Rapid Identification of Plasma DNA Samples with Increased ctDNA Levels by a Modified FAST-SeqS Approach

Belic, Jelena; Koch, Marina; Ulz, Peter; Auer, Martina; Gerhalter, Teresa; Mohan, Sumitra; Fischereder, Katja; Petru, Edgar; Bauernhofer, Thomas; Geigl, Jochen B.; Speicher, Michael R.; Heitzer, Ellen

doi:10.1373/clinchem.2014.234286

Cited by 96 publications

(118 citation statements)

References 25 publications

Supporting

Mentioning

111

Contrasting

Unclassified

Order By: Relevance

“…Each sample was classified via a ctDNA z-score measurement as “<=5” or “>5” based on low versus high genomic complexity in ctDNA as described previously 25 . The following clinical characteristics were also available for the samples together with ctDNA measurement: Prostate-specific antigen (PSA), alkaline phosphatase (ALP), lactate dehydrogenase (LDH) and presence of bone metastases.…”

Section: Methodsmentioning

confidence: 99%

Genomic alterations in plasma DNA from patients with metastasized prostate cancer receiving abiraterone or enzalutamide

Belic

Graf

Bauernhofer

et al. 2018

Intl Journal of Cancer

Self Cite

View full text Add to dashboard Cite

In patients with metastatic castrate resistant prostate cancer (mCRPC), circulating tumor DNA (ctDNA) analysis offers novel opportunities for the development of non-invasive biomarkers informative of treatment response with novel agents targeting the androgen-receptor (AR) pathway, such as abiraterone or enzalutamide. However, the relationship between ctDNA abundance, detectable somatic genomic alterations and clinical progression of mCRPC remains unexplored. Our study aimed to investigate changes in plasma DNA during disease progression and their associations with clinical variables in mCRPC patients. We analyzed ctDNA in two cohorts including 94 plasma samples from 25 treatment courses (23 patients) and 334 plasma samples from 125 patients, respectively. We conducted whole-genome sequencing (plasma-Seq) for genome-wide profiling of somatic copy number alterations and targeted sequencing of 31 prostate cancer-associated genes. The combination of plasma-Seq with targeted AR analyses identified prostate cancer-related genomic alterations in 16 of 25 (64%) treatment courses in the first cohort, in which we demonstrated that AR amplification does not always correlate with poor abiraterone and enzalutamide therapy outcome. As we observed a wide variability of ctDNA levels, we evaluated ctDNA levels and their association with clinical parameters and included the second, larger cohort for these analyses. Employing altogether 428 longitudinal plasma samples from 148 patients, we identified the presence of bone metastases, increased lactate dehydrogenase and prostate-specific antigen (PSA) as having the strongest association with high ctDNA levels. In summary, ctDNA alterations are observable in the majority of patients with mCRPC and may eventually be useful to guide clinical decision-making in this setting.

show abstract

Section: Methodsmentioning

confidence: 99%

Genomic alterations in plasma DNA from patients with metastasized prostate cancer receiving abiraterone or enzalutamide

Belic

Graf

Bauernhofer

et al. 2018

Intl Journal of Cancer

Self Cite

View full text Add to dashboard Cite

show abstract

“…One drawback is that our method only yields informative results if approximately 5%-10% of tumor DNA is present in the circulation. Due to the fact that even in highly metastasized patients there are clinical situations where ctDNA is present below optimal levels for the detection of genomewide alterations [31,39,55,60], and approximately 20%-30% of analyses would not yield informative results, we now use our recently published mFAST-SeqS method in order to preselect samples with sufficient amounts of tumor DNA (Figure 2) [61]. As the calculated mFAST-SeqS-z-score highly correlates with mutant allele frequencies it can also be used as an untargeted approach for the establishment of changing ctDNA under a certain treatment.…”

Section: Monitoring Treatment Response and Tumor Evolutionmentioning

confidence: 99%

Potentials, challenges and limitations of a molecular characterization of circulating tumor DNA for the management of cancer patients

Ulz

Gerger

Belic

et al. 2016

LaboratoriumsMedizin

Self Cite

View full text Add to dashboard Cite

A liquid profiling, i.e. the analysis of cell-free circulating tumor DNA (ctDNA), enables a continuous non-invasive monitoring of tumor-specific changes during the entire course of the disease with respect to early detection, identification of minimal residual disease, assessment of treatment response and monitoring tumor evolution. Technological improvements, advances in understanding the nature of ctDNA, the implementation of ctDNA analyses in clinical trials as well as efforts for the establishment of benchmarks, will bring an actual widespread clinic use within reach in the near future. However, despite this progress there are still hurdles that have to be overcome, which are discussed in this review. Moreover, present knowledge and new findings about the biology of ctDNA as well as selected potential clinical applications for metastatic cancer patients are pointed out.

show abstract

“…Allerdings kann es sogar bei hochmetastasierten Patienten aufgrund der im ersten Abschnitt dargelegten Parameter vorkommen, dass dieser Cut-Off nicht erreicht wird [6,21,55,75] und bei rund 20-30 % der Patienten können mit diesen Methoden keine informativen Ergebnisse erzielt werden. Um jene Patienten vorab zu identifizieren, bei denen ausreichend Tumor-DNA für genomweite Analysen in der Zirkulation vorhanden ist, haben wir kürzlich eine pre-screening Methode entwickelt [88]. Das sog.…”

Section: Introductionunclassified

“…mFAST-SeqS basiert auf einer selektiven Amplifikation von LINE1-Sequenzen, die im gesamten Genom verteilt vorliegen. [88]. Ähnlich wie bei der genomweiten Kopienzahlanalyse werden die generierten LINE1-Sequenzen gegen das Genom kartiert und pro Chromosomenarm gezählt.…”

Section: Introductionunclassified

See 1 more Smart Citation

Neueste technologische Entwicklungen für die Analyse von zirkulierender Tumor-DNA

Ulz

Geigl

Speicher

et al. 2016

Medizinische Genetik

Self Cite

View full text Add to dashboard Cite

Zusammenfassung Die Analyse von zirkulierender Tumor-DNA, zusammen mit der Analyse von zirkulierenden Tumorzellen auch oft Liquid Biopsy genannt, ist ein sich rasch entwickelndes Feld in der medizinischen Forschung. Obwohl es von der Entdeckung der zellfreien DNA bis hin zur Erkenntnis, dass sie sich als Biomarker eignet, Jahrzehnte gedauert hat, wurde der klinische Nutzen der ctDNA hinsichtlich der Überwachung des Therapieansprechens, der Identifizierung von Resistenzmechanismen und neu aufkommenden Therapiezielen sowie der Detektion von minimaler Resterkrankung mittlerweile in unzähligen Studien bewiesen. Aufgrund der hohen Variabilität, mit der ctDNA in der Zirkulation vorkommt, sowie der starken Fragmentierung, stellt die ctDNA aber einen schwierigen Analyten dar. In den letzten Jahren haben erhebliche technologische Fortschritte dazu beigetragen, dass eine Routineanwendung der ctDNA-Analysen tatsächlich realisierbar wird, sofern eine Reihe von regulatorischen Hürden überwunden wird.

show abstract

Rapid Identification of Plasma DNA Samples with Increased ctDNA Levels by a Modified FAST-SeqS Approach

Cited by 96 publications

References 25 publications

Genomic alterations in plasma DNA from patients with metastasized prostate cancer receiving abiraterone or enzalutamide

Genomic alterations in plasma DNA from patients with metastasized prostate cancer receiving abiraterone or enzalutamide

Potentials, challenges and limitations of a molecular characterization of circulating tumor DNA for the management of cancer patients

Neueste technologische Entwicklungen für die Analyse von zirkulierender Tumor-DNA

Contact Info

Product

Resources

About