RESUMO
Progressive meningiomas that have failed surgery and radiation have a poor prognosis and no standard therapy. While meningiomas are more common in females overall, progressive meningiomas are enriched in males. We performed a comprehensive molecular characterization of 169 meningiomas from 53 patients with progressive/high-grade tumors, including matched primary and recurrent samples. Exome sequencing in an initial cohort (n = 24) detected frequent alterations in genes residing on the X chromosome, with somatic intragenic deletions of the dystrophin-encoding and muscular dystrophy-associated DMD gene as the most common alteration (n = 5, 20.8%), along with alterations of other known X-linked cancer-related genes KDM6A (n =2, 8.3%), DDX3X, RBM10 and STAG2 (n = 1, 4.1% each). DMD inactivation (by genomic deletion or loss of protein expression) was ultimately detected in 17/53 progressive meningioma patients (32%). Importantly, patients with tumors harboring DMD inactivation had a shorter overall survival (OS) than their wild-type counterparts [5.1 years (95% CI 1.3-9.0) vs. median not reached (95% CI 2.9-not reached, p = 0.006)]. Given the known poor prognostic association of TERT alterations in these tumors, we also assessed for these events, and found seven patients with TERT promoter mutations and three with TERT rearrangements in this cohort (n = 10, 18.8%), including a recurrent novel RETREG1-TERT rearrangement that was present in two patients. In a multivariate model, DMD inactivation (p = 0.033, HR = 2.6, 95% CI 1.0-6.6) and TERT alterations (p = 0.005, HR = 3.8, 95% CI 1.5-9.9) were mutually independent in predicting unfavorable outcomes. Thus, DMD alterations identify a subset of progressive/high-grade meningiomas with worse outcomes.
Assuntos
Distrofina/genética , Deleção de Genes , Neoplasias Meníngeas/genética , Meningioma/genética , Idoso , Idoso de 80 Anos ou mais , Linhagem Celular Tumoral/patologia , Linhagem Celular Tumoral/ultraestrutura , Estudos de Coortes , Progressão da Doença , Distrofina/metabolismo , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Neoplasias Meníngeas/diagnóstico por imagem , Neoplasias Meníngeas/patologia , Meningioma/diagnóstico por imagem , Meningioma/patologia , Microscopia Eletrônica de Transmissão , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase Multiplex , RNA Mensageiro/metabolismo , Cromatina Sexual/genética , Telomerase/genética , Telomerase/metabolismo , Sequenciamento do ExomaRESUMO
Melanoma-derived brain metastases (MBM) represent an unmet clinical need because central nervous system progression is frequently an end stage of the disease. Immune checkpoint inhibitors (ICI) provide a clinical opportunity against MBM; however, the MBM tumor microenvironment (TME) has not been fully elucidated in the context of ICI. To dissect unique elements of the MBM TME and correlates of MBM response to ICI, we collected 32 fresh MBM and performed single-cell RNA sequencing of the MBM TME and T-cell receptor clonotyping on T cells from MBM and matched blood and extracranial lesions. We observed myeloid phenotypic heterogeneity in the MBM TME, most notably multiple distinct neutrophil states, including an IL8-expressing population that correlated with malignant cell epithelial-to-mesenchymal transition. In addition, we observed significant relationships between intracranial T-cell phenotypes and the distribution of T-cell clonotypes intracranially and peripherally. We found that the phenotype, clonotype, and overall number of MBM-infiltrating T cells were associated with response to ICI, suggesting that ICI-responsive MBMs interact with peripheral blood in a manner similar to extracranial lesions. These data identify unique features of the MBM TME that may represent potential targets to improve clinical outcomes for patients with MBM.
Assuntos
Neoplasias Encefálicas , Melanoma , Humanos , Inibidores de Checkpoint Imunológico , Microambiente TumoralRESUMO
Importance: 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.
Assuntos
DNA Tumoral Circulante/líquido cefalorraquidiano , Testes Diagnósticos de Rotina , Neoplasias Meníngeas/líquido cefalorraquidiano , Neoplasias Meníngeas/diagnóstico , Neoplasias Meníngeas/genética , Neoplasias/complicações , Neoplasias/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Segunda Neoplasia Primária/líquido cefalorraquidiano , Segunda Neoplasia Primária/diagnóstico , Segunda Neoplasia Primária/genética , Valor Preditivo dos TestesRESUMO
Leptomeningeal disease (LMD) is a devastating complication of solid tumor malignancies, with dire prognosis and no effective systemic treatment options. Over the past decade, the incidence of LMD has steadily increased due to therapeutics that have extended the survival of cancer patients, highlighting the need for new interventions. To examine the efficacy of immune checkpoint inhibitors (ICI) in patients with LMD, we completed two phase II clinical trials. Here, we investigate the cellular and molecular features underpinning observed patient trajectories in these trials by applying single-cell RNA and cell-free DNA profiling to longitudinal cerebrospinal fluid (CSF) draws from enrolled patients. We recover immune and malignant cell types in the CSF, characterize cell behavior changes following ICI, and identify genomic features associated with relevant clinical phenomena. Overall, our study describes the liquid LMD tumor microenvironment prior to and following ICI treatment and demonstrates clinical utility of cell-free and single-cell genomic measurements for LMD research.
Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Antígeno CTLA-4/imunologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Carcinomatose Meníngea/tratamento farmacológico , Neoplasias Meníngeas/tratamento farmacológico , Receptor de Morte Celular Programada 1/imunologia , Microambiente Tumoral/efeitos dos fármacos , Adulto , Idoso , Anticorpos Monoclonais Humanizados/uso terapêutico , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/secundário , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/genética , Ácidos Nucleicos Livres/genética , Ácidos Nucleicos Livres/imunologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Imunoterapia , Interferon gama/genética , Interferon gama/imunologia , Ipilimumab/uso terapêutico , Masculino , Carcinomatose Meníngea/imunologia , Carcinomatose Meníngea/mortalidade , Carcinomatose Meníngea/patologia , Neoplasias Meníngeas/imunologia , Neoplasias Meníngeas/mortalidade , Neoplasias Meníngeas/patologia , Pessoa de Meia-Idade , Nivolumabe/uso terapêutico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/genética , Análise de Célula Única , Análise de Sobrevida , Microambiente Tumoral/genética , Microambiente Tumoral/imunologiaRESUMO
PURPOSE: Previous studies have shown that the PI3K/Akt/mTOR pathway is activated in up to 70% of breast cancer brain metastases, but there are no approved agents for affected patients. GDC-0084 is a brain penetrant, dual PI3K/mTOR inhibitor that has shown promising activity in a preclinical model of glioblastoma. The aim of this study was to analyze the efficacy of PI3K/mTOR blockade in breast cancer brain metastases models.Experimental Design: The efficacy of GDC-0084 was evaluated in PIK3CA-mutant and PIK3CA wild-type breast cancer cell lines and the isogenic pairs of PIK3CA wild-type and mutant (H1047R/+) MCF10A cells in vitro. In vitro studies included cell viability and apoptosis assays, cell-cycle analysis, and Western blots. In vivo, the effect of GDC-0084 was investigated in breast cancer brain metastasis xenograft mouse models and assessed by bioluminescent imaging and IHC. RESULTS: In vitro, GDC-0084 considerably decreased cell viability, induced apoptosis, and inhibited phosphorylation of Akt and p70 S6 kinase in a dose-dependent manner in PIK3CA-mutant breast cancer brain metastatic cell lines. In contrast, GDC-0084 led only to growth inhibition in PIK3CA wild-type cell lines in vitro. In vivo, treatment with GDC-0084 markedly inhibited the growth of PIK3CA-mutant, with accompanying signaling changes, and not PIK3CA wild-type brain tumors. CONCLUSIONS: The results of this study suggest that the brain-penetrant PI3K/mTOR targeting GDC-0084 is a promising treatment option for breast cancer brain metastases with dysregulated PI3K/mTOR signaling pathway conferred by activating PIK3CA mutations. A national clinical trial is planned to further investigate the role of this compound in patients with brain metastases.