The Clinical Utilization of Circulating Cell Free DNA (CCFDNA) in Blood of Cancer Patients

Elshimali, Yahya; Khaddour, Husseina; Sarkissyan, Marianna; Wu, Yanyuan; Vadgama, Jaydutt V.

doi:10.3390/ijms140918925

Cited by 210 publications

(168 citation statements)

References 193 publications

(175 reference statements)

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“…However, ctDNA assays only identify mutations after tumor cells outgrow the blood supply, become hypoxic, and undergo apoptosis or necrosis, releasing DNA into the peripheral blood (14). Potential explanations for our findings include inability to capture ctDNA at very low detection thresholds, fewer ctDNA variants released into the peripheral blood, differences in biology of particular cancer types, and different sequencing and detection methods within the genes examined (16,41).…”

Section: Discussionmentioning

confidence: 99%

Concordance of Genomic Alterations by Next-Generation Sequencing in Tumor Tissue versus Circulating Tumor DNA in Breast Cancer

Chae

Davis

Jain

et al. 2017

Molecular Cancer Therapeutics

116

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While identifying genomic alterations in tumor tissue is the current gold-standard technique for molecular profiling, circulating tumor DNA (ctDNA) represents a noninvasive method of assessing genomic alterations using peripheral blood. The concordance of genomic alterations between two commercially available ctDNA and tissue biopsies was compared in 45 patients with breast cancer using paired next-generation sequencing tissue and ctDNA biopsies. Across all genes, concordance between the two platforms was 91.0% to 94.2%. When only considering genomic alterations in either assay (e.g., excluding wild type/wild type genes), concordance was 10.8% to 15.1% with full plus partial concordance of 13.8% to 19.3%. Concordant mutations were associated with significantly higher variant allele frequency. Over half of mutations detected in either technique were not detected using the other biopsy technique. Including variants of unknown significance, the average number of alterations per patient was significantly higher for tissue (4.56) compared with ctDNA (2.16). When eliminating alterations not detectable in the ctDNA assay, mean number of alterations for tissue and ctDNA was similar (2.67 for tissue, 2.16 for ctDNA). Across five representative genes (TP53, PIK3CA, ERBB2, BRCA1, and BRCA2), sensitivity and specificity were 35.7% and 95.0%, respectively. Concordance when genomic alterations was detected in either tissue or ctDNA was low with each technique detecting a significant amount of nonoverlapping mutations. Potential explanations for the lack of concordance include tumor heterogeneity, different sequencing techniques, spatial and temporal factors, and potential germline DNA contamination. The study indicates that both tissue and blood-based NGS may be necessary to describe the complex biology of breast cancer.

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Section: Discussionmentioning

confidence: 99%

Concordance of Genomic Alterations by Next-Generation Sequencing in Tumor Tissue versus Circulating Tumor DNA in Breast Cancer

Chae

Davis

Jain

et al. 2017

Molecular Cancer Therapeutics

116

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“…The observed discordance could be due to several reasons: poor mutation detection in cfDNA due to low cfDNA concentrations in the bloodstream (23); presence of the mutation in allele frequencies below the detection limit of our method; true disease heterogeneity (24); and poor DNA quality (25), true genetic differences between cfDNA (released mainly from necrotic cells) and tDNA. Ongoing technological advances are likely to improve the cfDNA analysis method and further increase the concordance between tDNA and cfDNA.…”

Section: Discussionmentioning

confidence: 99%

Circulating Cell-Free Tumor DNA Analysis of 50 Genes by Next-Generation Sequencing in the Prospective MOSCATO Trial

Jovelet

Ileana

Deley

et al. 2016

Clinical Cancer Research

101

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Purpose: Liquid biopsies based on circulating cell-free DNA (cfDNA) analysis are described as surrogate samples for molecular analysis. We evaluated the concordance between tumor DNA (tDNA) and cfDNA analysis on a large cohort of patients with advanced or metastatic solid tumor, eligible for phase I trial and with good performance status, enrolled in MOSCATO 01 trial (clinical trial NCT01566019).Experimental Design: Blood samples were collected at inclusion and cfDNA was extracted from plasma for 334 patients. Hotspot mutations were screened using next-generation sequencing for 50 cancer genes.Results: Among the 283 patients with tDNA-cfDNA pairs, 121 had mutation in both, 99 in tumor only, 5 in cfDNA only, and for 58 patients no mutation was detected, leading to a 55.0% estimated sensitivity [95% confidence interval (CI), 48.4%-61.6%] at the patient level. Among the 220 patients with mutations in tDNA, the sensitivity of cfDNA analysis was significantly linked to the number of metastatic sites, albumin level, tumor type, and number of lines of treatment. A sensitivity prediction score could be derived from clinical parameters. Sensitivity is 83% in patients with a high score (!8). In addition, we analyzed cfDNA for 51 patients without available tissue sample. Mutations were detected for 22 patients, including 19 oncogenic variants and 8 actionable mutations.Conclusions: Detection of somatic mutations in cfDNA is feasible for prescreening phase I candidates with a satisfactory specificity; overall sensitivity can be improved by a sensitivity score allowing to select patients for whom cfDNA constitutes a reliable noninvasive surrogate to screen mutations.

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“…Few studies have satisfactorily designed such multiplexed assays (6 ) and, because there is no guarantee that any given pool of probes detects the presence of all possible mutant alleles (25 ), there is a risk of false negatives associated with such assays. Because ctDNA can be present at levels as low as 1 mutant copy per 10000 wild-type copies during initial or residual stages of the disease (1,(3)(4), or in cancers affecting the central nervous system (26 ), conventional PCR-based methods do not offer enough analytical sensitivity (27)(28)(29). Nevertheless, droplet digital PCR (ddPCR) has fuelled powerful approaches for the absolute quantification of ctDNA, holding promise for the early detection and more comprehensive monitoring of cancer malignancies (30 -32 ).…”

mentioning

confidence: 99%

Multiplex Droplet Digital PCR Quantification of Recurrent Somatic Mutations in Diffuse Large B-Cell and Follicular Lymphoma

Alcaide

Bushell

et al. 2016

Clinical Chemistry

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BACKGROUND:A plethora of options to detect mutations in tumor-derived DNA currently exist but each suffers limitations in analytical sensitivity, cost, or scalability. Droplet digital PCR (ddPCR) is an appealing technology for detecting the presence of specific mutations based on a priori knowledge and can be applied to tumor biopsies, including formalin-fixed paraffin embedded (FFPE) tissues. More recently, ddPCR has gained popularity in its utility in quantifying circulating tumor DNA.

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The Clinical Utilization of Circulating Cell Free DNA (CCFDNA) in Blood of Cancer Patients

Cited by 210 publications

References 193 publications

Concordance of Genomic Alterations by Next-Generation Sequencing in Tumor Tissue versus Circulating Tumor DNA in Breast Cancer

Concordance of Genomic Alterations by Next-Generation Sequencing in Tumor Tissue versus Circulating Tumor DNA in Breast Cancer

Circulating Cell-Free Tumor DNA Analysis of 50 Genes by Next-Generation Sequencing in the Prospective MOSCATO Trial

Multiplex Droplet Digital PCR Quantification of Recurrent Somatic Mutations in Diffuse Large B-Cell and Follicular Lymphoma

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