scholarly journals Cell-free DNA analysis in current cancer clinical trials: a review

Author(s):  
M. Cisneros-Villanueva ◽  
L. Hidalgo-Pérez ◽  
M. Rios-Romero ◽  
A. Cedro-Tanda ◽  
C. A. Ruiz-Villavicencio ◽  
...  

AbstractCell-free DNA (cfDNA) analysis represents a promising method for the diagnosis, treatment selection and clinical follow-up of cancer patients. Although its general methodological feasibility and usefulness has been demonstrated, several issues related to standardisation and technical validation must be addressed for its routine clinical application in cancer. In this regard, most cfDNA clinical applications are still limited to clinical trials, proving its value in several settings. In this paper, we review the current clinical trials involving cfDNA/ctDNA analysis and highlight those where it has been useful for patient stratification, treatment follow-up or development of novel approaches for early diagnosis. Our query included clinical trials, including the terms ‘cfDNA’, ‘ctDNA’, ‘liquid biopsy’ AND ‘cancer OR neoplasm’ in the FDA and EMA public databases. We identified 1370 clinical trials (FDA = 1129, EMA = 241) involving liquid-biopsy analysis in cancer. These clinical trials show promising results for the early detection of cancer and confirm cfDNA as a tool for real-time monitoring of acquired therapy resistance, accurate disease-progression surveillance and improvement of treatment, situations that result in a better quality of life and extended overall survival for cancer patients.

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Filippo Martignano ◽  
Uday Munagala ◽  
Stefania Crucitta ◽  
Alessandra Mingrino ◽  
Roberto Semeraro ◽  
...  

AbstractIn the “precision oncology” era the characterization of tumor genetic features is a pivotal step in cancer patients’ management. Liquid biopsy approaches, such as analysis of cell-free DNA from plasma, represent a powerful and noninvasive strategy to obtain information about the genomic status of the tumor. Sequencing-based analyses of cell-free DNA, currently performed with second generation sequencers, are extremely powerful but poorly scalable and not always accessible also due to instrumentation costs. Third generation sequencing platforms, such as Nanopore sequencers, aim at overcoming these obstacles but, unfortunately, are not designed for cell-free DNA analysis.Here we present a customized workflow to exploit low-coverage Nanopore sequencing for the detection of copy number variations from plasma of cancer patients. Whole genome molecular karyotypes of 6 lung cancer patients and 4 healthy subjects were successfully produced with as few as 2 million reads, and common lung-related copy number alterations were readily detected.This is the first successful use of Nanopore sequencing for copy number profiling from plasma DNA. In this context, Nanopore represents a reliable alternative to Illumina sequencing, with the advantages of minute instrumentation costs and extremely short analysis time.The availability of protocols for Nanopore-based cell-free DNA analysis will make this analysis finally accessible, exploiting the full potential of liquid biopsy both for research and clinical purposes.


2018 ◽  
Vol 20 ◽  
Author(s):  
Ana Barbosa ◽  
Ana Peixoto ◽  
Pedro Pinto ◽  
Manuela Pinheiro ◽  
Manuel R. Teixeira

AbstractCirculating cell-free DNA (cfDNA) consists of small fragments of DNA that circulate freely in the bloodstream. In cancer patients, a fraction of cfDNA is derived from tumour cells, therefore containing the same genetic and epigenetic alterations, and is termed circulating cell-free tumour DNA. The potential use of cfDNA, the so-called ‘liquid biopsy’, as a non-invasive cancer biomarker has recently received a lot of attention. The present review will focus on studies concerning the potential clinical applications of cfDNA in ovarian cancer patients.


2018 ◽  
Vol 4 (Supplement 2) ◽  
pp. 244s-244s
Author(s):  
M. Kohli

Background and context: Translation of underlying individual genomic heterogeneity in cancer into precision medicine practice requires annotated cancer biorepositories. The potential for practice of precise medicine is also coupled to saving vital resources in low to middle–income countries. An overview of experience and outcomes from a tertiary level cancer center in a high-income country for liquid biobank established since 2009 is presented. Aim: To understand the challenges of building economically viable biorepositories that can be used for molecular diagnostics while delivering cancer care. Strategy/Tactics: An institutional ethics–approved prospective liquid biorepository was established in September of 2009 for advanced cancer patients. Informed consent–approved collection of 29.5 mL blood/urine was performed serially on enrolled patients and clinical annotation was obtained during follow-up including previous, current and future treatments and their outcomes. All specimens were processed using a uniform protocol in which extraction of germline DNA from buffy coats; serum for proteomics; platelet-poor and platelet-rich plasma (in citrate and EDTA anticoagulants) for microRNA and cell-free DNA extractions; and extraction of PAXgene RNA/DNA from whole blood was performed. Processing was done within 45 minutes of sample acquisition and storage in −80°C freezers with no freeze–thaw cycles. Program/Policy process: Biobanking for cancer care. Outcomes: Between September of 2009 and January of 2015, 535 advanced-stage prostate cancer patients in hormone-sensitive and castrate-resistant stage; 250 advanced kidney cancer patients; 110 testicular cancer patients were enrolled and 1550 collections were performed serially. This generated >60,000 plasma/serum/DNA/RNA aliquots. Nucleic acids (DNA/RNA) from buffy coats and whole blood of 500-1000 ng volume each were also extracted. Cell-free DNA for somatic mutational and copy number analysis; single nucleotide profiling from germline DNA; RNA expression profiling from whole blood and microRNA analysis in plasma has been performed from this cohort along with proteomics using tandem mass spectrometry. By 2017, this has resulted in >35 scientific publications; 5 patents; multiple national and international grant awards and enhanced precision cancer care for patient care. The cost burden for establishing the infrastructure was highly economical. What was learned: In our experience, liquid biopsy repositories can augment clinical cancer globally, but do not find this discussed in low to middle–income nations. Advancing and applying molecular oncology and team science to prospectively collected and retrospectively annotated biobanks can be a cost-efficient resource in a global cancer healthcare delivery system and a useful tool for scientific and economic opportunities and collaborations.


2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 5529-5529
Author(s):  
Chris Maher ◽  
Ha X. Dang ◽  
Pradeep S. Chauhan ◽  
Haley Ellis ◽  
Wenjia Feng ◽  
...  

5529 Background: Predicting primary resistance to androgen receptor (AR)-directed therapies is critical for personalizing treatment of metastatic prostate cancer (mPCa). Analyses of liquid biopsies are potential tools but remained underutilized due to limited sensitivity. We developed a cell-free DNA (cfDNA) assay (EnhanceAR-Seq) to monitor genomic alterations in mPCa including AR enhancer duplication, a resistance marker recently discovered in ~81% of mPCa patients. Here we show that applying EnhanceAR-Seq to plasma cfDNA to monitor alterations of AR gene and enhancer ( AR/enhancer) predicted primary resistance with high sensitivity and outperformed the clinically validated CTC AR-V7 assay. Methods: Forty mPCa patients were prospectively enrolled at the Washington University School of Medicine Siteman Cancer Center with plasma cfDNA analyzed by EnhanceAR-Seq. Twenty-five of them also had the Oncotype DX AR-V7 Nucleus Detect CTC assay performed at a similar timepoint at the discretion of the treating oncologist. All patients received AR-directed therapy (eg. abiraterone, enzalutamide) and underwent standard-of-care clinical and laboratory follow-up. Primary resistance was defined as PSA progression, change of treatment or death within 4 months of treatment initiation, or radiographic progression within 6 months. Results: Median clinical follow up after diagnosis was 50 months. EnhanceAR-Seq detected alterations targeting AR/enhancer in 18 patients (45%), TP53 in 8 patients (20%), and PTEN in 6 patients (15%). We found that AR/enhancer alterations (copy gain, tandem duplication, and point mutation) in cfDNA were strongly predictive of primary resistance to AR-directed therapy (PPV = 100%, Sens. = 89%). Our assay outperformed the CTC AR-V7 assay, which was positive in only two patients (PPV = 50%, Sens. = 6%). Furthermore, patients with AR/enhancer alterations had significantly worse progression-free survival (P = 0.0015; HR = 11.5) and overall survival (P = 0.0002; HR = 6.8). Finally, serial cell-free DNA analysis of 10 patients showed that AR/enhancer copy number gain was maintained or acquired in 5 of 6 AR-resistant cases, and neutrality maintained in 4 of 4 AR-sensitive cases. Conclusions: cfDNA-based AR/enhancer locus genomic alterations could potentially be used to predict primary resistance to AR-directed therapy with higher sensitivity than the clinically validated CTC AR-V7 assay, be used for serial timepoint monitoring and guiding personalized clinical decision-making.


2021 ◽  
Author(s):  
Thais Sabedot ◽  
Tathiane Malta ◽  
James Snyder ◽  
Kevin Nelson ◽  
Michael Wells ◽  
...  

Abstract Background The detection of somatic mutations in cell-free DNA (cfDNA) from liquid biopsy has emerged as a non-invasive tool to monitor the follow-up of cancer patients. However, the significance of cfDNA clinical utility remains uncertain in patients with brain tumors, primarily because of the limited sensitivity cfDNA has to detect real tumor-specific somatic mutations. This unresolved challenge has prevented accurate follow-up of glioma patients with non-invasive approaches. Methods Genome-wide DNA methylation profiling of tumor tissue and serum cell-free DNA of glioma patients. Results Here, we developed a non-invasive approach to profile the DNA methylation status in the serum of patients with gliomas and identified a cfDNA-derived methylation signature that is associated with the presence of gliomas and related immune features. By testing the signature in an independent discovery and validation cohorts, we developed and verified a score metric (the “glioma epigenetic liquid biopsy score” or GeLB) that optimally distinguished patients with or without glioma (sensitivity: 100%, specificity: 97.78%). Furthermore, we found that changes in GeLB score reflected clinicopathological changes during surveillance (e.g., progression, pseudoprogression or response to standard or experimental treatment). Conclusions Our results suggest that the GeLB score can be used as a complementary approach to diagnose and follow up patients with glioma.


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