scholarly journals Circulating Tumor Cells and Circulating Tumor DNA Detection in Potentially Resectable Metastatic Colorectal Cancer: A Prospective Ancillary Study to the Unicancer Prodige-14 Trial

Cells ◽  
2019 ◽  
Vol 8 (6) ◽  
pp. 516 ◽  
Author(s):  
François-Clément Bidard ◽  
Nicolas Kiavue ◽  
Marc Ychou ◽  
Luc Cabel ◽  
Marc-Henri Stern ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Circulating Tumor Cell ◽  
Circulating Tumor Dna ◽  
Detection Sensitivity ◽  
Clinical Validity ◽  
Mutational Status ◽  
Prospective Phase ◽  
Polymerase Chain ◽  
Digital Polymerase Chain Reaction ◽  
Tumor Dna

The management of patients with colorectal cancer (CRC) and potentially resectable liver metastases (LM) requires quick assessment of mutational status and of response to pre-operative systemic therapy. In a prospective phase II trial (NCT01442935), we investigated the clinical validity of circulating tumor cell (CTC) and circulating tumor DNA (ctDNA) detection. CRC patients with potentially resectable LM were treated with first-line triplet or doublet chemotherapy combined with targeted therapy. CTC (Cellsearch®) and Kirsten RAt Sarcoma (KRAS) ctDNA (droplet digital polymerase chain reaction (PCR)) levels were assessed at inclusion, after 4 weeks of therapy and before LM surgery. 153 patients were enrolled. The proportion of patients with high CTC counts (≥3 CTC/7.5mL) decreased during therapy: 19% (25/132) at baseline, 3% (3/108) at week 4 and 0/57 before surgery. ctDNA detection sensitivity at baseline was 91% (N=42/46) and also decreased during treatment. Interestingly, persistently detectable KRAS ctDNA (p = 0.01) at 4 weeks was associated with a lower R0/R1 LM resection rate. Among patients who had a R0/R1 LM resection, those with detectable ctDNA levels before liver surgery had a shorter overall survival (p < 0.001). In CRC patients with limited metastatic spread, ctDNA could be used as liquid biopsy tool. Therefore, ctDNA detection could help to select patients eligible for LM resection.

Correlation Between Tumor-Specific Mutated and Methylated DNA in Colorectal Cancer

2019 ◽  
pp. 1-8 ◽  
Author(s):  
Caroline Brenner Thomsen ◽  
Rikke F. Andersen ◽  
Jan Lindebjerg ◽  
Torben F. Hansen ◽  
Lars Henrik Jensen ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Neuropeptide Y ◽  
Circulating Tumor Dna ◽  
Methylated Dna ◽  
Healthy Donors ◽  
Localized Disease ◽  
Polymerase Chain ◽  
Potential Improvement ◽  
Digital Polymerase Chain Reaction ◽  
Tumor Dna

PURPOSE Analysis of circulating tumor DNA (ctDNA) is a potential improvement in precision medicine. In colorectal cancer (CRC), somatic mutations such as RAS and RAF in the blood (mut-ctDNA) are investigated for prognostic and predictive purposes. However, they are only present in approximately 60% of patients. Recently, ctDNA has been detected in patients with RAS/ RAF wild type (WT) by methylated ctDNA (meth-ctDNA). The aim of this study was to compare mutated DNA with methylated DNA in malignant and nonmalignant tissue and plasma from CRC cohorts to establish a universal biomarker for ctDNA in all patients with CRC. MATERIALS AND METHODS Tissue (n = 170) and plasma (n = 147) samples were analyzed for RAS/ RAF mutations and neuropeptide Y methylation by droplet digital polymerase chain reaction. Tissue originated from nonmalignant WT and RAS/ RAF-mutated adenomas, tumor-adjacent colorectal tissue, and WT and RAS/ RAF-mutated tumor tissue. Plasma samples represented healthy donors and localized and metastatic CRCs. RESULTS The level of neuropeptide Y–methylated DNA in the tissue cohorts differed between nonmalignant and malignant/premalignant tissues with minimal overlap. Furthermore, meth-ctDNA was detected in plasma from 100% of patients with metastatic disease, compared with 67% of those with localized disease and 8% of healthy donors. Median fraction of meth-ctDNA in metastatic and localized cancers was 13.25% and 0.04%, respectively. Correlation between mut-ctDNA and meth-ctDNA was high ( r = 0.77 and 0.80 in localized and metastatic settings, respectively). CONCLUSION Mut-ctDNA is interchangeable with meth-ctDNA in patients with CRC. On the basis of our results, meth-ctDNA should be considered a universal biomarker in metastatic CRC, but additional investigations of clinical utility are warranted.

scholarly journals MLH1 single-nucleotide variant in circulating tumor DNA predicts overall survival of patients with hepatocellular carcinoma

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Soon Sun Kim ◽  
Jung Woo Eun ◽  
Ji-Hye Choi ◽  
Hyun Goo Woo ◽  
Hyo Jung Cho ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Overall Survival ◽  
Circulating Tumor Dna ◽  
Single Nucleotide Variants ◽  
Poor Overall Survival ◽  
Single Nucleotide ◽  
Strong Basis ◽  
Polymerase Chain ◽  
Digital Polymerase Chain Reaction ◽  
Tumor Dna

Abstract Liquid biopsy can provide a strong basis for precision medicine. We aimed to identify novel single-nucleotide variants (SNVs) in circulating tumor DNA (ctDNA) in patients with hepatocellular carcinoma (HCC). Deep sequencing of plasma-derived ctDNA from 59 patients with HCC was performed using a panel of 2924 SNVs in 69 genes. In 55.9% of the patients, at least one somatic mutation was detected. Among 25 SNVs in 12 genes, four frequently observed SNVs, MLH1 (13%), STK11 (13%), PTEN (9%), and CTNNB1 (4%), were validated using droplet digital polymerase chain reaction with ctDNA from 62 patients with HCC. Three candidate SNVs were detected in 35.5% of the patients, with a frequency of 19% for MLH1 chr3:37025749T>A, 11% for STK11 chr19:1223126C>G, and 8% for PTEN chr10:87864461C>G. The MLH1 and STK11 SNVs were also confirmed in HCC tissues. The presence of the MLH1 SNV, in combination with an increased ctDNA level, predicted poor overall survival among 107 patients. MLH1 chr3:37025749T>A SNV detection in ctDNA is feasible, and thus, ctDNA can be used to detect somatic mutations in HCC. Furthermore, the presence or absence of the MLH1 SNV in ctDNA, combined with the ctDNA level, can predict the prognosis of patients with HCC.

scholarly journals Circulating Tumor DNA Analysis: Clinical Implications for Colorectal Cancer Patients. A Systematic Review

2019 ◽  
Vol 3 (3) ◽  
Author(s):  
Sander Bach ◽  
Nina R Sluiter ◽  
Jamie J Beagan ◽  
Joost M Mekke ◽  
Johannes C F Ket ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Systematic Review ◽  
Mutation Analysis ◽  
Kras Mutation ◽  
Copy Number ◽  
Circulating Tumor Dna ◽  
Detection Sensitivity ◽  
Methylation Analysis ◽  
Ctdna Analysis ◽  
Tumor Dna

AbstractBackgroundLiquid biopsies could improve diagnosis, prognostication, and monitoring of colorectal cancer (CRC). Mutation, chromosomal copy number alteration, and methylation analysis in circulating tumor DNA (ctDNA) from plasma or serum has gained great interest. However, the literature is inconsistent on preferred candidate markers, hampering a clear direction for further studies and clinical translation. This review assessed the potential of ctDNA analysis for clinical utility.MethodsA systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines was conducted up to December 3, 2018, followed by methodological quality assessment. Primary endpoints were accuracy for detection, prognostication, and monitoring.ResultsEighty-four studies were included. For CRC detection, sensitivity was 75% using ctDNA mutation analysis and up to 96% using copy number analysis. Septin 9 (SEPT9) hypermethylation analysis showed sensitivities of 100% and specificities of 97%. Regarding prognostication, ctDNA KRAS mutations were associated with oncological outcome and could predict response to anti–epidermal growth factor receptor therapy. For monitoring, sequential ctDNA KRAS mutation analysis showed promise for detection of relapses or therapy resistance.ConclusionsThis comprehensive overview of ctDNA candidate markers demonstrates SEPT9 methylation analysis to be promising for CRC detection, and KRAS mutation analysis could assist in prognostication and monitoring. Prospective evaluation of marker panels in clinical decision making should bring ctDNA analysis into practice.

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