Diagnosis Of Leptomeningeal Disease Research Articles

A single center retrospective cohort study of patients with metastatic breast cancer and leptomeningeal disease: Updated survival data and subgroup analyses by breast cancer subtype.

1108 Background: Patients (pts) with metastatic breast cancer (MBC) and leptomeningeal disease (LMD) have a poor prognosis with limited therapies. We previously reported data from our retrospective LMD registry; here we provide an update with additional pts and subgroup analyses highlighting differences in treatment and survival by breast cancer subtype. Methods: In this single center retrospective cohort study, we identified pts with MBC and LMD who received care from 2000-2024 and abstracted key clinical, treatment, and overall survival (OS) data. Results: We identified 111 pts with MBC and LMD, including pts 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%). The majority of pts had concurrent brain metastasis (n=82, 73.9%). Median time from diagnosis of MBC to LMD was 16.4 months (mo) (range 0-101.3 mo). Pts received a median of 3 lines of therapy prior to the diagnosis of LMD (range 0-10) and 1 line after the diagnosis of LMD (range 0-4). Most pts received central nervous system-directed (CNS)-directed therapy (n=94, 84.7%), including intrathecal (IT) therapy (n=42, 37.8%) and/or CNS radiation (n=70, 63.1%). Median OS from the diagnosis of LMD to death was 4.1 mo (range 0.1-78.1 mo) and varied by subtype, with pts with HR+/HER2- or HER2+ MBC and LMD living longer than those with TNBC and LMD (4.2 and 6.8 mo respectively vs. 2.0 mo, p<0.01, HR 2.15, 95% CI 1.36-3.39). There was no difference in OS by histology ductal vs. lobular or by presence or absence of concurrent parenchymal brain metastases. Pts who received IT therapy survived longer than those who did not (7.1 vs. 2.7 mo, p=0.01, HR 0.60, 95% CI 0.40-0.90). There was difference in OS by receipt of CNS-directed radiation therapy. Pts diagnosed with LMD from 2015-2024 lived longer than those diagnosed from 2000-2014 (6.4 vs. 2.9 mo, 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). Conclusions: This study represents one of the largest case series of pts with MBC and LMD, including the most pts diagnosed after 2015 to our knowledge. Pts with lobular histology, HER2+ BC, TNBC, and those with de novo MBC were over-represented compared to the general MBC population. Pts with HR+/HER2- or HER2+ disease, LMD diagnosed after 2015, and those who received IT therapy survived longer than their respective cohorts. Novel diagnostic and therapeutic strategies for pts with MBC and LMD remains an area of unmet clinical need.

A Microfluidic, Multi-Antibody Cell Capture Method to Evaluate Tumor Cells in Cerebrospinal Fluid in Patients With Suspected Leptomeningeal Metastases.

Leptomeningeal disease (LMD) is a clinical sequela of central nervous system metastasis involving the cerebrospinal fluid (CSF), often seen in late-stage solid tumors. It has a grave prognosis without urgent treatment. Standard of care methodologies to diagnose LMD include CSF cytology, magnetic resonance imaging, and clinical evaluation. These methods offer limited sensitivity and specificity for the evaluation of LMD. Here, we describe the analytic performance characteristics of a microfluidic-based tumor cell enrichment and detection assay optimized to detect epithelial cells in CSF using both contrived samples as well as CSF from patients having suspected or confirmed LMD from carcinomas. To demonstrate the feasibility of using a microfluidic, multi-antibody cell capture assay to identify and quantify tumor cells in CSF. An artificial CSF solution was spiked with 34 different human carcinoma cell lines at different concentrations and assayed for the ability to detect tumor cells to assess analytic accuracy. Two cell lines were selected to assess linearity, intra-assay precision, interinstrument precision, and sample stability. Clinical verification was performed on 65 CSF specimens from patients. Parameters assessed included the number of tumor cells, coefficient of variation percentage, and percentage of tumor cell capture (TCC). Among contrived samples, average tumor cell capture ranged from 50% to 82% (261 of 522; 436 of 531), and coefficients of variation ranged from 7% to 67%. The cell capture assay demonstrated a sensitivity of 92% and a specificity of 95% among clinical samples. This assay demonstrated the ability to detect and enumerate epithelial cells in contrived and clinical specimens in an accurate and reproducible fashion. The use of cell capture assays in CSF may be useful as a sensitive test for the diagnosis and longitudinal monitoring of LMD from solid tumors.

Abstract PO4-20-11: Excellent Response to Trastuzumab Deruxtecan in “HER-2 Low” Leptomeningeal Breast Cancer and Diagnostic and Monitoring Utility of CNSide Assay

Abstract A 72-year-old female presented to the emergency department with sudden onset of imbalance and cognitive decline. Two years ago, she was diagnosed with stage III estrogen receptor (ER) positive, progesterone receptor (PR) negative and human epidermal growth factor receptor 2 (HER2) negative (immunohistochemistry score: 0) invasive breast cancer. She subsequently underwent lumpectomy, adjuvant radiation and chemotherapy. She had been taking adjuvant letrozole at the time of presentation. Magnetic resonance imaging (MRI) of the brain showed obstructive hydrocephalus without any parenchymal lesion or leptomeningeal enhancement. MRI of spine, computerized tomography of chest/abdomen/pelvis and bone scan were unrevealing except a left adrenal mass which was equivocal for metastasis. Cerebrospinal fluid (CSF) analysis showed rare malignant cells. Based on the morphology of malignant cells and the patient’s prior history of breast cancer, the diagnosis of leptomeningeal disease with breast primary was made. There were insufficient cells for additional studies. CNSide, a microfluidic platform that uses antibody capture method to detect CSF tumor cells, showed 4678 tumor cells per milliliter (ml) of CSF. Immunocytochemistry of these cells showed that the cells were ER negative (criterion: < 2.6% ER positive cells) and programmed cell death ligand 1 (PD-L1) negative (criterion: < 3.4% PD-L1 positive cells). Fluorescence in situ hybridization (FISH) testing showed 22% of tumor cells with HER2 amplification (either HER2 to CEP17 ratio >/= 2.0 or HER2 copy number >/= 6). She underwent ventriculoperitoneal (VP) shunt placement with complete recovery of her neurological symptoms. Five weeks later, she was started on trastuzumab deruxtecan (T-DXd) mainly because of the HER2 FISH results from CNSide. She did not receive central nervous system(CNS) irradiation due to complete resolution of neurological symptoms with VP shunt placement. After two cycles of T-DXd, MRI brain showed mild leptomeningeal enhancement along bilateral superior cerebellar sulci. Positron emission tomography/computed tomography(PET/CT) scan showed a new sclerotic rib focus, thought to represent treatment response. It also showed decrease in size of the adrenal mass. The adrenal mass was hypermetabolic on PET, consistent with malignancy. CSF cytology was negative, while CSF tumor cell count significantly reduced to 6.72 cells/ml using CNSide. There were no new neurological symptoms. Despite MRI brain findings, she was continued on T-DXd given overall favorable clinical, radiological and CSF data. After 7th cycle of T-DXd, repeat CSF cytology continued to remain negative, CNSide CSF tumor cell count decreased further to 6.27 cells/ml, MRI brain showed interval resolution of prior leptomeningeal enhancement, CT scan showed further decrease in size of the adrenal mass (baseline 5.4cm to 3cm), stable rib sclerotic lesion and no additional metastatic lesion. To date, she has undergone eight cycles of T-DXd which has effectively controlled her disease for a period of seven months. She has not needed VP shunt revision and continues to do well. To our knowledge, this is the first case demonstrating the activity of T-DXd against CSF tumor cells where a small subset exhibited HER2 amplification. This case also highlights the benefits of using advanced and highly sensitive CSF assays to diagnose and surveil leptomeningeal disease and to assess HER2 signaling. This case is well-timed especially in the era of next-generation, CNS penetrating, potent HER2-directed antibody-drug conjugate like T-DXd which can mount antitumor activity even with minimal HER2 expression in tumors. Citation Format: Sarah Stanford, Zeni Kharel, Lauryn Hemminger, Tyler Schmidt, Sara Hardy, Jason Zittel, Nimish Mohile, Ajay Dhakal. Excellent Response to Trastuzumab Deruxtecan in “HER-2 Low” Leptomeningeal Breast Cancer and Diagnostic and Monitoring Utility of CNSide Assay [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 PO4-20-11.

Pachymeningeal disease: a systematic review and metanalysis.

Pachymeningeal disease (PMD) is a newly recognized pattern of brain metastasis (BrM) failure that specifically occurs following surgery with adjuvant stereotactic radiosurgery (SRS) and has unique prognostic implications relative to leptomeningeal disease (LMD). Here, we report its prevalence, prognostic implications, and associated risk factors. A literature search was performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses on PUBMED and Cochrane from January 2000 to June 2023. We identified 12 studies that included a total of 3992 BrM patients, 659 (16.5%) of whom developed meningeal disease (MD) following surgery plus adjuvant SRS, including either PMD or LMD. The mean prevalence of MD across studies was 20.9% (7.9-38.0%), with PMD accounting for 54.6% of this prevalence and LMD comprising the remaining 45.4%. Mean of the median overall survivals following diagnosis of PMD and LMD was 10.6 months and 3.7 months p = 0.007, respectively, a significant difference. Only 2 risk factors for PMD were reported in ≥ 2 studies and also identified as statistically significant per our meta-analysis: infratentorial location and controlled systemic disease status. While PMD has a superior prognosis to LMD, it is nevertheless a critical oncologic event associated with significant mortality and remains poorly recognized. PMD is predominantly observed in patients with controlled systemic disease status and infratentorial location. Future treatment strategies should focus on reducing surgical seeding and sterilizing surgical cavities.

Comparison of preoperative versus postoperative treatment dosimetry plans of single-fraction stereotactic radiosurgery for surgically resected brain metastases.

Stereotactic radiosurgery (SRS) for operative brain metastasis (BrM) is usually administered 1 to 6 weeks after resection. Preoperative versus postoperative timing of SRS delivery related to surgery remains a critical question, as a pattern of failure is the development of leptomeningeal disease (LMD) in as many as 35% of patients who undergo postoperative SRS or the occurrence of radiation necrosis. As they await level I clinical data from ongoing trials, the authors aimed to bridge the gap by comparing postoperative with simulated preoperative single-fraction SRS dosimetry plans for patients with surgically resected BrM. The authors queried their institutional database to retrospectively identify patients who underwent postoperative Gamma Knife SRS (GKSRS) after resection of BrM between January 2014 and January 2021. Exclusion criteria were prior radiation delivered to the lesion, age < 18 years, and prior diagnosis of LMD. Once identified, a simulated preoperative SRS plan was designed to treat the unresected BrM and compared with the standard postoperative treatment delivered to the resection cavity per Radiation Therapy Oncology Group (RTOG) 90-05 guidelines. Numerous comparisons between preoperative and postoperative GKSRS treatment parameters were then made using paired statistical analyses. The authors' cohort included 45 patients with a median age of 59 years who were treated with GKSRS after resection of a BrM. Primary cancer origins included colorectal cancer (27%), non-small cell lung cancer (22%), breast cancer (11%), melanoma (11%), and others (29%). The mean tumor and cavity volumes were 15.06 cm3 and 12.61 cm3, respectively. In a paired comparison, there was no significant difference in the planned treatment volumes between the two groups. When the authors compared the volume of surrounding brain that received 12 Gy or more (V12Gy), an important predictor of radiation necrosis, 64% of patient plans in the postoperative SRS group (29/45, p = 0.008) recorded greater V12 volumes. Preoperative plans were more conformal (p < 0.001) and exhibited sharper dose drop-off at the lesion margins (p = 0.0018) when compared with postoperative plans. Comparison of simulated preoperative and delivered postoperative SRS plans administered to the BrM or resection cavity suggested that preoperative SRS allows for more highly conformal lesional coverage and sharper dose drop-off compared with postoperative plans. Furthermore, V12Gy was lower in the presurgical GKSRS plans, which may account for the decreased incidence of radiation necrosis seen in prior retrospective studies.

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

1108 Background: Patients (pts) with metastatic breast cancer (MBC) and leptomeningeal disease (LMD) have a poor prognosis with limited therapeutic options. It is critical to better understand the risk factors and natural history of this condition, including pts in a modern cohort. Methods: In this single center retrospective cohort study, we identified pts with radiographic and/or cytologic evidence of LMD who received care at the University of California San Francisco (UCSF) from 2000-2023. To identify pts, we used the UCSF Pathology Database, the UCSF Radiation Oncology Database, and EMERSE, a searchable copy of the medical record. We conducted chart review to identify demographic and clinical characteristics, treatment history, and overall survival (OS). Results: 106 pts with MBC and radiographic and/or cytologic evidence of LMD were identified. All but one pt was female (n=105; 99.1%); most pts were non-Hispanic (n=93, 87.7%) and white (n=74, 69.8%). Median age at the time of MBC diagnosis was 51.9 years; 25 pts (20%) had de novo metastatic disease. Most pts had invasive ductal carcinoma (n=71, 66.9%), with invasive lobular carcinoma making up 21.7% (n=23) of cases. Pts presented with the following BC subtypes: Hormone receptor (HR) positive, HER2 negative (n=50, 47.1%), HR+/HER2+ (n=19, 17.9%), HR-/HER2+ (n=9, 8.5%), and triple negative (TNBC; n=23, 21.7%). Most pts had brain metastasis (n=78, 73.6%) in addition to LMD. Median time from diagnosis of MBC to LMD was 17.6 months (0-101.2 months). Pts received a median of 3.0 lines of therapy prior to the diagnosis of LMD (range 0-11.0) and 1.0 lines after the diagnosis of LMD (range 0-4.0). Many pts received intrathecal (IT) therapy (n=42, 39.6%) and/or whole brain radiation therapy or spinal radiation (n=49, 46.2%). Median OS from the diagnosis of LMD to death was 3.3 months. There was no significant difference in median OS by subtype: HR+/HER2- 3.5 months, HER2+ 4.7 months, and TNBC 2.2 months (p=0.45). There was no significant difference in median OS by histology: ductal (3.3 months) vs. lobular (4.7 months) (p=0.56). Pts who received IT therapy survived longer than those not treated with IT therapy (4.7 vs. 2.5 months, p=0.01). There was no significant difference in median OS among pts diagnosed with LMD between 2000-2015 (2.9 months) vs. 2016-2023 (3.6 months) (p=0.74). Conclusions: This study represents one of the largest reported case series of pts with MBC and LMD, including a more modern cohort. There appeared to be an over-representation of pts with lobular cancer and those with de novo metastatic disease. Most pts had brain metastases in addition to LMD. Survival was short in all pts, particularly those who did not receive IT therapy. There was no significant difference in median OS in pts diagnosed with LMD from 2000-2015 vs. 2016-2023; this remains an area of unmet clinical need.

Outcomes of Patients with Neoplastic Meningitis Undergoing Ventriculoperitoneal Shunting and Intrathecal Chemotherapy, A Single Institution Retrospective Review (P10-13.006)

<h3>Objective:</h3> To present the outcomes of a retrospective cohort of patients with leptomeningeal disease (LMD) who received placement of ventriculoperitoneal shunt (VPS) and Ommaya reservoir for intrathecal chemotherapy. <h3>Background:</h3> LMD is a devastating complication of cancer and confers a poor prognosis. Treatment modalities include radiation, intrathecal and/or systemic chemotherapy. Hydrocephalus occurs in more than half of these patients and is associated with poor prognosis. <h3>Design/Methods:</h3> We performed an in-depth chart review using electronic medical records of patients with LMD who had undergone placement of VPS and Ommaya in a single institution over a three-year period. <h3>Results:</h3> Eighteen patients with LMD underwent VPS placement and Ommaya reservoir for intrathecal chemotherapy. Eleven patients had breast cancer, four had lung cancer, and the remaining three patients had thyroid, esophageal and uterine cancer respectively. Seventeen patients are deceased, and one patient was lost to follow up, and not included in our analysis. Sixteen (94%) patients had brain metastases. Eleven patients (61.1%) received radiotherapy prior to VPS placement. Karnofsky scores ranged from 60 to 90. Seven (41%) patients did not receive intrathecal chemotherapy due to rapid LMD progression. Ten (59%) patients received intrathecal Topotecan, and one received Cytarabine at the time of disease progression. The overall survival of these patients from time of VPS placement was 15.15 weeks (range 4.1–203.2), of which seven (41%) survived less than eight weeks. Six (60%) patients died from LMD progression, three (30%) from systemic disease progression, and one (10%) died of medical complications. <h3>Conclusions:</h3> Hydrocephalus in LMD patients usually portends a rapid decline in neurologic and functional status, resulting in a poorer prognosis. Our retrospective analysis suggests urgency for early diagnosis of LMD with increased intracranial pressure, along with spinal fluid diversion procedures for intrathecal chemotherapy administration. These interventions may allow for prolongation and improvement in quality of life. <b>Disclosure:</b> Dr. Gottiparthy has nothing to disclose. Mrs. Orda-Nguyen has nothing to disclose. Mrs. Morrow has nothing to disclose. Dr. Loghin has nothing to disclose.

DDEL-02. LUMBAR OMMAYA RESERVOIR- A COST EFFECTIVE ALTERNATIVE TO INTRAVENTRICULAR OMMAYA RESERVOIR FOR TREATMENT OF LEPTOMENINGEAL DISEASE

Abstract Introduction Lumbar puncture (LP) is a well-established approach for intrathecal (IT) delivery of chemotherapeutics for leptomeningeal disease (LMD). Intraventricular Ommaya reservoir (OR) has supplanted LPs as an easier and safer route for IT administration. Radiotherapy for treatment of LMD must be delayed in order for surgical wound healing following OR placement. Furthermore, prior cranial radiation can thin the scalp, predisposing to wound breakdown. Placement of lumbar Ommaya reservoir (LOR) provides an alternative to IT delivery, but this has not reached a wide-spread acceptance. Objective Provide cost-analysis and report patient outcomes after placement of LOR. METHODS Following IRB approval, all patients undergoing LOR placement between 2018 and 2020 were retrospectively reviewed. Patients age, primary tumor, survival lengths and complications were reviewed. Average procedure-related treatment cost was obtained from an uncomplicated representative case excluding the surgeon’s fee. RESULTS Fourteen patients (mean age 46.35 years) were identified. The mean follow-up was 440.7 (25-1003) days post-surgery. Acute lymphoblastic leukemia (n = 4), acute myeloblastic leukemia (n = 3), breast carcinoma (n = 3), ependymoma (n = 3), lymphoma (n = 2) and lung adenocarcinoma (n = 1) were identified as underlying malignancy. LMD was diagnosed on average after 581.1 days after the diagnosis of the underlying malignancy. 8 patients succumbed to their malignancy on average after 463.9 and 314.6 days after the diagnosis of LMD and LOR surgery, respectively. There were 2 complications – pain at the site of the LOR and a fractured catheter caused by inadvertent puncture of the catheter. No infections or wound healing complications were noted. Typical cost for placement of LOR and OR was – 17,350 USD and 29,052 USD, respectively. Placement of the LOR proved to be more cost-effective in this cohort by approximately 40% cost reduction. CONCLUSION Placement of LOR is a cost effective alternative to cranial OR with low complication profile, and well tolerated by patients.

PATH-18. SHOULD LEPTOMENINGEAL DISSEMINATION (LMD) AT DIAGNOSIS WITH AN H3K27M MUTATION BE ENOUGH TO BE CONSIDERED A DIFFUSE MIDLINE GLIOMA (DMG) H3K27M ALTERED?

Abstract Currently diffuse midline glioma (DMG) H3K27M-altered is defined as a diffuse, infiltrating midline glioma with an altered H3K27M pathway. A number of brain tumors have been reported with alterations in H3K27M that do not meet DMG diagnostic criteria and the clinical significance of H3K27M alteration in these tumors is unknown. Patients with extensive leptomeningeal disease often do not undergo large tumor resections and as a result there is limited tissue available for histologic evaluation. We present two patients who presented with leptomeningeal disease (LMD) and given extent of disease were only able to undergo subtotal resection. In both of these cases, the pathology specimens were found to have H3K27M alterations by immunohistochemistry but did not meet the diagnostic criteria for DMG due to the lack of histologic evidence of infiltration. Both patients were young women (age 23 and 28) who presented with new headaches, nausea, and vomiting and were found to have extensive LMD. Both were treated initially with proton craniospinal radiation and concurrent temozolomide. Within 1 year of initial diagnosis, both had radiographic and clinical progression of both parenchymal and LMD. Despite aggressive treatment, both patients clinically declined and transitioned to hospice within 2 years of diagnosis. Our understanding of the H3K27M altered pathway at this time is limited, and the significance of this mutation is unknown in tumors where an infiltrating component is not captured histologically. While LMD is rare at initial presentation of DMG, it is seen commonly at disease progression. We propose that the presence of H3K27M alteration with known leptomeningeal disease at diagnosis should be considered grade 4 histology and DMG for the purposes of prognostication and clinical trial consideration. Given ability to detect this mutation in CSF sampling, this may spare patients from surgical intervention and expedite time to treatment.

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.

Advances in Diagnosis and Treatment for Leptomeningeal Disease in Melanoma.

Melanoma has one of the highest incidences of causing leptomeningeal disease (LMD) among solid tumors. LMD patients have very poor prognosis with a dismal survival despite aggressive management. In this article, we review the current approaches in the management of patients with LMD secondary to melanoma, including updates in diagnosis, treatment, up-to-date clinical studies, and future directions. Cerebrospinal fluid (CSF) cytology remains the gold standard for diagnosis, and alternatively, MRI based on clinical presentation can be used. Other approaches such as "liquid biopsies" that detect circulating tumor cells and cell-free DNA have the potential to considerably enhance the diagnosis of LMD from melanoma. As for treatment options, several systemic therapies, involving systemic targeted and immunotherapies have evolved that showed to have possible benefit in LMD patients. Intrathecal chemotherapy, cellular therapy, and immunotherapy are currently under evaluation in Phase I/II clinical trials. In addition, new radiation therapy approaches such as proton cranial-spinal irradiation (CSI) are currently under investigation. LMD management still remains challenging. Future studies are critical to elucidate the pathophysiology of LMD in order to develop new urgently needed diagnostic tools and therapies. Clinical trials ought to be expanded to include patients with LMD. Future clinical studies should also integrate tissue interrogation, scientifically designed therapies, and aggressive, early intervention in patients with suspected LMD.

Major Differences in Lymphocyte Subpopulations Between Cerebrospinal Fluid and Peripheral Blood in Non-Hodgkin Lymphoma Without Leptomeningeal Involvement: Flow Cytometry Evidence of a Cerebral Lymphatic System.

Cerebrospinal fluid (CSF) flow cytometry has a crucial role in the diagnosis of leptomeningeal disease in onco-hematology. This report describes the flow cytometry characterization of 138 CSF samples from patients affected by non-Hodgkin lymphoma, negative for disease infiltration. The aim was to focus on the CSF non-neoplastic population, to compare the cellular composition of the CSF with paired peripheral blood samples and to document the feasibility of flow cytometry in hypocellular samples. Despite the extremely low cell count (1 cell/µl, range 1.0–35) the study was successfully conducted in 95% of the samples. T lymphocytes were the most abundant subset in CSF (77%; range 20–100%) with a predominance of CD4-positive over CD8-positive T cells (CD4/CD8 ratio = 2) together with a minority of monocytes (15%; range 0–70%). No B cells were identified in 90% of samples. Of relevance, a normal, non-clonal B-cell population was documented in 5/7 (71%) patients with primary central nervous system lymphoma at diagnosis (p<0.0001), suggesting a possible involvement of blood-brain barrier cell permeability in the pathogenesis of cerebral B-cell lymphomas. The highly significant differences between CSF and paired peripheral blood lymphoid phenotype (p<0.0001) confirms the existence of an active mechanism of lymphoid migration through the meninges.

Leptomeningeal disease from melanoma—Poor prognosis despite new therapeutic modalities

ObjectiveThe development of leptomeningeal disease (LMD) among melanoma patients is associated with short survival. Unspecific clinical symptoms and imprecise diagnostic criteria often delay diagnosis. Because melanoma patients with LMD have been excluded from most clinical trials, the efficacy of immune checkpoint blockade (ICB) and targeted therapies (TTs) has not been adequately investigated among these patients. MethodsWe performed a retrospective study in two tertiary-referral skin cancer centres to evaluate the clinical characteristics, diagnostics, treatments, and overall survival (OS) of melanoma patients with LMD between June 2011 and March 2019. ResultsIn total, 52 patients were included. The median age at LMD diagnosis was 58 years. Most patients (n = 30, 58%) were men. The median time from the first diagnosis of unresectable disease to the first diagnosis of LMD was 8.5 months (range 0–91.5 months). Most patients (65%, n = 34) were BRAF V600 mutated. Sixteen patients (31%) presented with LMD only, whereas 36 patients (69%) presented with concomitant brain metastases at LMD diagnosis. Eleven patients (21%) showed no evidence of extracranial disease. Forty-four patients (85%) had clinical symptoms at LMD diagnosis. Forty-two patients (81%) had received at least one prior therapy. Forty patients (77%) received at least one treatment after LMD diagnosis, including TT (n = 17), ICB (n = 13), bevacizumab (n = 1), radiotherapy (n = 3), and intrathecal chemotherapy (n = 1); five patients received both TT and ICB. Twelve patients (23%) received no treatment because of rapid progression of LMD. The median OS for the entire cohort was 2.9 months (95% confidence interval [CI] 1.7–4.1). Among patients receiving systemic therapy, OS was 3.7 months (95% CI 2.4–4.9). ConclusionsSystemic treatment with TT or ICB seems to improve OS among patients with LMD. However, despite new therapy modalities, the prognosis of LMD remains poor.

Leptomeningeal disease in pancreas ductal adenocarcinoma: A manifestation of longevity

Background/Objectives: Pancreatic adenocarcinoma (PDAC) metastatic to the leptomeninges is a rare and lethal event. Leptomeningeal disease (LMD) research is limited in PDAC, and insights into clinical descriptors, possible disease predictors, and treatment strategies is necessitated. MethodsMemorial Sloan Kettering databases were queried with Institutional Review Board approval to identify patients with LMD and PDAC treated between January 2000 and June 2020. Medical record review was used to abstract clinical, genomic, pathologic, and radiographic data. Overall survival was calculated from date of PDAC diagnosis to date of death. Previously published literature on LMD from PDAC was reviewed. ResultsFour patients with LMD from PDAC were identified, two males and two females. Age at diagnosis ranged from 57 to 68 years. All four patients had predominant lung metastasis and a relatively low burden of intra-abdominal disease. Somatic testing indicated alterations typical of PDAC and no PDAC defining pathogenic germline mutations were identified. An extended clinical course prior to LMD diagnosis was observed in all patients, ranging from 16 to 148 months. Upon diagnosis of LMD, three patients elected for supportive care and one patient received a limited course of craniospinal radiation. The median survival following diagnosis of LMD was 1.6 months (range 0.5–2.8 months). ConclusionsLMD from PDAC is a rare occurrence that may be more frequent in patients with lung metastasis and/or a more indolent clinical course. Following diagnosis of LMD, prognosis is poor, and survival is short. New treatment strategies for this manifestation of PDAC are needed.

Leptomeningeal Disease in Breast Cancer, Bristol Experience

Purpose: Diagnosis of leptomeningeal disease (LMD) in breast cancer patients is associated with poor prognosis [1]; median overall survival is usually less than 12 months. Diagnosis of LMD can be elusive and requires a high level of clinical suspicion. Cerebrospinal fluid (CSF) cytology is considered the gold standard to diagnose LMD but lack of malignant cells in CSF even in symptomatic patients can be a diagnostic dilemma [2]. Magnetic resonance imaging (MRI) of the head can help diagnose LMD.

RARE-33. LEPTOMENINGEAL DISEASE IN PATIENTS WITH MIDLINE GLIOMAS HARBORING HISTONE H3 K27M MUTATIONS

Abstract INTRODUCTION The 2016 WHO classification describes a specific subtype of midline gliomas harboring histone 3 (H3) K27M mutations which compromise 15–40% of gliomas in children and young adults. 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 true incidence and the clinical behavior of this group has not been well-defined. METHODS This is a retrospective study of patients with H3K27M/I diffuse midline gliomas at MSKCC from 01/2012 to 01/2019. Mutations were identified through next-generation sequencing (NGS). RESULTS We identified 24 patients. Median age was 21 (6–70) and 13 were male. Thirteen tumors were in the thalamus, 6 in the brainstem, 4 in the spinal cord, and 1 in the pineal region. H3K27M mutations were detected by NGS from tumor tissue in 21 patients, from cerebral spinal fluid (CSF) circulating tumor DNA (ctDNA) in 2 and from tissue and CSF ctDNA in one. LMD was diagnosed in 17/24 (71%) patients radiographically. Of these, 8 underwent LP: CSF cytology was positive in 2/8 and CSF ctDNA was detected in 3/3. All patients received RT and one or more lines of chemotherapy. At analysis, thirteen patients remain alive. Median time to last follow up for all patients was 14.2 months. Median time from diagnosis to LMD was 13.2 months (0–45.1), with median OS of 6.5 months (0.3–27) after diagnosis of LMD. CONCLUSION Our study showed that more than two-thirds of the patients with H3 K27M diffuse midline developed LMD. Neuroaxis imaging should be performed in conjunction with CSF studies to diagnose LMD. Besides, CSF ctDNA represents an important tool to identify molecular profile of tumors when biopsy is not feasible or limited for the analysis.

Predictors of leptomeningeal disease following hypofractionated stereotactic radiotherapy for intact and resected brain metastases

The objective was to evaluate the risk and predictors of developing leptomeningeal disease (LMD) in patients with brain metastases treated with 5-fraction hypofractionated stereotactic radiotherapy (HSRT). Patients treated with HSRT for intact brain metastases and/or surgical cavities were reviewed from a prospectively maintained database. Radiographic patterns of LMD were classified as focal classical, diffuse classical, focal nodular, and diffuse nodular. HSRT was delivered, most commonly 30 Gy in 5 fractions, to 320 intracranial lesions (57% intact and 43% surgical cavities) in 235 patients. The median follow-up was 13.4 months (range, 0.8 to 60 mo). LMD developed in 19% of patients with a 1-year LMD rate of 12%. From the diagnosis of LMD, the median overall survival (OS) was 3.8 months (range, 2-20.8 mo). The most common LMD pattern was diffuse nodular (44%). No difference in OS was observed between LMD patterns (P = 0.203). Multivariable analysis identified surgical cavities at significantly higher risk of LMD compared with intact lesions (odds ratio [OR] = 2.30, 95% CI: 1.24, 4.29, P = 0.008). For cavities, radiosensitive tumors (OR = 2.35, 95% CI: 1.04, 5.35, P = 0.041) predicted for LMD, while, for intact metastases, patients receiving treatment with targeted agents or immunotherapy (TA/I) were at lower risk (OR = 0.178, 95% CI: 0.04, 0.79, P = 0.023). Patients who had a brain metastasis resected were at an increased risk of LMD. OS was poor despite treatment of LMD, and no differences in OS based on the pattern of LMD was observed. Treatment with TA/I was observed to be protective against LMD and requires further study.

LPTO-01. LEPTOMENINGEAL METASTASIS FROM OVARIAN CARCINOMA TREATED WITH SYSTEMIC HIGH-DOSE METHOTREXATE

BACKGROUND: Central nervous system metastasis in ovarian cancer is reported in approximately 1% of cases and typically localizes to the parenchyma. Leptomeningeal disease (LMD) is exceedingly rare. Prognosis is extremely poor with median survival of 60 days. Given the rarity of LMD in ovarian cancers, there is no consensus on the optimal treatment approach. High-dose systemic methotrexate (HD-MTX) has been studied in LMD. CASE REPORT: A 41-year-old Caucasian woman with a history of BRCA-positive stage IIIC ovarian carcinoma who was treated with cytoreduction and multiple rounds of intravenous and intraperitoneal chemotherapy presented to the emergency room with progressive headaches, vomiting and neck pain. Contrasted MRI of the brain showed nodular enhancement along the cerebellar folia, concerning for leptomeningeal disease. Cerebrospinal fluid cytology analysis was positive for malignancy and she was diagnosed with leptomeningeal metastasis 2.5 years after her diagnosis with ovarian carcinoma. Induction therapy with systemic HD-MTX was given every other week and complete response was achieved after two induction cycles. Serum CA-125 level decreased from 565.7 U/mL (prior to treatment) to 50.4 U/ML after the sixth induction cycle and she was transitioned to maintenance HD-MTX. Approximately 6 months after initiation of HD-MTX, contrasted MRI demonstrated LMD recurrence with corresponding rise in CA-125 to 395 U/mL. Whole body CT imaging did not show local disease recurrence. Temozolomide was added to the HD-MTX regimen and craniospinal radiation therapy was planned but her neurologic condition continued to decline. She died 8 months after her diagnosis of LMD. CONCLUSION: LMD has a dismal prognosis. HD-MTX may prolong the overall survival in patients with LMD secondary to ovarian carcinoma. In these patients, serum CA-125 level may serve as a biomarker for monitoring CNS disease burden. Due to the rarity of LMD, multi-institutional prospective studies are needed to explore novel therapeutics in LMD.

Diagnosis, treatment, and survival in spinal dissemination of primary intracranial glioblastoma: systematic literature review.

Spinal metastases from primary intracranial glioblastoma (GBM) are infrequently reported, and the disease has yet to be well characterized. A more accurate description of its clinical presentation and patient survival may improve understanding of this pathology, guide patient care, and advocate for increased inclusion in GBM research. The authors sought to describe the clinical presentation, treatment patterns, and survival in patients with drop metastases secondary to primary intracranial GBM. A systematic review was performed using the PRISMA guidelines. PubMed/MEDLINE, Scopus, Web of Science, and Cochrane databases were queried for abstracts that included patients with primary intracranial GBM and metastases to the spinal axis. Descriptive statistics were used to evaluate characteristics of the primary brain lesion, timing of spinal metastases, clinical symptoms, anatomical location of the metastases, and survival and treatment parameters. Kaplan-Meier analysis and log-rank analysis of the survival curves were performed for selected subgroups. Of 1225 abstracts that resulted from the search, 51 articles were selected, yielding 86 subjects. The patients' mean age was 46.78 years and 59.74% were male. The most common symptom was lumbago or cervicalgia (90.24%), and this was followed by paraparesis (86.00%). The actuarial median survival after the detection of spinal metastases was 2.8 months and the mean survival was 2.72 months (95% CI 2.59-4.85), with a 1-year cumulative survival probability of 2.7% (95% CI 0.51%-8.33%). A diagnosis of leptomeningeal disease, present in 53.54% of the patients, was correlated, and significantly worse survival was on log-rank analysis in patients with leptomeningeal disease (p = 0.0046; median survival 2.5 months [95% CI 2-3] vs 4.0 months [95% CI 2-6]). This study established baseline characteristics of GBMs metastatic to the spinal axis. The prognosis is poor, though these results will provide patients and clinicians with more accurate survival estimates. The quality of studies reporting on this disease pathology is still limited. There is significant need for improved reporting methods for spinal metastases, either through enrollment of these patients in clinical trials or through increased granularity of coding for metastatic central nervous system diseases in cancer databases.

Response to Selective RET Inhibition With LOXO-292 in a Patient With RET Fusion-Positive Lung Cancer With Leptomeningeal Metastases.

The development of leptomeningeal metastases is a poor prognostic factor in patients with advanced cancers.1–3 In non–small-cell lung cancers (NSCLCs), median overall survival of patients from the diagnosis of leptomeningeal disease is 1 to 2 months without treatment and up to 8 months with systemic therapy.4–6 Furthermore, patients with leptomeningeal disease have historically had limited access to novel therapies in clinical trials. Recent efforts from many groups, including the European Society for Medical Oncology and the US Food and Drug Administration (FDA), have encouraged the inclusion of patients with leptomeningeal metastases in clinical trials, in addition to promoting standardization of intracranial response assessments.7–9 These efforts are crucial given that many investigational agents have substantial CNS activity and may improve outcomes in driver-positive cancers with leptomeningeal involvement.5,10 RET fusions are actionable oncogenic drivers that are identified in 1% to 2% of NSCLCs.11,12 To date,chemotherapy and/or immunotherapy remain the only approved systemic therapies for these cancers. Multikinase inhibitors with activity against RET (eg, cabozantinib or vandetanib) were repurposed to treat patients with RET fusion-positive lung cancers. Although these agents were found to be active in a subset of these patients, outcomes are modest compared with targeted therapies in other driver-positive lung cancers, and intracranial activity is poor.13,14 Selective RET inhibitors currently in development, such as LOXO-292 and BLU-667, have improved outcomes for patients with RET fusion-positive cancers because of increased potency and less offtarget toxicity.15,16 In September of 2018, LOXO-292 received Breakthrough Therapy designation from the FDA for treatment of patients with metastatic RET fusion-positive NSCLCs (as well as RET fusion-positive thyroid cancers and RET-mutant medullary thyroid cancer). In addition, confirmed intracranial responses and durable disease control have been achieved in patients with brain metastases in an ongoing phase I/II trial of LOXO-292 for patients with RET fusion-positive cancers.15 Its activity in leptomeningeal disease, however, has not previously been characterized. In this article, we describe a patient with a RET fusion-positive lung cancer with brain and leptomeningeal metastases who had an impactful intracranial response to selective RET inhibition with LOXO-292.