregulated in medulloblastoma. MiR-216b-5p expression was also confirmed in patient-derived medulloblastoma cell lines and detected in cell free-media composition indicating extracellular release of miR216b-5p. CONCLUSIONS These results support the use of circulating miRNA in CSF as a potential biomarker for diagnosis and clinical monitoring of medulloblastoma. Further utilization of this approach provides a unique platform to inform liquid biopsy-based management in the clinical setting.

MDB-53. SALVAGE CRANIOSPINAL IRRADIATION FOR RELAPSED WNT-PATHWAY MEDULLOBLASTOMA PATIENTS TREATED WITH UPFRONT FOCAL CONFORMAL RADIOTHERAPY AND CHEMOTHERAPY AT INITIAL DIAGNOSIS: LONG-TERM AND MATURE OUTCOMES FROM A PROSPECTIVE DE-INTENSIFICATION STUDY

Abstract BACKGROUND Excellent long-term outcomes (5-year overall survival &amp;gt;90%) in WNT-pathway medulloblastoma (MB) patients have prompted systematic attempts at de-intensification of therapy to mitigate treatment-related toxicities. Mature outcomes of a prospective study (FOR-WNT) treating low-risk WNT-MB children with focal conformal radiotherapy (RT) and adjuvant systemic chemotherapy omitting upfront craniospinal irradiation (CSI) are being reported herein. METHODS Seven children with rigorously-defined low-risk WNT-MB were treated with post-operative focal conformal RT to the index tumor-bed (54Gy/30 fractions) followed by 6-cycles of adjuvant systemic chemotherapy after written informed consent/assent. Survival outcomes were computed using Kaplan-Meier method and reported as point estimate with 95% confidence intervals (CI). The trial was terminated prematurely due to unacceptably high risk of neuraxial failures. RESULTS One child succumbed to chemotherapy-related toxicity while 3 of 7 children were detected with leptomeningeal relapse on surveillance neuro-imaging within 2-years of index diagnosis. Full-dose salvage CSI (35Gy/21 fractions) at relapse followed by further chemotherapy led to excellent clinico-radiological response in all 3 children; however, one child developed further local recurrence and leptomeningeal metastases and succumbed to recurrent/progressive disease despite further aggressive salvage therapy. Five of 7 children including the other two treated with salvage CSI and systemic chemotherapy are alive and continue to remain in remission on long-term follow-up. At a median follow up of 61 months, the 5-year Kaplan-Meier estimates of event-free survival, relapse-free survival, and overall survival were 42.9% (95%CI: 18.2-100%), 50.0% (95%CI: 22.5-100%), and 71.4% (44.7-100%) respectively. CONCLUSIONS Omission of upfront CSI in low-risk WNT-MB is associated with unacceptably high-risk of neuraxial failure. Although full-dose salvage CSI achieves excellent response, remissions are not durable resulting in sub-optimal long-term overall survival. Judicious de-escalation with upfront low-dose CSI (18Gy) is currently being tested in a successor study (FOR-WNT 2).