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Circulating Tumor DNA
Circulating tumor DNA (ctDNA) are small fragments of DNA, typically 150-200 bp in size, shed by tumors into blood through tumor necrosis, apoptosis and potentially through extracellular vesicles. ctDNA can also be found in other fluid spaces susch as cerebrospinal fluid and pleural fluid.
Circulating free DNA (cfDNA) in peripheral blood originates from normal tissue remodeling with variable contributions by tumor necrosis, apoptosis and potentially through extracellular vesicles . cfDNA exists in a nucleosome protected 150–200 base pair sized fragments and has a half-life of approximately 2 h, allowing analysis of genomic material that reflects the current, real time status target(s) in question . The concentration of cfDNA in plasma is typically low (5–10 ng/mL), and the fraction that corresponds to ctDNA can be highly varied and range from as low as 0.1% to 30% of the total cfDNA .
1.1. Methodology Considerations
1.2. Molecular Testing
2. Clinical Use
|Author||Number of Patients||Platform||Main Findings|
|Chaudhuri et al. ||94||CAPP-seq (NGS)||Detectable ctDNA post-treatment preceded radiological evidence of progression in 72% of cases.
Of the patients that relapsed, 94% had detectable ctDNA after treatment with curative intent.
|Cho et al. ||36||PANAmutyper (PCR)||Factors associated with higher ctDNA in plasma included higher pathological tumor stage, nodal metastasis, solid adenocarcinoma subtype, tumor necrosis, greater tumor volume and frequent mitoses.|
|Li et al. ||26||WGS||Driver genes detected in all CSF ctDNA samples.
92.3% of patients had higher allele fractions in CSF than CSF precipitates or plasma.
EGFR T790M was detected in CSF of 30.4% samples from patients who progressed on TKI.
|Oxnard et al. ||216||BEAMing||Plasma detection of T790M was 70% sensitive.
OOR and PFS were similar T790M positive tumors detected through plasma ctDNA or biopsy.
|Papadopoulou et al. ||171||NGS||49% of NSCLC patients had at least 1 mutation detected at diagnosis by NGS.
86.1% concordance in clinically relevant mutations between ctDNA and tissue biopsy.
|Sabari et al. ||210||ResBio ctDx-Lung||ctDNA detection lower in patients on systemic treatment.
High concordance of ctDNA detected oncogenic drivers with tissue detection (91.6%).
|Tailor et al. ||33||SureSelect All Exon V5 + UTR||Patients with malignant nodules showed a significantly higher number of somatic mutations.
82% of malignant lesions identified through mutational analysis.
|Tsui et al. ||50||Tam-Seq PCR, digital PCR||Low levels of EGFR mutations in TKI naïve patients resulted in better PFS and OS.
Pre-treatment mutations in both EGFR and TP53 correlated with worse prognosis.
Progression without T790M mutation resulted in worse survival.
|Uchida et al. ||288||NGS||EGFR exon 19 deletion sensitivity was 50.9% and specificity was 98.0%.
L858R mutation sensitivity was 51.9% and specificity was 94.1%.
|Weber et al. ||199||Cobas EGFR test||91% concordance of EGFR mutations between tissue and plasma ctDNA samples.
Six EGFR mutations detected in ctDNA samples only.
|Yang et al. ||103||Gardant360||Poor survival if >3 mutations detected in ctDNA|
|Zhang et al. ||27||NGS||Overall ctDNA and tissue concordance for driver gene mutations was 85.2%, sensitivity and specificity was 87.0% and 75%, respectively.
Concordance reached 100% in cases of boney metastasis and/or concurrent TP53 mutations.
|Zhao et al. ||111||Mutant-enriched PCR||EGFR mutation concordance between paired plasma and tissue samples was 71.2%. Sensitivity was higher for poorly differentiated tumors (77.8%) compared to well differentiated (20%) and moderately differentiated (19%) tumors.|
The entry is from 10.3390/cancers13163923
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