CSF-ctDNA SMSEQ Analysis to Tailor the Treatment of a Patient with Brain Metastases: A Case Report

Huang, Wen-Tsung; Lu, Na-Mi; Hsu, Wen-Yuan; Chang, Silvia; Atkins, Alex; Mei, Rui; Javey, Manana

doi:10.1159/000486568

Cited by 13 publications

(13 citation statements)

References 19 publications

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“…Liquid biopsies collect and analyse circulating tumour cells (CTCs) and cell-free tumour (ctDNA) in body fluids (such as cerebrospinal fluid (CSF) and plasma); these can be a surrogate of tumour tissue in the management of both primary and secondary brain tumours [ 64 ]. For example, CSF ctDNA analysis has been successfully used in a case of multiple leptomeningeal and spinal cord metastases from CUP [ 65 ] (this case is discussed below).…”

Section: Gene Expression Profiling: a New Frontiermentioning

confidence: 99%

“…The problem of a lack of studies is even more evident in the subgroup of BM-CUP due to the rarity of cases, unfavourable prognosis, and frequent exclusion from clinical trials. Therefore, most information on innovative treatments comes from case reports [ 65 , 71 , 72 , 73 , 74 ]. Even if anecdotal, these reports offer good insight on feasible therapeutic strategies and potentially successful treatments in this rare and fatal disease ( Table 5 ).…”

Section: Managementmentioning

confidence: 99%

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Brain Metastasis from Unknown Primary Tumour: Moving from Old Retrospective Studies to Clinical Trials on Targeted Agents

Balestrino

Rudà

Soffietti

2020

Cancers

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Brain metastases (BMs) are the most common intracranial tumours in adults and occur up to 3–10 times more frequently than primary brain tumours. BMs may be the cause of the neurological presenting symptoms in patients with otherwise previously undiagnosed cancer. In up to 15% of patients with BMs, the primary tumour cannot be identified. These cases are known as BM of cancer of unknown primary (CUP) (BM-CUP). CUP has an early and aggressive metastatic spread, poor response to chemotherapy, and poor prognosis. The pathogenesis of CUP seems to be characterized by a specific underlying pro-metastatic signature. The understanding of BM-CUP, despite its relative frequency and unfavourable outcome, is still incomplete and clear indications on management are missing. Advances in diagnostic tools, molecular characterization, and target therapy have shifted the paradigm in the approach to metastasis from CUP: while earlier studies stressed the importance of finding the primary tumour and deciding on treatment based on the primary diagnosis, most recent studies focus on the importance of identifying targetable molecular markers in the metastasis itself. The aim of this review is to summarize current evidence on BM-CUP, from the diagnosis and pathogenesis to the treatment, with a focus on available studies and ongoing clinical trials.

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Section: Gene Expression Profiling: a New Frontiermentioning

confidence: 99%

Section: Managementmentioning

confidence: 99%

Brain Metastasis from Unknown Primary Tumour: Moving from Old Retrospective Studies to Clinical Trials on Targeted Agents

Balestrino

Rudà

Soffietti

2020

Cancers

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“…In addition to validation with peripheral blood, we have previously tested OncoLBx with other body fluids known to harbor ctDNA, such as pleural effusion and cerebral spinal fluid [43–46]. In many of these cases, we are able to identify variants with therapy options from the non-blood body fluids.…”

Section: Discussionmentioning

confidence: 99%

Detection of Circulating Tumor DNA with a Single-Molecule Sequencing Analysis Validated for Targeted and Immunotherapy Selection

Atkins¹,

Gupta²,

Zhang

et al. 2019

Mol Diagn Ther

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Introduction Comprehensive genetic cancer profiling using circulating tumor DNA has enabled the detection of National Comprehensive Cancer Network (NCCN) guideline-recommended somatic alterations from a single, non-invasive blood draw. However, reliably detecting somatic variants at low variant allele fractions (VAFs) remains a challenge for next-generation sequencing (NGS)-based tests. We have developed the single-molecule sequencing (SMSEQ) platform to address these challenges. Methods The OncoLBx assay utilizes the SMSEQ platform to optimize cell-free DNA extraction and library preparation with variant type-specific calling algorithms to improve sensitivity and specificity. OncoLBx is a pan-cancer panel for solid tumors targeting 75 genes and five microsatellite sites analyzing five classes of NCCN-recommended somatic variants: single-nucleotide variants (SNVs), insertions and deletions (indels), copy number variants (CNVs), fusions and microsatellite instability (MSI). Circulating DNA was extracted from plasma, followed by library preparation using SMSEQ. Analytical validation was performed according to recently published American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology (AMP) guidelines and established the limit of detection (LOD), sensitivity, specificity, accuracy and reproducibility using 126 gold-standard reference samples, healthy donor samples verified by whole-exome sequencing by an external College of American Pathologists (CAP) reference lab and cell lines with known variants. Results were analyzed using a locus-specific modeling algorithm. Results We have demonstrated that OncoLBx detects VAFs of ≥ 0.1% for SNVs and indels, ≥ 0.5% for fusions, ≥ 4.5 copies for CNVs and ≥ 2% for MSI, with all variant types having specificity ≥ 99.999%. Diagnostic performance of paired samples displays 80% sensitivity and > 99.999% clinical specificity. Clinical utility and performance were assessed in 416 solid tumor samples. Variants were detected in 79% of samples, for which 87.34% of positive samples had available targeted therapy. Electronic supplementary material The online version of this article (10.1007/s40291-019-00406-0) contains supplementary material, which is available to authorized users.

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“…So, it is important to identify specific genomic mutations in the CSF and provide novel targeted therapeutic agents against these mutations in the treatment of BMs. Huang et al 68 identified somatic mutations in the CSF of a patient with metastatic brain adenocarcinoma of an unknown primary tumor using the SMSEQ NGS assay, and the patient was given tailored treatments that led to clinical remission. To put it briefly, a CSF-ctDNA analysis helps with the characterization of tumor mutational profiles that may refine the treatment protocols further and tailor the tumor management plan.…”

Section: Ctdna As a Predictive Biomarker Identifying Therapeutic Targetsmentioning

confidence: 99%

<p>Clinical Applications of Cerebrospinal Fluid Circulating Tumor DNA as a Liquid Biopsy for Central Nervous System Tumors</p>

Yan¹,

Zhu²,

Yu³

2020

OTT

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Central nervous system (CNS) malignancies are associated with poor prognosis, as well as exceptional morbidity and mortality, likely as a result of low rates of early diagnosis and limited knowledge of the tumor growth and resistance mechanisms, dissemination, and evolution in the CNS. Monitoring patients with CNS malignancies for treatment response and tumor recurrence can be challenging because of the difficulty and risks of brain biopsies and the low specificity and sensitivity of the less invasive methodologies that are currently available. Therefore, there is an urgent need to detect and validate reliable and minimally invasive biomarkers for CNS tumors that can be used separately or in combination with current clinical practices. The circulating tumor DNA (ctDNA) of cerebrospinal fluid (CSF) samples can outline the genetic landscape of entire CNS tumors effectively and is a promising, suitable biomarker, though its role in managing CNS malignancies has not been studied extensively. This review summarizes recent studies that explore the diagnostic, prognostic, and predictive roles of CSF-ctDNA as a liquid biopsy with primary and metastatic CNS malignancies.

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CSF-ctDNA SMSEQ Analysis to Tailor the Treatment of a Patient with Brain Metastases: A Case Report

Cited by 13 publications

References 19 publications

Brain Metastasis from Unknown Primary Tumour: Moving from Old Retrospective Studies to Clinical Trials on Targeted Agents

Brain Metastasis from Unknown Primary Tumour: Moving from Old Retrospective Studies to Clinical Trials on Targeted Agents

Detection of Circulating Tumor DNA with a Single-Molecule Sequencing Analysis Validated for Targeted and Immunotherapy Selection

<p>Clinical Applications of Cerebrospinal Fluid Circulating Tumor DNA as a Liquid Biopsy for Central Nervous System Tumors</p>

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