scholarly journals Case Report: Vemurafenib Treatment in Brain Metastases of BRAFS365L-Mutant Lung Papillary Cancer by Genetic Sequencing of Cerebrospinal Fluid Circulating Tumor DNA Detection

2021 ◽  
Vol 11 ◽  
Author(s):  
Jianing Jiang ◽  
Jinqi Gao ◽  
Gang Wang ◽  
Jinyan Lv ◽  
Wenting Chen ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Brain Metastases ◽  
Therapeutic Option ◽  
Circulating Tumor Dna ◽  
Accurate Information ◽  
Papillary Cancer ◽  
Genetic Sequencing ◽  
First Case ◽  
Effective Therapeutic Option ◽  
Tumor Dna

BRAF mutations, primarily sensitizing mutations, such as BRAFV600E, have been proven to response to the BRAF inhibitor, Dabrafenib combined with trametinib therapy, but there have been no data demonstrating that it has activity against NSCLC-related brain metastases (BM). How patients harboring BRAFS365L mutation (a rare mutation following BRAFV600E-inhibitor treatment) in NSCLC is unknown. Vemurafenib, another BRAF inhibitor, can reverse the resistance that develops with the BRAFS365L mutation following dabrafenib combined with trametentinib treatment in melanoma, but none has been reported in NSCLC. Lung papillary cancer, as a rare typing, occupies about 4% of NSCLC. Hence, we reported the first case of a patient with BM of lung papillary carcinoma harboring a BRAFV600E mutation who benefited from dabrafenib combined with trametinib, and following the development of the BRAFS365L mutation, vemurafenib remained an effective therapeutic option. Moreover, we found that the next-generation sequencing (NGS) of cerebrospinal fluid (CSF) circulating tumor DNA (ctDNA) may potentially provide more accurate information about intracranial lesions than ctDNA in the blood serum, which will be a better detection method.

Utilizing phenotypic characteristics of metastatic brain tumors to predict the probability of circulating tumor DNA detection from cerebrospinal fluid.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 2507-2507
Author(s):  
Meichen Li ◽  
Delan Li ◽  
Xue Hou ◽  
Xiangheng Zhang ◽  
Na Wang ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Brain Metastases ◽  
Detection Rate ◽  
Cross Validation ◽  
Lesion Size ◽  
Circulating Tumor Dna ◽  
Intracranial Lesion ◽  
Shortest Distance ◽  
The Impact ◽  
Tumor Dna

2507 Background: Brain metastases occur in approximately 20% of tumor patients and is often associated with terminal events and poor prognosis. Cerebrospinal fluid (CSF) can be a promising source for detecting circulating tumor DNA (ctDNA) specific to the central nervous system (CNS) instead of peripheral blood due to the blood-brain barrier. However, CSF’s suboptimal ctDNA detection rate might limit its clinical application. Precise screening of suitable patients is needed to maximize clinical benefit. Methods: We sequenced 425 cancer-relevant genes in CSF and matched extracranial tissue or blood samples obtained from 67 lung cancer patients with brain metastases. The impact of clinical factors, including age, gender, tumor size, number of lesions, and distance of lesions to the ventricle on CSF ctDNA detection was then evaluated by univariate logistic regression. To predict the probability of successful CSF ctDNA detection, best subsets regression was employed for feature selection and cross validation was used for performance assessment to determine the final model. Results: We detected somatic alterations in 39/67 (58%) CSF ctDNA, 57/66 (86%) plasma ctDNA and 45/49 (92%) tissue samples. Mutation detection rate of CSF ctDNA was significantly lower than that from extracranial tissue and plasma (P < 0.001). Univariate analysis revealed significant association (P < 0.05) of high CSF ctDNA detection rate with the following features: (1) intracranial lesion size ( T), (2) shortest distance between the largest lesion and the ventricle ( Dtop), and (3) shortest distance between all intracranial lesion and the ventricle ( Dall). We also revealed a trend of higher detection rate in patients with CNS symptoms ( SCNS). Subsequent best subsets analysis and cross validation suggested best prediction power with lesion size and largest lesion-ventriclar distance (area under curve [AUC], 0.76 [95% CI, 0.71 to 0.85]; accuracy, 0.75 [95% CI, 0.70 to 0.81]). Final probability can then be derived from Logit P = 0.11×T−0.16×Dall (AUC, 0.82; sensitivity, 0.91; specificity, 0.74). The detection of CSF ctDNA was significantly improved from 58% to 83% (P = 0.03) based on the model. Conclusions: This study established a regression model to predict the probability of CSF ctDNA that can be useful to facilitate clinical decisions and avoid excessive practice when monitoring tumor evolution in the brain.

scholarly journals PATH-06. ASSESSMENT OF CIRCULATING TUMOR DNA IN CEREBROSPINAL FLUID BY WHOLE EXOME SEQUENCING TO DETECT GENOMIC ALTERATIONS OF GLIOBLASTOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii165-ii165
Author(s):  
Hao Duan ◽  
Zhenqiang He ◽  
Zhenghe Chen ◽  
Yonggao Mou
Keyword(s):  
Cerebrospinal Fluid ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Tumor Tissue ◽  
Circulating Tumor Dna ◽  
Genomic Alterations ◽  
Tissue Samples ◽  
Whole Exome ◽  
Resected Tumor ◽  
Tumor Dna

Abstract Cerebrospinal fluid (CSF) has been demonstrated as a better source of circulating tumor DNA (ctDNA) than plasma for brain tumors. However, it is unclear whether whole exome sequencing (WES) is qualified for detection of ctDNA in CSF. The aim of this study was to determine if assessment of ctDNA in CSF by WES is a feasible approach to detect genomic alterations of glioblastoma. CSFs of ten glioblastoma patients were collected pre-operatively at the Department of Neurosurgery, Sun Yat-sen University Cancer Center. ctDNA in CSF and genome DNA in the resected tumor were extracted and subjected to WES. The identified glioblastoma-associated mutations from ctDNA in CSF and genome DNA in the resected tumor were compared. Due to the ctDNA in CSF was unqualified for exome sequencing for one patient, nine patients were included into the final analysis. More glioblastoma-associated mutations tended to be detected in CSF comparing with the corresponding tumor tissue samples (3.56±0.75 vs. 2.22±0.32, P=0.097), while the statistical significance was limited by the small sample size. The average mutation frequencies were similar in CSF and tumor tissue samples (74.12% ± 6.03% vs. 73.83% ± 5.95%, P = 0.924). The R132H mutation of isocitrate dehydrogenase 1 and the G34V mutation of H3F3A which had been reported in the pathological diagnoses were also detected from ctDNA in CSF by WES. Patients who received temozolomide chemotherapy previously or those whose tumor involved subventricular zone tended to harbor more mutations in their CSF. Assessment of ctDNA in CSF by WES is a feasible approach to detect genomic alterations of glioblastoma, which may provide useful information for the decision of treatment strategy.

Circulating tumor DNA mutation as a prognostic marker in melanoma with brain metastasis.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21560-e21560
Author(s):  
Tapas Ranjan Behera ◽  
Jung Min Song ◽  
Donald Matthew Eicher ◽  
Brian Gastman ◽  
Daniel H. Farkas ◽  
...  
Keyword(s):  
Brain Metastasis ◽  
Brain Metastases ◽  
Metastatic Disease ◽  
Braf Mutation ◽  
Mutation Detection ◽  
Objective Response ◽  
Unmet Need ◽  
Circulating Tumor Dna ◽  
Metastatic Setting ◽  
Tumor Dna

e21560 Background: Prognosis in melanoma with brain metastasis is poor with a median survival of four months and a one-year survival rate of 10–20%. There is an unmet need for surveillance methods that can supplement imaging at regular intervals. Serial analysis of circulating tumor DNA (ctDNA) may aid surveillance and prognostication. A PCR-based, “specimen in/result out” testing device was employed to detect BRAF variants in plasma-derived ctDNA to evaluate the utility of rapid biomarker detection in the management of melanoma with brain metastasis. Methods: Serial blood samples from patients diagnosed with BRAF mutation-positive metastatic melanoma were collected at regular intervals. We employed a real-time PCR-based automated mutation detection system (Idylla; Biocartis, Belgium) to interrogate the plasma samples. The ctDNA mutation detection trend was analyzed relative to disease progression. Results: 39 patients with BRAF mutation positive melanoma were enrolled. 29 patients were treated in the metastatic setting, 10 in the adjuvant setting. 18 of the 29 patients with metastatic disease (62%) had brain metastases. Circulating BRAF mutation was detected in 17 of the 29 (59%) patients with metastatic disease, and was not detected in any patients treated adjuvantly. In the group with metastatic disease, this circulating biomarker changed from undetectable to detectable in eight (28%) and detectable to undetectable in three (10%). No change in circulating mutation status occurred in 18 (62%). In the eight patients who had an initial negative test that later became positive, seven (87%) had brain metastases. In three patients, ctDNA mutation detection occurred before the diagnosis of brain metastases on imaging, with a median lead time of five weeks (range, 3-12 weeks). In one patient with de novo metastatic disease admitted to the ICU, tissue was unavailable for BRAF testing but plasma was found to be positive for ctDNA BRAF detection. BRAF/MEK targeted therapy resulted in a sustained objective response. Five of six (83%) patients that had persistent ctDNA positivity had brain metastases. Among patients with brain metastases, median overall survival (mOS) of patients demonstrating >50% test positivity was numerically longer than those with <50% positivity (mOS 12.3 vs 53.5 months; p = 0.133). Conclusions: Plasma-based, rapid ctDNA testing may be useful as an aid in detecting progression and gauging prognosis in patients with melanoma treated in the metastatic setting. The dynamics of ctDNA test positivity may indicate a need for more urgent imaging, particularly of the brain. Blood-based, semi-automated ctDNA detection may serve as an attractive adjunct to scheduled imaging surveillance in melanoma.

scholarly journals Cerebrospinal Fluid Access Devices in Pediatric Diffuse Midline Glioma Patients: Literature Review and Evaluation of Institutional Practices

Neurosurgery ◽  
2019 ◽  
Vol 66 (Supplement_1) ◽  
Author(s):  
Daphne Li ◽  
Wendy Stellpflug ◽  
Amanda Muhs Saratsis
Keyword(s):  
Cerebrospinal Fluid ◽  
Liquid Biopsy ◽  
Tumor Biology ◽  
Significant Proportion ◽  
Circulating Tumor Dna ◽  
Response To Treatment ◽  
Institutional Practices ◽  
Medline Search ◽  
Tumor Dna ◽  
Diffuse Midline Glioma

Abstract INTRODUCTION Diffuse midline gliomas (DMG) are the number one cause of cancer death in children. H3K27M mutations occur in 80% of DMG, with distinct tumor biology and poorer response to treatment. H3K27M is detectable in cerebrospinal fluid (CSF) circulating tumor DNA (ctDNA), depending on CSF tumor proximity, and correlates with tumor volume and treatment response. Ventricular access devices (VAD) for serial CSF sampling (liquid biopsy) could therefore play a significant role in DMG management. Here, we set to characterize VAD placement practices in pediatric DMG. METHODS A retrospective review of patients <21 yr treated for DMG at our institution was performed (1984-2019). A MEDLINE search was conducted to identify reports of VAD placement in DMG. Full-text English reports of patients = 21 yr with VAD outcomes were analyzed. RESULTS A total of 106 DMG patients at our institution were identified. In total 49% had brainstem disease (n = 52). A total of 46.23% (n = 49) had VADs: 32.65% transient (ETV n = 5, EVD n = 11), 67.35% permanent (reservoir n = 7, shunt n = 26). A total of 17 had ETV at biopsy, 7 with concurrent reservoir placement. Of 10 ETV patients without initial reservoir, 5 ultimately underwent permanent VAD placement (reservoir n = 1, shunt n = 4). A total of 9 patients received EVDs at tumor surgery, 8 required EVD for acute hydrocephalus (HCP), with 6 converted to shunts. A total of 15 shunts were placed at tumor diagnosis: 4 required revision (27%). A total of 14 articles describing 240 DMG patients cited HCP in 22%-100%, with VAD placement in 22%-63%, and shunt-induced extraneural metastases in 7. Ventricular chemotherapy via indwelling reservoirs (481 patients) was associated with 29 infectious and 50 noninfectious complications. Standardized reservoir access procedures decreased infection rates. CONCLUSION VAD placement is clinically indicated in a significant proportion of pediatric DMG patients, with low morbidity. Ventricular CSF is superior to lumbar for ctDNA sequencing and quantification. VAD placement should therefore be considered to facilitate liquid biopsy in DMG.

scholarly journals Evaluating Circulating Tumor DNA From the Cerebrospinal Fluid of Patients With Melanoma and Leptomeningeal Disease

2018 ◽  
Vol 77 (7) ◽  
pp. 628-635 ◽  
Author(s):  
Leomar Y Ballester ◽  
Isabella C Glitza Oliva ◽  
Dzifa Y Douse ◽  
Melissa M Chen ◽  
Chieh Lan ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Circulating Tumor Dna ◽  
Leptomeningeal Disease ◽  
Tumor Dna

scholarly journals Evaluation of the Oncomine Pan-Cancer Cell-Free Assay for Analyzing Circulating Tumor DNA in the Cerebrospinal Fluid in Patients with Central Nervous System Malignancies

2021 ◽  
Vol 23 (2) ◽  
pp. 171-180
Author(s):  
Mauli Shah ◽  
Takeshi Takayasu ◽  
Soheil Zorofchian Moghadamtousi ◽  
Octavio Arevalo ◽  
Melissa Chen ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Cerebrospinal Fluid ◽  
Nervous System ◽  
Cancer Cell ◽  
Circulating Tumor Dna ◽  
Pan Cancer ◽  
Tumor Dna

scholarly journals Detection of genes mutations in cerebrospinal fluid circulating tumor DNA from neoplastic meningitis patients using next generation sequencing

2019 ◽  
Author(s):  
Yue Zhao ◽  
JunYing He ◽  
Li Guo ◽  
YueLi Zou ◽  
JunZhao Cui ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Next Generation Sequencing ◽  
Gene Mutations ◽  
Circulating Tumor Dna ◽  
Copy Number Variations ◽  
Neoplastic Meningitis ◽  
Diagnostic Strategy ◽  
Next Generation ◽  
Tumor Dna ◽  
Generation Sequencing

Abstract Background This study profiled the somatic gene mutations and the copy number variations (CNVs) in cerebrospinal fluid (CSF)-circulating tumor DNA (ctDNA) from patients with neoplastic meningitis (NM).Methods A total of 62 CSF ctDNA samples were collected from 58 NM patients for the next generation sequencing. The data were blasted in GenBank and bioinformatically analyzed.Results Cancer-associated gene mutations occurred in all 62 CSF ctDNA samples in TP53 (54/62; 87.10%), EGFR (44/62; 70.97%), PTEN (39/62; 62.90%), CDKN2A (32/62; 51.61%), APC (27/62: 43.55%), TET2 (27/62; 43.55%), GNAQ (18/62; 29.03%), NOTCH1 (17/62; 27.42%), VHL (17/62; 27.42%), FLT3 (16/62; 25.81%), PTCH1 (15/62; 24.19%), BRCA2 (13/62; 20.97%), KDR (10/62; 16.13%), KIT (9/62; 14.52%), MLH1 (9/62; 14.52%), ATM (8/62; 12.90%), CBL (8/62; 12.90%), and DNMT3A (7/62; 11.29%). The mutated genes enriched by the KEGG pathway analysis were the PI3K-Akt, which included the genes of TP53 , EGFR , PTEN , KIT and KDR. After receiving intrathecal and systemic chemotherapy, the ERK1/2 signaling pathways of these CSF samples were activated. Furthermore, the CNVs of these genes were also identified in these 62 samples.Conclusions This study identified gene mutations in all CSF ctDNA samples, indicating that such an approach could be useful as a second-line diagnostic strategy for NM patients. PI3K-Akt signaling may be the potential NM metastasis mechanism.

scholarly journals Detection of genes mutations in cerebrospinal fluid circulating tumor DNA from neoplastic meningitis patients using next generation sequencing

2020 ◽  
Author(s):  
Yue Zhao ◽  
JunYing He ◽  
JunZhao Cui ◽  
Zi-Qi Meng ◽  
YueLi Zou ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Next Generation Sequencing ◽  
Signaling Pathway ◽  
Gene Mutations ◽  
Circulating Tumor Dna ◽  
Akt Signaling ◽  
Neoplastic Meningitis ◽  
Akt Signaling Pathway ◽  
Tumor Dna ◽  
Generation Sequencing

Abstract Background: This study profiled the somatic gene mutations and the copy number variations (CNVs) in cerebrospinal fluid (CSF)-circulating tumor DNA (ctDNA) from patients with neoplastic meningitis (NM). Methods: A total of 62 CSF ctDNA samples were collected from 58 NM patients for the next generation sequencing. The data were bioinformatically analyzed by (Database for Annotation, Visualization and Integrated Discovery) DAVID software. Results: The most common mutated gene was TP53 (54/62; 87.10%), followed by EGFR (44/62; 70.97%), PTEN (39/62; 62.90%), CDKN2A (32/62; 51.61%), APC (27/62: 43.55%), TET2 (27/62; 43.55%), GNAQ (18/62; 29.03%), NOTCH1 (17/62; 27.42%), VHL (17/62; 27.42%), FLT3 (16/62; 25.81%), PTCH1 (15/62; 24.19%), BRCA2 (13/62; 20.97%), KDR (10/62; 16.13%), KIT (9/62; 14.52%), MLH1 (9/62; 14.52%), ATM (8/62; 12.90%), CBL (8/62; 12.90%), and DNMT3A (7/62; 11.29%). The mutated genes were enriched in the PI3K-Akt signaling pathway by the KEGG pathway analysis. Furthermore, the CNVs of these genes were also identified in these 62 samples. The mutated genes in CSF samples receiving intrathecal chemotherapy and systemic therapy were enriched in the ERK1/2 signaling pathway. Conclusions: This study identified gene mutations in all CSF ctDNA samples, indicating that these mutated genes may be acted as a kind of biomarker for diagnosis of NM, and these mutated genes may affect meningeal metastasis through PI3K-Akt signaling pathway.

NGS to reveal heterogeneity between cerebrospinal fluid and plasma ctDNA among non-small cell lung cancer patients with leptomeningeal carcinomatosis.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 9022-9022 ◽  
Author(s):  
Ben-Yuan Jiang ◽  
Yangsi LI ◽  
Shaokun Chuai ◽  
Zhou Zhang ◽  
Jin-Ji Yang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cerebrospinal Fluid ◽  
Small Cell Lung Cancer ◽  
Liquid Biopsy ◽  
Leptomeningeal Carcinomatosis ◽  
Circulating Tumor Dna ◽  
Small Cell ◽  
Small Cell Lung ◽  
Nsclc Patients ◽  
Tumor Dna

9022 Background: In current clinical setting, NSCLC patients harboring specific driver mutation were usually treated guiding by prior profiling of the primary tumor when developed to brain metastasis. Some studies have shown that circulating tumor DNA (ctDNA) derived from cerebrospinal fluid (CSF) can reveal unique genomic alterations present in brain malignancies. We assessed CSF as a liquid biopsy media and compared to matched plasma. Methods: We performed capture-based ultra deep sequencing on ctDNA derived from matched CSF, plasma of 40 non-small cell lung cancer (NSCLC) patients with suspected leptomeningeal carcinomatosis (LC) using a panel consisting of 168 genes. Results: Among the 40 suspected LC cases, 35 were confirmed to have LC, ctDNA in CSF from the 5 non-LC cases are all undetectable. Circulating tumor DNA was detected in 93.8% of CSF and 66.7% of plasma. We compared mutation profiles and identified 86 and 46 SNVs from CSF and plasma, respectively, with 42 SNVs overlapping. Furthermore, ctDNA from CSF revealed many copy number variations (CNVs) that were not detected from plasma (189 CNVs vs. 3 CNVs). The average maximum allelic fraction (AF) of CSF ctDNA is significantly higher than in plasma (56.7% vs. 4.4% p < 10^-6). Twenty-eight patients were pre-treated with EGFR-TKIs and developed subsequent resistance. EGFR T790M and MET amplification were detected in 21% and 39% in CSF, respectively, showing a unique resistance profile among leptomeningeal metastases patients compared to the general population. Interestingly, 60% of CSF samples harbor TP53 loss of heterozygosity, only 11% of which were detected in the matched plasma samples. Such heterogeneity may reflect unique biological themes for brain metastatic tumor sub-clones. Furthermore, 26 patients received molecular targeted therapy based on the results from CSF, and 23 reported alleviation of symptoms at subsequent evaluations. Conclusions: Collectively, our data reveal that ctDNA derived from CSF provides a unique and more comprehensive characterization of genomic alterations of leptomeningeal carcinomatosis than plasma, supporting the importance of CSF as a liquid biopsy media.

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