Unique genetic profiles from cerebrospinal fluid cell-free DNA in leptomeningeal metastases of EGFR-mutant non-small-cell lung cancer: a new medium of liquid biopsy

Li, Y.S.; Jiang, Ben‐Yuan; Yang, Jing; Zhang, X.C.; Zhang, Z.; Ye, J.Y.; Zhong, Wen‐Zhao; Tu, Hai‐Yan; Chen, H.J.; Wang, Z.; Xu, Chong-Rui; Wang, B.C.; Du, Haijian; Chuai, Shaokun; Han‐Zhang, Han; Su, Jian; Zhou, Qing; Yang, Xue‐Ning; Guo, Wenbing; Yan, Hong‐Hong; Liu, Y.H.; Yan, Li; Huang, Biao; Zheng, Meiyu; Wu, Yi‐Long

doi:10.1093/annonc/mdy009

Cited by 220 publications

(293 citation statements)

References 19 publications

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“…In the present study, consistent with previously reported findings, our results also reveal that MPE supernatant is a superior sample to MPE cell pellet, based on both mutation detection rate and median maxAF value. Moreover, our findings are also in agreement with a recent report of the superiority of cell‐free DNA derived from CSF, compared to its corresponding cell pellet . It has been reported that the fraction of tumor‐derived DNA is significantly higher in the supernatant than its corresponding cell pellet in CSF .…”

Section: Discussionsupporting

confidence: 93%

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Malignant pleural effusion supernatant is an alternative liquid biopsy specimen for comprehensive mutational profiling

et al. 2019

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Background The clinical utility of malignant pleural effusion (MPE) to detect mutation has been well documented; however, routine practice of the use of MPE involves collection of the cell pellet to detect mutation, and limited studies have interrogated the MPE supernatant as an alternative source of tumor‐derived DNA for mutation profiling. In this study, we investigated the potential of MPE supernatant as a liquid biopsy specimen by comparing its mutation profile with that of matched MPE cell pellets, tissue, and plasma samples. Methods Sequencing data from 17 patients with matched lung tissue, plasma, and MPE samples were retrospectively analyzed. Capture‐based targeted sequencing was performed on matched plasma and MPE supernatant samples obtained from 154 patients with advanced lung adenocarcinoma. Results MPE supernatants had significantly higher median maximum allelic fractions (maxAFs) than their corresponding cell pellets ( P = 0.008) and plasma samples ( P = 0.036), and a comparable maxAF value to that of tissue samples ( P = 0.675). Comparison of MPE supernatant and matched plasma samples from the larger cohort ( n = 154) revealed a comparable mutation detection rate; however, MPE supernatant had a significantly higher median maxAF than plasma (20.3% vs. 1.13%; P < 0.001). Furthermore, the concordance rates between MPE supernatant and plasma for single‐nucleotide and copy number variations were 56% and 18%, respectively, suggesting that MPE supernatant reveals a more comprehensive mutation spectrum, particularly for copy number variations. Conclusion Overall, our study shows that MPE supernatant is an optimal alternative source of tumor‐derived DNA for comprehensive mutation profiling.

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Section: Discussionsupporting

confidence: 93%

“…NGS libraries were prepared according to a previous publication . A minimum of 50 ng of DNA was required for NGS library construction.…”

Section: Methodsmentioning

confidence: 99%

Malignant pleural effusion supernatant is an alternative liquid biopsy specimen for comprehensive mutational profiling

et al. 2019

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“…In terms of EGFR ‐driven genes, the results from brain lesion tissues were consistent with those from CSF, as supported by Li et al . The detection of EGFR mutations in CSF might also reveal uncommon EGFR mutations that could be targeted with specific treatments .…”

Section: Discussionsupporting

confidence: 72%

“…Variant gene mutations of tumor cells often lead to different proliferation activities, and the location of the resulting metastasis may also differ . Recently, studies indicated that CSF was more representative of the EGFR mutation status in brain metastasis than peripheral blood and could better guide medical treatments . Nevertheless, that previous study did not evaluate the genetic characteristics of lung cancer with brain metastasis in cotesting of lung tumor tissue, brain metastases, peripheral blood, and CSF.…”

Section: Discussionmentioning

confidence: 99%

Detection of circulating tumor DNA from non‐small cell lung cancer brain metastasis in cerebrospinal fluid samples

Yang

Xing

et al. 2020

Thoracic Cancer

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Background Evaluating the molecular characteristics of brain metastases is limited by difficult access and by the blood–brain barrier, which prevents circulating tumor DNA (ctDNA) from entering the blood. In this study, we aimed to compare the sequencing results from cerebrospinal fluid (CSF) ctDNA versus plasma ctDNA, plasma circulating tumor cells (CTCs), and brain tissue specimens from patients with brain metastasis from non‐small cell lung cancer (NSCLC). Methods This was a prospective study of 21 consecutive patients with NSCLC and brain metastasis diagnosed between April 2018 and January 2019. Samples of CSF and peripheral blood were obtained from all 21 patients. Brain tissues were obtained from five patients after surgical resection. Next‐generation sequencing was performed using the Ion system. Single nucleotide variants (SNVs) and small insertions or deletions (indels) were searched. Results Mutations were detected in the CSF ctDNA of 20 (95.2%) patients. The detection rate of epidermal growth factor receptor (EGFR) mutations in CSF ctDNA was 57.1% (12/21) whereas this rate was only 23.8% (5/21) in peripheral blood ctDNA and in CTCs. EGFR mutations were found in the CSF of 9 of 11 (81.8%) patients with leptomeningeal metastases, as compared with three of 10 (30%) patients with brain parenchymal metastases. Mutations were also detected in KIT, PIK3CA, TP53, SMAD4, ATM, SMARCB1, PTEN, FLT3, GNAS, STK11, MET, CTNNB1, APC, FBXW7, ERBB4, and KDR (all >10%). The status of EGFR and TP53 mutations was consistent between CSF ctDNA and brain lesion tissue in all five patients. Conclusion Sequencing of CSF ctDNA revealed specific mutation patterns in driver genes among patients with NSCLC and brain metastasis. Key points In some small‐sample studies, the importance of cerebrospinal fluid in guiding the treatment of cancerous brain lesions has been verified in that it may reflect genomic mutations of brain tumors relatively accurately. Cerebrospinal fluid is a new form of liquid biopsy that can be helpful in improving the management of patients with brain metastasis from non‐small cell lung cancer by detecting genetic abnormalities specific to brain metastases.

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“…However, because of the invasiveness and difficulty of obtaining BM samples, the molecular mechanisms and evolution of BMs have not been extensively studied in lung cancer. 11 However, additional studies including larger patient cohorts need to be performed. 11 However, additional studies including larger patient cohorts need to be performed.…”

Section: Introductionmentioning

confidence: 99%

Genes associated with increased brain metastasis risk in non–small cell lung cancer: Comprehensive genomic profiling of 61 resected brain metastases versus primary non–small cell lung cancer (Guangdong Association Study of Thoracic Oncology 1036)

Wang

Ou²,

et al. 2019

Cancer

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BACKGROUND: Patients with brain metastases (BMs) have a poor prognosis and limited therapeutic options. Lung cancer is the most common primary malignancy giving rise to BMs; thus, understanding the molecular mechanisms behind increased BM risk is essential for identifying therapeutic targets and developing effective interventions. METHODS: Sixty-one patients who underwent surgical resection of primary non-small cell lung cancer (NSCLC) and BMs were retrospectively studied. Comprehensive genomic profiling of primary NSCLC and matched BMs was performed with next-generation sequencing targeting 416 cancer-relevant genes. RESULTS: Mutations of major drivers, including EGFR, KRAS, TP53, and ALK, were highly concordant between primary NSCLC and matched BMs (>80%), whereas discordance suggested the unique genomic evolution and oncogenic mechanisms of NSCLC BMs. BMs also demonstrated higher levels of copy number variations in comparison with primary NSCLC. Furthermore, the alterations of genes encoding CDK4/CCND1, CDKN2A/2B, and PI3K signaling pathways were enriched in BMs, and this suggested their correlation with increased metastatic risk. Indeed, patients with activated PI3K signaling in their primary NSCLC had significantly shorter BM-free survival (hazard ratio, 8.49; P = .0005). In addition, mutated TP53 or an activated WNT pathway via CTNNB1, APC, and AXIN2 mutations trended toward shorter BM-free intervals but not significantly so. CONCLUSIONS: These findings yield detailed insights into the genomic complexity and heterogeneity of primary NSCLC and matched BMs. This study highlights the significant correlation of PI3K signaling with increased metastatic risk in patients with NSCLC and identifies genomic alterations enriched in NSCLC BMs that could serve as prognostic markers and potential therapeutic targets for treating patients with NSCLC BMs. Cancer 2019;125:3535-3544.

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Unique genetic profiles from cerebrospinal fluid cell-free DNA in leptomeningeal metastases of EGFR-mutant non-small-cell lung cancer: a new medium of liquid biopsy

Abstract: CSF cfDNA could reveal the unique genetic profiles of LM and should be considered as the most representative liquid biopsy medium for LM in EGFR-mutant NSCLC.

Cited by 220 publications

References 19 publications

Malignant pleural effusion supernatant is an alternative liquid biopsy specimen for comprehensive mutational profiling

Malignant pleural effusion supernatant is an alternative liquid biopsy specimen for comprehensive mutational profiling

Detection of circulating tumor DNA from non‐small cell lung cancer brain metastasis in cerebrospinal fluid samples

Genes associated with increased brain metastasis risk in non–small cell lung cancer: Comprehensive genomic profiling of 61 resected brain metastases versus primary non–small cell lung cancer (Guangdong Association Study of Thoracic Oncology 1036)

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