Leptomeningeal Disease Diagnosis Research Articles

Effect of breast cancer receptor subtypes and CSF cytology status on survival for patients with leptomeningeal disease.

2025 Background: Leptomeningeal disease (LMD) in metastatic breast cancer (MBC) carries a poor prognosis. Data on the effect of BC sub types and CSF cytology results on overall survival (OS) are lacking. This single institution retrospective study compares OS among MBC with LMD across BC sub types and CSF cytology results. Methods: This study included patients (pts) diagnosed with MBC LMD from Jan 2010 to Jan 2023. BC sub types were defined as (1) ER positive (+)/HER2 negative (-), HER2+, triple-negative BC (TNBC), (2) HER2 0 [immunohistochemistry (IHC) score 0], HER 2 low [ IHC 2+ with fluorescence in-situ hybridization negative OR IHC 1+], HER2+. ER and HER2 positivity were defined per ASCO/CAP criteria. CSF cytology sub types were CSF+ (for malignant cells), CSF-, and CSF not tested. Baseline characteristics were compared using Fisher’s Exact and Wilcoxon rank-sum tests. OS among sub types was evaluated using Kaplan-Meier analysis and compared using log rank test. For multivariate analysis, a step wise model selection was performed after inclusion of sub type of interest; and variables meeting entry (p<0.10) and staying criteria (p<0.05) were included in final Cox model. Results: Out of 219 patients screened, 69 pts were registered. Median OS and associated 95% confidence interval (CI) within BC sub types in analyses 1 and 2 and CSF sub type analysis are shown in the table. OS in analysis 1 was not significantly different by BC sub types. In multivariate analysis, TNBC sub type had significantly shorter OS than ER+/HER2- group [Hazard Ratio (HR) 2.64, 95% CI (1.23, 5.80) (p=0.04)] after adjusting for interval from MBC to LMD diagnosis and CSF cytology status. OS by BC sub types in analysis 2 was not significantly different in unadjusted and multivariate analyses. CSF- group had significantly better OS compared to CSF+ or CSF not tested group in unadjusted analysis (Table) and multivariate analysis [CSF+ vs CSF- HR 4.5 95% CI (1.75-12.11); CSF not tested vs CSF- HR 2.91 95% CI (1.45-6.26), overall p=0.002]. Conclusions: This single institution study on MBC pts with LMD showed that BC receptor sub types were significantly associated with OS when adjusted for the interval from MBC to LMD diagnosis and CSF cytology group. This study showed significantly improved OS among patients with negative CSF cytology compared to those with positive cytology or those not tested, indicating a novel prognostic value of CSF cytology (currently on diagnostic value) for MBC LMD. These findings will be further validated. [Table: see text]

Quantification of cerebrospinal fluid tumor DNA in lung cancer patients with suspected leptomeningeal carcinomatosis

Cerebrospinal fluid tumor-derived DNA (CSF-tDNA) analysis is a promising approach for monitoring the neoplastic processes of the central nervous system. We applied a lung cancer-specific sequencing panel (CAPP-Seq) to 81 CSF, blood, and tissue samples from 24 lung cancer patients who underwent lumbar puncture (LP) for suspected leptomeningeal disease (LMD). A subset of the cohort (N = 12) participated in a prospective trial of osimertinib for refractory LMD in which serial LPs were performed before and during treatment. CSF-tDNA variant allele fractions (VAFs) were significantly higher than plasma circulating tumor DNA (ctDNA) VAFs (median CSF-tDNA, 32.7%; median plasma ctDNA, 1.8%; P < 0.0001). Concentrations of tumor DNA in CSF and plasma were positively correlated (Spearman’s ρ, 0.45; P = 0.03). For LMD diagnosis, cytology was 81.8% sensitive and CSF-tDNA was 91.7% sensitive. CSF-tDNA was also strongly prognostic for overall survival (HR = 7.1; P = 0.02). Among patients with progression on targeted therapy, resistance mutations, such as EGFR T790M and MET amplification, were common in peripheral blood but were rare in time-matched CSF, indicating differences in resistance mechanisms based on the anatomic compartment. In the osimertinib cohort, patients with CNS progression had increased CSF-tDNA VAFs at follow-up LP. Post-osimertinib CSF-tDNA VAF was strongly prognostic for CNS progression (HR = 6.2, P = 0.009). Detection of CSF-tDNA in lung cancer patients with suspected LMD is feasible and may have clinical utility. CSF-tDNA improves the sensitivity of LMD diagnosis, enables improved prognostication, and drives therapeutic strategies that account for spatial heterogeneity in resistance mechanisms.

Abstract PO5-06-01: Loss of hormone receptor expression in breast cancer is associated with increased brain tropism and accelerated progression of leptomeningeal disease

Abstract The four breast cancer subtypes—luminal A, luminal B, HER2-overexpressing, and triple-negative breast cancer (TNBC) – are classified based on gene expression profiles of hormone receptors (HRs) (estrogen receptor (ER) and progesterone receptor (PR)) and human epidermal growth factor receptor 2 (HER2/ERBB2). Negative hormone receptor status is known to be associated with more aggressive breast cancer. Compared to other breast cancer subtypes, the HR-negative TNBC and HER2-overexpressing subtypes are characterized by high rates of recurrence and a notable increase in brain metastases and in particular, leptomeningeal disease (LMD). LMD – the most aggressive form of central nervous system (CNS) metastasis, in which cancer cells infiltrate leptomeninges of the brain and spine – carries a dismal prognosis due to a rapid progression, poor detection, and no effective treatment. Several studies that investigated the link between HR status and LMD suggest that HR-negative breast cancers have a shorter time to LMD diagnosis. This shortened timeline is consistent with higher migratory capabilities reported for TNBC and HER2 breast cancer cells. However, as it is known that breast cancers exhibit subtype-specific metastatic tropism (i.e., luminal subtypes tend to metastasize to bone and liver, while TNBCs metastasize to the CNS), the longer time between primary breast cancer diagnosis and LMD diagnosis for HR-positive breast cancers may also reflect a longer metastatic route that first includes a non-CNS location. In this study, we performed a retrospective analysis on 141 breast cancer patients with LMD treated at Stanford Hospital between 2008-2020. The Stanford LMD cohort was analyzed using linear regression analysis, Cox regression analysis, and Chi-squared analysis. HR status was recorded (when available) for local recurrences and distant metastases, and was included in our regression models as a time-dependent HR covariate. We tested if: (1) HR-negative breast cancers had shorter time between primary and LMD diagnosis as well as worse survival after LMD diagnosis versus HR-positive breast cancers, and if (2) HR loss (i.e., HR status changing from positive to negative) increased likelihood of the metastasis to CNS. In agreement with published studies, the Stanford LMD cohort showed that HR-negative cancers had shorter time to development of LMD (p = 0.0004 for ER, p = 0.0001 for PR) and increased mortality following LMD (p = 0.010 for ER, p = 0.009 for PR). We found that HR-negative status at primary breast cancer diagnosis increased risk of first metastasis to CNS versus non-CNS locations (p = 0.021 for ER, p = 0.043 for PR). HR status switch (also known as hormone discordance) between primary diagnosis and metastasis occurred in 15% of patients in Stanford cohort, consistent with other studies. Importantly, accounting for HR status switch strengthened the association between HR-negative status and the risk of CNS metastasis [Hazard Ratio = 2.506 (1.395 - 4.500) for “baseline ER status” versus Hazard Ratio = 3.509 (1.890 - 6.515) for “time-dependent ER status”, Hazard Ratio = 2.420 (1.310 - 4.471) for “baseline PR status” versus Hazard Ratio = 3.407 (1.815 - 6.395) for “time-dependent PR status”]. In conclusion, HR-negative status was associated with shorter time to development of LMD, higher CNS tropism, and shorter survival following LMD diagnosis. Taking into consideration hormone discordance between the primary tumor and metastatic sites strengthened this association. Our results suggest a potential value in testing HR status at all recurrences and advanced CNS monitoring following HR loss. Citation Format: Sophia Pribus, Maxine C. Umeh-Garcia, Bo Gu, Bryanna Godfrey, Summer Han, Sophia Chernikova, Melanie Hayden Gephart. Loss of hormone receptor expression in breast cancer is associated with increased brain tropism and accelerated progression of leptomeningeal disease [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-06-01.

Increased Survival and Symptom Relief Following Palliative Cerebrospinal Fluid Diversion for Neoplastic Leptomeningeal Disease: A Case Series and Systematic Review

INTRODUCTION: Leptomeningeal disease (LMD) indicates widespread or advanced cancer and can lead to symptomatic hydrocephalus, for which palliative cerebrospinal fluid (CSF) diversion may be indicated. METHODS: We analyzed survival and symptom relief outcomes from a 10-year period at a single institution of patients with LMD secondary to cancer, symptoms of obstructive hydrocephalus, and documented date of death. We also searched PubMed, Embase, and Web of Science from database inception until 8/20/2022, using search terms including ‘cancer’, ‘hydrocephalus’, and ‘shunt’. Preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines were followed. RESULTS: In our series of 50 patients, 30 (60%) underwent CSF diversion surgery after LMD diagnosis with comparable median age in both surgery (58.4 ± 14.4 years) and non-surgery (57.8 ± 14.5 years) groups. Twenty-three patients (76.7%) achieved symptom relief. The surgery group lived longer after LMD diagnosis than patients in the non-surgery group (6.6 ± 6.0 vs. 1.3 ± 4.3 months, p &lt; 0.001) and had higher likelihood of survival (hazard ratio 2.49, 95% confidence interval 1.37-4.52, p = 0.002). Median survival after surgery was 2.8 ± 3.8 months. Out of 23 articles reporting outcomes for 2895 patients, 995 (34.3%) presented with LMD. Postoperative complication rates were 0-37.7% with no cases of extraneural metastases. Symptom relief rates were 50-100%. Three studies reported median survival after surgery for LMD (2-3.3 months). CONCLUSIONS: A rare entity with dismal prognosis, LMD can present as symptomatic hydrocephalus in patients with cancer. Symptom relief can be achieved with palliative surgery for permanent CSF diversion with relatively low complication rates. Prospective studies are needed to further assess outcomes and needs of this patient population.

Survival and treatment outcomes in patients with leptomeningeal disease from metastatic melanoma.

Melanoma leptomeningeal disease (LMD) has a poor prognosis. However, the management of patients with advanced melanoma has evolved with time, including those with LMD. We reviewed a large cohort of melanoma LMD patients to assess factors associated with survival. Retrospective clinical data was collected on patients diagnosed with LMD at MD Anderson Cancer Center from 2015 to 2020. Overall survival (OS) was determined from LMD diagnosis to date of death or last follow-up. The Kaplan-Meier method and log-rank test were used to estimate OS and to assess univariate group differences, respectively. Multivariable associations of survival with variables of interest were determined using Cox proportional hazards regression models. A total of 172 patients were identified. The median age at LMD diagnosis was 53 (range 20-79) years, and all patients had radiographic evidence of LMD on magnetic resonance imaging of either brain or spine. In total 143 patients previously received systemic therapy (83%), with a median of 2 prior treatments (range 0-5). 81 patients (47%) had concurrent uncontrolled systemic disease and 80 patients (53%) had elevated serum LDH at the time of diagnosis. With a median follow-up of 4.0 months (range 0.1-65.3 months), median OS for all patients from LMD diagnosis was 4.9 months. Patients (n = 45) who received intrathecal therapy or systemic immunotherapy for LMD had a median OS of 8.0 months and 10.2 months, respectively. On multivariable analysis, decreased performance status, positive CSF cytology, elevated LDH, and whole brain radiation were associated with worse OS. Despite many advances in therapeutic options, the outcomes of melanoma patients with LMD remains poor. However, a subset of patients appears to derive benefit from LMD-directed treatment.

Prognostic value of cerebrospinal fluid tumor cell count in leptomeningeal disease from solid tumors.

Treatment decisions for leptomeningeal disease (LMD) rely on patient risk stratification, since clinicians lack objective prognostic tools. The introduction of rare cell capture technology for identification of cerebrospinal fluid tumor cells (CSF-TCs), such as CNSide assay, improved the sensitivity of LMD diagnosis, but prognostic value is unknown. This study assesses the prognostic value of CSF-TC density in patients with LMD from solid tumors. We conducted a retrospective cohort study of patients with newly diagnosed or previously treated LMD from a single institution who had CNSide assay testing for CSF-TCs from 2020 to 2023. Univariable and multivariable survival analyses were conducted with Cox proportional-hazards modeling. Maximally-selected rank statistics were used to determine an optimal cutpoint for CSF-TC density and survival. Of 31 patients, 29 had CSF-TCs detected on CNSide. Median (interquartile range [IQR]) CSF-TC density was 67.8 (4.7-639) TCs/mL. CSF cytology was positive in 16 of 29 patients with positive CNSide (CNSide diagnostic sensitivity = 93.5%, negative predictive value = 85.7%). Median (IQR) survival from time of CSF-TC detection was 176 (89-481) days. On univariable and multivariable analysis, CSF-TC density was significantly associated with survival. An optimal cutpoint for dichotomizing survival by CSF-TC density was 19.34 TCs/mL. The time-dependent sensitivity and specificity for survival using this stratification were 76% and 67% at 6 months and 65% and 67% at 1 year, respectively. CSF-TC density may carry prognostic value in patients with LMD from solid tumors. Integrating CSF-TC density into LMD patient risk-stratification may help guide treatment decisions.

Proton Craniospinal Irradiation with Immunotherapy in Two Patients with Leptomeningeal Disease from Melanoma.

Proton craniospinal irradiation (pCSI) is a treatment option for leptomeningeal disease (LMD), which permits whole neuroaxis treatment while minimizing toxicity. Despite this, patients inevitably experience progression. Adding systemic therapy to pCSI may improve outcomes. In this single-institution retrospective case series, we present the feasibility of treatment with pCSI (30Gy, 10 fractions) and an immune checkpoint inhibitor (ICI) in two sequential patients with LMD from melanoma. The first patient developed LMD related to BRAF V600E-mutant melanoma after prior ICI and BRAF-targeted therapy. After pCSI with concurrent nivolumab, the addition of relatlimab, and BRAF-targeted therapy, he remained alive 7 months after LMD diagnosis despite central nervous system progression. The second patient developed LMD related to BRAF-wildtype melanoma after up-front ICI. He received pCSI with concurrent ipilimumab and nivolumab, then nivolumab maintenance. Though therapy was held for ICI hepatitis, the patient remained progression-free 5 months after LMD diagnosis. Adding an ICI to pCSI is feasible for patients with LMD and demonstrates a tolerable toxicity profile. While prospective evaluation is ultimately warranted, pCSI with ICI may confer survival benefits, even after prior ICI.

Comparative evaluation of the diagnostic and prognostic performance of CNSide™ versus standard cytology for leptomeningeal disease.

This retrospective study compares the real-world performance of cerebrospinal fluid (CSF) CNSide™ versus cytology in leptomeningeal disease (LMD). Consecutive patients with suspected LMD who underwent lumbar punctures for CSF cytology and CNSide™ from January 2020 to December 2022 were reviewed. LMD was classified by EANO criteria. Descriptive statistics, confusion matrix, Kaplan-Meier curves, and Cox proportional regression were used. Median age for 87 evaluable patients was 63 years (range: 23-93); 82 (94%) met EANO criteria for possible/probable/confirmed LMD (EANO/LMD). The commonest primary cancers were breast (36,44.0%) and lung (34,41.5%). Primary lung harbored actionable mutations in 18 (53.0%); primary breast expressed hormone receptors in 27 (75%), and HER2 amplification in 8 (22%). Uncontrolled systemic disease was detected in 35 (40%), while 25 (46%) received systemic therapy with medium/high CNS penetrance at LMD diagnosis. The median time from initial cancer to LMD diagnosis was 31 months (range: 13-73). LMD was confirmed by CSF cytology in 23/82 (28%), all identified by CNSide™. CNSide™ identified 13 additional cases (36/82, 43.9%), increasing diagnostic yield by 56.5%. Median overall survival (mOS) was 31 weeks (95%CI: 21-43), significantly worse for CNSide™ positive versus negative: 4.0 versus 16.0 weeks, respectively (HR = 0.50, P = .010). While survival since LMD diagnosis did not differ by histology, time to LMD diagnosis from initial cancer diagnosis was longer for breast (48.5 months, IQR: 30.0-87.5) versus lung (8 months, IQR:0.5-16.0) cohorts. mOS was longer for patients eligible for intrathecal chemotherapy (HR: 0.189, 95%CI: 0.053-0.672, P = .010). This retrospective, real-world analysis of CNSide™ showed increased sensitivity versus cytology and provided clinically relevant molecular CSF analyses.

PATH-01. COMPARATIVE EVALUATION OF THE DIAGNOSTIC AND PROGNOSTIC PERFORMANCE OF CNSIDE™ VERSUS STANDARD CYTOLOGY FOR LEPTOMENINGEAL DISEASE

Abstract OBJECTIVE We compared the real-world performance of the cerebrospinal fluid (CSF) CNSide™ versus cytology assays in diagnosing leptomeningeal disease (LMD). METHODS Consecutive patients with suspected LMD from January 2020 to December 2022 who underwent lumbar punctures for CSF cytology and CNSide™ analyses were reviewed. LMD diagnosis was defined by EANO criteria. We used descriptive statistics, confusion matrix, Kaplan Meier curves, and Cox proportional regression methods to analyze outcomes. RESULTS 87 patients with median age of 63 years (range:23-93) were evaluated, of which 82 (94%) met EANO positive (possible, probable, or confirmed criteria) cohort. Of the EANO cohort, 33 (40%) had uncontrolled systemic disease and 25 (46%) were on systemic therapy with medium/high CNS penetrance. The median time from initial cancer diagnosis to LMD was 31 months (range:21-43). LMD was diagnosed by CSF cytology (EANO confirmed) in 23 cases, all identified by CNSide™. CNSide™ identified an additional 13 cases, increasing diagnostic yield by 56.5%. Commonest primary histologies in the EANO cohort were breast (36, 44.0%) and lung (34, 41.5%); 18 (53.0%) of lung cancers harbored actionable molecular alterations, while breast cancers expressed hormone receptors in 27 (75%) and HER2 alterations in 8 (22%). Median overall survival (OS) for the CNSide™ cohort was 19.5 weeks (95%CI:11.0-28.0) and 31 weeks (95%CI:21-43) for EANO positive cases. Median OS for breast patients in CNSide™ cohort was 42 (R: 15-65) weeks, about 7-fold that of lung (median 6.5, R: 2-20). There was no correlation between OS and cell density by CNSide™ (HR:1.000, 95%CI:0.999-1.001, p=0.909). OS was higher for cases treated with intrathecal chemotherapy (HR:0.189, 95%CI:0.053-0.672, p=0.010), but not statistically different by radiotherapy modality (HR, 0.583, 95%CI:0.264-1.287, p=0.181). CONCLUSIONS This retrospective, single-institution, real-world analysis of CNSide™ showed increased sensitivity versus cytology and provided clinically relevant, cell-based molecular CSF analyses.

Identification of risk factors associated with leptomeningeal disease after resection of brain metastases.

Resection of brain metastases (BMs) may be associated with increased risk of leptomeningeal disease (LMD). This study examined rates and predictors of LMD, including imaging subtypes, in patients who underwent resection of a BM followed by postoperative radiation. A retrospective, single-center study was conducted examining overall LMD, classic LMD (cLMD), and nodular LMD (nLMD) risk. Logistic regression, Cox proportional hazards, and random forest analyses were performed to identify risk factors associated with LMD. Of the 217 patients in the cohort, 47 (21.7%) developed postoperative LMD, with 19 cases (8.8%) of cLMD and 28 cases (12.9%) of nLMD. Six-, 12-, and 24-month LMD-free survival rates were 92.3%, 85.6%, and 71.4%, respectively. Patients with cLMD had worse survival outcomes from the date of LMD diagnosis compared with nLMD (median 2.4 vs 6.9 months, p = 0.02, log-rank test). Cox proportional hazards analysis identified cerebellar/insular/occipital location (hazard ratio [HR] 3.25, 95% confidence interval [CI] 1.73-6.11, p = 0.0003), absence of extracranial disease (HR 2.49, 95% CI 1.27-4.88, p = 0.008), and ventricle contact (HR 2.82, 95% CI 1.5-5.3, p = 0.001) to be associated with postoperative LMD. A predictive model using random forest analysis with an area under the receiver operating characteristic curve of 0.87 in a test cohort identified tumor location, systemic disease status, and tumor volume as the most important factors associated with LMD. Tumor location, absence of extracranial disease at the time of surgery, ventricle contact, and increased tumor volume were associated with LMD. Further work is needed to determine whether escalating therapies in patients at risk of LMD prevents disease dissemination.

Factors associated with overall survival in patients with melanoma leptomeningeal disease (M-LMD): A single institution retrospective review.

e21548 Background: Leptomeningeal disease (LMD) is characterized by tumor metastasis to the membranes and cerebrospinal fluid (CSF) surrounding the brain and spinal cord. This devastating complication confers a poor overall survival (OS) measured in weeks for untreated patients. Melanoma has one of the highest rates of dissemination to the leptomeninges. The advances in targeted and immune therapies have revolutionized OS for patients with melanoma systemic metastases and there is a growing number of individual case reports showing clinical responses to these agents in patients with melanoma-LMD (M-LMD) . However, few studies have examined the association between these and other therapies with the OS of a large cohort of melanoma-LMD (M-LMD) patients. Methods: M-LMD patients treated at Moffitt Cancer Center between 2011 and 2020 were retrospectively identified. M-LMD diagnosis was confirmed radiographically via magnetic resonance imaging (MRI) and/or positive CSF cytology indicating the presence of malignant cells. Demographic data and pre/post LMD diagnosis treatment data were collected and analyzed using the Kaplan-Meier method to determine factors that improve OS. Results: 86 M-LMD patients were identified. 50 were male and 36 were female, but patient gender did not have an impact on OS. 53 patients were diagnosed via MRI only and 33 patients had positive CSF cytology confirming M-LMD diagnosis. 34 patients did not receive any treatment post-LMD diagnosis and had a median OS of 3.72 weeks, while 52 patients receiving treatment (i.e. systemic, intrathecal [IT], and/or whole brain radiation therapy [WBRT]) had a median OS of 10.80 weeks (p &lt; 0.0001). More specifically, 30 patients receiving targeted BRAF/MEKi treatment had an 18.8 week median OS compared to 6.68 weeks for the 56 patients who did not receive such treatments (p = 0.0015). Furthermore, 44 patients received immune therapy and had a median OS of 12.00 weeks compared to 5.88 weeks for those who did not (p = 0.002). The 16 Patients that received IT chemotherapy had a prolonged median OS when compared to the 70 patients who did not (9.72 weeks vs 4.72 weeks, p = 0.009). Furthermore, WBRT also improved median OS in the 22 patients that received the therapy (15.72 weeks vs 7.88 weeks, p = 0.0007). The 36 patients that received BRAF/MEKi treatment prior to their LMD diagnosis had a slightly shorter OS (7.00 weeks) compared to the 46 patients that did not receive such treatment beforehand (10.80 weeks, p = 0.005). Conclusions: The current data supports the use of systemic, IT, and radiation therapies to prolong OS for M-LMD patients; however, the OS for these patients remains grim despite advances in such therapies. Further research is necessary to understand the pathophysiology of LMD, and new clinical trials are urgently needed to identify novel therapies that improve M-LMD prognosis.

SURG-05. SUPERVISED MACHINE LEARNING IDENTIFIES RISK FACTORS ASSOCIATED WITH LEPTOMENINGEAL DISEASE AFTER SURGICAL RESECTION OF BRAIN METASTASES

Abstract INTRODUCTION Predictors of postoperative leptomeningeal disease (LMD) after resection of brain metastases (BMs) are not well defined. OBJECTIVE This study examined rates and predictors of LMD, including subtypes, in patients who underwent resection of a BM followed by postoperative radiation.Method: A retrospective, single-center study was conducted examining overall LMD, classical LMD (cLMD), and nodular LMD (nLMD) risk. Logistic regression and a Cox proportional hazards analyses were performed to identify risk factors associated with LMD. Random forest models were constructed to predict LMD and differentiate cLMD versus nLMD. Accuracy and the area under the receiver operating characteristic curve (AUROC) were calculated to evaluate the models.Result: Of the 217 patients in the cohort, 47 (21.7%) developed postoperative LMD with 19(8.8%) cLMD cases and 28(12.9%) nLMD cases . Six-, 12-, and 24-month LMD-free survival rates were 92.3%, 85.6%, and 71.4%, respectively. Patients with cLMD had worse survival outcomes from LMD diagnosis compared to nLMD (2.4 vs 6.9 mo, Log-rank p=0.02), and treatment of LMD was associated with improved survival for both cLMD and nLMD subtypes. Multivariate Cox hazard analysis identified cerebellar/insular/occipital location (HR 3.25, 95% CI 1.73-6.11, p=0.0003), absence of extracranial disease (HR 2.49, 95% CI 1.27-4.88, p=0.008), and ventricle contact (HR 2.82, 95% CI 1.5-5.3, p=0.001) to be associated with postoperative LMD. A predictive model using random forest analysis with an AUROC of 0.87 in a test cohort identified tumor location, systemic disease status, and tumor volume as the most important factors associated with LMD. Both regression analysis and random forest analysis identified postoperative systemic therapy exposure as the main factor differentiating cLMD from nLMD development. CONCLUSION Tumor location, absence of extracranial disease at the time of surgery, contact with a ventricle, and increased tumor volume are associated with LMD. Classical LMD is associated with worse prognosis compared to nLMD.

LOCL-06 SUPERVISED MACHINE LEARNING IDENTIFIES RISK FACTORS ASSOCIATED WITH LEPTOMENINGEAL DISEASE AFTER SURGICAL RESECTION OF BRAIN METASTASES

BACKGROUNDResection of brain metastases (BMs) can help with local disease control, yet predictors of leptomeningeal disease (LMD) after surgery are not well defined. This study examined rates and predictors of LMD in patients who underwent resection of a BM. METHODSA retrospective, single-center study was conducted examining LMD risk for adult patients with a BM that underwent resection with postoperative adjuvant radiation. Logistic regression analyses and a supervised machine learning algorithm (Random forest) were implemented to identify factors within the cohort that were associated with LMD. RESULTSOf the 182 patients in the cohort, 43 patients (23.6%) developed LMD in the postoperative setting with 18 cases of classical LMD (9.9%) and 25 cases of nodular LMD (13.7%). Median censored time to LMD was not reached, and 6-, 12-, and 24-month LMD-free rates from surgery were 93%, 86.3%, and 71.8%, respectively. Median time from surgery to classical and nodular LMD were 13.1 and 9.5 months, respectively (Log-rank p=0.71). Patients diagnosed with classical LMD had worse survival outcomes from LMD diagnosis compared to nodular LMD (2.6 vs 9.7 mo, Log-rank p=0.02), and LMD-subtype was significantly associated with overall survival from the date of surgery (classical vs nodular vs none: 16.1 vs 20 vs 36.7 mo, p <.0001). Random forest analysis identified primary cancer type, absence of extracranial disease, and tumor volume as the top 3 factors associated with LMD. On multivariate regression analysis, absence of extracranial disease at index surgery was associated with any LMD (OR 2.65, 95% CI 1.15-6.10, p=0.02). Treatment with postoperative checkpoint inhibitors, type of radiation, and performing additional craniotomies were not associated with risk of LMD. CONCLUSIONSClassical-type LMD is associated with worse prognosis compared to nodular-type LMD. Absence of extracranial disease at the time of surgery was the most consistent factor associated with LMD on follow-up.

Abstract 5257: Durable clinical and radiographic responses in a series of patients with HER2+ Breast Cancer (BC) Leptomeningeal Disease (LMD) treated with trastuzumab deruxtecan (T-DXd)

Abstract Background: LMD is a devastating clinical outcome of advanced BC with a median survival of 4.4 months for the HER2+ subtype. There are few effective treatments for LMD. T-DXd has shown excellent extracranial efficacy in the DESTINY-Breast01/03 trials for metastatic HER2+ BC, including the stable brain metastases (BrM) subgroups. The efficacy of T-DXd in HER2+ untreated BrM and LMD is unknown. We present a case series of 6 patients with HER2+ LMD treated with T-DXd. Methods: Six patients with HER2+ BC with LMD (based on imaging +/- positive cytology) who had received T-DXd prior to 10/18/21 and had undergone at least 1 restaging evaluation were identified at Duke Cancer Institute and Dana Farber Cancer Institute. Data was extracted from patients’ electronic medical records and entered into a secure, patient de-identified database. Objective MRI response was defined as neuroimaging with definitive improvement assessed by neuroradiologist review without signs of clinical progression. Clinical benefit (CB) is defined as stable disease or objective response by neuroimaging without clinical progression. Results: Of the 6 patients included, median age was 42.5 years with 5 median lines of prior therapy. All 6 patients (100%) derived CB and 5/6 (83.3%) had objective response on MRI. Patients were treated with a median 6.5 (5-23) cycles. Median duration of T-DXd therapy was 5.3 months (4.1-16.9) with 4/6 patients receiving ongoing treatment. The median survival from initial diagnosis of LMD to death or last follow-up was 12.5 months. Results are summarized in Table 1. Conclusion: In this case series, 5/6 patients had radiographic responses without clinical progression, with median duration of treatment nearing 6 months and 4/6 patients continuing T-DXd at data cutoff. This series provides rationale for prospective evaluation of T-DXd in HER2+ LMD patients across tumor types. Table 1. Demographic and clinical information T-DXd in HER2+ BC LMD - Demographic and Clinical Information*Data cut-off: 10/18/21 Demographic Characteristic (n=6) # (%) or median (range) Median age at T-DXd, years (range) 42.5 (37 - 56) ER Status Positive Negative 4 (66.7%)2 (33.3%) Site DFCI Duke 4 (66.7%)2 (33.3%) Clinical Information (n=6) # (%) or median (range) Median # of therapies prior to T-DXd Prior HER2 TKI 5 (4-6)6 (100%) T-DXd Treatment Median # cycles Total time on DS-8201 (months) 6.5 (5-23)5.3 (4.1-16.9) Response on first MRI post-C1D1 T-DXd Yes No 5 (83.3%)1 (16.6%) Still on T-DXd Treatment Yes No 4 (66.7%)2 (33.3%) Median survival since LMD diagnosis (months) 12.5 (6.8 - 20.6) Citation Format: Laura Alder, Dario Trapani, Amanda Van Swearingen, Mustafa Khasraw, Carey Anders, Nancy Lin, Sarah Sammons. Durable clinical and radiographic responses in a series of patients with HER2+ Breast Cancer (BC) Leptomeningeal Disease (LMD) treated with trastuzumab deruxtecan (T-DXd) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5257.

Challenges and Advances in Diagnosis and Treatment of Leptomeningeal Disease (LMD).

Leptomeningeal disease (LMD) is a devastating category of CNS metastasis with a very poor prognosis and limited treatment options. With maximal aggressive therapy, survival times remain short and, without treatment, prognosis is measured in weeks. Both LMD diagnosis and treatment are challenging topics within neuro-oncology. In this review, we discuss the advances in LMD diagnosis with a focus on the role of circulating tumor DNA (ctDNA) and discuss the role of targeted and immunotherapy in LMD treatment.

PATH-04. LEPTOMENINGEAL DISEASE IN PATIENTS WITH HISTONE-MUTANT GLIOMAS

Abstract INTRODUCTION The 2016 WHO classification describes a subtype of midline gliomas harboring histone 3 (H3) K27M mutations, and the upcoming 2021 edition may include a new subtype of hemispheric diffuse gliomas with H3 G34R/V mutations. Since we began to perform molecular profiling at Memorial Sloan Kettering Cancer Center (MSKCC) we have observed an increased prevalence of leptomeningeal disease (LMD) in this population. However, the incidence and clinical behavior of LMD has not been well defined. METHODS This is a retrospective study of patients with H3-mutant gliomas at MSKCC diagnosed from 01/2012 to 02/2021, either by tumor biopsy or by cerebrospinal fluid (CSF). Histone mutations were identified through next-generation sequencing (NGS). RESULTS We found 40 patients (pts) harboring H3 mutations (K27M mutations in 31 pts, G34R/V in 8, and both in one), with 2/40 (5%) mutations identified through CSF NGS only and rest in tumor tissue. Median age was 20.5 years (4-70); 25 were male. Tumor location was midline for K27M-mutant tumors (thalamus [N=15], brainstem [N=10], spine [N=5], pineal gland [N=1]) and hemispheric for G34R/V-mutant tumors; tumor with both mutations was thalamic. LMD was diagnosed in 22/40 (55%) pts radiographically, including 19/31 (61%) of K27M-mutant pts and 3/8 (38%) of G34R/V-mutant pts (patient with both mutations did not develop LMD). At analysis, 10 patients remain alive. Median time from diagnosis to LMD was 8.8 months (0-44.4), with median OS of 6.5 months (0.3-34) after LMD diagnosis. CONCLUSION More than half of patients with histone-mutant gliomas develop LMD, including over a third of patients with G34R/V mutations. Neuroaxis imaging should be performed in conjunction with CSF studies in histone-mutant gliomas. Besides, CSF NGS represents an important tool to identify molecular profile of tumors when biopsy is not feasible or there is limited tissue for analysis.

Leptomeningeal Disease in Breast Cancer: Pre-Treatment Prognostic Factors and Outcomes

Leptomeningeal disease (LMD) is a devastating diagnosis with limited treatment options and poor prognosis. With recent advances in treatment, women with breast cancer (BC) are living longer and the incidence of LMD in this population is increasing. There remains little data regarding the prognosis and optimal treatment of these patients. As such, we conducted a multi-institutional retrospective review of women with BC LMD and analyzed outcomes based on prognostic factors and treatments.We analyzed the records of women diagnosed with BC LMD via MRIs of their brain and/or spine between 2000 and 2020 at two academic medical centers. Demographic and clinical characteristics were abstracted from electronic medical records and an in-depth radiographic review was performed by a neuro-radiologist for each case. Univariate and multivariate Cox proportional-hazards models were generated to identify factors associated with prolonged survival. Collection and analysis of the data was approved by institutional IRB.We identified 227 women with BC LMD. Prior to developing LMD, most women initially presented with Stage I-III BC (62.1%) with ductal histology (67.0%) and biological subtypes including ER-positive/HER2-negative (56.8%), HER2-positive (17.6%), and triple-negative (22.0%). LMD was first diagnosed a median of 4.6 years (range: 0 to 34.1 years) after the initial diagnosis of BC, and the median age at LMD diagnosis was 54.6 years (range: 29.4 to 84.5 years). At time of LMD diagnosis, 146 (64.3%) women presented with a Karnofsky Performance Status (KPS) ≥ 70, 90 (39.6%) had a preceding parenchymal brain metastasis, and 23 (10.1%) had LMD as their only site of metastatic disease. Radiographically, classical LMD (61.7%) was observed more frequently than nodular-only LMD (13.2%). Brain-only LMD was present in 55.1% of patients, spine-only in 6.1% of patients, and both brain and spine in 38.8% of patients. Median survival from the time of LMD diagnosis was 4.5 months (95% CI: 3.4-7.8). Pre-treatment clinical factors associated with improved survival on univariate analysis included ER-positive/HER2-negative subtype (P = 0.010), KPS ≥ 70 (P < 0.001), LMD as the only site of metastasis (P = 0.004), stable or controlled extracranial metastases (P = 0.042), absence of leukopenia (P = 0.040) and the presence of nodular LMD (P < 0.001). After adjusting for these clinical factors, the receipt of radiation therapy (adjusted hazard ratio [AHR] 0.50, 95% CI: 0.37 - 0.68), systemic therapy (AHR 0.27, 95% CI: 0.19 - 0.38) and intrathecal chemotherapy (AHR 0.49, 95% CI: 0.33 - 0.75) were all associated with improved survival.In one of the largest multi-institutional reviews to date, we found that several pre-treatment clinical factors were significantly associated with improved survival among women with breast cancer LMD. However, despite treatment overall survival remains poor, and there is a need for new, effective therapies.M.G. Milligan: None. A. Aitelli: None. W.A. Mehan: Consultant; Kura Oncology. D.D. Shi: None. D.N. Cagney: Research Grant; Viewray, NhTheraguix. K.S. Oh: None. N. Wang: None. P. Brastianos: Research Grant; Merck, Eli Lily, BMS. Honoraria; Merck, Genentech. Consultant; Angiochem, Dantari Pharmaceuticals, Elevatebio, Eli Lily, Genentech, Pfizer, SK Life Sciences, Tesaro. B. Moy: Research Grant; PUMA biotechnology. N.U. Lin: Research Grant; Genentech, Merck, Pfizer, Seattle Genetics. Consultant; PUMA Biotechnology, Seattle Genetics, Daiichi Sankyo, Astra Zeneca, Denali Therapeutics, California Institute for Regenerative Medicine, Prelude Therapeutics. H.A. Shih: Employee; Dartmouth Hitchcock. Research Grant; AbbVie, NIH. Honoraria; UpToDate. Consultant; Cleveland Clinic. Speaker's Bureau; prIME Oncology. advisory; The Radiosurgery Society. director of clinical operations; Massachusetts General Hospital. clinical operational leader; Massachusetts General Hospital.

Survival Outcomes and Symptom Benefit From Palliative Radiotherapy in Breast Cancer Patients With Leptomeningeal Disease

The benefit of radiotherapy (RT) in poor-prognosis patients with leptomeningeal disease (LMD) is not well characterized. This study assessed the overall survival (OS) and clinical improvement of a largely symptomatic cohort of breast cancer patients with LMD, to identify patient subsets most likely to benefit from palliative RT.Patients with breast cancer and classic radiographic LMD (36% cytology-confirmed) treated with palliative whole brain and/or partial spine RT between 2000-2020 at a single academic institution were included in this retrospective analysis. OS was calculated from date of LMD diagnosis using the Kaplan-Meier method, and differences in subgroups were determined using the log-rank test. Multivariate Cox proportional hazards models adjusting for estrogen receptor (ER), progesterone receptor (PR), HER2, ECOG performance status (ECOG), and systemic disease status assessed factors associated with OS. Domain-specific and any symptom improvement were ascertained by chart review of patient- and physician-report, and a multivariate logistic regression model developed incorporating ER/PR status, HER2 status, ECOG and steroid use to identify factors associated with symptom benefit.Among 64 patients of median age 50 years (IQR 31-69), the radiographic distribution of LMD was in the brain (58%), spine (22%), or both (20%). A total of 63% had concurrent brain metastases, and 57% of patients had ER+ and/or PR+ tumors, 22% HER2+, and 38% triple-negative disease. Among 92% of symptomatic patients whose primary symptom domains were cranial nerve deficit (34%), sensory/motor deficits due to intracranial disease (25%) sensory/motor deficits due to spine disease (27%), and headaches/nausea (14%), 42% had > 1 reported symptom domain. Two-thirds of patients were on steroids prior to RT, and only 13% of patients received intrathecal therapy. Following a median dose of 30 Gy in 10 fractions, symptom improvement in any domain was noted in 59% of patients with symptoms pre-RT, with similar improvement rate across domains (12%, 15%, 19%, 14%, respectively); 21% of patients had improvement in > 1 symptom domain. Overall survival was only 2.1 months (95% CI 1.8-3.3) in the triple-negative subgroup, and higher among patients with HER2+ disease (5.2 months, 95% CI 3.8-NR, P = 0.003). On multivariate analysis, ER+ (HR 0.4, 95% CI 0.2-0.8, P = 0.009) and HER2+ (HR 0.4, 95% CI 0.2-0.9, P = 0.018) disease were associated with improved OS. Hormone receptor positivity was independently associated with symptom improvement following RT (OR 3.5, 95% CI 1.2-11, P = 0.029).Even in this poor-prognosis cohort of breast cancer patients with LMD, palliative RT yields symptomatic improvement, and may especially be of benefit among better-prognosis patients with hormone receptor-positive or HER2-positive disease.J. Takayesu: None. E. Sapir: Research Grant; LipoMedix, BioProtect. Consultant; AstraZeneca, MSD, Belong.Life. J. Xie: None. Y. Sun: None. A. Morikawa: Institutional research; Novartis, Lilly, Takeda, Eisai/H3b, Pfizer/National Comprehensive Cancer Network. L. Junck: Advisory Board; Orbus Therapeutics. D. Leung: None. Y. Umemura: None. J. Heth: None. W. Al-Holou: None. D.R. Wahl: Research Grant; Agios Inc, Innocrin Inc, American Cancer Society, NIH. Stock Options; Lycera Inc. Advisory Board Member; Agios Inc. T.S. Lawrence: None. C. Mayo: None. J.A. Hayman: Research Grant; Blue Cross Blue Shield of Michigan. M.M. Kim: Research Grant; Blue Earth Diagnostics.

LMD-09. Outcomes and symptom benefit from palliative radiotherapy for leptomeningeal disease in breast cancer patients

ObjectiveThe benefit of radiotherapy (RT) in patients with leptomeningeal disease (LMD) is poorly characterized. This study assessed the overall survival (OS) and clinical improvement of a largely symptomatic cohort of breast cancer patients with LMD, to identify patient subsets most likely to benefit from palliative RT.MethodsPatients with breast cancer-related classic radiographic LMD (36% cytology-confirmed) were treated with palliative whole brain and/or partial spine RT between 2000–2020 at a single academic institution in this retrospective analysis. OS was calculated from date of LMD diagnosis using the Kaplan-Meier method. A multivariate logistic regression model incorporating ER/PR status, HER2 status, ECOG and steroid use was developed to identify factors associated with symptom benefit, which was ascertained retrospectively by chart review.ResultsAmong 64 patients, the radiographic distribution of LMD was in the brain (58%), spine (22%), or both (20%). A total of 63% had brain metastases, and 57% of patients had ER+ and/or PR+, 22% HER2+, and 38% triple-negative disease. Of the symptomatic patients (94%), primary symptom domains included cranial nerve deficits (34%), sensory/motor deficits from intracranial disease (25%) or spinal disease (27%), and headaches/nausea (14%), with 42% of patients reporting >1 symptom domain. Two-thirds of patients were on steroids prior to RT, and 13% of patients received intrathecal therapy. OS was 3.75 months. Following a median dose of 30Gy in 10 fractions, 59% of symptomatic patients experienced symptom improvement, with similar improvement rate across domains (12%, 15%, 19%, 14%, respectively); 21% of patients had improvement in >1 symptom domain. Hormone receptor positivity was independently associated with symptom improvement following RT (OR 3.5, 95% CI 1.2–11, p=0.029).ConclusionsIn this poor-prognosis cohort of breast cancer patients with LMD, palliative RT yielded symptomatic improvement, and may be particularly beneficial among better-prognosis patients with hormone receptor-positive disease.

Intrathecal (IT) and intravenous (IV) nivolumab (N) for metastatic melanoma (MM) patients (pts) with leptomeningeal disease (LMD).

9519 Background: MM pts with LMD have a dismal prognosis, with median overall survival (OS) &lt; 3 months, no approved therapies and extremely limited clinical trial options. We previously reported initial safety findings from an open label, single arm, single center phase I/IB trial (NCT03025256), in which IT and IV N were well tolerated, without any CNS-specific or unexpected toxicity. Here we report an update on safety and maximum tolerated dose (MTD) for all patients enrolled, and efficacy for the completed dose cohorts. Methods: MM patients aged &gt;18 with evidence of LMD by MRI and/or CSF cytology, ECOG PS ≤2 were treated with IT and IV N. Dexamethasone ≤4mg/daily and concurrent BRAF/MEK inhibitor(i) treatment was allowed. For cycle 1, IT N was administered via intraventricular reservoir on day (D)1. For subsequent cycles (every 14 days), pts received IT N on D1, followed by IV N 240 mg on D2. IT N doses evaluated were 5, 10, 20 mg and 50 mg. Blood and CSF were collected at multiple time points for translational research. The primary objectives of this first-in-human study were to determine the safety and MTD of IT N given with IV N in MM pts with LMD. Bayesian mTPI methodology was used to define the MTD. Results: To date, 23 pts have been treated: two at 5, three at 10, fourteen at 20 mg and four at 50 mg IT N. Median age at LMD diagnosis was 42 (28-73); 12 pts are male. All pts had radiographic evidence of LMD and neurological symptoms; 14 pts had positive CSF cytology at baseline. 21 pts received prior therapies for their metastatic melanoma: anti-PD1 (n = 19), BRAFi/MEKi (n = 14), chemo (n = 2), IT IL2 (n = 4) other (n = 2). 19 pts had prior XRT, including whole brain RT (n = 7). Two pts were treatment-naïve. The median number of IT N doses was five (1- 66). The combination regimen was well tolerated by all evaluable pts (n=23), with only five pts (22%) experiencing gr 3 AEs, and no reported gr 4 or 5 toxicities. Nausea (30%), diarrhea (26%), and rash (22%) were the most common AEs. Eight pts (23%) experienced AEs after IT N administration, all gr 1. Initial efficacy analysis included only pts (n=19) treated with first three dose levels (5-20mg). Median follow-up for these pts is 4.5 months (mos) (1.1, 31.5 mos) and median OS is 63 % at 3 mos, 42 % at 6 mos and 30% at 12 mos. Conclusions: The trial demonstrates the feasibility and safety of IT administration of modern immunotherapy for MM pts with LMD. No unexpected systemic or neurological toxicity was observed with 20mg IT N. 2 additional patients are required to complete the 50mg IT N cohort. OS rates at 6 and 12 mos are encouraging and support further evaluation of IT administration of immunotherapy agents for pts with MM and LMD. Final presentation will include results of LMD for all dose cohorts, composite response assessment and comparative analysis of longitudinal CSF samples to assess immunologic effects. Clinical trial information: NCT03025256.