scholarly journals Circulating tumor DNA (ctDNA) as a pan-cancer screening test: is it finally on the horizon?

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Michael J. Duffy ◽  
Eleftherios P. Diamandis ◽  
John Crown
Keyword(s):  
Cancer Screening ◽  
Screening Test ◽  
Early Stage ◽  
Circulating Tumor Dna ◽  
Cancer Type ◽  
Protein Biomarkers ◽  
Cancer Screening Test ◽  
Copy Number Changes ◽  
Pan Cancer ◽  
Tumor Dna

Abstract The detection of cancer at an early stage while it is curable by surgical resection is widely believed to be one of the most effective strategies for reducing cancer mortality. Hence, the intense interests in the development of a simple pan-cancer screening test. Lack of sensitivity and specificity when combined with the low prevalence of most types of cancer types in the general population limit the use of most of the existing protein biomarkers for this purpose. Like proteins, tumor DNA also can be released into the circulation. Such circulating tumor DNA (ctDNA) can be differentiated from normal cell DNA by the presence of specific genetic alteration such as mutations, copy number changes, altered methylation patterns or being present in different sized fragments. Emerging results with test such as CancerSEEK or GRAIL suggest that the use of ctDNA can detect cancer with specificities >99%. Sensitivity however, is cancer type and stage-dependent, varying from approximately 40% in stage I disease to approximately 80% in stage III disease. It is important to stress however, that most of the studies published to date have used patients with an established diagnosis of cancer while the control population were healthy individuals. Although the emerging results are promising, evidence of clinical utility will require demonstration of reduced mortality following evaluation in a prospective randomized screening trial.

scholarly journals Pan-cancer circulating tumor DNA detection in over 10,000 Chinese patients

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yongliang Zhang ◽  
Yu Yao ◽  
Yaping Xu ◽  
Lifeng Li ◽  
Yan Gong ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Circulating Tumor Dna ◽  
Small Cell ◽  
Chinese Patients ◽  
Plasma Samples ◽  
Small Cell Lung ◽  
Pan Cancer ◽  
Tumor Dna

AbstractCirculating tumor DNA (ctDNA) provides a noninvasive approach to elucidate a patient’s genomic landscape and actionable information. Here, we design a ctDNA-based study of over 10,000 pan-cancer Chinese patients. Using parallel sequencing between plasma and white blood cells, 14% of plasma cell-free DNA samples contain clonal hematopoiesis (CH) variants, for which detectability increases with age. After eliminating CH variants, ctDNA is detected in 73.5% of plasma samples, with small cell lung cancer (91.1%) and prostate cancer (87.9%) showing the highest detectability. The landscape of putative driver genes revealed by ctDNA profiling is similar to that in a tissue-based database (R2 = 0.87, p < 0.001) but also shows some discrepancies, such as higher EGFR (44.8% versus 25.2%) and lower KRAS (6.8% versus 27.2%) frequencies in non-small cell lung cancer, and a higher TP53 frequency in hepatocellular carcinoma (53.1% versus 28.6%). Up to 41.2% of plasma samples harbor drug-sensitive alterations. These findings may be helpful for identifying therapeutic targets and combined treatment strategies.

scholarly journals Detection of KRAS Mutations in Circulating Tumor DNA by Digital PCR in Early Stages of Pancreatic Cancer

2016 ◽  
Vol 62 (11) ◽  
pp. 1482-1491 ◽  
Author(s):  
Nora Brychta ◽  
Thomas Krahn ◽  
Oliver von Ahsen
Keyword(s):  
Pancreatic Cancer ◽  
Early Stage ◽  
Digital Pcr ◽  
Circulating Tumor Dna ◽  
Surgical Removal ◽  
Plasma Samples ◽  
Kras Mutations ◽  
Detection Rates ◽  
Early Stages ◽  
Tumor Dna

Abstract BACKGROUND Since surgical removal remains the only cure for pancreatic cancer, early detection is of utmost importance. Circulating biomarkers have potential as diagnostic tool for pancreatic cancer, which typically causes clinical symptoms only in advanced stage. Because of their high prevalence in pancreatic cancer, KRAS proto-oncogene, GTPase [KRAS (previous name: Kirsten rat sarcoma viral oncogene homolog)] mutations may be used to identify tumor-derived circulating plasma DNA. Here we tested the diagnostic sensitivity of chip based digital PCR for the detection of KRAS mutations in circulating tumor DNA (ctDNA) in early stage pancreatic cancer. METHODS We analyzed matched plasma (2 mL) and tumor samples from 50 patients with pancreatic cancer. Early stages (I and II) were predominant (41/50) in this cohort. DNA was extracted from tumor and plasma samples and tested for the common codon 12 mutations G12D, G12V, and G12C by chip-based digital PCR. RESULTS We identified KRAS mutations in 72% of the tumors. 44% of the tumors were positive for G12D, 20% for G12V, and 10% for G12C. One tumor was positive for G12D and G12V. Analysis of the mutations in matched plasma samples revealed detection rates of 36% for G12D, 50% for G12V, and 0% for G12C. The detection appeared to be correlated with total number of tumor cells in the primary tumor. No KRAS mutations were detected in 20 samples of healthy control plasma. CONCLUSIONS Our results support further evaluation of tumor specific mutations as early diagnostic biomarkers using plasma samples as liquid biopsy.

Which colon cancer screening test? A comparison of costs, effectiveness, and compliance

2001 ◽  
Vol 111 (8) ◽  
pp. 593-601 ◽  
Author(s):  
Sandeep Vijan ◽  
Erica W Hwang ◽  
Timothy P Hofer ◽  
Rodney A Hayward
Keyword(s):  
Colon Cancer ◽  
Cancer Screening ◽  
Screening Test ◽  
Colon Cancer Screening ◽  
Cancer Screening Test

scholarly journals Ultra-low Input Circulating Tumor DNA Detection by MED-Amp in Early-Stage Pancreatic Cancer

2021 ◽  
Author(s):  
Erica D Pratt ◽  
David B Zhen ◽  
Robert W Cowan ◽  
Heather Cameron ◽  
Kara Schradle ◽  
...  
Keyword(s):  
Early Stage ◽  
Locally Advanced ◽  
Progression Free Survival ◽  
Circulating Tumor Dna ◽  
Fold Change ◽  
Diagnostic Sensitivity ◽  
Ductal Adenocarcinoma ◽  
Kras Mutations ◽  
The Relationship ◽  
Tumor Dna

Purpose: The clinical utility of circulating tumor DNA (ctDNA) has been shown in advanced pancreatic ductal adenocarcinoma (PDA). However, diagnostic sensitivity of many ctDNA assays is low in resectable and locally advanced disease, where tumor burden is substantially lower. We have previously described Multiplex Enrichment using Droplet Pre-Amplification (MED-Amp), a multiplexed panel for the detection of the most common oncogenic KRAS mutations in PDA. In this study, we aimed to assess the diagnostic sensitivity of MED-Amp for detection of rare mutant alleles present in the plasma of patients with localized PDA. Experimental Design: We retrospectively analyzed ninety-eight plasma samples from 51 patients with various stages of localized disease. For comparison, we measured ctDNA levels in 20 additional patients with metastatic PDA. The MED-Amp assay was used to measure the abundance of the four most common KRAS codon 12 mutations (G12C/D/R/V). We correlated the presence and quantity of ctDNA with overall survival (OS) as well as progression-free survival (PFS). Using serial plasma draws, we also assessed the relationship between changes in ctDNA allelic frequency and progression. Results: KRAS-positive ctDNA was detected in 52.9% of localized PDA and 75% of metastatic samples tested using DNA inputs as low as 2 ng. As previously reported, the presence of KRAS mutant ctDNA was correlated with worse OS for all disease stages (p = 0.02). In patients with localized PDA high ctDNA levels also correlated with significantly worse median OS (533 days vs 1090 days) and PFS (192 days vs 787 days). We also studied a small cohort of serial plasma draws to observe the relationship between ctDNA fold change and PFS. We found 83% of patients with increased fold change in mutant KRAS experienced disease progression (n=6). In contrast, 75% (n=4) of patients with decreased fold change remained disease-free (p=0.03). Conclusions: MED-Amp is a flexible and cost-effective approach for measurement of ctDNA in patients with localized cancer. Though this study focused on KRAS mutation detection, this assay could be adapted for a number of common oncogenic alterations.

Virtual colonoscopy: a kinder, gentler colorectal cancer screening test?

The Lancet ◽  
1999 ◽  
Vol 354 (9184) ◽  
pp. 1048-1049 ◽  
Author(s):  
Martina M Mor rin ◽  
Richard J Farrell ◽  
Jonathan B Kruskal ◽  
J Thomas LaMont
Keyword(s):  
Colorectal Cancer ◽  
Cancer Screening ◽  
Colorectal Cancer Screening ◽  
Screening Test ◽  
Virtual Colonoscopy ◽  
Cancer Screening Test

Validation of a high performing blood test for multiple major cancer screenings.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 10561-10561
Author(s):  
Linhao Xu ◽  
Jun Wang ◽  
Weifeng Ma ◽  
Xin Liu ◽  
Sihui Li ◽  
...  
Keyword(s):  
Cancer Screening ◽  
Blood Test ◽  
Retrospective Cohort ◽  
Early Stage ◽  
Stage I ◽  
Cancer Type ◽  
Data Set ◽  
Specificity And Sensitivity ◽  
Cancer Types ◽  
Stage Stage

10561 Background: Early detection at the localized stage is pivotal for the successful treatment of various cancer types. Although several cancers already have routine screening approaches, the comprehensive utilities are impeded for various reasons, e.g., low accuracy, high cost, limited availability of required facilities, especially in the developing countries. Therefore, an accurate, cost-effective, and non-invasive test for multiple major cancer screening is in high demand. We previously reported a cfDNA methylation test, which can detect five major cancer types with high specificity and sensitivity, especially at the early stage (stage I). These five major cancers, including lung cancer (LC), breast cancer (BC), colorectal cancer (CRC), gastric cancer (GC), and esophageal cancer (EC), account for 56% of new cancer cases and 60% of cancer-related deaths yearly in China. Here, we report the result in an independent cohort as a further validation of this multi-cancer screening test. Methods: The high-throughput targeted methylation profiling platform, Aurora, was used to analyze the plasma samples from an independent retrospective cohort containing 505 healthy controls and ̃200 cases for each cancer type. A locked model based on our previous pilot study (reported in AACR 2020 and 2021) was applied to this data set to assess the overall performance. Results: The Area Under Curves (AUC) of the classifier for LC, BC, CRC, GC and EC are 97.3%, 96.2%, 92.0%, 94.0% and 93.5%, respectively. At a fixed specificity of 99%, the sensitivities for LC, BC, CRC, GC and EC are 84%, 75%, 82%, 85% and 78%, respectively. Conclusions: A methylation blood test for five major cancer screening has been validated in a large retrospective cohort. Its high sensitivity for each cancer type, especially at the early stage (stage I), and easy to use suggests it can be implemented in real clinical world. A large prospective clinical trial is undergoing to further validate this test in asymptomatic populations.

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