Leptomeningeal disease (LMD) is a devastating complication of cancer that is frequently underdiagnosed owing to the low sensitivity of cerebrospinal fluid (CSF) cytologic assessment, the current benchmark diagnostic method. Improving diagnostic sensitivity may lead to improved treatment decisions.
Objective
To assess whether cell-free DNA (cfDNA) analysis of CSF may be used to diagnose LMD more accurately than cytologic analysis.
Design, Setting, and Participants
This diagnostic study conducted in a neuro-oncology clinic at 2 large, tertiary medical centers assessed the use of genomic sequencing of CSF samples obtained from 30 patients with suspected or confirmed LMD from 2015 through 2018 to identify tumor-derived cfDNA. From the same CSF samples, cytologic analyses were conducted, and the results of the 2 tests were compared. This study consisted of 2 patient populations: 22 patients with cytologically confirmed LMD without parenchymal tumors abutting their CSF and 8 patients with parenchymal brain metastases with no evidence of LMD. Patients were considered positive for the presence of LMD if previous CSF cytologic analysis was positive for malignant cells. The analysis was conducted from 2015 to 2018.
Main Outcomes and Measures
The primary outcome was the diagnostic accuracy of cfDNA analysis, defined as the number of tests that resulted in correct diagnoses out of the total number of tests assayed. Hypotheses were formed before data collection.
Results
In total, 30 patients (23 women [77%]; median age, 51 years [range, 28-81 years]), primarily presenting with metastatic solid malignant neoplasms, participated in this study. For 48 follow-up samples from patients previously diagnosed via cytologic analysis as having LMD with no parenchymal tumor abutting CSF, cfDNA findings were accurate in the assessment of LMD in 45 samples (94%; 95% CI, 83%-99%), whereas cytologic analysis was accurate in 36 samples (75%; 95% CI, 60%-86%), a significant difference (P = .02). Of 43 LMD-positive samples, CSF cfDNA analysis was sensitive to LMD in 40 samples (93%; 95% CI, 81%-99%), and cytologic analysis was sensitive to LMD in 31 samples (72%; 95% CI, 56%-85%), a significant difference (P = .02). For 3 patients with parenchymal brain metastases abutting the CSF and no suspicion of LMD, cytologic findings were negative for LMD in all 3 patients, whereas cfDNA findings were positive in all 3 patients.
Conclusions and Relevance
This diagnostic study found improved sensitivity and accuracy of cfDNA CSF testing vs cytologic assessment for diagnosing LMD with the exception of parenchymal tumors abutting CSF, suggesting improved ability to diagnosis LMD. Consideration of incorporating CSF cfDNA analysis into clinical care is warranted.
2001 Background: Systemic treatments are limited for patients with meningiomas that have progressed after surgery and/or radiation. Loss of NF2and CDKN2A/Bare common in higher grade meningiomas and promote meningioma progression in preclinical models. We evaluated the efficacy of abemaciclib, a cyclin-dependent kinase (CDK) 4/6 inhibitor, as part of Alliance umbrella trial A071401, a genomically driven phase II study in recurrent or progressive meningiomas. Methods: Eligible patients (pts) with grade 2/3 tumors and NF2 mutations or CDK pathway alterations were treated with abemaciclib 200 mg orally twice daily until progressive disease. Two co-primary endpoints were used: progression-free survival at 6 months (PFS6) and response rate (RR) by Macdonald criteria; the trial would be declared positive if either endpoint was met. Twenty-four evaluable pts provided >85% power to detect a PFS6 >41.5% (vs. null 15%; alpha =0.02). The threshold for promising results for PFS6 was 8+/24 pts. For RR, 24 evaluable pts provided >89% power to detect RR >20% (vs. null 2.5%; alpha = 0.021). The threshold for promising results for RR was 3+/24 pts. Results: Of 83 pts screened while the abemaciclib arm was open between September 15, 2021 and October 3, 2022, 36 eligible pts received treatment. The mean number of treatment cycles administered was 7 and median follow-up since start of treatment was 11 months. The first 24 pts that met eligibility criteria and began treatment were considered evaluable for the primary endpoint analysis. Of the 24 pts evaluated, 58% were female and the median age was 62 years. The observed PFS6 rate was 54% (13/24 pts, 95% confidence interval 33-75%), thus the study met PFS6 endpoint. No objective responses were observed. Of the 36 pts who started treatment, eight had a grade 3 and two had a grade 4 adverse event at least possibly related to treatment. Grade 3 toxicities included anemia (2), neutropenia (2), leukopenia (1), blurry vision (1), diarrhea (2), fatigue (2), ALT elevation (1), dehydration (1), hyperkalemia (1), hyponatremia (1), dizziness (1), acute kidney injury (1), and thromboembolic event (1). Grade 4 toxicities included ALT elevation (1), AST elevation (1) and vomiting (1). Conclusions: Abemaciclib was well tolerated and resulted in an improved PFS6. The overall trial endpoint was met. Abemaciclib warrants further investigation for the treatment of patients with progressive grade 2/3 meningiomas. Support: U10CA180821, U10CA180882; UG1CA189867 (NRG Oncology); Eli Lilly; https://acknowledgments.alliancefound.org . Clinical trial information: NCT02523014 .
<p>Supplemental Tables. Supplemental Tables S1-6. Table S1. Antibodies used for quantification and concentrations. Table S2. Antibodies that could not be quantified in the model systems under fixation conditions used to identify Texas Red dextran permeability. Table S3. Summary statistics for analysis of brain metastases vs. uninvolved brain for each analyzed immunofluorescence marker. Table S4. Summary statistics for analysis of highly permeable vs. poorly permeable brain metastases for each analyzed immunofluorescence marker. Table S5. Antibodies that could not be quantified in human specimens. Table S6: Summary of immunofluorescence analysis of human brain metastasis specimens Supplemental Figures. Supplemental Figures S1-9. Figure S1. Homogenous HER2 staining in a SUM190-BR3 brain metastasis. Figure S2. No significant trend in Claudin-5 expression in three models of brain metastasis. Figure S3. Increased VEGF expression in brain metastasis. Figure S4. Decreased ZO-1 expression in brain metastasis. Figure S5. Decreased AQP4 expression and an alteration in the AQP4 expression pattern in brain metastasis. Figure S6: Heterogeneous trends in Collagen IV expression in three models of brain metastasis. Figure S7: Colocalization of Desmin+ pericytes and CD13+ pericytes with PDGFR-β. Figure S8: Desmin immunofluorescent staining in human specimens. Figure S9. Examples of immunofluorescent staining in human specimen #5 Supplemental Experimental Procedures. Detailed experimental procedures that were not included in the body of the manuscript. These include SUM190-BR3 cell line derivation, animal experiments, immunofluorescence, image analysis, statistical analysis, and human craniotomy specimen preparation.</p>
Melanoma is the third most common systemic cancer that leads to brain metastases. The annual incidence of melanoma has increased over time, with brain metastases developing in 40% to 50% of patients with advanced melanoma. Traditional management of melanoma-related brain metastases has focused on symptom control as a result of the significant neurologic morbidity associated with the disease. Median overall survival for these patients, if untreated, is approximately 3 months. As with other brain metastases, a multidisciplinary treatment approach that includes surgery and radiation therapy is typically used, with historically little role for systemic, cytotoxic therapy. During the past decade, advancement within the field of genomics has led to the identification of melanoma-specific mutations, namely, v-Raf murine sarcoma viral oncogene homolog B and neuroblastoma RAS viral oncogene homolog, as well as to the development of agents that target these driver mutations. In addition, the advent of immunotherapies, specifically, agents that target cytotoxic T-lymphocyte antigen-4, anti-programmed death-1, and programmed death ligand-1, has increased the potential therapeutic options available to patients with both systemic and brain disease. With these advances, early trials have demonstrated improved overall survival in patients with brain metastases who receive these therapies either as single agents or as part of multimodality treatment regimens.
Abstract Leptomeningeal metastasis (LMD) is a late complication of cancer with poor prognosis and median survival of approximately 4-6 weeks without treatment. Whole brain radiation remains the mainstay of treatment, however it can cause significant neurocognitive sequelae and has not been shown to prolong overall survival. Thus, new treatment strategies are urgently needed to improve outcomes in patients with LMD. Results from recent Phase 2 studies of immune checkpoint inhibitors in LMD shows promising improvement in overall survival. Combining anti-VEGF therapy and immunotherapy may control symptoms due to inflammation and tumor-induced irritation, minimize steroid use, and promote improved efficacy of immunotherapy through modulation of the tumor immune microenvironment. We designed a multi-institutional, single-arm Phase 2 study of pembrolizumab in combination with lenvatinib in patients with LMD from any solid tumor. The primary objective is to estimate the overall survival rate at 6 months (OS6). A Simon two-stage design with a total sample size of 19 evaluable patients will be used to compare a null hypothesis of OS6 of 25% against an alternative hypothesis of 55%. Secondary objectives include assessing safety of pembrolizumab and lenvatinib in this patient population, systemic response rate, intracranial/intraspinal response rate, and progression-free survival. We will also explore clinician-reported neurologic outcomes and patient-reported quality of life and symptom burden. Blood, cerebrospinal fluid, and tissue biomarkers will be analyzed to determine predictors of response. Patients must be on minimal doses of steroids prior to study enrollment and cannot have received prior immune checkpoint inhibitor or anti-VEGF therapy. Response to treatment will be determined using RANO-BM for intracranial disease and RECIST 1.1 for systemic disease. Study accrual is anticipated over 12-24 months with anticipated total study duration of 30 months.
Abstract BACKGROUND Papillary meningiomas (PM) are rare WHO grade III tumors that are associated with frequent recurrences and metastatic disease in spite of surgery and radiation. Due to their low incidence and scarcity of tumor tissues available for genomic analyses, the genetic alterations associated with PM remain unclear. MATERIAL AND METHODS We mined data collected as part of our clinical comprehensive genomic profiling (CGP) initiative which has to date analyzed 8 PM (>50% papillary morphology) and 22 meningiomas with focal papillary features (10–50%) amongst over 500 additional meningiomas of other subtypes. The samples were analyzed in a CAP/CLIA-accredited laboratory (Foundation Medicine, Cambridge, MA). GCP was performed on hybridization-captured, adaptor ligation-based libraries to a mean coverage depth of >650x for 236 or 315 genes plus the introns from 19 or 28 genes frequently involved in cancer. RESULTS In our cohort of 8 PMs, we identified three cases with inactivation of PBRM1; two cases with a truncating mutation in PBRM1 and one with homozygous deletion of PBRM1. Of the 22 meningiomas with only focal papillary features, 8 cases were PBRM1-mutant. Thus, 11 of 30 cases (36.7%) with at least focal (>10%) papillary morphology had inactivation of PBRM1.In the entire cohort of 562 meningiomas, we identified five additional cases with inactivating alterations in PBRM1 that did not display overt papillary morphology in the H&E sections available for analysis. Thus, 11 of 16 PBRM1-mutant cases (69%) occurred in meningioma with papillary histologic features as opposed to 19 of 546 wild-type cases (3.5%), supporting a significant association between papillary features and PBRM1 mutation (p<0.0001). The majority of PBRM1-mutant meningiomas occurred in female patients (n=10/16, 62.5%), and median age was 51 years. Most cases were located supratentorially (n=10). CONCLUSION We identified the tumor suppressor gene PBRM1 as a recurrently altered gene in meningiomas with papillary histomorphology. Further investigational studies are needed to assess outcomes of PBRM1-mutant meningioma and to determine whether mutation is an independent negative prognostic biomarker.
