A Multianalyte Panel Consisting of Extracellular Vesicle miRNAs and mRNAs, cfDNA, and CA19-9 Shows Utility for Diagnosis and Staging of Pancreatic Ductal Adenocarcinoma

Yang, Zijian; LaRiviere, Michael J.; Ko, Jina; Till, Jacob E.; Christensen, Theresa; Yee, Stephanie S.; Black, Taylor A.; Tien, Kyle; Lin, Andrew A.; Shen, Hanfei; Bhagwat, Neha; Herman, Daniel S.; Adallah, Andrew; O’Hara, Mark H.; Vollmer, Charles M.; Katona, Bryson W.; Stanger, Ben Z.; Issadore, David; Carpenter, Erica L.

doi:10.1158/1078-0432.ccr-19-3313

Cited by 77 publications

(72 citation statements)

References 46 publications

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“…Through the analysis of obtained markers, information from the source tissues can be reflected and cancers or other diseases can be monitored. For example, several recent studies have successfully applied liquid biopsy to achieve diagnosis and staging of PC [ 9 , 10 ]. One of the biomarkers of liquid biopsy, circulating tumor DNA (ctDNA) arises from the apoptosis, necrosis, and lysis of circulating tumor cells, as well as active secretion from tumors [ 11 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

Prognostic value of circulating tumor DNA in pancreatic cancer: a systematic review and meta-analysis

Fang

Meng

Zhang

et al. 2020

Aging

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Increasing evidence has revealed the potential correlation between circulating tumor DNA (ctDNA) and the prognosis of pancreatic cancer, but inconsistent findings have been reported. Therefore, a meta-analysis was performed to evaluate the prognostic value of ctDNA in pancreatic cancer. The Embase, MEDLINE, and Web of Science databases were searched for relevant articles published until April 2020. Articles reporting the correlation between ctDNA and the prognosis of pancreatic cancer were identified through database searches. The pooled hazard ratios (HRs) for prognostic data were calculated and analyzed using Stata software. A total of 2326 patients pooled from 25 eligible studies were included in the meta-analysis to evaluate the prognostic value of ctDNA in pancreatic cancer. Patients with mutations detected or high concentrations of ctDNA had a significantly poorer overall survival (OS) (univariate: HR = 2.54; 95% CI, 2.05-3.14; multivariate: HR = 2.07; 95% CI, 1.69-2.54) and progression-free survival (PFS) (univariate: HR = 2.18; 95% CI, 1.41-3.37; multivariate: HR = 2.20; 95% CI, 1.38-3.52). In conclusion, the present meta-analysis indicates that mutations detected or high concentrations of ctDNA are significant predictors of OS and PFS in patients with pancreatic cancer.

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Section: Introductionmentioning

confidence: 99%

Prognostic value of circulating tumor DNA in pancreatic cancer: a systematic review and meta-analysis

Fang

Meng

Zhang

et al. 2020

Aging

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“…The above study [ 54 ] and the more recent studies indicate the “expansion” of the biomarker field, moving from the “traditional” DNA, RNA and protein biomarkers to novel, versatile analytes and their combinations, such as non-coding RNAs, epigenetic markers, lipids and metabolites, as well as circulating tumor cells and extracellular vesicles (EV) [ 88 ]. For example, Yang et al [ 83 ] performed a multi-parametric analysis of blood tumor-associated EV miRNA and mRNA, circulating cell-free DNA concentration and KRAS G12D/V/R mutations with CA19-9, and demonstrated their higher accuracy for PDAC staging (84%) than imaging alone (accuracy = 64%; P < 0.05). Furthermore, recent advances in computer science, machine learning and artificial intelligence (AI) have given rise to the emerging field of bioinformatics and computational biology which allow analyses of large collections of biological data [ 89 ].…”

Section: Resultsmentioning

confidence: 99%

Non-Invasive Biomarkers for Earlier Detection of Pancreatic Cancer—A Comprehensive Review

Brezgyte

Shah

Jach

et al. 2021

Cancers

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Pancreatic ductal adenocarcinoma (PDAC) carries a deadly diagnosis, due in large part to delayed presentation when the disease is already at an advanced stage. CA19-9 is currently the most commonly utilized biomarker for PDAC; however, it lacks the necessary accuracy to detect precursor lesions or stage I PDAC. Novel biomarkers that could detect this malignancy with improved sensitivity (SN) and specificity (SP) would likely result in more curative resections and more effective therapeutic interventions, changing thus the present dismal survival figures. The aim of this study was to systematically and comprehensively review the scientific literature on non-invasive biomarkers in biofluids such as blood, urine and saliva that were attempting earlier PDAC detection. The search performed covered a period of 10 years (January 2010—August 2020). Data were extracted using keywords search in the three databases: MEDLINE, Web of Science and Embase. The Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool was applied for study selection based on establishing the risk of bias and applicability concerns in Patient Selection, Index test (biomarker assay) and Reference Standard (standard-of-care diagnostic test). Out of initially over 4000 published reports, 49 relevant studies were selected and reviewed in more detail. In addition, we discuss the present challenges and complexities in the path of translating the discovered biomarkers into the clinical setting. Our systematic review highlighted several promising biomarkers that could, either alone or in combination with CA19-9, potentially improve earlier detection of PDAC. Overall, reviewed biomarker studies should aim to improve methodological and reporting quality, and novel candidate biomarkers should be investigated further in order to demonstrate their clinical usefulness. However, challenges and complexities in the path of translating the discovered biomarkers from the research laboratory to the clinical setting remain and would have to be addressed before a more realistic breakthrough in earlier detection of PDAC is achieved.

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“…The reported sensitivity of only one analyte was around 50% and the sensitivity of the multi-analyte strategy was 89% and is similar to the results in this paper from 26 MBC patients and four LBAs. Yang et al recently studied the feasibility of a multi-modal liquid biopsy approach, which included tumor-associated EV miRNA and mRNA, cfDNA, cfDNA KRAS mutations, and CA19-9, for early diagnosis of pancreatic cancer in 204 subjects [ 56 ]. They developed an initial classification model using 14 biomarker candidates, trained a machine-learning model, and achieved a sensitivity of 88% and a specificity of 95% in the validation cohort, thus validating the benefits of a multi-modal approach using a completely different method of analysis.…”

Section: Discussionmentioning

confidence: 99%

Integrative statistical analyses of multiple liquid biopsy analytes in metastatic breast cancer

et al. 2021

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Background Single liquid biopsy analytes (LBAs) have been utilized for therapy selection in metastatic breast cancer (MBC). We performed integrative statistical analyses to examine the clinical relevance of using multiple LBAs: matched circulating tumor cell (CTC) mRNA, CTC genomic DNA (gDNA), extracellular vesicle (EV) mRNA, and cell-free DNA (cfDNA). Methods Blood was drawn from 26 hormone receptor-positive, HER2-negative MBC patients. CTC mRNA and EV mRNA were analyzed using a multi-marker qPCR. Plasma from CTC-depleted blood was utilized for cfDNA isolation. gDNA from CTCs was isolated from mRNA-depleted CTC lysates. CTC gDNA and cfDNA were analyzed by targeted sequencing. Hierarchical clustering was performed within each analyte, and its results were combined into a score termed Evaluation of multiple Liquid biopsy analytes In Metastatic breast cancer patients All from one blood sample (ELIMA.score), which calculates the contribution of each analyte to the overall survival prediction. Singular value decomposition (SVD), mutual information calculation, k-means clustering, and graph-theoretic analysis were conducted to elucidate the dependence between individual analytes. Results A combination of two/three/four LBAs increased the prevalence of patients with actionable signals. Aggregating the results of hierarchical clustering of individual LBAs into the ELIMA.score resulted in a highly significant correlation with overall survival, thereby bolstering evidence for the additive value of using multiple LBAs. Computation of mutual information indicated that none of the LBAs is independent of the others, but the ability of a single LBA to describe the others is rather limited—only CTC gDNA could partially describe the other three LBAs. SVD revealed that the strongest singular vectors originate from all four LBAs, but a majority originated from CTC gDNA. After k-means clustering of patients based on parameters of all four LBAs, the graph-theoretic analysis revealed CTC ERBB2 variants only in patients belonging to one particular cluster. Conclusions The additional benefits of using all four LBAs were objectively demonstrated in this pilot study, which also indicated a relative dominance of CTC gDNA over the other LBAs. Consequently, a multi-parametric liquid biopsy approach deconvolutes the genomic and transcriptomic complexity and should be considered in clinical practice.

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A Multianalyte Panel Consisting of Extracellular Vesicle miRNAs and mRNAs, cfDNA, and CA19-9 Shows Utility for Diagnosis and Staging of Pancreatic Ductal Adenocarcinoma

Abstract: Purpose: To determine whether a multi-analyte liquid biopsy can improve the detection and staging of pancreatic adenocarcinoma (PDAC).

Cited by 77 publications

References 46 publications

Prognostic value of circulating tumor DNA in pancreatic cancer: a systematic review and meta-analysis

Prognostic value of circulating tumor DNA in pancreatic cancer: a systematic review and meta-analysis

Non-Invasive Biomarkers for Earlier Detection of Pancreatic Cancer—A Comprehensive Review

Integrative statistical analyses of multiple liquid biopsy analytes in metastatic breast cancer

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