Abstract IA05: Circulating tumor DNA as a tool for prognostication, translational discovery, and early cancer detection

2020 ◽  
Author(s):  
Brian Crompton
Keyword(s):  
Cancer Detection ◽  
Early Cancer ◽  
Circulating Tumor Dna ◽  
Early Cancer Detection ◽  
Tumor Dna

Can a Broad Molecular Screen Based on Circulating Tumor DNA Aid in Early Cancer Detection?

2020 ◽  
Vol 5 (6) ◽  
pp. 1372-1377
Author(s):  
Clare Fiala ◽  
Eleftherios P Diamandis
Keyword(s):  
Sensitivity And Specificity ◽  
Cancer Detection ◽  
Early Cancer ◽  
Circulating Tumor Dna ◽  
Genetic Alterations ◽  
Population Screening ◽  
Early Cancer Detection ◽  
Potential Applicability ◽  
American Society ◽  
Tumor Dna

Abstract Early detection of cancer has been a major research focus for almost a century. Current methods for early cancer detection suffer from suboptimal sensitivity and specificity, especially when used for population screening. For most major cancers, including breast, prostate, lung, ovarian, and pancreatic cancer, population screening is still controversial or is not recommended by expert bodies. Circulating tumor DNA (ctDNA) is an exciting new cancer biomarker with potential applicability to all cancer types. Recent investigations have shown that genetic alterations or epigenetic modifications in ctDNA could be used for cancer detection with a liquid biopsy (i.e., a tube of blood). Tests based on ctDNA have attracted considerable attention for various applications, such as patient management, prognosis, early diagnosis, and population screening. Recently, new biotechnology companies were founded, with the goal of revolutionizing early cancer detection by using ctDNA. We previously examined this technology, as published by various academic laboratories and of one leading company, Grail, and drew attention to potential obstacles. After 3 years of intense development, this technology seems to have made some progress. Here, we will analyze the latest clinical data presented by Grail in October 2019, during the inaugural American Society of Clinical Oncology (ASCO) 2019 Breakthrough Conference. Despite considerable technical improvements, it seems that the sensitivity and specificity of the Grail test as a pan-cancer screening tool are still too low for clinical use. The prospects that this test could be further improved are also discussed.

scholarly journals A mathematical model of ctDNA shedding predicts tumor detection size

2020 ◽  
Vol 6 (50) ◽  
pp. eabc4308
Author(s):  
Stefano Avanzini ◽  
David M. Kurtz ◽  
Jacob J. Chabon ◽  
Everett J. Moding ◽  
Sharon Seiko Hori ◽  
...  
Keyword(s):  
Mathematical Model ◽  
Cancer Detection ◽  
Early Cancer ◽  
Circulating Tumor Dna ◽  
Early Cancer Detection ◽  
Tumor Evolution ◽  
Cancer Early Detection ◽  
Annual Screening ◽  
Detection Strategies ◽  
Tumor Dna

Early cancer detection aims to find tumors before they progress to an incurable stage. To determine the potential of circulating tumor DNA (ctDNA) for cancer detection, we developed a mathematical model of tumor evolution and ctDNA shedding to predict the size at which tumors become detectable. From 176 patients with stage I to III lung cancer, we inferred that, on average, 0.014% of a tumor cell’s DNA is shed into the bloodstream per cell death. For annual screening, the model predicts median detection sizes of 2.0 to 2.3 cm representing a ~40% decrease from the current median detection size of 3.5 cm. For informed monthly cancer relapse testing, the model predicts a median detection size of 0.83 cm and suggests that treatment failure can be detected 140 days earlier than with imaging-based approaches. This mechanistic framework can help accelerate clinical trials by precomputing the most promising cancer early detection strategies.

scholarly journals Circulating Tumor DNA for Early Cancer Detection

2018 ◽  
Vol 3 (2) ◽  
pp. 300-313 ◽  
Author(s):  
Clare Fiala ◽  
Vathany Kulasingam ◽  
Eleftherios P Diamandis
Keyword(s):  
Sensitivity And Specificity ◽  
Cancer Detection ◽  
High Throughput Sequencing ◽  
Early Cancer ◽  
Genetic Material ◽  
Circulating Tumor Dna ◽  
Early Cancer Detection ◽  
Blood Draw ◽  
Early Stage Disease ◽  
Tumor Dna

AbstractBackgroundCancer cells release circulating tumor DNA (ctDNA) into the bloodstream, which can now be quantified and examined using novel high-throughput sequencing technologies. This has led to the emergence of the “liquid biopsy,” which proposes to analyze this genetic material and extract information on a patient's cancer using a simple blood draw.ContentctDNA has been detected in many advanced cancers. It has also been proven to be a highly sensitive indicator of relapse and prognosis. Sequencing the genetic material has also led to the discovery of mutations targetable by existing therapies. Although ctDNA screening is more expensive, it is showing promise against circulating tumor cells and traditional cancer biomarkers. ctDNA has also been detected in other bodily fluids, including cerebrospinal fluid, urine, saliva, and stool. The utility of ctDNA for early cancer detection is being studied. However, a blood test for cancer faces heavy obstacles, such as extremely low ctDNA concentrations in early-stage disease and benign mutations caused by clonal hematopoiesis, causing both sensitivity and specificity concerns. Nonetheless, companies and academic laboratories are highly active in developing such a test.ConclusionCurrently, ctDNA is unlikely to perform at the high level of sensitivity and specificity required for early diagnosis and population screening. However, ctDNA in blood and other fluids has important clinical applications for cancer monitoring, prognosis, and selection of therapy that require further investigation.

scholarly journals Can Circulating Tumor DNA Support a Successful Screening Test for Early Cancer Detection? The Grail Paradigm

Diagnostics ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. 2171
Author(s):  
Oscar D. Pons-Belda ◽  
Amaia Fernandez-Uriarte ◽  
Eleftherios P. Diamandis
Keyword(s):  
Cancer Detection ◽  
Early Cancer ◽  
Circulating Tumor Dna ◽  
Tumor Burden ◽  
Diagnostic Methods ◽  
Stage I ◽  
Early Cancer Detection ◽  
Early Cancer Diagnosis ◽  
Pan Cancer ◽  
Tumor Dna

Circulating tumor DNA (ctDNA) is a new pan-cancer tumor marker with important applications for patient prognosis, monitoring progression, and assessing the success of the therapeutic response. Another important goal is an early cancer diagnosis. There is currently a debate if ctDNA can be used for early cancer detection due to the small tumor burden and low mutant allele fraction (MAF). We compare our previous calculations on the size of detectable cancers by ctDNA analysis with the latest experimental data from Grail’s clinical trial. Current ctDNA-based diagnostic methods could predictably detect tumors of sizes greater than 10–15 mm in diameter. When tumors are of this size or smaller, their MAF is about 0.01% (one tumor DNA molecule admixed with 10,000 normal DNA molecules). The use of 10 mL of blood (4 mL of plasma) will likely contain less than a complete cancer genome, thus rendering the diagnosis of cancer impossible. Grail’s new data confirm the low sensitivity for early cancer detection (<30% for Stage I–II tumors, <20% for Stage I tumors), but specificity was high at 99.5%. According to these latest data, the sensitivity of the Grail test is less than 20% in Stage I disease, casting doubt if this test could become a viable pan-cancer clinical screening tool.

scholarly journals Circulating tumor DNA as an early cancer detection tool

2020 ◽  
Vol 207 ◽  
pp. 107458 ◽  
Author(s):  
Andrea Campos-Carrillo ◽  
Jeffrey N. Weitzel ◽  
Prativa Sahoo ◽  
Russell Rockne ◽  
Janet V. Mokhnatkin ◽  
...  
Keyword(s):  
Cancer Detection ◽  
Early Cancer ◽  
Circulating Tumor Dna ◽  
Early Cancer Detection ◽  
Detection Tool ◽  
Tumor Dna

scholarly journals A mathematical model of ctDNA shedding predicts tumor detection size

2020 ◽  
Author(s):  
Stefano Avanzini ◽  
David M. Kurtz ◽  
Jacob J. Chabon ◽  
Everett J. Moding ◽  
Sharon Seiko Hori ◽  
...  
Keyword(s):  
Mathematical Model ◽  
Cancer Detection ◽  
Lung Tumor ◽  
Early Cancer ◽  
Early Stage ◽  
A Priori ◽  
Circulating Tumor Dna ◽  
Early Cancer Detection ◽  
Tumor Evolution ◽  
Early Stage Lung Cancer

AbstractEarly cancer detection aims to find tumors before they progress to an incurable stage. We developed a stochastic mathematical model of tumor evolution and circulating tumor DNA (ctDNA) shedding to determine the potential and the limitations of cancer early detection tests. We inferred normalized ctDNA shedding rates from 176 early stage lung cancer subjects and calculated that a 15 mL blood sample contains on average 1.7 genome equivalents of ctDNA for lung tumors with a volume of 1 cm3. For annual screening, the model predicts median detection sizes between 3.8 and 6.6 cm3 corresponding to lead times between 310 and 450 days compared to current lung tumor sizes at diagnosis. For monthly cancer relapse testing based on 20 a priori known mutations, the model predicts a median detection size of 0.26 cm3 corresponding to a lead time of 150 days. This mechanistic framework can help to optimize early cancer detection approaches.

scholarly journals Can circulating tumor DNA be used for direct and early stage cancer detection?

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 2129 ◽  
Author(s):  
Eleftherios P. Diamandis ◽  
Clare Fiala
Keyword(s):  
Patient Outcomes ◽  
Cancer Detection ◽  
Early Cancer ◽  
Early Stage ◽  
Circulating Tumor Dna ◽  
Major Advance ◽  
Early Cancer Diagnosis ◽  
Asymptomatic Individuals ◽  
Stage 1 ◽  
Tumor Dna

In the August 16th issue of Science Translational Medicine, Phallen et al propose a method for early cancer diagnosis by using circulating tumor DNA (1). One major advance of this paper includes optimized sequencing of cell-free/circulating tumor DNA (ctDNA) without knowledge of tumor mutations. Evaluation of 200 patients with colorectal, breast, lung and ovarian cancer revealed mutations in ctDNA in approx. 60-70% of all patients, including stage 1 and stage 2 disease. If this data can be reproduced in asymptomatic individuals, they will likely have a major impact on early cancer detection and patient outcomes. In this commentary, we examine the feasibility of this approach for detecting small, asymptomatic tumors, based on previously published empirical data.

scholarly journals Circulating Tumor DNA: Clinical Monitoring and Early Detection

2019 ◽  
Vol 3 (1) ◽  
pp. 187-201
Author(s):  
Ryan B. Corcoran
Keyword(s):  
Cancer Detection ◽  
Early Cancer ◽  
Circulating Tumor Dna ◽  
Clinical Applications ◽  
High Impact ◽  
Clinical Monitoring ◽  
Blood Draw ◽  
Mutational Profiling ◽  
Broad Array ◽  
Tumor Dna

Roughly 70 years after the presence of cell-free DNA (cfDNA) in circulating blood was discovered, cfDNA has emerged as a transformative technology in clinical oncology. The ability to assess the presence, level, and composition of tumor DNA from a routine, noninvasive blood draw has opened the door to a broad array of high-impact clinical applications. While cfDNA is rapidly gaining clinical favor as a means of tumor mutational profiling without the need for an invasive biopsy, emerging applications in the areas of clinical monitoring and early cancer detection hold tremendous promise. These developing applications of cfDNA are reviewed herein.

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