scholarly journals Prognostic Utility of Pre- and Postoperative Circulating Tumor DNA Liquid Biopsies in Patients with Peritoneal Metastases

2020 ◽  
Vol 27 (9) ◽  
pp. 3259-3267
Author(s):  
Joel M. Baumgartner ◽  
Paul Riviere ◽  
Richard B. Lanman ◽  
Kaitlyn J. Kelly ◽  
Jula Veerapong ◽  
...  
Keyword(s):  
Circulating Tumor Dna ◽  
Peritoneal Metastases ◽  
Liquid Biopsies ◽  
Prognostic Utility ◽  
Tumor Dna

scholarly journals Toward liquid biopsies in cancer treatment: application of circulating tumor DNA

Apmis ◽  
2019 ◽  
Vol 127 (5) ◽  
pp. 329-336 ◽  
Author(s):  
Lise Barlebo Ahlborn ◽  
Olga Østrup
Keyword(s):  
Cancer Treatment ◽  
Circulating Tumor Dna ◽  
Liquid Biopsies ◽  
Tumor Dna ◽  
Treatment Application

scholarly journals High-Accuracy Determination of Microsatellite Instability Compatible with Liquid Biopsies

2020 ◽  
Vol 66 (4) ◽  
pp. 606-613 ◽  
Author(s):  
Amanda Bortolini Silveira ◽  
François-Clément Bidard ◽  
Amélie Kasperek ◽  
Samia Melaabi ◽  
Marie-Laure Tanguy ◽  
...  
Keyword(s):  
Microsatellite Instability ◽  
Large Scale ◽  
Digital Pcr ◽  
Circulating Tumor Dna ◽  
Diagnostic Tools ◽  
Tumor Biomarker ◽  
Analytical Sensitivity ◽  
Liquid Biopsies ◽  
Tumor Dna ◽  
Large Scale Screening

Abstract Background Microsatellite instability (MSI) has recently emerged as a predictive pan-tumor biomarker of immunotherapy efficacy, stimulating the development of diagnostic tools compatible with large-scale screening of patients. In this context, noninvasive detection of MSI from circulating tumor DNA stands as a promising diagnostic and posttreatment monitoring tool. Methods We developed drop-off droplet-digital PCR (ddPCR) assays targeting BAT-26, activin A receptor type 2A (ACVR2A), and defensin beta 105A/B (DEFB105A/B) microsatellite markers. Performances of the assays were measured on reconstitution experiments of various mutant allelic fractions, on 185 tumor samples with known MSI status, and on 72 blood samples collected from 42 patients with advanced colorectal or endometrial cancers before and/or during therapy. Results The 3 ddPCR assays reached analytical sensitivity <0.1% variant allelic frequency and could reliably detect and quantify MSI in both tumor and body fluid samples. High concordance between MSI status determination by the three-marker ddPCR test and the reference pentaplex method were observed (100% for colorectal tumors and 93% for other tumor types). Moreover, the 3 assays showed correlations with r ≥ 0.99 with other circulating tumor DNA markers and their dynamic during treatment correlated well with clinical response. Conclusions This innovative approach for MSI detection provides a noninvasive, cost-effective, and fast diagnostic tool, well suited for large-scale screening of patients that may benefit from immunotherapy agents, as well as for monitoring treatment responses.

scholarly journals Favorable Outcomes in FGFR Fusion-Positive Cholangiocarcinomas and Evolution on Treatment Noted on Circulating Tumor DNA Liquid Biopsies

2020 ◽  
Vol 13 (2) ◽  
pp. 941-947
Author(s):  
Pashtoon Murtaza Kasi
Keyword(s):  
Selective Pressure ◽  
Performance Status ◽  
Growth Factor Receptor ◽  
Circulating Tumor Dna ◽  
Temporal Heterogeneity ◽  
Liquid Biopsies ◽  
Extrahepatic Cholangiocarcinoma ◽  
Molecular Aberrations ◽  
Provider Bias ◽  
Tumor Dna

Cholangiocarcinoma is a very heterogenous cancer and “target-rich” disease. While the current classifications are based on the anatomic location of these tumors (intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and gallbladder cancer), tumors within and across these disease groups have unique and often mutually exclusive molecular aberrations. Amongst these, fibroblast growth factor receptor 2 (FGFR2) fusion is one of the first amongst the list of “actionable” targets for which the US Food and Drug Administration just approved pemigatinib. This is for patients with cholangiocarcinoma who have received prior treatment and have FGFR2 fusion or another rearrangement. This was based on the results from the clinical trial FIGHT-202 (NCT02924376). At present, several FGFR inhibitors are actively being tested in several agnostic and tumor-specific clinical trials. Patients also have had the opportunity of getting access to some of these oral drugs through compassionate use programs. As a consequence, these patients have more options in addition to chemotherapy. These all tend to have “good” initial responses and improvement in performance status and later “acquired” mechanisms of resistance. The latter tend to often be gatekeeper mutations that bypass the inhibitory effects of these selective FGFR inhibitors and/or cause steric hindrance. These tumors, therefore, evolve on selective pressure (temporal heterogeneity). This can be captured noninvasively using “liquid biopsies” (circulating tumor DNA testing). Here we present cases (several years into treatment on average) showing the feasibility of using liquid biopsies (ctDNA testing) as well as the gain and later potential loss of intratumoral and temporal heterogeneity exhibited under selective pressure of these novel FGFR inhibitors, chemotherapy and/or locoregional therapies. Despite limitations in sample size and provider bias, it is important to identify these “exceptional responders” and/or better outcomes that may be inherent to the biology of FGFR fusion-positive cholangiocarcinomas.

scholarly journals ctDNAtools: An R package to work with sequencing data of circulating tumor DNA

2020 ◽  
Author(s):  
Amjad Alkodsi ◽  
Leo Meriranta ◽  
Annika Pasanen ◽  
Sirpa Leppä
Keyword(s):  
Residual Disease ◽  
Fragment Size ◽  
R Package ◽  
Monte Carlo Sampling ◽  
Circulating Tumor Dna ◽  
Cancer Diagnostics ◽  
Sequencing Data ◽  
Liquid Biopsies ◽  
Tumor Dna

AbstractSummarySequencing of cell-free DNA (cfDNA) including circulating tumor DNA (ctDNA) in minimally-invasive liquid biopsies is rapidly maturing towards clinical utility for cancer diagnostics. However, the publicly available bioinformatics tools for the specialized analysis of ctDNA sequencing data are still scarce. Here, we present the ctDNAtools R package, which provides functionalities for testing minimal residual disease (MRD) and analyzing cfDNA fragmentation. MRD detection in ctDNAtools utilizes a Monte Carlo sampling approach to test ctDNA positivity through tracking a set of pre-detected reporter mutations in follow-up samples. Additionally, ctDNAtools includes various functionalities to study cfDNA fragment size histograms, profiles and fragment ends patterns.AvailabilityThe ctDNAtools package is freely available under MIT license at https://github.com/alkodsi/ctDNAtools.

scholarly journals Accurate detection of circulating tumor DNA using nanopore consensus sequencing

2020 ◽  
Author(s):  
Alessio Marcozzi ◽  
Myrthe Jager ◽  
Martin Elferink ◽  
Roy Straver ◽  
Joost H. van Ginkel ◽  
...  
Keyword(s):  
Point Of Care ◽  
Circulating Tumor Dna ◽  
Tumor Burden ◽  
Liquid Biopsies ◽  
Genomic Locus ◽  
Base Calling ◽  
Accurate Detection ◽  
Tumor Diagnostics ◽  
A New Technique ◽  
Tumor Dna

ABSTRACTLevels of circulating tumor DNA (ctDNA) in liquid biopsies may serve as a sensitive biomarker for real-time, minimally-invasive tumor diagnostics and monitoring. However, detecting ctDNA is challenging, as much fewer than 5% of the cell-free DNA in the blood typically originates from the tumor. To detect lowly abundant ctDNA molecules based on somatic variants, extremely sensitive sequencing methods are required. Here, we describe a new technique, CyclomicsSeq, which is based on Oxford Nanopore sequencing of concatenated copies of a single DNA molecule. Consensus calling of the DNA copies increased the base-calling accuracy ∼60x, enabling accurate detection of TP53 mutations at frequencies down to 0.02%. We demonstrate that a TP53-specific CyclomicsSeq assay can be successfully used to monitor tumor burden during treatment for head-and-neck cancer patients. CyclomicsSeq can be applied to any genomic locus and offers an accurate diagnostic liquid biopsy approach that can be implemented in point-of-care clinical workflows.

Circulating tumor DNA in patients with metastatic urothelial cancer: concordance of genomic findings with matched tissue biopsies.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e16036-e16036 ◽  
Author(s):  
Jean-Michel Lavoie ◽  
Gillian Vandekerkhove ◽  
Matti Annala ◽  
Nora Sundahl ◽  
Takeshi Sano ◽  
...  
Keyword(s):  
Urothelial Cancer ◽  
Stage Iv ◽  
Circulating Tumor Dna ◽  
Blood Collection ◽  
Liquid Biopsies ◽  
Tissue Samples ◽  
Metastatic Urothelial Cancer ◽  
Platinum Based Chemotherapy ◽  
Matched Tissue ◽  
Tumor Dna

e16036 Background: Patients (pts) with metastatic urothelial cancer (mUC) now have access to many different treatment options. This creates an incentive for molecular profiling of their tumors, with the aim of developing biomarkers. Genomic profiling may leverage the presence of circulating tumor DNA (ctDNA), but it has not been shown whether this recapitulates the findings from tissue samples. Methods: Whole blood samples were collected for next-generation sequencing of leukocyte and cell-free DNA (cfDNA). Deep targeted sequencing was performed across a UC-specific custom 50-gene panel (median depth of 986x). Matched archival tissue was profiled using the same assay for 65 pts. Results: Between 11/2011 and 12/2017, 90 pts developed mUC (87 evaluable). Baseline characteristics: median age 67, 83% male, 14% upper-tract disease, 17% stage IV at initial presentation. Treatments delivered: 76% platinum-based chemotherapy, 47% PD-1/PD-L1 inhibitor. At a median follow-up of 12.8 mo., 45% remain alive. We found ctDNA fractions above 2% in at least one blood collection in 81% of cases. For 17 pts, matched metastatic biopsies and cfDNA collection were available; in those cases 82% of coding somatic mutations identified in tissue were independently detected in cfDNA. Half of discordant findings could be attributed to low ctDNA fraction. Most (89%) mutations detected in primary tissue (cystectomy or nephrectomy) were present in later cfDNA collections. ctDNA detected mutations in TP53 and ARID1A in 64% and 29% of pts, respectively. A tumor mutation burden ≥25 mutation per Mb was observed in 27% of cases. Conclusions: There is a high concordance between genomic findings from ctDNA and matched tissue of pts with mUC. This supports the use of liquid biopsies to study potential biomarkers in this disease.

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