Concordance of circulating and solid tumor DNA through comprehensive genomic profiling in a large integrated cancer network.
William A. LaFramboiseAli H. ZaidiCasey J. AllenZhadyra BizhanovaEmily DaltonBela BapatPatti PetroskoPhillip H. GalloL. King L. GilJ. LamRobin -St CebulaPatrick WagnerDavid L. Bartlett
1
Citation
0
Reference
10
Related Paper
Citation Trend
Abstract:
3059 Background: Comprehensive Genomic Profiling (CGP) of solid tumors is crucial in diagnosing and treating cancer patients. Circulating Tumor DNA (ctDNA) is a potential biomarker for detecting mutations when tissue samples are limited or unavailable. However, the sensitivity of ctDNA tests vary greatly, making concordance studies with tissue samples critical to validate clinical use. This study presents results of CGP in paired tumor tissue and plasma samples from representative cancer patients treated in a community-based, Integrated Network Cancer Program. Methods: Over 2000 cancer patients have provided solid tumor and/or blood samples to date including serial follow-up blood samples. To optimize ctDNA integrity, we collected blood using a membrane stabilizer (Streck), ensured courier transport in ≤ 72 hours, separated plasma via differential centrifugation x 3, extracted cell free DNA with magnetic beads, and performed Next Generation Sequencing (NGS) using the ct-TSO500 assay (Illumina). In cases where patients provided both a solid tumor and concurrent blood sample, st-TSO500 NGS results from the solid tumor were compared to the ctDNA results for these matching specimens. Clinical actionability of variants was determined using the OncoKB database at levels 1, 2, and R1. Results: 146 matched blood and solid tumor specimens were analyzed to date. CGP studies revealed 1179 ± 102 unique variants across 20 different cancer types. Coding mutations from these specimens averaged 183 ± 25 variants. The ctDNA contained 96.5% of initial variants (1088 ± 95) and 95.1% of coding mutations (163 ± 20) found in the respective matched solid tumor. 76 patients had one or more oncogenic mutations detected only in the ctDNA and 28 (36.8%) of these included an actionable anticancer pharmacotherapy. Concordance by selective tumor type for clinical oncogenic variants was 95.8% (prostate), 95.0% (pancreas), 92.8% (lung and ovarian), 90.0% (endometrium), 84.3% (colon) and 82.4% for breast cancer. There was no difference in concordance between stage IV (91.0%) and stage I-III (86.5%) tumors (p = 0.14). An average of 6.2 ± 2.5 oncogenic variants were detected in both ctDNA and tissue. 99.3% of all patients contained an oncogenic biomarker in both ctDNA and tissue assays. Conclusions: We developed a prospective tissue and plasma repository of patients across a large integrated cancer network. These data demonstrate high concordance between circulating and solid tumor DNA using an “in-house” CGP assay. With no loss of concordance across cancer stages, ctDNA can identify actionable mutations not found in solid tumor analysis. This study is an important step toward incorporating “in-house” ctDNA CGP into routine cancer care. Future goals are to utilize these data for development of novel prognostic and predictive classifiers for use in a community-based hospital system across various disease sites.Keywords:
Concordance
Circulating tumor DNA
Liquid biopsy
Solid tumor
Liquid biopsy
Circulating tumor cell
Circulating tumor DNA
Cite
Citations (62)
Precision medicine in the clinical management of cancer may be achieved through the diagnostic platform called "liquid biopsy". This method utilizes the detection of biomarkers in blood for prognostic and predictive purposes. One of the latest blood born markers under investigation in the field of liquid biopsy in cancer patients is circulating tumor DNA (ctDNA). ctDNA is released by tumor cells through different mechanisms and can therefore provide information about the genomic make-up of the tumor currently present in the patient. Through longitudinal ctDNA-based liquid biopsies, tumor dynamics may be monitored to predict and assess drug response and/or resistance. However, because ctDNA is highly fragmented and because its concentration can be extremely low in a high background of normal circulating DNA, screening for clinical relevant mutations is challenging. Although significant progress has been made in advancing the detection and analysis of ctDNA in the last few years, the current challenges include standardization and increasing current techniques to single molecule sensitivity in combination with perfect specificity. This review focuses on the potential role of ctDNA in the clinical management of cancer patients, the current technologies that are being employed, and the hurdles that still need to be taken to achieve ctDNA-based liquid biopsy towards precision medicine.
Liquid biopsy
Circulating tumor DNA
Circulating tumor cell
Personalized Medicine
Cite
Citations (304)
Precision medicine has been well recognized since it was proposed, and the invention of liquid biopsy meets the needs of this era. Circulating tumor DNA (ctDNA), one of the most promising components of liquid biopsies, has quickly become the focus of research in recent years because of its unique advantages in clinical application. This article reviews the clinical application of ctDNA in breast cancer detection in recent years and its potential clinical value.
Liquid biopsy
Circulating tumor DNA
Cite
Citations (4)
Liquid biopsy
Circulating tumor DNA
Circulating tumor cell
Cite
Citations (0)
Circulating tumor DNA (ctDNA) is DNA released by cancer cells into body fluids. The collection of body fluids that contains ctDNA, also known as lliquid biopsy, allows to access tumor DNA through a minimally invasive procedure. ctDNA has been proposed alternative source of tumor DNA for genotyping purposes and for longitudinal genetic monitoring. Also, ctDNA is radiation-free tool that allows the early identification of chemorefractory patients. We will discuss clinical applications of the liquid biopsy in lymphomas and the controversies around this biomarker. Keywords: liquid biopsy, minimal residual disease No conflicts of interests pertinent to the abstract.
Liquid biopsy
Circulating tumor DNA
Minimal Residual Disease
Cite
Citations (1)
With the recent advances in noninvasive approaches for cancer diagnosis and surveillance, the term “liquid biopsy” has become more familiar to clinicians, including hematologists. Liquid biopsy provides a variety of clinically useful genetic data. In this era of personalized medicine, genetic information is critical to early diagnosis, aiding risk stratification, directing therapeutic options, and monitoring disease relapse. The validity of circulating tumor DNA (ctDNA)-mediated liquid biopsies has received increasing attention. This review summarizes the current knowledge of liquid biopsy ctDNA in hematological malignancies, focusing on the feasibility, limitations, and key areas of clinical application. We also highlight recent advances in the minimal residual disease monitoring of leukemia using ctDNA. This article will be useful to those involved in the clinical practice of hematopoietic oncology.
Liquid biopsy
Circulating tumor DNA
Minimal Residual Disease
Risk Stratification
Hematological Malignancy
Personalized Medicine
Circulating tumor cell
Disease monitoring
Cite
Citations (13)
Abstract “Liquid biopsy” focusing on the analysis of circulating tumor cells (CTC) and circulating cell-free tumor DNA (ctDNA) in the blood of patients with cancer has received enormous attention because of its obvious clinical implications for personalized medicine. Analyses of CTCs and ctDNA have paved new diagnostic avenues and are, to date, the cornerstones of liquid biopsy diagnostics. The present review focuses on key areas of clinical applications of CTCs and ctDNA, including detection of cancer, prediction of prognosis in patients with curable disease, monitoring systemic therapies, and stratification of patients based on the detection of therapeutic targets or resistance mechanisms. Significance: The application of CTCs and ctDNA for the early detection of cancer is of high public interest, but it faces serious challenges regarding specificity and sensitivity of the current assays. Prediction of prognosis in patients with curable disease can already be achieved in several tumor entities, particularly in breast cancer. Monitoring the success or failure of systemic therapies (i.e., chemotherapy, hormonal therapy, or other targeted therapies) by sequential measurements of CTCs or ctDNA is also feasible. Interventional studies on treatment stratification based on the analysis of CTCs and ctDNA are needed to implement liquid biopsy into personalized medicine. Cancer Discov; 6(5); 479–91. ©2016 AACR.
Liquid biopsy
Circulating tumor cell
Circulating tumor DNA
Cite
Citations (1,227)
Abstract Recent technological advances have enabled the detection and detailed characterization of circulating tumor cells (CTC) and circulating tumor DNA (ctDNA) in blood samples from patients with cancer. Often referred to as a “liquid biopsy,” CTCs and ctDNA are expected to provide real-time monitoring of tumor evolution and therapeutic efficacy, with the potential for improved cancer diagnosis and treatment. In this review, we focus on these opportunities as well as the challenges that should be addressed so that these tools may eventually be implemented into routine clinical care. Clin Cancer Res; 21(21); 4786–800. ©2015 AACR.
Circulating tumor cell
Liquid biopsy
Circulating tumor DNA
Cite
Citations (336)
Liquid biopsy
Circulating tumor DNA
Circulating tumor cell
Extracellular Vesicles
Minimal Residual Disease
Acquired resistance
Cite
Citations (0)
For many decades it has been known that tumor DNA is shed into the blood. As a consequence of technological limitations, researchers were unable to comprehensively characterize circulating DNA. The advent of ultrasensitive and highly specific molecular assays has provided a comprehensive profile of the molecular characteristics and dynamics of circulating DNA in healthy subjects and cancer patients. With these new tools in hand, significant interest has been provoked for an innovative type of tumor biopsy termed a "liquid biopsy". Liquid biopsies are obtained by minimal invasive blood draws from cancer patients. Circulating cancer cells, exosomes and a variety of molecules contained within the liquid biopsy including cell-free circulating tumor DNA (ctDNA) can serve as promising tools to track cancer evolution. Attractive features of ctDNA are that ctDNA isolation is straightforward, ctDNA levels increase or decrease in response to the degree of tumor burden and ctDNA contains DNA mutations found in both primary and metastatic lesions. Consequently, the analysis of circulating DNA for cancer-specific mutations might prove to be a valuable tool for cancer detection. Moreover, the capacity to screen for ctDNA in serial liquid biopsies offers the possibility to monitor tumor progression and responses to therapy and to influence treatment decisions that ultimately may improve patient survival. Here we focus on mutation detection in ctDNA and provide an overview of the characteristics of ctDNA, detection methods for ctDNA and the feasibility of ctDNA to monitor tumor dynamics. Current challenges associate with ctDNA will also be discussed.
Liquid biopsy
Circulating tumor DNA
Cell-free fetal DNA
Circulating tumor cell
Cite
Citations (101)