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Salomon R, Razavi Bazaz S, Mutafopulos K, Gallego-Ortega D, Warkiani M, Weitz D, Jin D. Challenges in blood fractionation for cancer liquid biopsy: how can microfluidics assist? LAB ON A CHIP 2025; 25:1097-1127. [PMID: 39775440 DOI: 10.1039/d4lc00563e] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/11/2025]
Abstract
Liquid biopsy provides a minimally invasive approach to characterise the molecular and phenotypic characteristics of a patient's individual tumour by detecting evidence of cancerous change in readily available body fluids, usually the blood. When applied at multiple points during the disease journey, it can be used to monitor a patient's response to treatment and to personalise clinical management based on changes in disease burden and molecular findings. Traditional liquid biopsy approaches such as quantitative PCR, have tended to look at only a few biomarkers, and are aimed at early detection of disease or disease relapse using predefined markers. With advances in the next generation sequencing (NGS) and single-cell genomics, simultaneous analysis of both circulating tumour DNA (ctDNA) and circulating tumour cells (CTCs) is now a real possibility. To realise this, however, we need to overcome issues with current blood collection and fractionation processes. These include overcoming the need to add a preservative to the collection tube or the need to rapidly send blood tubes to a centralised processing lab with the infrastructure required to fractionate and process the blood samples. This review focuses on outlining the current state of liquid biopsy and how microfluidic blood fractionation tools can be used in cancer liquid biopsy. We describe microfluidic devices that can separate plasma for ctDNA analysis, and devices that are important in isolating the cellular component(s) in liquid biopsy, i.e., individual CTCs and CTC clusters. To facilitate a better understanding of these devices, we propose a new categorisation system based on how these devices operate. The three categories being 1) solid Interaction devices, 2) fluid Interaction devices and 3) external force/active devices. Finally, we conclude that whilst some assays and some cancers are well suited to current microfluidic techniques, new tools are necessary to support broader, clinically relevant multiomic workflows in cancer liquid biopsy.
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Affiliation(s)
- Robert Salomon
- Children's Cancer Institute, Lowy Cancer Research Centre, UNSW, Sydney, Australia.
- Institute for Biomedical Materials and Devices (IBMD)/Faculty of Science, University of Technology Sydney, Sydney, NSW, 2007 Australia
| | - Sajad Razavi Bazaz
- Children's Cancer Institute, Lowy Cancer Research Centre, UNSW, Sydney, Australia.
| | - Kirk Mutafopulos
- Department of Physics, Harvard University, Cambridge, MA, 02138, USA
| | - David Gallego-Ortega
- Institute for Biomedical Materials and Devices (IBMD)/Faculty of Science, University of Technology Sydney, Sydney, NSW, 2007 Australia
- School of Clinical Medicine, Faculty of Medicine, University of New South Wales, Sydney, NSW, 2052, Australia
- School of Biomedical Engineering, University of Technology Sydney, Sydney, New South Wales 2007, Australia
- Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia
| | - Majid Warkiani
- Institute for Biomedical Materials and Devices (IBMD)/Faculty of Science, University of Technology Sydney, Sydney, NSW, 2007 Australia
- School of Biomedical Engineering, University of Technology Sydney, Sydney, New South Wales 2007, Australia
| | - David Weitz
- Department of Physics, Harvard University, Cambridge, MA, 02138, USA
| | - Dayong Jin
- Institute for Biomedical Materials and Devices (IBMD)/Faculty of Science, University of Technology Sydney, Sydney, NSW, 2007 Australia
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Lu J, Zhou C, Pan F, Liu H, Jiang H, Zhong H, Han B. Role of silent mutations in KRAS -mutant tumors. Chin Med J (Engl) 2025; 138:278-288. [PMID: 39654099 PMCID: PMC11771717 DOI: 10.1097/cm9.0000000000003405] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2024] [Indexed: 01/29/2025] Open
Abstract
ABSTRACT Silent mutations within the RAS gene have garnered increasing attention for their potential roles in tumorigenesis and therapeutic strategies. Kirsten-RAS ( KRAS ) mutations, predominantly oncogenic, are pivotal drivers in various cancers. While extensive research has elucidated the molecular mechanisms and biological consequences of active KRAS mutations, the functional significance of silent mutations remains relatively understudied. This review synthesizes current knowledge on KRAS silent mutations, highlighting their impact on cancer development. Silent mutations, which do not alter protein sequences but can affect RNA stability and translational efficiency, pose intriguing questions regarding their contribution to tumor biology. Understanding these mutations is crucial for comprehensively unraveling KRAS -driven oncogenesis and exploring novel therapeutic avenues. Moreover, investigations into the clinical implications of silent mutations in KRAS -mutant tumors suggest potential diagnostic and therapeutic strategies. Despite being in early stages, research on KRAS silent mutations holds promise for uncovering novel insights that could inform personalized cancer treatments. In conclusion, this review underscores the evolving landscape of KRAS silent mutations, advocating for further exploration to bridge fundamental biology with clinical applications in oncology.
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Affiliation(s)
- Jun Lu
- Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
- Shanghai Institute of Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
- Translational Medical Research Platform for Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
- Department of Bio-bank, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
| | - Chao Zhou
- Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
| | - Feng Pan
- Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
| | - Hongyu Liu
- Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
| | - Haohua Jiang
- Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
| | - Hua Zhong
- Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
- Translational Medical Research Platform for Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
| | - Baohui Han
- Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
- Shanghai Institute of Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
- Translational Medical Research Platform for Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
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Hussung S, Hess ME, Haghighi EB, Wittel UA, Boerries M, Fritsch RM. Integrated Analysis of Cell-Free DNA and Novel Protein Biomarkers for Stratification and Therapy Monitoring in Stage IV Pancreatic Cancer: A Preliminary Study. Diagnostics (Basel) 2024; 15:49. [PMID: 39795577 PMCID: PMC11720586 DOI: 10.3390/diagnostics15010049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2024] [Revised: 12/25/2024] [Accepted: 12/26/2024] [Indexed: 01/13/2025] Open
Abstract
Background: Given the poor prognosis of metastatic pancreatic adenocarcinoma (mPDAC), closer disease monitoring through liquid biopsy, most frequently based on serial measurements of cell-free mutated KRAS (KRASmut cfDNA), has become a highly active research focus, aimed at improving patients' long-term outcomes. However, most of the available data show only a limited predictive and prognostic value of single-parameter-based methods. We hypothesized that a combined longitudinal analysis of KRASmut cfDNA and novel protein biomarkers could improve risk stratification and molecular monitoring of patients with mPDAC. Methods: We prospectively collected 160 plasma samples from 47 patients with mPDAC at our institution. Highly sensitive single-target ddPCR assays were employed to detect and quantify KRASmut cfDNA. Additionally, analysis of ten protein biomarkers was performed through Enzyme-linked Immunosorbent Assay (ELISA), and Carbohydrate-Antigen 19-9 (CA 19-9) dynamics were registered. Results: KRASmut cfDNA was detectable in 37/47 (78.7%) patients throughout the course of study, and CA 19-9 levels were elevated in 40 out of 47 (85.1%) patients. KRASmut cfDNA increase at the time of the first follow-up could predict inferior progression-free survival (PFS) (Hazard ratio (HR) = 3.40, p = 0.0003) and overall survival (OS) (HR = 4.91, p < 0.0001). In contrast to CA 19-9 kinetics, which were not predictive of outcome, integrated analysis of KRASmut cfDNA combined with six evaluated circulating protein biomarkers allowed basal risk stratification at the time of the first follow-up (HR = 10.2, p = 0.0014). Conclusions: A combined longitudinal analysis of KRASmut cfDNA with selected protein biomarkers offers significantly improved prognostic value for patients with mPDAC compared to single-parameter methods. This innovative approach is a step forward in the molecular monitoring of mPDAC and should be validated in further prospective studies.
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Affiliation(s)
- Saskia Hussung
- Department of Medicine I (Hematology, Oncology and Stem Cell Transplantation), Freiburg University Medical Center, 79106 Freiburg, Germany;
- Department of Medical Oncology and Hematology, Zurich University Hospital, 8091 Zurich, Switzerland
| | - Maria E. Hess
- Institute of Medical Bioinformatics and Systems Medicine, Medical Center—University of Freiburg, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany; (M.E.H.); (E.B.H.); (M.B.)
- Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany
| | - Elham Bavafaye Haghighi
- Institute of Medical Bioinformatics and Systems Medicine, Medical Center—University of Freiburg, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany; (M.E.H.); (E.B.H.); (M.B.)
| | - Uwe A. Wittel
- Department of Surgery, Freiburg University Medical Center, 79106 Freiburg, Germany;
| | - Melanie Boerries
- Institute of Medical Bioinformatics and Systems Medicine, Medical Center—University of Freiburg, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany; (M.E.H.); (E.B.H.); (M.B.)
- German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- German Cancer Consortium (DKTK), Partner Site Freiburg, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- Comprehensive Cancer Center Freiburg (CCCF), Medical Center—University of Freiburg, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany
| | - Ralph M. Fritsch
- Department of Medicine I (Hematology, Oncology and Stem Cell Transplantation), Freiburg University Medical Center, 79106 Freiburg, Germany;
- Department of Medical Oncology and Hematology, Zurich University Hospital, 8091 Zurich, Switzerland
- Department of Surgery, Freiburg University Medical Center, 79106 Freiburg, Germany;
- German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- German Cancer Consortium (DKTK), Partner Site Freiburg, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
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Bravo AC, Morão B, Luz A, Dourado R, Oliveira B, Guedes A, Moreira-Barbosa C, Fidalgo C, Mascarenhas-Lemos L, Costa-Santos MP, Maio R, Paulino J, Viana Baptista P, Fernandes AR, Cravo M. Bringing Hope to Improve Treatment in Pancreatic Ductal Adenocarcinoma-A New Tool for Molecular Profiling of KRAS Mutations in Tumor and Plasma Samples. Cancers (Basel) 2024; 16:3544. [PMID: 39456638 PMCID: PMC11506488 DOI: 10.3390/cancers16203544] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Revised: 10/10/2024] [Accepted: 10/14/2024] [Indexed: 10/28/2024] Open
Abstract
BACKGROUND/OBJECTIVES Pancreatic ductal adenocarcinoma (PDAC) incidence is rising, and prognosis remains poor due to late diagnosis and limited effective therapies. Currently, patients are treated based on TNM staging, without molecular tumor characterization. This study aimed to validate a technique that combines the amplification refractory mutation system (ARMS) with high-resolution melting analysis (HRMA) for detecting mutations in codon 12 of KRAS in tumor and plasma, and to assess its prognostic value. METHODS Prospective study including patients with newly diagnosed PDAC with tumor and plasma samples collected before treatment. Mutations in codon 12 of KRAS (G12D, G12V, G12C, and G12R) were detected using ARMS-HRMA and compared to Sanger sequencing (SS). Univariate and multivariate analyses were used to evaluate the prognostic significance of these mutations. RESULTS A total of 88 patients, 93% with ECOG-PS 0-1, 57% with resectable disease. ARMS-HRMA technique showed a higher sensitivity than SS, both in tumor and plasma (77% vs. 51%; 25 vs. 0%, respectively). The most frequent mutation was G12D (n = 32, 36%), followed by G12V (n = 22, 25%). On multivariate analysis, patients with G12D and/or G12C mutations, either in tumor or plasma, had lower PFS (HR 1.792, 95% CI 1.061-3.028, p = 0.029; HR 2.081, 95% CI 1.014-4.272, p = 0.046, respectively) and lower OS (HR 1.757, 95% CI 1.013-3.049, p = 0.045; HR 2.229, 95% CI 1.082-4.594, p = 0.030, respectively). CONCLUSIONS ARMS-HRMA is a rapid and cost-effective method for detecting KRAS mutations in PDAC patients, offering the potential for stratifying prognosis and guiding treatment decisions. The presence of G12D and G12C mutations in both tumor and plasma is associated with a poorer prognosis.
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Affiliation(s)
- Ana Catarina Bravo
- Hospital Beatriz Ângelo, 2674-514 Loures, Portugal; (A.C.B.); (B.M.); (A.G.); (C.M.-B.); (C.F.); (R.M.)
| | - Bárbara Morão
- Hospital Beatriz Ângelo, 2674-514 Loures, Portugal; (A.C.B.); (B.M.); (A.G.); (C.M.-B.); (C.F.); (R.M.)
| | - André Luz
- Associate Laboratory i4HB—Institute for Health and Bioeconomy, NOVA School of Science and Technology, NOVA University Lisbon, 2829-516 Caparica, Portugal; (A.L.); (R.D.); (B.O.); (P.V.B.); (A.R.F.)
- UCIBIO—Applied Molecular Biosciences Unit, Department of Life Sciences, NOVA School of Science and Technology, NOVA University Lisbon, 2829-516 Caparica, Portugal
| | - Rúben Dourado
- Associate Laboratory i4HB—Institute for Health and Bioeconomy, NOVA School of Science and Technology, NOVA University Lisbon, 2829-516 Caparica, Portugal; (A.L.); (R.D.); (B.O.); (P.V.B.); (A.R.F.)
- UCIBIO—Applied Molecular Biosciences Unit, Department of Life Sciences, NOVA School of Science and Technology, NOVA University Lisbon, 2829-516 Caparica, Portugal
| | - Beatriz Oliveira
- Associate Laboratory i4HB—Institute for Health and Bioeconomy, NOVA School of Science and Technology, NOVA University Lisbon, 2829-516 Caparica, Portugal; (A.L.); (R.D.); (B.O.); (P.V.B.); (A.R.F.)
- UCIBIO—Applied Molecular Biosciences Unit, Department of Life Sciences, NOVA School of Science and Technology, NOVA University Lisbon, 2829-516 Caparica, Portugal
| | - Ana Guedes
- Hospital Beatriz Ângelo, 2674-514 Loures, Portugal; (A.C.B.); (B.M.); (A.G.); (C.M.-B.); (C.F.); (R.M.)
- Hospital da Luz Learning Health, Luz Saúde, 1500-650 Lisboa, Portugal
| | - Catarina Moreira-Barbosa
- Hospital Beatriz Ângelo, 2674-514 Loures, Portugal; (A.C.B.); (B.M.); (A.G.); (C.M.-B.); (C.F.); (R.M.)
- Hospital da Luz Learning Health, Luz Saúde, 1500-650 Lisboa, Portugal
| | - Catarina Fidalgo
- Hospital Beatriz Ângelo, 2674-514 Loures, Portugal; (A.C.B.); (B.M.); (A.G.); (C.M.-B.); (C.F.); (R.M.)
- Hospital da Luz, 1500-650 Lisboa, Portugal; (L.M.-L.); (J.P.)
| | - Luís Mascarenhas-Lemos
- Hospital da Luz, 1500-650 Lisboa, Portugal; (L.M.-L.); (J.P.)
- NOVA Medical School, 1169-056 Lisboa, Portugal
- Catolica Medical School, 1649-023 Lisboa, Portugal
| | | | - Rui Maio
- Hospital Beatriz Ângelo, 2674-514 Loures, Portugal; (A.C.B.); (B.M.); (A.G.); (C.M.-B.); (C.F.); (R.M.)
- Hospital da Luz, 1500-650 Lisboa, Portugal; (L.M.-L.); (J.P.)
- NOVA Medical School, 1169-056 Lisboa, Portugal
| | - Jorge Paulino
- Hospital da Luz, 1500-650 Lisboa, Portugal; (L.M.-L.); (J.P.)
- NOVA Medical School, 1169-056 Lisboa, Portugal
| | - Pedro Viana Baptista
- Associate Laboratory i4HB—Institute for Health and Bioeconomy, NOVA School of Science and Technology, NOVA University Lisbon, 2829-516 Caparica, Portugal; (A.L.); (R.D.); (B.O.); (P.V.B.); (A.R.F.)
- UCIBIO—Applied Molecular Biosciences Unit, Department of Life Sciences, NOVA School of Science and Technology, NOVA University Lisbon, 2829-516 Caparica, Portugal
| | - Alexandra R. Fernandes
- Associate Laboratory i4HB—Institute for Health and Bioeconomy, NOVA School of Science and Technology, NOVA University Lisbon, 2829-516 Caparica, Portugal; (A.L.); (R.D.); (B.O.); (P.V.B.); (A.R.F.)
- UCIBIO—Applied Molecular Biosciences Unit, Department of Life Sciences, NOVA School of Science and Technology, NOVA University Lisbon, 2829-516 Caparica, Portugal
| | - Marília Cravo
- Hospital da Luz, 1500-650 Lisboa, Portugal; (L.M.-L.); (J.P.)
- Lisbon School of Medicine, Universidade de Lisboa, 1649-028 Lisboa, Portugal
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Hálková T, Bunganič B, Traboulsi E, Minárik M, Zavoral M, Benešová L. Prognostic Role of Specific KRAS Mutations Detected in Aspiration and Liquid Biopsies from Patients with Pancreatic Cancer. Genes (Basel) 2024; 15:1302. [PMID: 39457426 PMCID: PMC11507146 DOI: 10.3390/genes15101302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Revised: 09/28/2024] [Accepted: 10/03/2024] [Indexed: 10/28/2024] Open
Abstract
Background/Objectives: Although the overall survival prognosis of patients in advanced stages of pancreatic ductal adenocarcinoma (PDAC) is poor, typically ranging from days to months from diagnosis, there are rare cases of patients remaining in therapy for longer periods of time. Early estimations of survival prognosis would allow rational decisions on complex therapy interventions, including radical surgery and robust systemic therapy regimens. Understandably, there is great interest in finding prognostic markers that can be used for patient stratification. We determined the role of various KRAS mutations in the prognosis of PDAC patients using biopsy samples and circulating tumor DNA. Methods: A total of 118 patients with PDAC, clinically confirmed by endoscopic ultrasound-guided fine-needle aspiration biopsy (EUS-FNB), were included in the study. DNA was extracted from cytological slides following a standard cytology evaluation to ensure adequacy (viability and quantity) and to mark the tumor cell fraction. Circulating tumor DNA (ctDNA) was extracted from plasma samples of 45 patients in stage IV of the disease. KRAS mutations in exons 12 and 13 were detected by denaturing capillary electrophoresis (DCE), revealing a minute presence of mutation-specific heteroduplexes. Kaplan-Meier survival curves were calculated for individual KRAS mutation types. Results:KRAS mutations were detected in 90% of tissue (106/118) and 44% of plasma (20/45) samples. All mutations were localized at exon 2, codon 12, with G12D (GGT > GAT) being the most frequent at 44% (47/106) and 65% (13/20), followed by other types including G12V (GGT > GTT) at 31% (33/106) and 10% (2/20), G12R (GGT > CGT) at 17% (18/106) and 10% (2/20), G12C (GGT/TGT) at 5% (5/106) and 0% (0/20) and G12S (GGT/AGT) at 1% (1/106) and 5% (1/20) in tissue and plasma samples, respectively. Two patients had two mutations simultaneously (G12V + G12S and G12D + G12S) in both types of samples (2%, 2/106 and 10%, 2/20 in tissue and plasma samples, respectively). The median survival of patients with the G12D mutation in tissues was less than half that of other patients (median survival 101 days, 95% CI: 80-600 vs. 228 days, 95% CI: 184-602), with a statistically significant overall difference in survival (p = 0.0080, log-rank test), and furthermore it was less than that of all combined patients with other mutation types (101 days, 95% CI: 80-600 vs. 210 days, 95% CI: 161-602, p = 0.0166). For plasma samples, the survival of patients with this mutation was six times shorter than that of patients without the G12D mutation (27 days, 95% CI: 8-334 vs. 161 days, 95% CI: 107-536, p = 0.0200). In contrast, patients with detected KRAS G12R in the tissue survived nearly twice as long as other patients in the aggregate (286 days, 95% CI: 70-602 vs. 162 days, 95% CI: 122-600, p = 0.0374) or patients with other KRAS mutations (286 days, 95% CI: 70-602 vs. 137 days, 95% CI: 107-600, p = 0.0257). Conclusions: Differentiation of specific KRAS mutations in EUS-FNB and ctDNA (above all, the crucial G12D and G12R) is feasible in routine management of PDAC patients and imperative for assessment of prognosis.
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Affiliation(s)
- Tereza Hálková
- Centre for Applied Genomics of Solid Tumors (CEGES), Genomac Research Institute, Drnovská 1112/60, 161 00 Prague, Czech Republic
- Department of Biochemistry, Faculty of Science, Charles University, Hlavova 8/2030, 128 00 Prague, Czech Republic
| | - Bohuš Bunganič
- Department of Medicine, First Faculty of Medicine, Charles University and Military University Hospital, U Vojenské Nemocnice 1200, 169 02 Prague, Czech Republic
| | - Eva Traboulsi
- Department of Pathology, Military University Hospital Prague, U Vojenské Nemocnice 1200, 169 02 Prague, Czech Republic
| | - Marek Minárik
- Department of Analytical Chemistry, Faculty of Science, Charles University, Hlavova 8/2030, 128 00 Prague, Czech Republic;
| | - Miroslav Zavoral
- Department of Medicine, First Faculty of Medicine, Charles University and Military University Hospital, U Vojenské Nemocnice 1200, 169 02 Prague, Czech Republic
| | - Lucie Benešová
- Centre for Applied Genomics of Solid Tumors (CEGES), Genomac Research Institute, Drnovská 1112/60, 161 00 Prague, Czech Republic
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Huerta M, Martín-Arana J, Gimeno-Valiente F, Carbonell-Asins JA, García-Micó B, Martínez-Castedo B, Robledo-Yagüe F, Camblor DG, Fleitas T, García Bartolomé M, Alfaro-Cervelló C, Garcés-Albir M, Dorcaratto D, Muñoz-Forner E, Seguí V, Mora-Oliver I, Gambardella V, Roselló S, Sabater L, Roda D, Cervantes A, Tarazona N. ctDNA whole exome sequencing in pancreatic ductal adenocarcinoma unveils organ-dependent metastatic mechanisms and identifies actionable alterations in fast progressing patients. Transl Res 2024; 271:105-115. [PMID: 38782356 DOI: 10.1016/j.trsl.2024.05.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Revised: 04/28/2024] [Accepted: 05/06/2024] [Indexed: 05/25/2024]
Abstract
Understanding progression mechanisms and developing new targeted therapies is imperative in pancreatic ductal adenocarcinoma (PDAC). In this study, 80 metastatic PDAC patients were prospectively recruited and divided into discovery (n=37) and validation (n=43) cohorts. Tumor and plasma samples taken at diagnosis were pair analyzed using whole exome sequencing (WES) in patients belonging to the discovery cohort alone. The variant allele frequency (VAF) of KRAS mutations was measured by ddPCR in plasma at baseline and response assessment in all patients. Plasma WES identified at least one pathogenic variant across the cohort, uncovering oncogenic mechanisms, DNA repair, microsatellite instability, and alterations in the TGFb pathway. Interestingly, actionable mutations were mostly found in plasma rather than tissue. Patients with shorter survival showed enrichment in cellular organization regulatory pathways. Through WES we could identify a specific molecular profile of patients with liver metastasis, which exhibited exclusive mutations in genes related to the adaptive immune response pathway, highlighting the importance of the immune system in liver metastasis development. Moreover, KRAS mutations in plasma (both at diagnosis and persistent at follow-up) correlated with shorter progression free survival (PFS). Patients presenting a reduction of over 84.75 % in KRAS VAF at response assessment had similar PFS to KRAS-negative patients. Overall, plasma WES reveals molecular profiles indicative of rapid progression, potentially actionable targets, and associations between adaptive immune response pathway alterations and liver tropism.
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Affiliation(s)
- Marisol Huerta
- Department of Medical Oncology, INCLIVA Biomedical Research Institute, University of Valencia, Valencia, Spain; CIBERONC, Instituto de Salud Carlos III, Madrid, Spain
| | - Jorge Martín-Arana
- Department of Medical Oncology, INCLIVA Biomedical Research Institute, University of Valencia, Valencia, Spain; CIBERONC, Instituto de Salud Carlos III, Madrid, Spain
| | - Francisco Gimeno-Valiente
- Cancer Evolution and Genome Instability Laboratory, University College London Cancer Institute, London, UK
| | | | - Blanca García-Micó
- Department of Medical Oncology, INCLIVA Biomedical Research Institute, University of Valencia, Valencia, Spain; CIBERONC, Instituto de Salud Carlos III, Madrid, Spain
| | - Belén Martínez-Castedo
- Department of Medical Oncology, INCLIVA Biomedical Research Institute, University of Valencia, Valencia, Spain; CIBERONC, Instituto de Salud Carlos III, Madrid, Spain
| | - Fabián Robledo-Yagüe
- Bioinformatics Unit, INCLIVA Biomedical Research Institute, University of Valencia, Spain
| | - Daniel G Camblor
- Department of Medical Oncology, INCLIVA Biomedical Research Institute, University of Valencia, Valencia, Spain
| | - Tania Fleitas
- Department of Medical Oncology, INCLIVA Biomedical Research Institute, University of Valencia, Valencia, Spain; CIBERONC, Instituto de Salud Carlos III, Madrid, Spain
| | - Miguel García Bartolomé
- Department of Medical Oncology, INCLIVA Biomedical Research Institute, University of Valencia, Valencia, Spain
| | - Clara Alfaro-Cervelló
- Department of Pathology, INCLIVA Biomedical Research Institute, University of Valencia, Valencia, Spain
| | - Marina Garcés-Albir
- Liver, Biliary and Pancreatic Unit, Department of General Surgery, INCLIVA Biomedical Research Institute, Hospital Clínico Universitario de Valencia, University of Valencia, Valencia, Spain
| | - Dimitri Dorcaratto
- Liver, Biliary and Pancreatic Unit, Department of General Surgery, INCLIVA Biomedical Research Institute, Hospital Clínico Universitario de Valencia, University of Valencia, Valencia, Spain
| | - Elena Muñoz-Forner
- Liver, Biliary and Pancreatic Unit, Department of General Surgery, INCLIVA Biomedical Research Institute, Hospital Clínico Universitario de Valencia, University of Valencia, Valencia, Spain
| | - Víctor Seguí
- Department of Medical Oncology, INCLIVA Biomedical Research Institute, University of Valencia, Valencia, Spain
| | - Isabel Mora-Oliver
- Liver, Biliary and Pancreatic Unit, Department of General Surgery, INCLIVA Biomedical Research Institute, Hospital Clínico Universitario de Valencia, University of Valencia, Valencia, Spain
| | - Valentina Gambardella
- Department of Medical Oncology, INCLIVA Biomedical Research Institute, University of Valencia, Valencia, Spain; CIBERONC, Instituto de Salud Carlos III, Madrid, Spain
| | - Susana Roselló
- Department of Medical Oncology, INCLIVA Biomedical Research Institute, University of Valencia, Valencia, Spain; CIBERONC, Instituto de Salud Carlos III, Madrid, Spain
| | - Luis Sabater
- Liver, Biliary and Pancreatic Unit, Department of General Surgery, INCLIVA Biomedical Research Institute, Hospital Clínico Universitario de Valencia, University of Valencia, Valencia, Spain
| | - Desamparados Roda
- Department of Medical Oncology, INCLIVA Biomedical Research Institute, University of Valencia, Valencia, Spain; CIBERONC, Instituto de Salud Carlos III, Madrid, Spain
| | - Andrés Cervantes
- Department of Medical Oncology, INCLIVA Biomedical Research Institute, University of Valencia, Valencia, Spain; CIBERONC, Instituto de Salud Carlos III, Madrid, Spain.
| | - Noelia Tarazona
- Department of Medical Oncology, INCLIVA Biomedical Research Institute, University of Valencia, Valencia, Spain; CIBERONC, Instituto de Salud Carlos III, Madrid, Spain.
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Mishra M, Ahmed R, Das DK, Pramanik DD, Dash SK, Pramanik A. Recent Advancements in the Application of Circulating Tumor DNA as Biomarkers for Early Detection of Cancers. ACS Biomater Sci Eng 2024; 10:4740-4756. [PMID: 38950521 PMCID: PMC11322919 DOI: 10.1021/acsbiomaterials.4c00606] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2024] [Revised: 05/24/2024] [Accepted: 06/21/2024] [Indexed: 07/03/2024]
Abstract
Early detection of cancer is vital for increasing patient survivability chances. The three major techniques used to diagnose cancers are instrumental examination, tissue biopsy, and tumor biomarker detection. Circulating tumor DNA (ctDNA) has gained much attention in recent years due to advantages over traditional technology, such as high sensitivity, high specificity, and noninvasive nature. Through the mechanism of apoptosis, necrosis, and circulating exosome release in tumor cells, ctDNA can spread throughout the circulatory system and carry modifications such as methylations, mutations, gene rearrangements, and microsatellite instability. Traditional gene-detection technology struggles to achieve real-time, low-cost, and portable ctDNA measurement, whereas electrochemical biosensors offer low cost, high specificity alongside sensitivity, and portability for the detection of ctDNA. Therefore, this review focuses on describing the recent advancements in ctDNA biomarkers for various cancer types and biosensor developments for real-time, noninvasive, and rapid ctDNA detection. Further in the review, ctDNA sensors are also discussed in regards to their selections of probes for receptors based on the electrode surface recognition elements.
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Affiliation(s)
- Mahima Mishra
- Amity Institute
of Biotechnology, Amity University, Noida 201301, India
| | - Rubai Ahmed
- Department of Physiology, University of Gour Banga, Malda-732103, West Bengal, India
| | - Deepak Kumar Das
- Department
of Chemistry and Nanoscience, GLA University, Mathura, 281406 Uttar Pradesh, India
| | | | - Sandeep Kumar Dash
- Department of Physiology, University of Gour Banga, Malda-732103, West Bengal, India
| | - Arindam Pramanik
- Amity Institute
of Biotechnology, Amity University, Noida 201301, India
- School of Medicine, University of Leeds, Leeds LS53RL, United Kingdom
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8
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Turabi K, Klute K, Radhakrishnan P. Decoding the Dynamics of Circulating Tumor DNA in Liquid Biopsies. Cancers (Basel) 2024; 16:2432. [PMID: 39001494 PMCID: PMC11240538 DOI: 10.3390/cancers16132432] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2024] [Revised: 06/27/2024] [Accepted: 06/28/2024] [Indexed: 07/16/2024] Open
Abstract
Circulating tumor DNA (ctDNA), a fragment of tumor DNA found in the bloodstream, has emerged as a revolutionary tool in cancer management. This review delves into the biology of ctDNA, examining release mechanisms, including necrosis, apoptosis, and active secretion, all of which offer information about the state and nature of the tumor. Comprehensive DNA profiling has been enabled by methods such as whole genome sequencing and methylation analysis. The low abundance of the ctDNA fraction makes alternative techniques, such as digital PCR and targeted next-generation exome sequencing, more valuable and accurate for mutation profiling and detection. There are numerous clinical applications for ctDNA analysis, including non-invasive liquid biopsies for minimal residual disease monitoring to detect cancer recurrence, personalized medicine by mutation profiling for targeted therapy identification, early cancer detection, and real-time evaluation of therapeutic response. Integrating ctDNA analysis into routine clinical practice creates promising avenues for successful and personalized cancer care, from diagnosis to treatment and follow-up.
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Affiliation(s)
- Khadija Turabi
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA
- Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Kelsey Klute
- Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA
- Division of Oncology and Hematology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Prakash Radhakrishnan
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA
- Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA
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9
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Huang L, Lv Y, Guan S, Yan H, Han L, Wang Z, Han Q, Dai G, Shi Y. High somatic mutations in circulating tumor DNA predict response of metastatic pancreatic ductal adenocarcinoma to first-line nab-paclitaxel plus S-1: prospective study. J Transl Med 2024; 22:184. [PMID: 38378604 PMCID: PMC10877900 DOI: 10.1186/s12967-024-04989-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2023] [Accepted: 02/12/2024] [Indexed: 02/22/2024] Open
Abstract
AIMS We previously showed that the nab-paclitaxel plus S-1 (NPS) regimen had promising effects against metastatic pancreatic ducal adenocarcinoma (mPDAC), whose efficacy however could not be precisely predicted by routine biomarkers. This prospective study aimed to investigate the values of mutations in circulating tumor DNA (ctDNA) and their dynamic changes in predicting response of mPDAC to NPS chemotherapy. METHODS Paired tumor tissue and blood samples were prospectively collected from patients with mPDAC receiving first-line NPS chemotherapy, and underwent next-generation sequencing with genomic profiling of 425 genes for ctDNA. High mutation allelic frequency (MAF) was defined as ≥ 30% and ≥ 5% in tumor tissue and blood, respectively. Kappa statistics were used to assess agreement between mutant genes in tumor and ctDNA. Associations of mutations in ctDNA and their dynamic changes with tumor response, overall survival (OS), and progression-free survival (PFS) were assessed using the Kaplan-Meier method, multivariable-adjusted Cox proportional hazards regression, and longitudinal data analysis. RESULTS 147 blood samples and 43 paired tumor specimens from 43 patients with mPDAC were sequenced. The most common driver genes with high MAF were KRAS (tumor, 35%; ctDNA, 37%) and TP53 (tumor, 37%; ctDNA, 33%). Mutation rates of KRAS and TP53 in ctDNA were significantly higher in patients with liver metastasis, with baseline CA19-9 ≥ 2000 U/mL, and/or without an early CA19-9 response. κ values for the 5 most commonly mutated genes between tumor and ctDNA ranged from 0.48 to 0.76. MAFs of the genes mostly decreased sequentially during subsequent measurements, which significantly correlated with objective response, with an increase indicating cancer progression. High mutations of KRAS and ARID1A in both tumor and ctDNA, and of TP53, CDKN2A, and SMAD4 in ctDNA but not in tumor were significantly associated with shorter survival. When predicting 6-month OS, AUCs for the 5 most commonly mutated genes in ctDNA ranged from 0.59 to 0.84, larger than for genes in tumor (0.56 to 0.71) and for clinicopathologic characteristics (0.51 to 0.68). Repeated measurements of mutations in ctDNA significantly differentiated survival and tumor response. Among the 31 patients with ≥ 2 ctDNA tests, longitudinal analysis of changes in gene MAF showed that ctDNA progression was 60 and 58 days ahead of radiologic and CA19-9 progression for 48% and 42% of the patients, respectively. CONCLUSIONS High mutations of multiple driving genes in ctDNA and their dynamic changes could effectively predict response of mPDAC to NPS chemotherapy, with promising reliable predictive performance superior to routine clinicopathologic parameters. Inspiringly, longitudinal ctDNA tracking could predict disease progression about 2 months ahead of radiologic or CA19-9 evaluations, with the potential to precisely devise individualized therapeutic strategies for mPDAC.
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Affiliation(s)
- Lei Huang
- Medical Center on Aging of Ruijin Hospital, MCARJH, Shanghai Jiaotong University School of Medicine, 197 Ruijin Er Road, Shanghai, 200025, China.
- Department of Oncology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
| | - Yao Lv
- Department of Medical Oncology, Chinese PLA General Hospital, 28 Fuxing Road, Beijing, 100853, China
| | - Shasha Guan
- Department of Medical Oncology, Chinese PLA General Hospital, 28 Fuxing Road, Beijing, 100853, China
| | - Huan Yan
- Department of Medical Oncology, Chinese PLA General Hospital, 28 Fuxing Road, Beijing, 100853, China
| | - Lu Han
- Department of Medical Oncology, Chinese PLA General Hospital, 28 Fuxing Road, Beijing, 100853, China
| | - Zhikuan Wang
- Department of Medical Oncology, Chinese PLA General Hospital, 28 Fuxing Road, Beijing, 100853, China.
| | - Quanli Han
- Department of Medical Oncology, Chinese PLA General Hospital, 28 Fuxing Road, Beijing, 100853, China.
| | - Guanghai Dai
- Department of Medical Oncology, Chinese PLA General Hospital, 28 Fuxing Road, Beijing, 100853, China.
| | - Yan Shi
- Department of General Surgery, Shanghai Seventh People's Hospital, Shanghai University of Traditional Chinese Medicine, 358 Datong Road, Gaoqiao Town, Shanghai, 200137, China.
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10
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Motobayashi H, Kitahata Y, Okada KI, Miyazawa M, Ueno M, Hayami S, Miyamoto A, Shimizu A, Sato M, Yoshimura T, Nakamura Y, Takemoto N, Nakai T, Hyo T, Matsumoto K, Yamaue H, Kawai M. Short-term serial circulating tumor DNA assessment predicts therapeutic efficacy for patients with advanced pancreatic cancer. J Cancer Res Clin Oncol 2024; 150:35. [PMID: 38277079 PMCID: PMC10817839 DOI: 10.1007/s00432-023-05594-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2023] [Accepted: 12/22/2023] [Indexed: 01/27/2024]
Abstract
PURPOSE We investigated the potential clinical utility of short-term serial KRAS-mutated circulating cell-free tumor DNA (ctDNA) assessment for predicting therapeutic response in patients undergoing first-line chemotherapy for advanced pancreatic cancer. METHODS We collected 144 blood samples from 18 patients with locally advanced or metastatic cancer that were undergoing initial first-line chemotherapy of gemcitabine plus nab-paclitaxel (GEM plus nab-PTX). Analysis of KRAS-mutated ctDNA was quantified by digital droplet polymerase chain reaction (ddPCR) as mutant allele frequency (MAF). This study investigated pretreatment KRAS-mutated ctDNA status and ctDNA kinetics every few days (days 1, 3, 5 and 7) after initiation of chemotherapy and their potential as predictive indicators. RESULTS Of the 18 enrolled patients, an increase in KRAS-mutated ctDNA MAF values from day 0-7 after initiation of chemotherapy was significantly associated with disease progression (P < 0.001). Meanwhile, positive pretreatment ctDNA status (MAF ≥ 0.02%) (P = 0.585) and carbohydrate antigen 19-9 (CA19-9) values above the median (P = 0.266) were not associated with disease progression. In univariate analysis, this short-term increase in ctDNA MAF values (day 0-7) was found to be associated with significantly shorter progression free survival (PFS) (hazard ration [HR], 24.234; range, (2.761-212.686); P = 0.0002). CONCLUSION This short-term ctDNA kinetics assessment may provide predictive information to reflect real-time therapeutic response and lead to effective refinement of regimen in patients with advanced pancreatic cancer undergoing systemic chemotherapy.
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Affiliation(s)
- Hideki Motobayashi
- Second Department of Surgery, School of Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama, 641-8510, Japan
| | - Yuji Kitahata
- Second Department of Surgery, School of Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama, 641-8510, Japan.
| | - Ken-Ichi Okada
- Second Department of Surgery, School of Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama, 641-8510, Japan
| | - Motoki Miyazawa
- Second Department of Surgery, School of Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama, 641-8510, Japan
| | - Masaki Ueno
- Second Department of Surgery, School of Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama, 641-8510, Japan
| | - Shinya Hayami
- Second Department of Surgery, School of Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama, 641-8510, Japan
| | - Atsushi Miyamoto
- Second Department of Surgery, School of Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama, 641-8510, Japan
| | - Atsushi Shimizu
- Second Department of Surgery, School of Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama, 641-8510, Japan
| | - Masatoshi Sato
- Second Department of Surgery, School of Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama, 641-8510, Japan
| | - Tomohiro Yoshimura
- Second Department of Surgery, School of Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama, 641-8510, Japan
| | - Yuki Nakamura
- Second Department of Surgery, School of Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama, 641-8510, Japan
| | - Norio Takemoto
- Second Department of Surgery, School of Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama, 641-8510, Japan
| | - Tomoki Nakai
- Second Department of Surgery, School of Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama, 641-8510, Japan
| | - Takahiko Hyo
- Second Department of Surgery, School of Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama, 641-8510, Japan
| | - Kyohei Matsumoto
- Second Department of Surgery, School of Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama, 641-8510, Japan
| | - Hiroki Yamaue
- Department of Cancer Immunology, Wakayama Medical University, Wakayama, Japan
| | - Manabu Kawai
- Second Department of Surgery, School of Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama, 641-8510, Japan
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Stosic K, Senar OA, Tarfouss J, Bouchart C, Navez J, Van Laethem JL, Arsenijevic T. A Comprehensive Review of the Potential Role of Liquid Biopsy as a Diagnostic, Prognostic, and Predictive Biomarker in Pancreatic Ductal Adenocarcinoma. Cells 2023; 13:3. [PMID: 38201207 PMCID: PMC10778087 DOI: 10.3390/cells13010003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 12/13/2023] [Accepted: 12/15/2023] [Indexed: 01/12/2024] Open
Abstract
Pancreatic ductal adenocarcinoma is one of the most lethal malignant diseases, with a mortality rate being close to incidence. Due to its heterogeneity and plasticity, as well as the lack of distinct symptoms in the early phases, it is very often diagnosed at an advanced stage, resulting in poor prognosis. Traditional tissue biopsies remain the gold standard for making a diagnosis, but have an obvious disadvantage in their inapplicability for frequent sampling. Blood-based biopsies represent a non-invasive method which potentially offers easy and repeated sampling, leading to the early detection and real-time monitoring of the disease and hopefully an accurate prognosis. Given the urgent need for a reliable biomarker that can estimate a patient's condition and response to an assigned treatment, blood-based biopsies are emerging as a potential new tool for improving patients' survival and surveillance. In this article, we discuss the current advances and challenges in using liquid biopsies for pancreatic cancer, focusing on circulating tumour DNA (ctDNA), extracellular vesicles (EVs), and circulating tumour cells (CTCs), and compare the performance and reliability of different biomarkers and combinations of biomarkers.
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Affiliation(s)
- Kosta Stosic
- Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, 1070 Brussels, Belgium (O.A.S.); (C.B.)
| | - Oier Azurmendi Senar
- Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, 1070 Brussels, Belgium (O.A.S.); (C.B.)
| | - Jawad Tarfouss
- Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, 1070 Brussels, Belgium (O.A.S.); (C.B.)
| | - Christelle Bouchart
- Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, 1070 Brussels, Belgium (O.A.S.); (C.B.)
- Department of Radiation Oncology, Hopital Universitaire de Bruxelles (H.U.B.), Université Libre de Bruxelles (ULB), 1070 Brussels, Belgium
| | - Julie Navez
- Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, 1070 Brussels, Belgium (O.A.S.); (C.B.)
- Department of Hepato-Biliary-Pancreatic Surgery, Hopital Universitaire de Bruxelles (H.U.B.), Université Libre de Bruxelles (ULB), 1070 Brussels, Belgium
| | - Jean-Luc Van Laethem
- Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, 1070 Brussels, Belgium (O.A.S.); (C.B.)
- Department of Gastroenterology, Hepatology and Digestive Oncology, Hopital Universitaire de Bruxelles (H.U.B.), Université Libre de Bruxelles (ULB), Route de Lennik 808, 1070 Brussels, Belgium
| | - Tatjana Arsenijevic
- Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, 1070 Brussels, Belgium (O.A.S.); (C.B.)
- Department of Gastroenterology, Hepatology and Digestive Oncology, Hopital Universitaire de Bruxelles (H.U.B.), Université Libre de Bruxelles (ULB), Route de Lennik 808, 1070 Brussels, Belgium
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12
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Wang K, Wang X, Pan Q, Zhao B. Liquid biopsy techniques and pancreatic cancer: diagnosis, monitoring, and evaluation. Mol Cancer 2023; 22:167. [PMID: 37803304 PMCID: PMC10557192 DOI: 10.1186/s12943-023-01870-3] [Citation(s) in RCA: 34] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Accepted: 09/25/2023] [Indexed: 10/08/2023] Open
Abstract
Pancreatic cancer (PC) is one of the most common malignancies. Surgical resection is a potential curative approach for PC, but most patients are unsuitable for operations when at the time of diagnosis. Even with surgery, some patients may still experience tumour metastasis during the operation or shortly after surgery, as precise prognosis evaluation is not always possible. If patients miss the opportunity for surgery and resort to chemotherapy, they may face the challenging issue of chemotherapy resistance. In recent years, liquid biopsy has shown promising prospects in disease diagnosis, treatment monitoring, and prognosis assessment. As a noninvasive detection method, liquid biopsy offers advantages over traditional diagnostic procedures, such as tissue biopsy, in terms of both cost-effectiveness and convenience. The information provided by liquid biopsy helps clinical practitioners understand the molecular mechanisms underlying tumour occurrence and development, enabling the formulation of more precise and personalized treatment decisions for each patient. This review introduces molecular biomarkers and detection methods in liquid biopsy for PC, including circulating tumour cells (CTCs), circulating tumour DNA (ctDNA), noncoding RNAs (ncRNAs), and extracellular vesicles (EVs) or exosomes. Additionally, we summarize the applications of liquid biopsy in the early diagnosis, treatment response, resistance assessment, and prognostic evaluation of PC.
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Affiliation(s)
- Kangchun Wang
- Department of Organ Transplantation and Hepatobiliary, The First Affiliated Hospital of China Medical University, Shenyang, 110001, China
| | - Xin Wang
- Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Qi Pan
- Department of Organ Transplantation and Hepatobiliary, The First Affiliated Hospital of China Medical University, Shenyang, 110001, China.
| | - Bei Zhao
- Department of Ultrasound, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, China.
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13
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Edland KH, Tjensvoll K, Oltedal S, Dalen I, Lapin M, Garresori H, Glenjen N, Gilje B, Nordgård O. Monitoring of circulating tumour DNA in advanced pancreatic ductal adenocarcinoma predicts clinical outcome and reveals disease progression earlier than radiological imaging. Mol Oncol 2023; 17:1857-1870. [PMID: 37341038 PMCID: PMC10483602 DOI: 10.1002/1878-0261.13472] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 05/03/2023] [Accepted: 06/19/2023] [Indexed: 06/22/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with a need for better tools to guide treatment selection and follow-up. The aim of this prospective study was to investigate the prognostic value and treatment monitoring potential of longitudinal circulating tumour DNA (ctDNA) measurements in patients with advanced PDAC undergoing palliative chemotherapy. Using KRAS peptide nucleic acid clamp-PCR, we measured ctDNA levels in plasma samples obtained at baseline and every 4 weeks during chemotherapy from 81 patients with locally advanced and metastatic PDAC. Cox proportional hazard regression showed that ctDNA detection at baseline was an independent predictor of progression-free and overall survival. Joint modelling demonstrated that the dynamic ctDNA level was a strong predictor of time to first disease progression. Longitudinal ctDNA measurements during chemotherapy successfully revealed disease progression in 20 (67%) of 30 patients with ctDNA detected at baseline, with a median lead time of 23 days (P = 0.01) over radiological imaging. Here, we confirmed the clinical relevance of ctDNA in advanced PDAC with regard to both the prediction of clinical outcome and disease monitoring during treatment.
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Affiliation(s)
| | - Kjersti Tjensvoll
- Department of Hematology and OncologyStavanger University HospitalNorway
| | - Satu Oltedal
- Department of Hematology and OncologyStavanger University HospitalNorway
| | - Ingvild Dalen
- Section of Biostatistics, Department of ResearchStavanger University HospitalNorway
| | - Morten Lapin
- Department of Hematology and OncologyStavanger University HospitalNorway
| | - Herish Garresori
- Department of Hematology and OncologyStavanger University HospitalNorway
| | - Nils Glenjen
- Department of OncologyHaukeland University HospitalBergenNorway
| | - Bjørnar Gilje
- Department of Hematology and OncologyStavanger University HospitalNorway
| | - Oddmund Nordgård
- Department of Hematology and OncologyStavanger University HospitalNorway
- Department of Chemistry, Bioscience and Environmental Technology, Faculty of Science and TechnologyUniversity of StavangerNorway
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14
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Ma Y, Gan J, Bai Y, Cao D, Jiao Y. Minimal residual disease in solid tumors: an overview. Front Med 2023; 17:649-674. [PMID: 37707677 DOI: 10.1007/s11684-023-1018-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Accepted: 06/24/2023] [Indexed: 09/15/2023]
Abstract
Minimal residual disease (MRD) is termed as the small numbers of remnant tumor cells in a subset of patients with tumors. Liquid biopsy is increasingly used for the detection of MRD, illustrating the potential of MRD detection to provide more accurate management for cancer patients. As new techniques and algorithms have enhanced the performance of MRD detection, the approach is becoming more widely and routinely used to predict the prognosis and monitor the relapse of cancer patients. In fact, MRD detection has been shown to achieve better performance than imaging methods. On this basis, rigorous investigation of MRD detection as an integral method for guiding clinical treatment has made important advances. This review summarizes the development of MRD biomarkers, techniques, and strategies for the detection of cancer, and emphasizes the application of MRD detection in solid tumors, particularly for the guidance of clinical treatment.
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Affiliation(s)
- Yarui Ma
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Jingbo Gan
- Genetron Health (Beijing) Co. Ltd., Beijing, 102206, China
| | - Yinlei Bai
- Genetron Health (Beijing) Co. Ltd., Beijing, 102206, China
| | - Dandan Cao
- Genetron Health (Beijing) Co. Ltd., Beijing, 102206, China
| | - Yuchen Jiao
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
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15
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Shabunin AV, Ptushkin VV, Tavobilov MM, Titov KS, Kobzev JN, Karpov AA, Kudryash EB. The role of circulating tumor DNA in diagnosis and optimization of treatment of localized and local pancreatic cancer. RUSSIAN JOURNAL OF BIOTHERAPY 2023; 22:27-33. [DOI: 10.17650/1726-9784-2023-22-2-27-33] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
Abstract
Pancreatic cancer (PC) is a malignant highly aggressive tumor that arises and grows under conditions of inflammation and tissue hypoxia. In PC, one of the key processes in progression is epithelial-mesenchymal transition, which leads to early dissemination and rapid realization of metastatic disease, which accounts for low overall survival rates. The tumor, by releasing a wide range of different molecules (circulating DNA, exosomes, proteins and lipids), allows to identify and use them as potential, diagnostic and prognostic biomarkers.This review introduces readers to the liquid biopsy technique. The main applications of the technique in patients with ductal adenocarcinoma of the pancreas are shown. Liquid biopsy is a modern diagnostic method of molecular oncology, the principle of which is to detect circulating tumor cells, DNA, exosomes in biological fluids. Publications evaluating the potential of the method to assess minimal residual disease, evaluate tumor response to systemic therapy, and determine prognosis are discussed. Liquid biopsy is particularly relevant in cases of malignant tumors of difficult localization, in particular, PC. Modern methods of morphological verification of pancreatic tumors (fine needle biopsy under endosonographic control and percutaneous biopsy) have essential disadvantages: low information value, multiple repeated interventions, postmanipulative complications (pancreatitis, bleeding, etc.). Taking into consideration obvious advantages and perspectives of this method over traditional methods of morphological verification, liquid biopsy seems to be a promising diagnostic tool in personalized oncology for pancreatic cancer.
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Affiliation(s)
- A. V. Shabunin
- Botkin City Clinical Hospital of the Moscow Healhcare Department; Russian Medical Academy of Continuous Professional Education
| | - V. V. Ptushkin
- Botkin City Clinical Hospital of the Moscow Healhcare Department; Pirogov Russian National Research Medical University
| | - M. M. Tavobilov
- Botkin City Clinical Hospital of the Moscow Healhcare Department; Russian Medical Academy of Continuous Professional Education
| | - K. S. Titov
- Botkin City Clinical Hospital of the Moscow Healhcare Department; RUDN University
| | - Ju. N. Kobzev
- Botkin City Clinical Hospital of the Moscow Healhcare Department
| | - A. A. Karpov
- Botkin City Clinical Hospital of the Moscow Healhcare Department
| | - E. B. Kudryash
- Russian Medical Academy of Continuous Professional Education
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Reutter T, Fassunke J, Püsken M, Weber JP, Binot E, Eisert A, Fischer R, Nogova L, Riedel R, Schaufler D, Scharpenseel H, Scheffler M, Schulz H, Waldschmidt DT, Zander T, Merkelbach-Bruse S, Schirmacher P, Büttner R, Wolf J, Michels S. Durable Response With Sequential Tyrosine Kinase Inhibitor Treatment in a Patient With ROS1 Fusion-Positive Pancreatic Adenocarcinoma: A Case Report. JCO Precis Oncol 2023; 7:e2200467. [PMID: 37079858 DOI: 10.1200/po.22.00467] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/22/2023] Open
Affiliation(s)
- Theresa Reutter
- Department I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Lung Cancer Group Cologne, University of Cologne, Cologne, Germany
| | - Jana Fassunke
- Department of Pathology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Michael Püsken
- Faculty of Medicine and University Hospital Cologne, Institute for Diagnostic and Interventional Radiology, University of Cologne, Cologne, Germany
| | - Jan-Phillip Weber
- Department I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Lung Cancer Group Cologne, University of Cologne, Cologne, Germany
| | - Elke Binot
- Department of Pathology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Anna Eisert
- Department I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Lung Cancer Group Cologne, University of Cologne, Cologne, Germany
| | - Rieke Fischer
- Department I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Lung Cancer Group Cologne, University of Cologne, Cologne, Germany
| | - Lucia Nogova
- Department I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Lung Cancer Group Cologne, University of Cologne, Cologne, Germany
| | - Richard Riedel
- Department I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Lung Cancer Group Cologne, University of Cologne, Cologne, Germany
| | - Diana Schaufler
- Department I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Lung Cancer Group Cologne, University of Cologne, Cologne, Germany
| | - Heather Scharpenseel
- Department I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Lung Cancer Group Cologne, University of Cologne, Cologne, Germany
| | - Matthias Scheffler
- Department I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Lung Cancer Group Cologne, University of Cologne, Cologne, Germany
| | - Holger Schulz
- Practice for Clinical Hematology and Oncology, Frechen, Germany
| | - Dirk-Thomas Waldschmidt
- Department of Gastroenterology and Hepatology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Thomas Zander
- Department I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Lung Cancer Group Cologne, University of Cologne, Cologne, Germany
| | - Sabine Merkelbach-Bruse
- Department of Pathology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Peter Schirmacher
- Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
| | - Reinhard Büttner
- Department of Pathology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Jürgen Wolf
- Department I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Lung Cancer Group Cologne, University of Cologne, Cologne, Germany
| | - Sebastian Michels
- Department I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Lung Cancer Group Cologne, University of Cologne, Cologne, Germany
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Ren XD, Su N, Sun XG, Li WM, Li J, Li BW, Li RX, Lv J, Xu QY, Kong WL, Huang Q. Advances in liquid biopsy-based markers in NSCLC. Adv Clin Chem 2023; 114:109-150. [PMID: 37268331 DOI: 10.1016/bs.acc.2023.02.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/04/2023]
Abstract
Lung cancer is the second most-frequently occurring cancer and the leading cause of cancer-associated deaths worldwide. Non-small cell lung cancer (NSCLC), the most common type of lung cancer is often diagnosed in middle or advanced stages and have poor prognosis. Diagnosis of disease at an early stage is a key factor for improving prognosis and reducing mortality, whereas, the currently used diagnostic tools are not sufficiently sensitive for early-stage NSCLC. The emergence of liquid biopsy has ushered in a new era of diagnosis and management of cancers, including NSCLC, since analysis of circulating tumor-derived components, such as cell-free DNA (cfDNA), circulating tumor cells (CTCs), cell-free RNAs (cfRNAs), exosomes, tumor-educated platelets (TEPs), proteins, and metabolites in blood or other biofluids can enable early cancer detection, treatment selection, therapy monitoring and prognosis assessment. There have been great advances in liquid biopsy of NSCLC in the past few years. Hence, this chapter introduces the latest advances on the clinical application of cfDNA, CTCs, cfRNAs and exosomes, with a particular focus on their application as early markers in the diagnosis, treatment and prognosis of NSCLC.
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Affiliation(s)
- Xiao-Dong Ren
- Department of Laboratory Medicine, Daping Hospital, Army Medical University, Chongqing, P.R. China
| | - Ning Su
- Department of Laboratory Medicine, Daping Hospital, Army Medical University, Chongqing, P.R. China
| | - Xian-Ge Sun
- Department of Laboratory Medicine, Daping Hospital, Army Medical University, Chongqing, P.R. China
| | - Wen-Man Li
- Department of Laboratory Medicine, Daping Hospital, Army Medical University, Chongqing, P.R. China
| | - Jin Li
- Department of Laboratory Medicine, Daping Hospital, Army Medical University, Chongqing, P.R. China
| | - Bo-Wen Li
- Department of Laboratory Medicine, Daping Hospital, Army Medical University, Chongqing, P.R. China
| | - Ruo-Xu Li
- Department of Laboratory Medicine, Daping Hospital, Army Medical University, Chongqing, P.R. China
| | - Jing Lv
- Department of Laboratory Medicine, Daping Hospital, Army Medical University, Chongqing, P.R. China
| | - Qian-Ying Xu
- Department of Laboratory Medicine, Daping Hospital, Army Medical University, Chongqing, P.R. China
| | - Wei-Long Kong
- Department of Laboratory Medicine, Daping Hospital, Army Medical University, Chongqing, P.R. China
| | - Qing Huang
- Department of Laboratory Medicine, Daping Hospital, Army Medical University, Chongqing, P.R. China.
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18
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Sellahewa R, Moghaddam SM, Lundy J, Jenkins BJ, Croagh D. Circulating Tumor DNA Is an Accurate Diagnostic Tool and Strong Prognostic Marker in Pancreatic Cancer. Pancreas 2023; 52:e188-e195. [PMID: 37751379 DOI: 10.1097/mpa.0000000000002239] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 09/28/2023]
Abstract
OBJECTIVE The objectives of the study are to investigate the sensitivity and specificity of circulating tumor DNA (ctDNA) for the diagnosis of pancreatic cancer and to assess the utility of ctDNA as a prognostic marker in this disease. METHODS Cell-free DNA was extracted from plasma of patients who underwent endoscopic ultrasound fine-needle aspiration or surgical resections for pancreatic cancer. The cell-free DNA was then analyzed using droplet digital polymerase chain reaction for KRAS G12/13 mutations. Eighty-one patients with pancreatic cancer and 30 patients with benign pancreatic disease were analyzed. RESULTS ctDNA KRAS G12/13 mutations were detected in 63% of all patients with pancreatic cancer and in 76% of those patients who also had KRAS G12/13 mutations detected in the pancreatic primary. Specificity and tissue concordance were both 100%. Circulating tumor DNA corresponded with tumor size and stage, and high ctDNA was associated with significantly worse prognosis on both univariate and multivariate testing. CONCLUSION Our study shows that ctDNA is an accurate diagnostic tool and strong prognostic marker in patients with pancreatic cancer. The continued investigation of ctDNA will enable its implementation in clinical practice to optimize the care and survival outcomes of patients with pancreatic cancer.
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Nitschke C, Markmann B, Walter P, Badbaran A, Tölle M, Kropidlowski J, Belloum Y, Goetz MR, Bardenhagen J, Stern L, Tintelnot J, Schönlein M, Sinn M, van der Leest P, Simon R, Heumann A, Izbicki JR, Pantel K, Wikman H, Uzunoglu FG. Peripheral and Portal Venous KRAS ctDNA Detection as Independent Prognostic Markers of Early Tumor Recurrence in Pancreatic Ductal Adenocarcinoma. Clin Chem 2023; 69:295-307. [PMID: 36644936 DOI: 10.1093/clinchem/hvac214] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Accepted: 11/17/2022] [Indexed: 01/17/2023]
Abstract
BACKGROUND KRAS circulating tumor DNA (ctDNA) has shown biomarker potential for pancreatic ductal adenocarcinoma (PDAC) but has not been applied in clinical routine yet. We aim to improve clinical applicability of ctDNA detection in PDAC and to study the impact of blood-draw site and time point on the detectability and prognostic role of KRAS mutations. METHODS 221 blood samples from 108 PDAC patients (65 curative, 43 palliative) were analyzed. Baseline peripheral and tumor-draining portal venous (PV), postoperative, and follow-up blood were analyzed and correlated with prognosis. RESULTS Significantly higher KRAS mutant detection rates and copy numbers were observed in palliative compared to curative patients baseline blood (58.1% vs 24.6%; P = 0.002; and P < 0.001). Significantly higher KRAS mutant copies were found in PV blood compared to baseline (P < 0.05) samples. KRAS detection in pre- and postoperative and PV blood were significantly associated with shorter recurrence-free survival (all P < 0.015) and identified as independent prognostic markers. KRAS ctDNA status was also an independent unfavorable prognostic factor for shorter overall survival in both palliative and curative cohorts (hazard ratio [HR] 4.9, P = 0.011; HR 6.9, P = 0.008). CONCLUSIONS KRAS ctDNA detection is an independent adverse prognostic marker in curative and palliative PDAC patients-at all sites of blood draw and a strong follow-up marker. The most substantial prognostic impact was seen for PV blood, which could be an effective novel tool for identifying prognostic borderline patients-guiding future decision-making on neoadjuvant treatment despite anatomical resectability. In addition, higher PV mutant copy numbers contribute to an improved technical feasibility.
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Affiliation(s)
- Christine Nitschke
- Department of General, Visceral and Thoracic Surgery, University Hospital Hamburg-Eppendorf, Hamburg 20246, Germany
- Mildred Scheel Cancer Career Center, Hamburg 20246, Germany
- Institute of Tumor Biology, University Hospital Hamburg-Eppendorf, Hamburg 20246, Germany
| | - Benedikt Markmann
- Department of General, Visceral and Thoracic Surgery, University Hospital Hamburg-Eppendorf, Hamburg 20246, Germany
- Institute of Tumor Biology, University Hospital Hamburg-Eppendorf, Hamburg 20246, Germany
| | - Philipp Walter
- Department of General, Visceral and Thoracic Surgery, University Hospital Hamburg-Eppendorf, Hamburg 20246, Germany
- Institute of Tumor Biology, University Hospital Hamburg-Eppendorf, Hamburg 20246, Germany
| | - Anita Badbaran
- Clinic for Stem Cell Transplantation, University Hospital Hamburg-Eppendorf, Hamburg 20246, Germany
| | - Marie Tölle
- Department of General, Visceral and Thoracic Surgery, University Hospital Hamburg-Eppendorf, Hamburg 20246, Germany
- Institute of Tumor Biology, University Hospital Hamburg-Eppendorf, Hamburg 20246, Germany
| | - Jolanthe Kropidlowski
- Institute of Tumor Biology, University Hospital Hamburg-Eppendorf, Hamburg 20246, Germany
| | - Yassine Belloum
- Institute of Tumor Biology, University Hospital Hamburg-Eppendorf, Hamburg 20246, Germany
| | - Mara R Goetz
- Department of General, Visceral and Thoracic Surgery, University Hospital Hamburg-Eppendorf, Hamburg 20246, Germany
| | - Jan Bardenhagen
- Department of General, Visceral and Thoracic Surgery, University Hospital Hamburg-Eppendorf, Hamburg 20246, Germany
| | - Louisa Stern
- Department of General, Visceral and Thoracic Surgery, University Hospital Hamburg-Eppendorf, Hamburg 20246, Germany
| | - Joseph Tintelnot
- II. Medical Clinic and Polyclinic (Oncology), University Hospital Hamburg-Eppendorf, Hamburg 20246, Germany
| | - Martin Schönlein
- II. Medical Clinic and Polyclinic (Oncology), University Hospital Hamburg-Eppendorf, Hamburg 20246, Germany
| | - Marianne Sinn
- II. Medical Clinic and Polyclinic (Oncology), University Hospital Hamburg-Eppendorf, Hamburg 20246, Germany
| | - Paul van der Leest
- Department of Pathology, University Medical Center, University of Groningen, Groningen 9700 RB, Netherlands
| | - Ronald Simon
- Institute of Pathology, University Hospital Hamburg-Eppendorf, Hamburg 20246, Germany
| | - Asmus Heumann
- Department of General, Visceral and Thoracic Surgery, University Hospital Hamburg-Eppendorf, Hamburg 20246, Germany
| | - Jakob R Izbicki
- Department of General, Visceral and Thoracic Surgery, University Hospital Hamburg-Eppendorf, Hamburg 20246, Germany
| | - Klaus Pantel
- Institute of Tumor Biology, University Hospital Hamburg-Eppendorf, Hamburg 20246, Germany
| | - Harriet Wikman
- Institute of Tumor Biology, University Hospital Hamburg-Eppendorf, Hamburg 20246, Germany
| | - Faik G Uzunoglu
- Department of General, Visceral and Thoracic Surgery, University Hospital Hamburg-Eppendorf, Hamburg 20246, Germany
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Zhao Y, Tang J, Jiang K, Liu SY, Aicher A, Heeschen C. Liquid biopsy in pancreatic cancer - Current perspective and future outlook. Biochim Biophys Acta Rev Cancer 2023; 1878:188868. [PMID: 36842769 DOI: 10.1016/j.bbcan.2023.188868] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Revised: 01/14/2023] [Accepted: 01/16/2023] [Indexed: 02/27/2023]
Abstract
Pancreatic cancer is a lethal condition with a rising incidence and often presents at an advanced stage, contributing to abysmal five-year survival rates. Unspecific symptoms and the current lack of biomarkers and screening tools hamper early diagnosis. New technologies for liquid biopsies and their respective evaluation in pancreatic cancer patients have emerged over recent years. The term liquid biopsy summarizes the sampling and analysis of circulating tumor cells (CTCs), small extracellular vesicles (sEVs), and tumor DNA (ctDNA) from body fluids. The major advantages of liquid biopsies rely on their minimal invasiveness and repeatability, allowing serial sampling for dynamic insights to aid diagnosis, particularly early detection, risk stratification, and precision medicine in pancreatic cancer. However, liquid biopsies have not yet developed into a new pillar for clinicians' routine armamentarium. Here, we summarize recent findings on the use of liquid biopsy in pancreatic cancer patients. We discuss current challenges and future perspectives of this potentially powerful alternative to conventional tissue biopsies.
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Affiliation(s)
- Yaru Zhao
- Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jiajia Tang
- Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ke Jiang
- Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shin-Yi Liu
- Department of Biomedical Imaging and Radiological Science, China Medical University, Taichung, Taiwan; Research and Development Center for Immunology, China Medical University, Taichung, Taiwan
| | - Alexandra Aicher
- Precision Immunotherapy, Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan
| | - Christopher Heeschen
- Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Pancreatic Cancer Heterogeneity, Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Turin, Italy.
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21
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Labiano I, Huerta AE, Arrazubi V, Hernandez-Garcia I, Mata E, Gomez D, Arasanz H, Vera R, Alsina M. State of the Art: ctDNA in Upper Gastrointestinal Malignancies. Cancers (Basel) 2023; 15:1379. [PMID: 36900172 PMCID: PMC10000247 DOI: 10.3390/cancers15051379] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Revised: 02/14/2023] [Accepted: 02/20/2023] [Indexed: 02/24/2023] Open
Abstract
Circulating tumor DNA (ctDNA) has emerged as a promising non-invasive source to characterize genetic alterations related to the tumor. Upper gastrointestinal cancers, including gastroesophageal adenocarcinoma (GEC), biliary tract cancer (BTC) and pancreatic ductal adenocarcinoma (PADC) are poor prognostic malignancies, usually diagnosed at advanced stages when no longer amenable to surgical resection and show a poor prognosis even for resected patients. In this sense, ctDNA has emerged as a promising non-invasive tool with different applications, from early diagnosis to molecular characterization and follow-up of tumor genomic evolution. In this manuscript, novel advances in the field of ctDNA analysis in upper gastrointestinal tumors are presented and discussed. Overall, ctDNA analyses can help in early diagnosis, outperforming current diagnostic approaches. Detection of ctDNA prior to surgery or active treatment is also a prognostic marker that associates with worse survival, while ctDNA detection after surgery is indicative of minimal residual disease, anticipating in some cases the imaging-based detection of progression. In the advanced setting, ctDNA analyses characterize the genetic landscape of the tumor and identify patients for targeted-therapy approaches, and studies show variable concordance levels with tissue-based genetic testing. In this line, several studies also show that ctDNA serves to follow responses to active therapy, especially in targeted approaches, where it can detect multiple resistance mechanisms. Unfortunately, current studies are still limited and observational. Future prospective multi-center and interventional studies, carefully designed to assess the value of ctDNA to help clinical decision-making, will shed light on the real applicability of ctDNA in upper gastrointestinal tumor management. This manuscript presents a review of the evidence available in this field up to date.
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Affiliation(s)
- Ibone Labiano
- Oncobiona Group, Navarrabiomed-Instituto de Investigación Sanitaria de Navarra (IdiSNA), Irunlarrea 3, 31008 Pamplona, Spain
| | - Ana Elsa Huerta
- Oncobiona Group, Navarrabiomed-Instituto de Investigación Sanitaria de Navarra (IdiSNA), Irunlarrea 3, 31008 Pamplona, Spain
| | - Virginia Arrazubi
- Oncobiona Group, Navarrabiomed-Instituto de Investigación Sanitaria de Navarra (IdiSNA), Irunlarrea 3, 31008 Pamplona, Spain
- Medical Oncology Department, Hospital Universitario de Navarra (HUN), Irunlarrea 3, 31008 Pamplona, Spain
| | - Irene Hernandez-Garcia
- Oncobiona Group, Navarrabiomed-Instituto de Investigación Sanitaria de Navarra (IdiSNA), Irunlarrea 3, 31008 Pamplona, Spain
- Medical Oncology Department, Hospital Universitario de Navarra (HUN), Irunlarrea 3, 31008 Pamplona, Spain
| | - Elena Mata
- Oncobiona Group, Navarrabiomed-Instituto de Investigación Sanitaria de Navarra (IdiSNA), Irunlarrea 3, 31008 Pamplona, Spain
- Medical Oncology Department, Hospital Universitario de Navarra (HUN), Irunlarrea 3, 31008 Pamplona, Spain
| | - David Gomez
- Medical Oncology Department, Hospital Universitario de Navarra (HUN), Irunlarrea 3, 31008 Pamplona, Spain
| | - Hugo Arasanz
- Oncobiona Group, Navarrabiomed-Instituto de Investigación Sanitaria de Navarra (IdiSNA), Irunlarrea 3, 31008 Pamplona, Spain
- Medical Oncology Department, Hospital Universitario de Navarra (HUN), Irunlarrea 3, 31008 Pamplona, Spain
| | - Ruth Vera
- Oncobiona Group, Navarrabiomed-Instituto de Investigación Sanitaria de Navarra (IdiSNA), Irunlarrea 3, 31008 Pamplona, Spain
- Medical Oncology Department, Hospital Universitario de Navarra (HUN), Irunlarrea 3, 31008 Pamplona, Spain
| | - Maria Alsina
- Oncobiona Group, Navarrabiomed-Instituto de Investigación Sanitaria de Navarra (IdiSNA), Irunlarrea 3, 31008 Pamplona, Spain
- Medical Oncology Department, Hospital Universitario de Navarra (HUN), Irunlarrea 3, 31008 Pamplona, Spain
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Raufi AG, May MS, Hadfield MJ, Seyhan AA, El-Deiry WS. Advances in Liquid Biopsy Technology and Implications for Pancreatic Cancer. Int J Mol Sci 2023; 24:4238. [PMID: 36835649 PMCID: PMC9958987 DOI: 10.3390/ijms24044238] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Revised: 12/23/2022] [Accepted: 12/29/2022] [Indexed: 02/23/2023] Open
Abstract
Pancreatic cancer is a highly aggressive malignancy with a climbing incidence. The majority of cases are detected late, with incurable locally advanced or metastatic disease. Even in individuals who undergo resection, recurrence is unfortunately very common. There is no universally accepted screening modality for the general population and diagnosis, evaluation of treatment response, and detection of recurrence relies primarily on the use of imaging. Identification of minimally invasive techniques to help diagnose, prognosticate, predict response or resistance to therapy, and detect recurrence are desperately needed. Liquid biopsies represent an emerging group of technologies which allow for non-invasive serial sampling of tumor material. Although not yet approved for routine use in pancreatic cancer, the increasing sensitivity and specificity of contemporary liquid biopsy platforms will likely change clinical practice in the near future. In this review, we discuss the recent technological advances in liquid biopsy, focusing on circulating tumor DNA, exosomes, microRNAs, and circulating tumor cells.
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Affiliation(s)
- Alexander G. Raufi
- Division of Hematology/Oncology, Department of Medicine, Lifespan Health System, Providence, RI 02903, USA
- Legorreta Cancer Center, Brown University, Providence, RI 02903, USA
- Joint Program in Cancer Biology, Brown University, Providence, RI 02903, USA
| | - Michael S. May
- Division of Hematology/Oncology, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Matthew J. Hadfield
- Division of Hematology/Oncology, Department of Medicine, Lifespan Health System, Providence, RI 02903, USA
- Legorreta Cancer Center, Brown University, Providence, RI 02903, USA
| | - Attila A. Seyhan
- Legorreta Cancer Center, Brown University, Providence, RI 02903, USA
- Joint Program in Cancer Biology, Brown University, Providence, RI 02903, USA
- Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, Providence, RI 02903, USA
| | - Wafik S. El-Deiry
- Division of Hematology/Oncology, Department of Medicine, Lifespan Health System, Providence, RI 02903, USA
- Legorreta Cancer Center, Brown University, Providence, RI 02903, USA
- Joint Program in Cancer Biology, Brown University, Providence, RI 02903, USA
- Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, Providence, RI 02903, USA
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23
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An Efficient, Short Stimulus PANC-1 Cancer Cell Ablation and Electrothermal Therapy Driven by Hydrophobic Interactions. Pharmaceutics 2022; 15:pharmaceutics15010106. [PMID: 36678734 PMCID: PMC9867450 DOI: 10.3390/pharmaceutics15010106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2022] [Revised: 12/19/2022] [Accepted: 12/20/2022] [Indexed: 12/31/2022] Open
Abstract
Promising results in clinical studies have been demonstrated by the utilization of electrothermal agents (ETAs) in cancer therapy. However, a difficulty arises from the balance between facilitating the degradation of ETAs, and at the same time, increasing the electrothermal performance/stability required for highly efficient treatment. In this study, we controlled the thermal signature of the MoS2 by harnessing MoS2 nanostructures with M13 phage (MNM) via the structural assembling (hydrophobic interaction) phenomena and developed a combined PANC-1 cancer cell-MNM alternating current (AC)-stimulus framework for cancer cell ablation and electrothermal therapy. A percentage decrease in the cell viability of ~23% was achieved, as well as a degradation time of 2 weeks; a stimulus length of 100 μs was also achieved. Molecular dynamics (MD) simulations revealed the assembling kinetics in integrated M13 phage-cancer cell protein systems and the structural origin of the hydrophobic interaction-enabled increase in thermal conduction. This study not only introduced an 'ideal' agent that avoided the limitations of ETAs but also provided a proof-of-concept application of MoS2-based materials in efficacious cancer therapy.
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24
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Jo JH, Jung DE, Lee HS, Park SB, Chung MJ, Park JY, Bang S, Park SW, Cho S, Song SY. A phase I/II study of ivaltinostat combined with gemcitabine and erlotinib in patients with untreated locally advanced or metastatic pancreatic adenocarcinoma. Int J Cancer 2022; 151:1565-1577. [PMID: 35657348 PMCID: PMC9545559 DOI: 10.1002/ijc.34144] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 04/12/2022] [Accepted: 04/27/2022] [Indexed: 12/03/2022]
Abstract
This phase I/II study evaluated the safety and efficacy of a new histone deacetylase (HDAC) inhibitor, ivaltinostat, in combination with gemcitabine and erlotinib for advanced pancreatic ductal adenocarcinoma (PDAC). Patients diagnosed with unresectable, histologically confirmed PDAC who had not undergone previous therapy were eligible. Phase I had a 3 + 3 dose escalation design to determine the maximum tolerable dose (MTD) of ivaltinostat (intravenously on days 1, 8 and 15) with gemcitabine (1000 mg/m2 intravenously on days 1, 8 and 15) and erlotinib (100 mg/day, orally) for a 28-day cycle. In phase II, patients received a six-cycle treatment with the MTD of ivaltinostat determined in phase I. The primary endpoint was the objective response rate (ORR). Secondary endpoints included overall survival (OS), disease control rate (DCR) and progression-free survival (PFS). The MTD of ivaltinostat for the phase II trial was determined to be 250 mg/m2 . In phase II, 24 patients were enrolled. The median OS and PFS were 8.6 (95% confidence interval [CI]: 5.3-11.2) and 5.3 months (95% CI: 3.7-5.8). Of the 16 patients evaluated for response, ORR and DCR were 25.0% and 93.8% with a median OS/PFS of 10.8 (95% CI: 8.3-16.7)/5.8 (95% CI: 4.6-6.7) months. Correlative studies showed that mutation burden detected by cfDNA and specific blood markers such as TIMP1, pro-MMP10, PECAM1, proMMP-2 and IGFBP1 were associated with clinical outcomes. Although the result of a small study, a combination of ivaltinostat, gemcitabine and erlotinib appeared to be a potential treatment option for advanced PDAC.
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Affiliation(s)
- Jung Hyun Jo
- Division of Gastroenterology, Department of Internal MedicineYonsei University College of MedicineSeoulSouth Korea
| | - Dawoon E. Jung
- Division of Gastroenterology, Department of Internal MedicineYonsei University College of MedicineSeoulSouth Korea
| | - Hee Seung Lee
- Division of Gastroenterology, Department of Internal MedicineYonsei University College of MedicineSeoulSouth Korea
| | - Soo Been Park
- Division of Gastroenterology, Department of Internal MedicineYonsei University College of MedicineSeoulSouth Korea
| | - Moon Jae Chung
- Division of Gastroenterology, Department of Internal MedicineYonsei University College of MedicineSeoulSouth Korea
| | - Jeong Youp Park
- Division of Gastroenterology, Department of Internal MedicineYonsei University College of MedicineSeoulSouth Korea
| | - Seungmin Bang
- Division of Gastroenterology, Department of Internal MedicineYonsei University College of MedicineSeoulSouth Korea
| | - Seung Woo Park
- Division of Gastroenterology, Department of Internal MedicineYonsei University College of MedicineSeoulSouth Korea
| | - Sangsook Cho
- CG PharmaceuticalsOrindaCaliforniaUSA
- CrystalGenomicsSeongnamsi, GyeonggidoSouth Korea
| | - Si Young Song
- Division of Gastroenterology, Department of Internal MedicineYonsei University College of MedicineSeoulSouth Korea
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Liu B, Hu Z, Ran J, Xie N, Tian C, Tang Y, Ouyang Q. The circulating tumor DNA (ctDNA) alteration level predicts therapeutic response in metastatic breast cancer: Novel prognostic indexes based on ctDNA. Breast 2022; 65:116-123. [PMID: 35926241 PMCID: PMC9356206 DOI: 10.1016/j.breast.2022.07.010] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Revised: 07/13/2022] [Accepted: 07/14/2022] [Indexed: 11/18/2022] Open
Abstract
Purpose Circulating tumor DNA (ctDNA) has good clinical guiding value for metastatic breast cancer (MBC) patients. This study aimed to apply a novel genetic analysis approach for therapeutic prediction based on ctDNA alterations. Method This nonrandomized, multicenter study recruited 223 MBC patients (NCT05079074). Plasma samples were collected for target-capture deep sequencing of ctDNA at baseline, after the 2nd cycle of treatment, and when progressive disease (PD) was evaluated. Samples were categorized into four levels according to the number of ctDNA alterations: level 1 (no alterations), level 2 (1–2 alterations), level 3 (3–4 alterations) and level 4 (≥5 alterations). According to ctDNA alteration level and variant allele frequency (VAF), a novel ctDNA-level Response Evaluation Criterion in Solid Tumors (ctle-RECIST) was established to assess treatment response and predict progression-free survival (PFS). Results The median PFS in level 1 (6.63 months) patients was significantly longer than that in level 2–4 patients (level 2: 5.70 months; level 3–4: 4.90 months, p < 0.05). After 2 cycles of treatment, based on ctle-RECIST, the median PFS of level-based disease control rate (lev-DCR) patients was significantly longer than that of level-based PD (lev-PD) patients [HR 2.42 (1.52–3.85), p < 0.001]. In addition, we found that ctDNA level assessment could be a good supplement to radiologic assessment. The median PFS in the dual-DCR group tended to be longer than that in the single-DCR group [HR 1.41 (0.93–2.13), p = 0.107]. Conclusion The ctDNA alteration level and ctle-RECIST could be novel biomarkers of prognosis and could complement radiologic assessment in MBC.
Based on the number of ctDNA alterations, samples were categorized into four levels: level 1 to level 4. ctDNA alterations differed in different alteration level groups. Higher ctDNA alteration levels (levels 3–4) were associated with a higher probability of liver metastasis. According to ctDNA alteration level and variant allele frequency, a novel ctDNA-level RECIST (ctle-RECIST) was established to assess treatment response. ctle-RECIST can not only independently predict PFS, but also assist radiologic assessment and improve the clinical application value of prediction.
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Affiliation(s)
- Binliang Liu
- Department of Breast Cancer Medical Oncology, Hunan Cancer Hospital/the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, 410013, China
| | - Zheyu Hu
- Department of Breast Cancer Medical Oncology, Hunan Cancer Hospital/the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, 410013, China
| | - Jialu Ran
- Department of Biostatistics and Bioinformatics, Rollins School of Public Heath, Emory University, Atlanta, GA 30322, USA
| | - Ning Xie
- Department of Breast Cancer Medical Oncology, Hunan Cancer Hospital/the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, 410013, China
| | - Can Tian
- Department of Breast Cancer Medical Oncology, Hunan Cancer Hospital/the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, 410013, China
| | - Yu Tang
- Department of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, China
| | - Quchang Ouyang
- Department of Breast Cancer Medical Oncology, Hunan Cancer Hospital/the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, 410013, China.
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Braig D, Runkel A, Eisenhardt AE, Schmid A, Zeller J, Pauli T, Lausch U, Wehrle J, Bronsert P, Jung M, Kiefer J, Boerries M, Eisenhardt SU. Individualized Mini-Panel Sequencing of ctDNA Allows Tumor Monitoring in Complex Karyotype Sarcomas. Int J Mol Sci 2022; 23:ijms231810215. [PMID: 36142126 PMCID: PMC9499617 DOI: 10.3390/ijms231810215] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Revised: 08/31/2022] [Accepted: 09/04/2022] [Indexed: 11/28/2022] Open
Abstract
Soft tissue sarcomas (STS) are rare tumors of mesenchymal origin with high mortality. After curative resection, about one third of patients suffer from distant metastases. Tumor follow-up only covers a portion of recurrences and is associated with high cost and radiation burden. For metastasized STS, only limited inferences can be drawn from imaging data regarding therapy response. To date there are no established and evidence-based diagnostic biomarkers for STS due to their rarity and diversity. In a proof-of-concept study, circulating tumor DNA (ctDNA) was quantified in (n = 25) plasma samples obtained from (n = 3) patients with complex karyotype STS collected over three years. Genotyping of tumor tissue was performed by exome sequencing. Patient-individual mini-panels for targeted next-generation sequencing were designed encompassing up to 30 mutated regions of interest. Circulating free DNA (cfDNA) was purified from plasma and ctDNA quantified therein. ctDNA values were correlated with clinical parameters. ctDNA concentrations correlated with the tumor burden. In case of full remission, no ctDNA was detectable. Patients with a recurrence at a later stage showed low levels of ctDNA during clinical remission, indicating minimal residual disease. In active disease (primary tumor or metastatic disease), ctDNA was highly elevated. We observed direct response to treatment, with a ctDNA decline after tumor resections, radiotherapy, and chemotherapy. Quantification of ctDNA allows for the early detection of recurrence or metastases and can be used to monitor treatment response in STS. Therapeutic decisions can be made earlier, such as the continuation of a targeted adjuvant therapy or the implementation of extended imaging to detect recurrences. In metastatic disease, therapy can be adjusted promptly in case of no response. These advantages may lead to a survival benefit for patients in the future.
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Affiliation(s)
- David Braig
- Department of Plastic and Hand Surgery, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
- Division of Hand, Plastic and Aesthetic Surgery, University Hospital, Ludwig Maximilian University of Munich, 80336 Munich, Germany
- Correspondence:
| | - Alexander Runkel
- Department of Plastic and Hand Surgery, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Anja E. Eisenhardt
- Department of Plastic and Hand Surgery, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Adrian Schmid
- Department of Plastic and Hand Surgery, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Johannes Zeller
- Department of Plastic and Hand Surgery, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Thomas Pauli
- Institute of Medical Bioinformatics and Systems Medicine, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Ute Lausch
- Department of Plastic and Hand Surgery, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Julius Wehrle
- Department of Medicine I, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Peter Bronsert
- Institute for Surgical Pathology, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
- Tumorbank Comprehensive Cancer Center Freiburg, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Matthias Jung
- Department of Diagnostic and Interventional Radiology, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Jurij Kiefer
- Department of Plastic and Hand Surgery, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Melanie Boerries
- Institute of Medical Bioinformatics and Systems Medicine, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Steffen U. Eisenhardt
- Department of Plastic and Hand Surgery, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
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Sheel A, Addison S, Nuguru SP, Manne A. Is Cell-Free DNA Testing in Pancreatic Ductal Adenocarcinoma Ready for Prime Time? Cancers (Basel) 2022; 14:3453. [PMID: 35884515 PMCID: PMC9322623 DOI: 10.3390/cancers14143453] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 07/03/2022] [Accepted: 07/13/2022] [Indexed: 11/17/2022] Open
Abstract
Cell-free DNA (cfDNA) testing currently does not have a significant role in PDA management: it is insufficient to diagnose PDA, and its use is primarily restricted to identifying targetable mutations (if tissue is insufficient or unavailable). cfDNA testing has the potential to address critical needs in PDA management, such as pre-operative risk stratification (POR), prognostication, and predicting (and monitoring) treatment response. Prior studies have focused primarily on somatic mutations, specifically KRAS variants, and have shown limited success in addressing prognosis and POR. Recent studies have demonstrated the importance of other less prevalent mutations (ERBB2 and TP53), but no studies have provided reliable mutation panels for clinical use. Methylation aberrations in cfDNA (epigenetic markers) in PDA have been relatively less explored. However, early evidence has suggested they offer diagnostic and, to some extent, prognostic value. The inclusion of epigenetic markers of cfDNA adds another dimension to genomic testing and may open new therapeutic avenues beyond addressing critical areas of need in PDA treatment. For cfDNA to substantially influence PDA management, concerted efforts are required to include less frequent mutations and epigenetic markers. Furthermore, relying on KRAS mutations for PDA management will always be inadequate.
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Affiliation(s)
- Ankur Sheel
- Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, OH 432120, USA;
| | - Sarah Addison
- School of Medicine, The Ohio State University, Columbus, OH 432120, USA;
| | - Surya Pratik Nuguru
- Department of Internal Medicine, Kamineni Academy of Medical Sciences and Research Center, Hyderabad 500012, India;
| | - Ashish Manne
- Department of Internal Medicine, Division of Medical Oncology at the Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
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Verduijn GM, Capala ME, Sijtsema ND, Lauwers I, Hernandez Tamames JA, Heemsbergen WD, Sewnaik A, Hardillo JA, Mast H, van Norden Y, Jansen MPHM, van der Lugt A, van Gent DC, Hoogeman MS, Mostert B, Petit SF. The COMPLETE trial: HolistiC early respOnse assessMent for oroPharyngeaL cancEr paTiEnts; Protocol for an observational study. BMJ Open 2022; 12:e059345. [PMID: 35584883 PMCID: PMC9119182 DOI: 10.1136/bmjopen-2021-059345] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
INTRODUCTION The locoregional failure (LRF) rate in human papilloma virus (HPV)-negative oropharyngeal squamous cell carcinoma (OPSCC) remains disappointingly high and toxicity is substantial. Response prediction prior to or early during treatment would provide opportunities for personalised treatment. Currently, there are no accurate predictive models available for correct OPSCC patient selection. Apparently, the pivotal driving forces that determine how a OPSCC responds to treatment, have yet to be elucidated. Therefore, the holistiC early respOnse assessMent for oroPharyngeaL cancer paTiEnts study focuses on a holistic approach to gain insight in novel potential prognostic biomarkers, acquired before and early during treatment, to predict response to treatment in HPV-negative patients with OPSCC. METHODS AND ANALYSIS This single-centre prospective observational study investigates 60 HPV-negative patients with OPSCC scheduled for primary radiotherapy (RT) with cisplatin or cetuximab, according to current clinical practice. A holistic approach will be used that aims to map the macroscopic (with Intra Voxel Incoherent Motion Diffusion Kurtosis Imaging (IVIM-DKI); before, during, and 3 months after RT), microscopic (with biopsies of the primary tumour acquired before treatment and irradiated ex vivo to assess radiosensitivity), and molecular landscape (with circulating tumour DNA (ctDNA) analysed before, during and 3 months after treatment). The main end point is locoregional control (LRC) 2 years after treatment. The primary objective is to determine whether a relative change in the mean of the diffusion coefficient D (an IVIM-DKI parameter) in the primary tumour early during treatment, improves the performance of a predictive model consisting of tumour volume only, for 2 years LRC after treatment. The secondary objectives investigate the potential of other IVIM-DKI parameters, ex vivo sensitivity characteristics, ctDNA, and combinations thereof as potential novel prognostic markers. ETHICS AND DISSEMINATION The study was approved by the Medical Ethical Committee of Erasmus Medical Center. The main results of the trial will be presented in international meetings and medical journals. TRIAL REGISTRATION NUMBER NL8458.
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Affiliation(s)
- Gerda M Verduijn
- Radiotherapy, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Marta E Capala
- Radiotherapy, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Nienke D Sijtsema
- Radiotherapy, Erasmus Medical Center, Rotterdam, The Netherlands
- Radiology and Nuclear Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Iris Lauwers
- Radiotherapy, Erasmus Medical Center, Rotterdam, The Netherlands
| | | | | | - Aniel Sewnaik
- Otorhinolaryngology and Head and Neck surgery, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Jose A Hardillo
- Otorhinolaryngology and Head and Neck surgery, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Hetty Mast
- Oral and Maxillofacial surgery, Erasmus Medical Center, Rotterdam, The Netherlands
| | | | | | - Aad van der Lugt
- Radiology and Nuclear Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Dik C van Gent
- Molecular Genetics, Erasmus Medical Center, Rotterdam, The Netherlands
| | | | - Bianca Mostert
- Medical Oncology, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Steven F Petit
- Radiotherapy, Erasmus Medical Center, Rotterdam, The Netherlands
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Merz V, Mangiameli D, Zecchetto C, Quinzii A, Pietrobono S, Messina C, Casalino S, Gaule M, Pesoni C, Vitale P, Trentin C, Frisinghelli M, Caffo O, Melisi D. Predictive Biomarkers for a Personalized Approach in Resectable Pancreatic Cancer. Front Surg 2022; 9:866173. [PMID: 35599791 PMCID: PMC9114435 DOI: 10.3389/fsurg.2022.866173] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Accepted: 03/25/2022] [Indexed: 12/15/2022] Open
Abstract
The mainstay treatment for patients with immediate resectable pancreatic cancer remains upfront surgery, which represents the only potentially curative strategy. Nevertheless, the majority of patients surgically resected for pancreatic cancer experiences disease relapse, even when a combination adjuvant therapy is offered. Therefore, aiming at improving disease free survival and overall survival of these patients, there is an increasing interest in evaluating the activity and efficacy of neoadjuvant and perioperative treatments. In this view, it is of utmost importance to find biomarkers able to select patients who may benefit from a preoperative therapy rather than upfront surgical resection. Defined genomic alterations and a dynamic inflammatory microenvironment are the major culprits for disease recurrence and resistance to chemotherapeutic treatments in pancreatic cancer patients. Signal transduction pathways or tumor immune microenvironment could predict early recurrence and response to chemotherapy. In the last decade, distinct molecular subtypes of pancreatic cancer have been described, laying the bases to a tailored therapeutic approach, started firstly in the treatment of advanced disease. Patients with homologous repair deficiency, in particular with mutant germline BRCA genes, represent the first subgroup demonstrating to benefit from specific therapies. A fraction of patients with pancreatic cancer could take advantage of genome sequencing with the aim of identifying possible targetable mutations. These genomic driven strategies could be even more relevant in a potentially curative setting. In this review, we outline putative predictive markers that could help in the next future in tailoring the best therapeutic strategy for pancreatic cancer patients with a potentially curable disease.
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Affiliation(s)
- Valeria Merz
- Medical Oncology Unit, Santa Chiara Hospital, Trento, Italy
- Digestive Molecular Clinical Oncology Research Unit, Università degli Studi di Verona, Verona, Italy
| | - Domenico Mangiameli
- Digestive Molecular Clinical Oncology Research Unit, Università degli Studi di Verona, Verona, Italy
| | - Camilla Zecchetto
- Investigational Cancer Therapeutics Clinical Unit, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
| | - Alberto Quinzii
- Investigational Cancer Therapeutics Clinical Unit, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
| | - Silvia Pietrobono
- Digestive Molecular Clinical Oncology Research Unit, Università degli Studi di Verona, Verona, Italy
| | | | - Simona Casalino
- Investigational Cancer Therapeutics Clinical Unit, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
| | - Marina Gaule
- Investigational Cancer Therapeutics Clinical Unit, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
| | - Camilla Pesoni
- Investigational Cancer Therapeutics Clinical Unit, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
| | | | - Chiara Trentin
- Medical Oncology Unit, Santa Chiara Hospital, Trento, Italy
| | | | - Orazio Caffo
- Medical Oncology Unit, Santa Chiara Hospital, Trento, Italy
| | - Davide Melisi
- Digestive Molecular Clinical Oncology Research Unit, Università degli Studi di Verona, Verona, Italy
- Investigational Cancer Therapeutics Clinical Unit, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
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30
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Alese OB, Cook N, Ortega-Franco A, Ulanja MB, Tan L, Tie J. Circulating Tumor DNA: An Emerging Tool in Gastrointestinal Cancers. Am Soc Clin Oncol Educ Book 2022; 42:1-20. [PMID: 35471832 DOI: 10.1200/edbk_349143] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Circulating tumor DNA (ctDNA) is tumor-derived fragmented DNA in the bloodstream that has come from primary or metastatic cancer sites. Neoplasm-specific genetic and epigenetic abnormalities are increasingly being identified through liquid biopsy: a novel, minimally invasive technique used to isolate and analyze ctDNA in the peripheral circulation. Liquid biopsy and other emerging ctDNA technologies represent a paradigm shift in cancer diagnostics because they allow for the detection of minimal residual disease in patients with early-stage disease, improve risk stratification, capture tumor heterogeneity and genomic evolution, and enhance ctDNA-guided adjuvant and palliative cancer therapy. Moreover, ctDNA can be used to monitor the tumor response to neoadjuvant and postoperative therapy in patients with metastatic disease. Using clearance of ctDNA as an endpoint for escalation/de-escalation of adjuvant chemotherapy for patients considered to have high-risk disease has become an important area of research. The possibility of using ctDNA as a surrogate for treatment response-including for overall survival, progression-free survival, and disease-free survival-is an attractive concept; this surrogate will arguably reduce study duration and expedite the development of new therapies. In this review, we summarize the current evidence on the applications of ctDNA for the diagnosis and management of gastrointestinal tumors. Gastrointestinal cancers-including tumors of the esophagus, stomach, colon, liver, and pancreas-account for one-quarter of global cancer diagnoses and contribute to more than one-third of cancer-related deaths. Given the prevalence of gastrointestinal malignancies, ctDNA technology represents a powerful tool to reduce the global burden of disease.
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Affiliation(s)
- Olatunji B Alese
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA
| | - Natalie Cook
- Experimental Cancer Medicine Team, The Christie NHS Foundation Trust, Manchester, United Kingdom.,Division of Cancer Sciences, University of Manchester, Manchester, United Kingdom
| | - Ana Ortega-Franco
- Experimental Cancer Medicine Team, The Christie NHS Foundation Trust, Manchester, United Kingdom
| | - Mark B Ulanja
- Christus Ochsner St. Patrick Hospital, Lake Charles, LA
| | - Lavinia Tan
- Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia.,Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia
| | - Jeanne Tie
- Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia.,Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia.,Division of Personalized Oncology, Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia
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31
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Tjensvoll K, Lapin M, Gilje B, Garresori H, Oltedal S, Forthun RB, Molven A, Rozenholc Y, Nordgård O. Novel hybridization- and tag-based error-corrected method for sensitive ctDNA mutation detection using ion semiconductor sequencing. Sci Rep 2022; 12:5816. [PMID: 35388068 PMCID: PMC8986848 DOI: 10.1038/s41598-022-09698-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Accepted: 03/24/2022] [Indexed: 11/08/2022] Open
Abstract
Circulating tumor DNA (ctDNA) analysis has emerged as a clinically useful tool for cancer diagnostics and treatment monitoring. However, ctDNA detection is complicated by low DNA concentrations and technical challenges. Here we describe our newly developed sensitive method for ctDNA detection on the Ion Torrent sequencing platform, which we call HYbridization- and Tag-based Error-Corrected sequencing (HYTEC-seq). This method combines hybridization-based capture with molecular tags, and the novel variant caller PlasmaMutationDetector2 to eliminate background errors. We describe the validation of HYTEC-seq using control samples with known mutations, demonstrating an analytical sensitivity down to 0.1% at > 99.99% specificity. Furthermore, to demonstrate the utility of this method in a clinical setting, we analyzed plasma samples from 44 patients with advanced pancreatic cancer, revealing mutations in 57% of the patients at allele frequencies as low as 0.23%.
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Affiliation(s)
- Kjersti Tjensvoll
- Department of Hematology and Oncology, Laboratory for Molecular Biology, Stavanger University Hospital, 4068, Stavanger, Norway.
| | - Morten Lapin
- Department of Hematology and Oncology, Laboratory for Molecular Biology, Stavanger University Hospital, 4068, Stavanger, Norway
| | - Bjørnar Gilje
- Department of Hematology and Oncology, Laboratory for Molecular Biology, Stavanger University Hospital, 4068, Stavanger, Norway
| | - Herish Garresori
- Department of Hematology and Oncology, Laboratory for Molecular Biology, Stavanger University Hospital, 4068, Stavanger, Norway
| | - Satu Oltedal
- Department of Hematology and Oncology, Laboratory for Molecular Biology, Stavanger University Hospital, 4068, Stavanger, Norway
| | - Rakel Brendsdal Forthun
- Department of Medical Genetics, Haukeland University Hospital, 5020, Bergen, Norway
- Department of Internal Medicine, Hematology Section, Haukeland University Hospital, 5020, Bergen, Norway
| | - Anders Molven
- Gade Laboratory for Pathology, Department of Clinical Medicine, University of Bergen, 5020, Bergen, Norway
- Department of Pathology, Haukeland University Hospital, 5021, Bergen, Norway
| | - Yves Rozenholc
- BioSTM UR 7537, Faculté de Pharmacie de Paris, Université Paris Citè, 75006, Paris, France
| | - Oddmund Nordgård
- Department of Hematology and Oncology, Laboratory for Molecular Biology, Stavanger University Hospital, 4068, Stavanger, Norway
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Saha S, Araf Y, Promon SK. Circulating tumor DNA in cancer diagnosis, monitoring, and prognosis. J Egypt Natl Canc Inst 2022; 34:8. [PMID: 35187602 DOI: 10.1186/s43046-022-00109-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Accepted: 01/29/2022] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Circulating tumor DNA (ctDNA) has become one of the crucial components for cancer detection with the increase of precision medicine practice. ctDNA has great potential as a blood-based biomarker for the detection and treatment of cancer in its early stages. The purpose of this article was to discuss ctDNA and how it can be utilized to detect cancer. The benefits and drawbacks of this cancer detection technology, as well as the field's future possibilities in various cancer management scenarios, are discussed. MAIN TEXT: ctDNA has clinical applications in disease diagnosis and monitoring. It can be used to identify mutations of interest and genetic heterogeneity. Another use of ctDNA is to monitor the effects of therapy by detecting mutation-driven resistance. Different technologies are being used for the detection of ctDNA. Next-generation sequencing, digital PCR, real-time PCR, and mass spectrometry are used. Using dPCR makes it possible to partition and analyze individual target sequences from a complex mixture. Mass-spectrometry technology enables accurate detection and quantification of ctDNA mutations at low frequency. Surface-enhanced Raman spectroscopy (SERS) and UltraSEEK are two systems based on this technology. There is no unified standard for detecting ctDNA as it exists in a low concentration in blood. As there is no defined approach, false positives occur in several methods due to inadequate sensitivities. Techniques used in ctDNA are costly and there is a limitation in clinical settings. SHORT CONCLUSION A detailed investigation is urgently needed to increase the test's accuracy and sensitivity. To find a standard marker for all forms of cancer DNA, more study is needed. Low concentrations of ctDNA in a sample require improved technology to provide the precision that low concentrations of ctDNA in a sample afford.
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Affiliation(s)
- Sudeepto Saha
- Department of Life Sciences, School of Environment and Life Sciences, Independent University, Bangladesh (IUB), Dhaka, Bangladesh
| | - Yusha Araf
- Department of Genetic Engineering and Biotechnology, School of Life Sciences, Shahjalal University of Science and Technology, Sylhet, Bangladesh.
| | - Salman Khan Promon
- Department of Life Sciences, School of Environment and Life Sciences, Independent University, Bangladesh (IUB), Dhaka, Bangladesh.
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Vellan CJ, Jayapalan JJ, Yoong BK, Abdul-Aziz A, Mat-Junit S, Subramanian P. Application of Proteomics in Pancreatic Ductal Adenocarcinoma Biomarker Investigations: A Review. Int J Mol Sci 2022; 23:2093. [PMID: 35216204 PMCID: PMC8879036 DOI: 10.3390/ijms23042093] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 01/07/2022] [Accepted: 01/09/2022] [Indexed: 12/12/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC), a highly aggressive malignancy with a poor prognosis is usually detected at the advanced stage of the disease. The only US Food and Drug Administration-approved biomarker that is available for PDAC, CA 19-9, is most useful in monitoring treatment response among PDAC patients rather than for early detection. Moreover, when CA 19-9 is solely used for diagnostic purposes, it has only a recorded sensitivity of 79% and specificity of 82% in symptomatic individuals. Therefore, there is an urgent need to identify reliable biomarkers for diagnosis (specifically for the early diagnosis), ascertain prognosis as well as to monitor treatment response and tumour recurrence of PDAC. In recent years, proteomic technologies are growing exponentially at an accelerated rate for a wide range of applications in cancer research. In this review, we discussed the current status of biomarker research for PDAC using various proteomic technologies. This review will explore the potential perspective for understanding and identifying the unique alterations in protein expressions that could prove beneficial in discovering new robust biomarkers to detect PDAC at an early stage, ascertain prognosis of patients with the disease in addition to monitoring treatment response and tumour recurrence of patients.
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Affiliation(s)
- Christina Jane Vellan
- Department of Molecular Medicine, Faculty of Medicine, Universiti Malaya, Kuala Lumpur 50603, Malaysia; (C.J.V.); (A.A.-A.); (S.M.-J.)
| | - Jaime Jacqueline Jayapalan
- Department of Molecular Medicine, Faculty of Medicine, Universiti Malaya, Kuala Lumpur 50603, Malaysia; (C.J.V.); (A.A.-A.); (S.M.-J.)
- University of Malaya Centre for Proteomics Research (UMCPR), Universiti Malaya, Kuala Lumpur 50603, Malaysia
| | - Boon-Koon Yoong
- Department of Surgery, Faculty of Medicine, Universiti Malaya, Kuala Lumpur 50603, Malaysia;
| | - Azlina Abdul-Aziz
- Department of Molecular Medicine, Faculty of Medicine, Universiti Malaya, Kuala Lumpur 50603, Malaysia; (C.J.V.); (A.A.-A.); (S.M.-J.)
| | - Sarni Mat-Junit
- Department of Molecular Medicine, Faculty of Medicine, Universiti Malaya, Kuala Lumpur 50603, Malaysia; (C.J.V.); (A.A.-A.); (S.M.-J.)
| | - Perumal Subramanian
- Department of Biochemistry and Biotechnology, Annamalai University, Chidambaram 608002, Tamil Nadu, India;
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Nussinov R, Tsai CJ, Jang H. How can same-gene mutations promote both cancer and developmental disorders? SCIENCE ADVANCES 2022; 8:eabm2059. [PMID: 35030014 PMCID: PMC8759737 DOI: 10.1126/sciadv.abm2059] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Accepted: 11/22/2021] [Indexed: 05/05/2023]
Abstract
The question of how same-gene mutations can drive both cancer and neurodevelopmental disorders has been puzzling. It has also been puzzling why those with neurodevelopmental disorders have a high risk of cancer. Ras, MEK, PI3K, PTEN, and SHP2 are among the oncogenic proteins that can harbor mutations that encode diseases other than cancer. Understanding why some of their mutations can promote cancer, whereas others promote neurodevelopmental diseases, and why even the same mutations may promote both phenotypes, has important clinical ramifications. Here, we review the literature and address these tantalizing questions. We propose that cell type–specific expression of the mutant protein, and of other proteins in the respective pathway, timing of activation (during embryonic development or sporadic emergence), and the absolute number of molecules that the mutations activate, alone or in combination, are pivotal in determining the pathological phenotypes—cancer and (or) developmental disorders.
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Affiliation(s)
- Ruth Nussinov
- Computational Structural Biology Section, Frederick National Laboratory for Cancer Research in the Laboratory of Cancer Immunometabolism, National Cancer Institute, Frederick, MD 21702, USA
- Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel
| | - Chung-Jung Tsai
- Computational Structural Biology Section, Frederick National Laboratory for Cancer Research in the Laboratory of Cancer Immunometabolism, National Cancer Institute, Frederick, MD 21702, USA
| | - Hyunbum Jang
- Computational Structural Biology Section, Frederick National Laboratory for Cancer Research in the Laboratory of Cancer Immunometabolism, National Cancer Institute, Frederick, MD 21702, USA
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35
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Bunduc S, Gede N, Váncsa S, Lillik V, Kiss S, Dembrovszky F, Eróss B, Szakács Z, Gheorghe C, Mikó A, Hegyi P. Prognostic role of cell-free DNA biomarkers in pancreatic adenocarcinoma: A systematic review and meta-analysis. Crit Rev Oncol Hematol 2022; 169:103548. [PMID: 34843928 DOI: 10.1016/j.critrevonc.2021.103548] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Revised: 10/22/2021] [Accepted: 11/23/2021] [Indexed: 12/16/2022] Open
Abstract
This systematic review and meta-analysis evaluated the prognostic role of cell-free DNA (cfDNA) in pancreatic ductal adenocarcinoma (PDAC). Eligible studies reported differences in overall (OS) and progression-free survival (PFS) by cfDNA status. The random effect model yielded the pooled hazard ratios (HRs) and 95 % confidence intervals (CI). Detection of circulant-tumor DNA (ctDNA), KRAS mutations and other cfDNA alterations constitute detectable cfDNA biomarkers. Altogether, 38 studies (3,318 patients) were eligible. Progression-free and overall survival were decreased with detectable ctDNA (HR = 1.92, 95 %CI:(1.29,2.86); HR = 2.25, 95 %CI:(1.73,2.92)) and KRAS mutations (HR = 1.88, CI:1.22,2.92,); HR = 1.52, 95 %CI:(1.22,1.90)) respectively, across various stages. In unresectable cases, ctDNA (HR = 2.50, 95 %CI:(1.94,3.23)), but not KRAS mutations (HR = 1.16, 95 %CI:(0.46,2.94)) signaled risk for progression. Detectable cfDNA biomarkers correlated with worse prognosis in resectable cases and if detected during treatment. In conclusion, cfDNA biomarkers indicate accelerated progression and decreased survival in PDAC. Significance of KRAS mutations detection in unresectable cases is to be determined.
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Affiliation(s)
- Stefania Bunduc
- Carol Davila University of Medicine and Pharmacy, 020021, Bucharest, Dionisie Lupu street 37, Romania; Fundeni Clinical Institute, 022328, Fundeni street 258, Bucharest, Romania; Institute for Translational Medicine, Szentágothai Research Centre, Medical School, University of Pécs, 7624, Pécs, Szigeti út 12, Hungary; Centre for Translational Medicine, Semmelweis University, 1085, Budapest, Üllői út. 26, Hungary; Division of Pancreatic Diseases, Heart and Vascular Center, Semmelweis University, 1085, Budapest, Baross út. 8, Hungary.
| | - Noémi Gede
- Institute for Translational Medicine, Szentágothai Research Centre, Medical School, University of Pécs, 7624, Pécs, Szigeti út 12, Hungary.
| | - Szilárd Váncsa
- Institute for Translational Medicine, Szentágothai Research Centre, Medical School, University of Pécs, 7624, Pécs, Szigeti út 12, Hungary; Centre for Translational Medicine, Semmelweis University, 1085, Budapest, Üllői út. 26, Hungary; Division of Pancreatic Diseases, Heart and Vascular Center, Semmelweis University, 1085, Budapest, Baross út. 8, Hungary.
| | - Veronika Lillik
- Institute for Translational Medicine, Szentágothai Research Centre, Medical School, University of Pécs, 7624, Pécs, Szigeti út 12, Hungary; University of Pécs, Medical School, Department of Medical Genetics, 7624, Pécs, Szigeti út 12, Hungary.
| | - Szabolcs Kiss
- Institute for Translational Medicine, Szentágothai Research Centre, Medical School, University of Pécs, 7624, Pécs, Szigeti út 12, Hungary; Doctoral School of Clinical Medicine, University of Szeged, 6720, Szeged, Szeged, Dugonics tér 1, Hungary.
| | - Fanni Dembrovszky
- Institute for Translational Medicine, Szentágothai Research Centre, Medical School, University of Pécs, 7624, Pécs, Szigeti út 12, Hungary; Centre for Translational Medicine, Semmelweis University, 1085, Budapest, Üllői út. 26, Hungary.
| | - Bálint Eróss
- Institute for Translational Medicine, Szentágothai Research Centre, Medical School, University of Pécs, 7624, Pécs, Szigeti út 12, Hungary; Centre for Translational Medicine, Semmelweis University, 1085, Budapest, Üllői út. 26, Hungary; Division of Pancreatic Diseases, Heart and Vascular Center, Semmelweis University, 1085, Budapest, Baross út. 8, Hungary.
| | - Zsolt Szakács
- Institute for Translational Medicine, Szentágothai Research Centre, Medical School, University of Pécs, 7624, Pécs, Szigeti út 12, Hungary; First Department of Medicine, Medical School, University of Pécs, 7624, Pécs, Szigeti út 12, Hungary.
| | - Cristian Gheorghe
- Carol Davila University of Medicine and Pharmacy, 020021, Bucharest, Dionisie Lupu street 37, Romania; Fundeni Clinical Institute, 022328, Fundeni street 258, Bucharest, Romania.
| | - Alexandra Mikó
- Institute for Translational Medicine, Szentágothai Research Centre, Medical School, University of Pécs, 7624, Pécs, Szigeti út 12, Hungary; University of Pécs, Medical School, Department of Medical Genetics, 7624, Pécs, Szigeti út 12, Hungary.
| | - Péter Hegyi
- Institute for Translational Medicine, Szentágothai Research Centre, Medical School, University of Pécs, 7624, Pécs, Szigeti út 12, Hungary; Centre for Translational Medicine, Semmelweis University, 1085, Budapest, Üllői út. 26, Hungary; Division of Pancreatic Diseases, Heart and Vascular Center, Semmelweis University, 1085, Budapest, Baross út. 8, Hungary.
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36
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Olmedillas-López S, Olivera-Salazar R, García-Arranz M, García-Olmo D. Current and Emerging Applications of Droplet Digital PCR in Oncology: An Updated Review. Mol Diagn Ther 2021; 26:61-87. [PMID: 34773243 DOI: 10.1007/s40291-021-00562-2] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/17/2021] [Indexed: 12/14/2022]
Abstract
In the era of personalized medicine and targeted therapies for the management of patients with cancer, ultrasensitive detection methods for tumor genotyping, such as next-generation sequencing or droplet digital polymerase chain reaction (ddPCR), play a significant role. In the search for less invasive strategies for diagnosis, prognosis and disease monitoring, the number of publications regarding liquid biopsy approaches using ddPCR has increased substantially in recent years. There is a long list of malignancies in which ddPCR provides a reliable and accurate tool for detection of nucleic acid-based markers derived from cell-free DNA, cell-free RNA, circulating tumor cells, extracellular vesicles or exosomes when isolated from whole blood, plasma and serum, helping to anticipate tumor relapse or unveil intratumor heterogeneity and clonal evolution in response to treatment. This updated review describes recent developments in ddPCR platforms and provides a general overview about the major applications of liquid biopsy in blood, including its utility for molecular response and minimal residual disease monitoring in hematological malignancies or the therapeutic management of patients with colorectal or lung cancer, particularly for the selection and monitoring of treatment with tyrosine kinase inhibitors. Although plasma is the main source of genetic material for tumor genomic profiling, liquid biopsy by ddPCR is being investigated in a wide variety of biologic fluids, such as cerebrospinal fluid, urine, stool, ocular fluids, sputum, saliva, bronchoalveolar lavage, pleural effusion, mucin, peritoneal fluid, fine needle aspirate, bile or pancreatic juice. The present review focuses on these "alternative" sources of genetic material and their analysis by ddPCR in different kinds of cancers.
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Affiliation(s)
- Susana Olmedillas-López
- New Therapies Laboratory, Health Research Institute-Fundación Jiménez Díaz University Hospital (IIS-FJD), Avda. Reyes Católicos, 2, 28040, Madrid, Spain.
| | - Rocío Olivera-Salazar
- New Therapies Laboratory, Health Research Institute-Fundación Jiménez Díaz University Hospital (IIS-FJD), Avda. Reyes Católicos, 2, 28040, Madrid, Spain
| | - Mariano García-Arranz
- New Therapies Laboratory, Health Research Institute-Fundación Jiménez Díaz University Hospital (IIS-FJD), Avda. Reyes Católicos, 2, 28040, Madrid, Spain.,Department of Surgery, School of Medicine, Universidad Autónoma de Madrid (UAM), 28029, Madrid, Spain
| | - Damián García-Olmo
- New Therapies Laboratory, Health Research Institute-Fundación Jiménez Díaz University Hospital (IIS-FJD), Avda. Reyes Católicos, 2, 28040, Madrid, Spain.,Department of Surgery, School of Medicine, Universidad Autónoma de Madrid (UAM), 28029, Madrid, Spain.,Department of Surgery, Fundación Jiménez Díaz University Hospital (FJD), 28040, Madrid, Spain
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Si C, Chen C, Guo Y, Kang Q, Sun Z. Effect, Mechanism, and Applications of Coding/Non-coding RNA m6A Modification in Tumor Microenvironment. Front Cell Dev Biol 2021; 9:711815. [PMID: 34660577 PMCID: PMC8514707 DOI: 10.3389/fcell.2021.711815] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Accepted: 08/30/2021] [Indexed: 01/07/2023] Open
Abstract
The tumor microenvironment (TME), which includes immune cells, fibroblasts, and other components, is the site of tumor cell growth and metastasis and significantly impacts tumor development. Among them, N6-methyladenosine RNA modifications (m6A RNA modifications) are the most abundant internal modifications in coding and non-coding RNAs, which can significantly influence the cancer process and have potential as biomarkers and potential therapeutic targets for tumor therapy. This manuscript reviews the role of m6A RNA modifications in TME and their application in tumor therapy. To some extent, an in-depth understanding of the relationship between TME and m6A RNA modifications will provide new approaches and ideas for future cancer therapy.
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Affiliation(s)
- Chaohua Si
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,School of Life Sciences, Zhengzhou University, Zhengzhou, China
| | - Chen Chen
- School of Life Sciences, Zhengzhou University, Zhengzhou, China
| | - Yaxin Guo
- Henan Academy of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China.,School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Qiaozhen Kang
- School of Life Sciences, Zhengzhou University, Zhengzhou, China
| | - Zhenqiang Sun
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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Tang D, Kroemer G, Kang R. Oncogenic KRAS blockade therapy: renewed enthusiasm and persistent challenges. Mol Cancer 2021; 20:128. [PMID: 34607583 PMCID: PMC8489073 DOI: 10.1186/s12943-021-01422-7] [Citation(s) in RCA: 58] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Accepted: 09/08/2021] [Indexed: 02/08/2023] Open
Abstract
Across a broad range of human cancers, gain-of-function mutations in RAS genes (HRAS, NRAS, and KRAS) lead to constitutive activity of oncoproteins responsible for tumorigenesis and cancer progression. The targeting of RAS with drugs is challenging because RAS lacks classic and tractable drug binding sites. Over the past 30 years, this perception has led to the pursuit of indirect routes for targeting RAS expression, processing, upstream regulators, or downstream effectors. After the discovery that the KRAS-G12C variant contains a druggable pocket below the switch-II loop region, it has become possible to design irreversible covalent inhibitors for the variant with improved potency, selectivity and bioavailability. Two such inhibitors, sotorasib (AMG 510) and adagrasib (MRTX849), were recently evaluated in phase I-III trials for the treatment of non-small cell lung cancer with KRAS-G12C mutations, heralding a new era of precision oncology. In this review, we outline the mutations and functions of KRAS in human tumors and then analyze indirect and direct approaches to shut down the oncogenic KRAS network. Specifically, we discuss the mechanistic principles, clinical features, and strategies for overcoming primary or secondary resistance to KRAS-G12C blockade.
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Affiliation(s)
- Daolin Tang
- The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, China. .,Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA.
| | - Guido Kroemer
- Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, INSERM U1138, Institut Universitaire de France, Paris, France. .,Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France. .,Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France.
| | - Rui Kang
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA.
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Tsoi KM, Gokgoz N, Darville-O'Quinn P, Prochazka P, Malekoltojari A, Griffin AM, Ferguson PC, Wunder JS, Andrulis IL. Detection and utility of cell-free and circulating tumour DNA in bone and soft-tissue sarcomas. Bone Joint Res 2021; 10:602-610. [PMID: 34558310 PMCID: PMC8479566 DOI: 10.1302/2046-3758.109.bjr-2021-0014.r1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Aims Cell-free DNA (cfDNA) and circulating tumour DNA (ctDNA) are used for prognostication and monitoring in patients with carcinomas, but their utility is unclear in sarcomas. The objectives of this pilot study were to explore the prognostic significance of cfDNA and investigate whether tumour-specific alterations can be detected in the circulation of sarcoma patients. Methods Matched tumour and blood were collected from 64 sarcoma patients (n = 70 samples) prior to resection of the primary tumour (n = 57) or disease recurrence (n = 7). DNA was isolated from plasma, quantified, and analyzed for cfDNA. A subset of cases (n = 6) underwent whole exome sequencing to identify tumour-specific alterations used to detect ctDNA using digital droplet polymerase chain reaction (ddPCR). Results Cell-free was present in 69 of 70 samples above 0.5 ng/ml. Improved disease-free survival was found for patients with lower cfDNA levels (90% vs 48% at one-year for ≤ 6 ng/ml and > 6 ng/ml, respectively; p = 0.005). Digital droplet PCR was performed as a pilot study and mutant alleles were detectable at 0.5% to 2.5% of the wild type genome, and at a level of 0.25 ng tumour DNA. Tumour-specific alterations (ctDNA) were found in five of six cases. Conclusion This work demonstrates the feasibility and potential utility of cfDNA and ctDNA as biomarkers for bone and soft-tissue sarcomas, despite the lack of recurrent genomic alterations. A larger study is required to validate these findings. Cite this article: Bone Joint Res 2021;10(9):602–610.
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Affiliation(s)
- Kim M Tsoi
- University of Toronto Musculoskeletal Oncology Unit, Sinai Health System, Toronto, Canada.,Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Canada.,Department of Surgery, University of Toronto, Toronto, Canada
| | - Nalan Gokgoz
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Canada
| | | | - Patrick Prochazka
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Canada
| | - Ainaz Malekoltojari
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Canada
| | - Anthony M Griffin
- University of Toronto Musculoskeletal Oncology Unit, Sinai Health System, Toronto, Canada
| | - Peter C Ferguson
- University of Toronto Musculoskeletal Oncology Unit, Sinai Health System, Toronto, Canada.,Department of Surgery, University of Toronto, Toronto, Canada
| | - Jay S Wunder
- University of Toronto Musculoskeletal Oncology Unit, Sinai Health System, Toronto, Canada.,Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Canada.,Department of Surgery, University of Toronto, Toronto, Canada
| | - Irene L Andrulis
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Canada.,Department of Molecular Genetics, University of Toronto, Toronto, Canada.,Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada
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40
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Moati E, Taly V, Garinet S, Didelot A, Taieb J, Laurent-Puig P, Zaanan A. Role of Circulating Tumor DNA in Gastrointestinal Cancers: Current Knowledge and Perspectives. Cancers (Basel) 2021; 13:4743. [PMID: 34638228 PMCID: PMC8507552 DOI: 10.3390/cancers13194743] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Revised: 09/06/2021] [Accepted: 09/18/2021] [Indexed: 12/21/2022] Open
Abstract
Gastrointestinal (GI) cancers are major health burdens worldwide and biomarkers are needed to improve the management of these diseases along their evolution. Circulating tumor DNA (ctDNA) is a promising non-invasive blood and other bodily-fluid-based biomarker in cancer management that can help clinicians in various cases for the detection, diagnosis, prognosis, monitoring and personalization of treatment in digestive oncology. In addition to the well-studied prognostic role of ctDNA, the main real-world applications appear to be the assessment of minimal residual disease to further guide adjuvant therapy and predict relapse, but also the monitoring of clonal evolution to tailor treatments in metastatic setting. Other challenges such as predicting response to treatment including immune checkpoint inhibitors could also be among the potential applications of ctDNA. Although the level of advancement of ctDNA development in the different tumor localizations is still inhomogeneous, it might be now reliable enough to be soon used in clinical routine for colorectal cancers and shows promising results in other GI cancers.
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Affiliation(s)
- Emilie Moati
- Department of Gastroenterology and Digestive Oncology, Institut du Cancer Paris Carpem, Assistance Publique des Hôpitaux de Paris, European Georges Pompidou Hospital, 75015 Paris, France; (E.M.); (J.T.)
| | - Valerie Taly
- Centre de Recherche des Cordeliers, INSERM UMRS1138, Centre National de la Recherche Scientifique, Sorbonne Université, USPC, Université de Paris, Equipe Labellisée Ligue Nationale Contre le Cancer, CNRS SNC 5096, 75006 Paris, France; (V.T.); (S.G.); (A.D.); (P.L.-P.)
| | - Simon Garinet
- Centre de Recherche des Cordeliers, INSERM UMRS1138, Centre National de la Recherche Scientifique, Sorbonne Université, USPC, Université de Paris, Equipe Labellisée Ligue Nationale Contre le Cancer, CNRS SNC 5096, 75006 Paris, France; (V.T.); (S.G.); (A.D.); (P.L.-P.)
- Department of Biochemistry, Institut du Cancer Paris Carpem, Assistance Publique des Hôpitaux de Paris, European Georges Pompidou Hospital, 75015 Paris, France
| | - Audrey Didelot
- Centre de Recherche des Cordeliers, INSERM UMRS1138, Centre National de la Recherche Scientifique, Sorbonne Université, USPC, Université de Paris, Equipe Labellisée Ligue Nationale Contre le Cancer, CNRS SNC 5096, 75006 Paris, France; (V.T.); (S.G.); (A.D.); (P.L.-P.)
| | - Julien Taieb
- Department of Gastroenterology and Digestive Oncology, Institut du Cancer Paris Carpem, Assistance Publique des Hôpitaux de Paris, European Georges Pompidou Hospital, 75015 Paris, France; (E.M.); (J.T.)
- Centre de Recherche des Cordeliers, INSERM UMRS1138, Centre National de la Recherche Scientifique, Sorbonne Université, USPC, Université de Paris, Equipe Labellisée Ligue Nationale Contre le Cancer, CNRS SNC 5096, 75006 Paris, France; (V.T.); (S.G.); (A.D.); (P.L.-P.)
| | - Pierre Laurent-Puig
- Centre de Recherche des Cordeliers, INSERM UMRS1138, Centre National de la Recherche Scientifique, Sorbonne Université, USPC, Université de Paris, Equipe Labellisée Ligue Nationale Contre le Cancer, CNRS SNC 5096, 75006 Paris, France; (V.T.); (S.G.); (A.D.); (P.L.-P.)
- Department of Biochemistry, Institut du Cancer Paris Carpem, Assistance Publique des Hôpitaux de Paris, European Georges Pompidou Hospital, 75015 Paris, France
| | - Aziz Zaanan
- Department of Gastroenterology and Digestive Oncology, Institut du Cancer Paris Carpem, Assistance Publique des Hôpitaux de Paris, European Georges Pompidou Hospital, 75015 Paris, France; (E.M.); (J.T.)
- Centre de Recherche des Cordeliers, INSERM UMRS1138, Centre National de la Recherche Scientifique, Sorbonne Université, USPC, Université de Paris, Equipe Labellisée Ligue Nationale Contre le Cancer, CNRS SNC 5096, 75006 Paris, France; (V.T.); (S.G.); (A.D.); (P.L.-P.)
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van der Sijde F, Azmani Z, Besselink MG, Bonsing BA, de Groot JWB, Groot Koerkamp B, Haberkorn BCM, Homs MYV, van IJcken WFJ, Janssen QP, Lolkema MP, Luelmo SAC, Mekenkamp LJM, Mustafa DAM, van Schaik RHN, Wilmink JW, Vietsch EE, van Eijck CHJ. Circulating TP53 mutations are associated with early tumor progression and poor survival in pancreatic cancer patients treated with FOLFIRINOX. Ther Adv Med Oncol 2021; 13:17588359211033704. [PMID: 34422118 PMCID: PMC8377319 DOI: 10.1177/17588359211033704] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Accepted: 06/30/2021] [Indexed: 01/05/2023] Open
Abstract
Background: Biomarkers predicting treatment response may be used to stratify pancreatic ductal adenocarcinoma (PDAC) patients for therapy. The aim of this study was to identify circulating tumor DNA (ctDNA) mutations that associate with tumor progression during FOLFIRINOX chemotherapy, and overall survival (OS). Methods: Circulating cell-free DNA was analyzed with a 57 gene next-generation sequencing panel using plasma samples of 48 PDAC patients of all disease stages. Patients received FOLFIRINOX as initial treatment. Chemotherapy response was determined on CT scans as disease control (n = 30) or progressive disease (n = 18) within eight cycles of FOLFIRINOX, based on RECIST 1.1 criteria. Results: Detection of a TP53 ctDNA mutation before start of FOLFIRINOX [odds ratio (OR) 10.51, 95% confidence interval (CI) 1.40–79.14] and the presence of a homozygous TP53 Pro72Arg germline variant (OR 6.98, 95% CI 1.31–37.30) were predictors of early tumor progression during FOLFIRINOX in multivariable analysis. Five patients presented with the combination of a TP53 ctDNA mutation before start of FOLFIRINOX and the homozygous Pro72Arg variant. All five patients showed progression during FOLFIRINOX. The combination of the TP53 mutation and TP53 germline variant was associated with shorter survival (median OS 4.4 months, 95% CI 2.6–6.2 months) compared with patients without any TP53 alterations (median OS 13.0 months, 95% CI 8.6–17.4 months). Conclusion: The combination of a TP53 ctDNA mutation before start of FOLFIRINOX and a homozygous TP53 Pro72Arg variant is a promising biomarker, associated with early tumor progression during FOLFIRINOX and poor OS. The results of this exploratory study need to be validated in an independent cohort.
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Affiliation(s)
- Fleur van der Sijde
- Department of Surgery, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
| | - Zakia Azmani
- Center for Biomics, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
| | - Marc G. Besselink
- Department of Surgery, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, Noord-Holland, The Netherlands
| | - Bert A. Bonsing
- Department of Surgery, Leiden University Medical Center, Leiden, Zuid-Holland, The Netherlands
| | | | - Bas Groot Koerkamp
- Department of Surgery, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
| | | | - Marjolein Y. V. Homs
- Department of Medical Oncology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
| | | | - Quisette P. Janssen
- Department of Surgery, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
| | - Martijn P. Lolkema
- Department of Medical Oncology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
| | - Saskia A. C. Luelmo
- Department of Medical Oncology, Leiden University Medical Center, Leiden, Zuid-Holland, The Netherlands
| | - Leonie J. M. Mekenkamp
- Department of Medical Oncology, Medisch Spectrum Twente, Enschede, Overijssel, The Netherlands
| | - Dana A. M. Mustafa
- Department of Pathology, Tumor Immuno-Pathology Laboratory, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
| | - Ron H. N. van Schaik
- Department of Clinical Chemistry, Erasmus MC, University Medical Center, Rotterdam, Zuid-Holland, The Netherlands
| | - Johanna W. Wilmink
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
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Balendran-Braun S, Kieler M, Liebmann-Reindl S, Unseld M, Bianconi D, W Prager G, Streubel B. Bead-Based Isolation of Circulating Tumor DNA from Pancreatic Cancer Patients Enables High Fidelity Next Generation Sequencing. Cancer Manag Res 2021; 13:6249-6261. [PMID: 34393517 PMCID: PMC8357621 DOI: 10.2147/cmar.s308029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Accepted: 06/07/2021] [Indexed: 11/23/2022] Open
Abstract
INTRODUCTION Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers and poses a challenge to the treating clinician. With the emergence of genomic profiling technologies, circulating tumor DNA (ctDNA) is increasingly recognized as a versatile biomarker for risk stratification and disease monitoring. We aimed to compare two commercially available NGS panels in a cohort of patients with advanced PDAC undergoing palliative chemotherapy. METHODS CtDNA was isolated with a magnetic bead-based protocol from two consecutive blood samples before and during chemotherapy in 21 patients with PDAC. Mutations were assessed by using a panel covering 15 (GP15) or 50 (GP50) cancer-associated genes. Results were compared to tumor tissue (GP15), if available. RESULTS Isolation of ctDNA resulted in a high mean value of 1.9 ng/µL (total volume of ~40 µL). Although the same number of patients were positive for at least one mutation (76%), the most commonly mutated oncogene in PDAC, KRAS, was detectable in an additional 25% of all patients with the GP15 panel due to a higher coverage. The genomic concordance rate between tissue DNA and ctDNA analyses was 65.22%. DISCUSSION Our study demonstrates the feasibility of an NGS-based approach for ctDNA analysis and underlines the importance of using a disease-specific panel with a sufficiently high coverage.
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Affiliation(s)
| | - Markus Kieler
- Department of Medicine I, Division of Oncology, Comprehensive Cancer Center, Medical University, Vienna, Austria
| | | | - Matthias Unseld
- Department of Medicine I, Division of Oncology, Comprehensive Cancer Center, Medical University, Vienna, Austria
| | - Daniela Bianconi
- Department of Medicine I, Division of Oncology, Comprehensive Cancer Center, Medical University, Vienna, Austria
| | - Gerald W Prager
- Department of Medicine I, Division of Oncology, Comprehensive Cancer Center, Medical University, Vienna, Austria
| | - Berthold Streubel
- Department of Pathology, Medical University of Vienna, Vienna, Austria
- Core Facility Genomics, Medical University of Vienna, Vienna, Austria
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Palacín-Aliana I, García-Romero N, Asensi-Puig A, Carrión-Navarro J, González-Rumayor V, Ayuso-Sacido Á. Clinical Utility of Liquid Biopsy-Based Actionable Mutations Detected via ddPCR. Biomedicines 2021; 9:906. [PMID: 34440110 PMCID: PMC8389639 DOI: 10.3390/biomedicines9080906] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 07/22/2021] [Accepted: 07/23/2021] [Indexed: 01/10/2023] Open
Abstract
Cancer is one of the leading causes of death worldwide and remains a major public health challenge. The introduction of more sensitive and powerful technologies has permitted the appearance of new tumor-specific molecular aberrations with a significant cancer management improvement. Therefore, molecular pathology profiling has become fundamental not only to guide tumor diagnosis and prognosis but also to assist with therapeutic decisions in daily practice. Although tumor biopsies continue to be mandatory in cancer diagnosis and classification, several studies have demonstrated that liquid biopsies could be used as a potential tool for the detection of cancer-specific biomarkers. One of the main advantages is that circulating free DNA (cfDNA) provides information about intra-tumoral heterogeneity, reflecting dynamic changes in tumor burden. This minimally invasive tool has become an accurate and reliable instrument for monitoring cancer genetics. However, implementing liquid biopsies across the clinical practice is still ongoing. The main challenge is to detect genomic alterations at low allele fractions. Droplet digital PCR (ddPCR) is a powerful approach that can overcome this issue due to its high sensitivity and specificity. Here we explore the real-world clinical utility of the liquid biopsy ddPCR assays in the most diagnosed cancer subtypes.
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Affiliation(s)
- Irina Palacín-Aliana
- Atrys Health, 08025 Barcelona, Spain; (I.P.-A.); (A.A.-P.); (V.G.-R.)
- Fundación de Investigación HM Hospitales, HM Hospitales, 28015 Madrid, Spain
- Faculty of Science, Universidad de Alcalá, 28801 Madrid, Spain
| | - Noemí García-Romero
- Faculty of Experimental Sciences, Universidad Francisco de Vitoria, 28223 Madrid, Spain; (N.G.-R.); (J.C.-N.)
- Brain Tumor Laboratory, Fundación Vithas, Grupo Hospitales Vithas, 28043 Madrid, Spain
| | - Adrià Asensi-Puig
- Atrys Health, 08025 Barcelona, Spain; (I.P.-A.); (A.A.-P.); (V.G.-R.)
| | - Josefa Carrión-Navarro
- Faculty of Experimental Sciences, Universidad Francisco de Vitoria, 28223 Madrid, Spain; (N.G.-R.); (J.C.-N.)
- Brain Tumor Laboratory, Fundación Vithas, Grupo Hospitales Vithas, 28043 Madrid, Spain
| | | | - Ángel Ayuso-Sacido
- Faculty of Experimental Sciences, Universidad Francisco de Vitoria, 28223 Madrid, Spain; (N.G.-R.); (J.C.-N.)
- Brain Tumor Laboratory, Fundación Vithas, Grupo Hospitales Vithas, 28043 Madrid, Spain
- Faculty of Medicine, Universidad Francisco de Vitoria, 28223 Madrid, Spain
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Milin-Lazovic J, Madzarevic P, Rajovic N, Djordjevic V, Milic N, Pavlovic S, Veljkovic N, Milic NM, Radenkovic D. Meta-Analysis of Circulating Cell-Free DNA's Role in the Prognosis of Pancreatic Cancer. Cancers (Basel) 2021; 13:3378. [PMID: 34298594 PMCID: PMC8303288 DOI: 10.3390/cancers13143378] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Revised: 06/13/2021] [Accepted: 06/23/2021] [Indexed: 01/14/2023] Open
Abstract
INTRODUCTION The analysis of cell-free DNA (cfDNA) for genetic abnormalities is a promising new approach for the diagnosis and prognosis of pancreatic cancer patients. Insights into the molecular characteristics of pancreatic cancer may provide valuable information, leading to its earlier detection and the development of targeted therapies. MATERIAL AND METHODS We conducted a systematic review and a meta-analysis of studies that reported cfDNA in pancreatic ductal adenocarcinoma (PDAC). The studies were considered eligible if they included patients with PDAC, if they had blood tests for cfDNA/ctDNA, and if they analyzed the prognostic value of cfDNA/ctDNA for patients' survival. The studies published before 22 October 2020 were identified through the PubMED, EMBASE, Web of Science and Cochrane Library databases. The assessed outcomes were the overall (OS) and progression-free survival (PFS), expressed as the log hazard ratio (HR) and standard error (SE). The summary of the HR effect size was estimated by pooling the individual trial results using the Review Manager, version 5.3, Cochrane Collaboration. The heterogeneity was assessed using the Cochran Q test and I2 statistic. RESULTS In total, 48 studies were included in the qualitative review, while 44 were assessed in the quantitative synthesis, with the total number of patients included being 3524. Overall negative impacts of cfDNA and KRAS mutations on OS and PFS in PDAC (HR = 2.42, 95% CI: 1.95-2.99 and HR = 2.46, 95% CI: 2.01-3.00, respectively) were found. The subgroup analysis of the locally advanced and metastatic disease presented similar results (HR = 2.51, 95% CI: 1.90-3.31). In the studies assessing the pre-treatment presence of KRAS, there was a moderate to high degree of heterogeneity (I2 = 87% and I2 = 48%, for OS and PFS, respectively), which was remarkably decreased in the analysis of the studies measuring post-treatment KRAS (I2 = 24% and I2 = 0%, for OS and PFS, respectively). The patients who were KRAS positive before but KRAS negative after treatment had a better prognosis than the persistently KRAS-positive patients (HR = 5.30, 95% CI: 1.02-27.63). CONCLUSION The assessment of KRAS mutation by liquid biopsy can be considered as an additional tool for the estimation of the disease course and outcome in PDAC patients.
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Affiliation(s)
- Jelena Milin-Lazovic
- Institute for Medical Statistics and Informatics, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia; (J.M.-L.); (P.M.); (N.R.); (N.M.M.)
| | - Petar Madzarevic
- Institute for Medical Statistics and Informatics, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia; (J.M.-L.); (P.M.); (N.R.); (N.M.M.)
| | - Nina Rajovic
- Institute for Medical Statistics and Informatics, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia; (J.M.-L.); (P.M.); (N.R.); (N.M.M.)
| | - Vladimir Djordjevic
- Department of Surgery, University Clinical Center of Serbia, 11000 Belgrade, Serbia;
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia;
| | - Nikola Milic
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia;
| | - Sonja Pavlovic
- Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, 11000 Belgrade, Serbia;
| | - Nevena Veljkovic
- Vinca Institute of Nuclear Sciences, National Institute of the Republic of Serbia, University of Belgrade, 11000 Belgrade, Serbia;
- Heliant Ltd., 11000 Belgrade, Serbia
| | - Natasa M. Milic
- Institute for Medical Statistics and Informatics, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia; (J.M.-L.); (P.M.); (N.R.); (N.M.M.)
- Department of Internal Medicine, Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55902, USA
| | - Dejan Radenkovic
- Department of Surgery, University Clinical Center of Serbia, 11000 Belgrade, Serbia;
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia;
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Heredia-Soto V, Rodríguez-Salas N, Feliu J. Liquid Biopsy in Pancreatic Cancer: Are We Ready to Apply It in the Clinical Practice? Cancers (Basel) 2021; 13:1986. [PMID: 33924143 PMCID: PMC8074327 DOI: 10.3390/cancers13081986] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2021] [Revised: 04/14/2021] [Accepted: 04/16/2021] [Indexed: 12/11/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) exhibits the poorest prognosis of all solid tumors, with a 5-year survival of less than 10%. To improve the prognosis, it is necessary to advance in the development of tools that help us in the early diagnosis, treatment selection, disease monitoring, evaluation of the response and prognosis. Liquid biopsy (LB), in its different modalities, represents a particularly interesting tool for these purposes, since it is a minimally invasive and risk-free procedure that can detect both the presence of genetic material from the tumor and circulating tumor cells (CTCs) in the blood and therefore distantly reflect the global status of the disease. In this work we review the current status of the main LB modalities (ctDNA, exosomes, CTCs and cfRNAs) for detecting and monitoring PDAC.
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Affiliation(s)
- Victoria Heredia-Soto
- Translational Oncology Research Laboratory, Biomedical Research Institute, La Paz University Hospital, IdiPAZ, Paseo de la Castellana 261, 28046 Madrid, Spain; (V.H.-S.); (N.R.-S.)
- Centro de Investigación Biomédica en Red de Cáncer, CIBERONC, Instituto de Salud Carlos III, Monforte de Lemos 5, 28029 Madrid, Spain
| | - Nuria Rodríguez-Salas
- Translational Oncology Research Laboratory, Biomedical Research Institute, La Paz University Hospital, IdiPAZ, Paseo de la Castellana 261, 28046 Madrid, Spain; (V.H.-S.); (N.R.-S.)
- Centro de Investigación Biomédica en Red de Cáncer, CIBERONC, Instituto de Salud Carlos III, Monforte de Lemos 5, 28029 Madrid, Spain
- Cátedra UAM-AMGEN, Medical Oncology Department, La Paz University Hospital, Paseo de la Castellana 261, 28046 Madrid, Spain
| | - Jaime Feliu
- Translational Oncology Research Laboratory, Biomedical Research Institute, La Paz University Hospital, IdiPAZ, Paseo de la Castellana 261, 28046 Madrid, Spain; (V.H.-S.); (N.R.-S.)
- Centro de Investigación Biomédica en Red de Cáncer, CIBERONC, Instituto de Salud Carlos III, Monforte de Lemos 5, 28029 Madrid, Spain
- Cátedra UAM-AMGEN, Medical Oncology Department, La Paz University Hospital, Paseo de la Castellana 261, 28046 Madrid, Spain
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Asano K, Mikata R, Chiba T, Kan M, Maruta S, Yamada T, Miura Y, Shima Y, Sensui M, Nagashima H, Yokoyama M, Ohyama H, Kusakabe Y, Yasui S, Sugiyama H, Ohno I, Kato J, Takano S, Ohtsuka M, Kato N. Analysis of circulating cell-free DNA after endoscopic ultrasound-guided fine needle aspiration in pancreatic ductal adenocarcinoma. Pancreatology 2021; 21:S1424-3903(21)00140-X. [PMID: 33865724 DOI: 10.1016/j.pan.2021.04.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Revised: 03/20/2021] [Accepted: 04/01/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND/OBJECTIVES Recently, increase in cell-free DNA (cfDNA) concentration or newly detected KRAS mutation after endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) biopsy were reported to be related to the occurrence of new distant metastasis. In this study, we investigated whether cfDNA concentration increased with the release of tumor components into the blood after EUS-FNA and whether its increase was related to prognosis. METHODS Sixty-eight patients underwent EUS-FNA and were pathologically confirmed as having pancreatic ductal adenocarcinoma (PDAC). We measured plasma cfDNA concentration and the copy number of KRAS mutation in 68 patients and circulating tumor cells in 8 before and after EUS-FNA. RESULTS The average cfDNA concentration after EUS-FNA (672.5 ± 919.6 ng/mL) was significantly higher than that before EUS-FNA (527.7 ± 827.3 ng/mL) (P < 0.001). KRAS mutation in plasma was detected in 8 patients (11.8%), however a significant increase in cfDNA concentration after EUS-FNA was not related to the change in KRAS-mutant copy number. Minimal increase in circulating tumor cells was observed in 3 of 8 patients. New distant metastasis was observed within 286 days to initial metastasis detection in 6 of 12 patients with ≥2-fold increase in cfDNA concentration and 26 of 56 patients with <2-fold increase within 185 days. In 32 patients who underwent surgery, ≥2-fold increase in cfDNA did not affect early recurrence. CONCLUSIONS The increase in cfDNA concentration after EUS-FNA was not caused by tumor cell components released into blood vessels. Hence, the risk of seeding via the blood stream after EUS-FNA may need not be considered.
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Affiliation(s)
- Kosho Asano
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Rintaro Mikata
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan.
| | - Tetsuhiro Chiba
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Motoyasu Kan
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Shikiko Maruta
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Toshihito Yamada
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Yoshifumi Miura
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Yukiko Shima
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Miyuki Sensui
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Hiroki Nagashima
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Masayuki Yokoyama
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Hiroshi Ohyama
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan; Department of Gastroenterology, Yamanashi Central Hospital, Yamanashi, Japan
| | - Yuko Kusakabe
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Shin Yasui
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Harutoshi Sugiyama
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Izumi Ohno
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Jun Kato
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Shigetsugu Takano
- Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Masayuki Ohtsuka
- Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Naoya Kato
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
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Pietri E, Balsano R, Coriano M, Gelsomino F, Leonardi F, Bui S, Gnetti L, Valle RD, Garajová I. The implication of liquid biopsies to predict chemoresistance in pancreatic cancer. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2021; 4:559-572. [PMID: 35582309 PMCID: PMC9094078 DOI: 10.20517/cdr.2021.01] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/03/2021] [Revised: 03/08/2021] [Accepted: 03/29/2021] [Indexed: 12/11/2022]
Abstract
Pancreatic cancer is one of the most aggressive diseases among solid tumors. Most patients are diagnosed with advanced or metastatic disease and are characterized by poor chemosensitivity. Therefore, earlier diagnosis and novel therapeutic possibilities for pancreatic cancer patients are urgently needed. Liquid biopsy is an emerging technology that allows the noninvasive sampling of tumor material. Nowadays, liquid biopsy has shown promising results as diagnostic, prognostic and predictive biomarkers, but it has not yet been universally adopted into regular use by clinicians. In this review, we describe different components of liquid biopsy, especially circulating tumor cells, circulating tumor DNA and exosomes and their potential clinical utility for pancreatic cancer patients.
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Affiliation(s)
- Elisabetta Pietri
- Medical Oncology Unit, University Hospital of Parma, Parma 43126, Italy
- Authors contributed equally
| | - Rita Balsano
- Medical Oncology Unit, University Hospital of Parma, Parma 43126, Italy
- Authors contributed equally
| | - Matilde Coriano
- Medical Oncology Unit, University Hospital of Parma, Parma 43126, Italy
| | - Fabio Gelsomino
- Department of Oncology and Hematology, University Hospital of Modena, Modena 41124, Italy
| | | | - Simona Bui
- Medical Oncology Unit, University Hospital of Parma, Parma 43126, Italy
| | - Letizia Gnetti
- Unit of Pathological Anatomy, University Hospital of Parma, Parma 43126, Italy
| | | | - Ingrid Garajová
- Medical Oncology Unit, University Hospital of Parma, Parma 43126, Italy
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Li A, Feng L, Niu X, Zeng Q, Li B, You Z. Downregulation of OIP5-AS1 affects proNGF-induced pancreatic cancer metastasis by inhibiting p75NTR levels. Aging (Albany NY) 2021; 13:10688-10702. [PMID: 33820868 PMCID: PMC8064169 DOI: 10.18632/aging.202847] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Accepted: 09/28/2020] [Indexed: 02/06/2023]
Abstract
We aimed to explore the mechanism by which long non-coding RNA (lncRNA) OIP5-AS1 affects proNGF (precursor nerve growth factor)-induced pancreatic cancer metastasis by targeting the miR-186-5p/NGFR axis. Bioinformatics was used to analyse whether OIP5-AS1 targets miR-186-5p/NGFR and their expression characteristics in pancreatic cancer. OIP5-AS1 and NGFR were overexpressed in pancreatic cancer, and their levels showed a significant positive correlation. Clinical trials also demonstrated that high expression of OIP5-AS1 and NGFR and low expression of miR-186-5p played a pro-cancer role in pancreatic cancer. MiR-186-5p inhibited the migration and invasion of colon cancer cells by targeting NGFR-regulated p75NTR. OIP5-AS1 regulated the action of miR-186-5p on NGFR mRNA and p75NTR by targeting miR-186-5p. Downregulation of NGFR inhibited the expression of p75NTR protein and blocked the role of proNGF in promoting the migration and invasion of pancreatic cancer cells. Animal experiments also showed that the knockdown of miR-186-5p promoted cancer via the expression of NGFR mRNA and p75NTR protein, while the downregulation of proNGF blocked the effects. OIP5-AS1, as a ceRNA, promotes the progression of pancreatic cancer by targeting miR-186-5p/NGFR and affecting the prognosis of patients, which may be related to the action of proNGF.
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Affiliation(s)
- Ang Li
- Department of Pancreatic Surgery, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Lei Feng
- Department of Biliary Surgery, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Xiaoya Niu
- Department of Biliary Surgery, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Qihui Zeng
- Department of Biliary Surgery, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Bei Li
- Department of Biliary Surgery, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Zhen You
- Department of Biliary Surgery, West China Hospital of Sichuan University, Chengdu 610041, China
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Clinical Perspective on Proteomic and Glycomic Biomarkers for Diagnosis, Prognosis, and Prediction of Pancreatic Cancer. Int J Mol Sci 2021; 22:ijms22052655. [PMID: 33800786 PMCID: PMC7961509 DOI: 10.3390/ijms22052655] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 02/26/2021] [Accepted: 03/02/2021] [Indexed: 02/07/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is known as a highly aggressive malignant disease. Prognosis for patients is notoriously poor, despite improvements in surgical techniques and new (neo)adjuvant chemotherapy regimens. Early detection of PDAC may increase the overall survival. It is furthermore foreseen that precision medicine will provide improved prognostic stratification and prediction of therapeutic response. In this review, omics-based discovery efforts are presented that aim for novel diagnostic and prognostic biomarkers of PDAC. For this purpose, we systematically evaluated the literature published between 1999 and 2020 with a focus on protein- and protein-glycosylation biomarkers in pancreatic cancer patients. Besides genomic and transcriptomic approaches, mass spectrometry (MS)-based proteomics and glycomics of blood- and tissue-derived samples from PDAC patients have yielded new candidates with biomarker potential. However, for reasons discussed in this review, the validation and clinical translation of these candidate markers has not been successful. Consequently, there has been a change of mindset from initial efforts to identify new unimarkers into the current hypothesis that a combination of biomarkers better suits a diagnostic or prognostic panel. With continuing development of current research methods and available techniques combined with careful study designs, new biomarkers could contribute to improved detection, prognosis, and prediction of pancreatic cancer.
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Huerta M, Roselló S, Sabater L, Ferrer A, Tarazona N, Roda D, Gambardella V, Alfaro-Cervelló C, Garcés-Albir M, Cervantes A, Ibarrola-Villava M. Circulating Tumor DNA Detection by Digital-Droplet PCR in Pancreatic Ductal Adenocarcinoma: A Systematic Review. Cancers (Basel) 2021; 13:cancers13050994. [PMID: 33673558 PMCID: PMC7956845 DOI: 10.3390/cancers13050994] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 02/11/2021] [Accepted: 02/23/2021] [Indexed: 02/07/2023] Open
Abstract
Simple Summary Pancreatic cancer is a digestive tumor that is most difficult to treat and carries one of the worst prognoses. The anatomical location of the pancreas makes it very difficult to obtain enough tumor material to establish a molecular diagnosis, so knowing the biology of this tumor and implementing new targeted-therapies is still a pending issue. The use of liquid biopsy, a blood sample test to detect circulating-tumor DNA fragments (ctDNA), is key to overcoming this difficulty and improving the evolution of this tumor. Liquid biopsies are equally representative of the tissue from which they come and allow relevant molecular and diagnostic information to be obtained in a faster and less invasive way. One challenge related to ctDNA is the lack of consistency in the study design. Moreover, ctDNA accounts for only a small percentage of the total cell-free circulating DNA and prior knowledge about particular mutations is usually required. Thus, our aim was to understand the current role and future perspectives of ctDNA in pancreatic cancer using digital-droplet PCR technology. Abstract Pancreatic cancer (PC) is one of the most devastating malignant tumors, being the seventh leading cause of cancer-related death worldwide. Researchers and clinicians are endeavoring to develop strategies for the early detection of the disease and the improvement of treatment results. Adequate biopsy is still challenging because of the pancreas’s poor anatomic location. Recently, circulating tumor DNA (ctDNA) could be identified as a liquid biopsy tool with huge potential as a non-invasive biomarker in early diagnosis, prognosis and management of PC. ctDNA is released from apoptotic and necrotic cancer cells, as well as from living tumor cells and even circulating tumor cells, and it can reveal genetic and epigenetic alterations with tumor-specific and individual mutation and methylation profiles. However, ctDNA sensibility remains a limitation and the accuracy of ctDNA as a biomarker for PC is relatively low and cannot be currently used as a screening or diagnostic tool. Increasing evidence suggests that ctDNA is an interesting biomarker for predictive or prognosis studies, evaluating minimal residual disease, longitudinal follow-up and treatment management. Promising results have been published and therefore the objective of our review is to understand the current role and the future perspectives of ctDNA in PC.
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Affiliation(s)
- Marisol Huerta
- Department of Medical Oncology, INCLIVA Biomedical Research Institute, University of Valencia, 46010 Valencia, Spain; (M.H.); (S.R.); (A.F.); (N.T.); (D.R.); (V.G.); (A.C.)
| | - Susana Roselló
- Department of Medical Oncology, INCLIVA Biomedical Research Institute, University of Valencia, 46010 Valencia, Spain; (M.H.); (S.R.); (A.F.); (N.T.); (D.R.); (V.G.); (A.C.)
- CIBERONC, Medical Oncology Unit, INCLIVA Biomedical Research Institute, University of Valencia, 46010 Valencia, Spain
| | - Luis Sabater
- Liver, Biliary and Pancreatic Unit, Department of Surgery, Hospital Clínico Universitario of Valencia, University of Valencia, INCLIVA Biomedical Research Institute, 46010 Valencia, Spain; (L.S.); (M.G.-A.)
| | - Ana Ferrer
- Department of Medical Oncology, INCLIVA Biomedical Research Institute, University of Valencia, 46010 Valencia, Spain; (M.H.); (S.R.); (A.F.); (N.T.); (D.R.); (V.G.); (A.C.)
- CIBERONC, Medical Oncology Unit, INCLIVA Biomedical Research Institute, University of Valencia, 46010 Valencia, Spain
| | - Noelia Tarazona
- Department of Medical Oncology, INCLIVA Biomedical Research Institute, University of Valencia, 46010 Valencia, Spain; (M.H.); (S.R.); (A.F.); (N.T.); (D.R.); (V.G.); (A.C.)
- CIBERONC, Medical Oncology Unit, INCLIVA Biomedical Research Institute, University of Valencia, 46010 Valencia, Spain
| | - Desamparados Roda
- Department of Medical Oncology, INCLIVA Biomedical Research Institute, University of Valencia, 46010 Valencia, Spain; (M.H.); (S.R.); (A.F.); (N.T.); (D.R.); (V.G.); (A.C.)
- CIBERONC, Medical Oncology Unit, INCLIVA Biomedical Research Institute, University of Valencia, 46010 Valencia, Spain
| | - Valentina Gambardella
- Department of Medical Oncology, INCLIVA Biomedical Research Institute, University of Valencia, 46010 Valencia, Spain; (M.H.); (S.R.); (A.F.); (N.T.); (D.R.); (V.G.); (A.C.)
- CIBERONC, Medical Oncology Unit, INCLIVA Biomedical Research Institute, University of Valencia, 46010 Valencia, Spain
| | - Clara Alfaro-Cervelló
- Department of Pathology, INCLIVA Biomedical Research Institute, University of Valencia, 46010 Valencia, Spain;
| | - Marina Garcés-Albir
- Liver, Biliary and Pancreatic Unit, Department of Surgery, Hospital Clínico Universitario of Valencia, University of Valencia, INCLIVA Biomedical Research Institute, 46010 Valencia, Spain; (L.S.); (M.G.-A.)
| | - Andrés Cervantes
- Department of Medical Oncology, INCLIVA Biomedical Research Institute, University of Valencia, 46010 Valencia, Spain; (M.H.); (S.R.); (A.F.); (N.T.); (D.R.); (V.G.); (A.C.)
- CIBERONC, Medical Oncology Unit, INCLIVA Biomedical Research Institute, University of Valencia, 46010 Valencia, Spain
| | - Maider Ibarrola-Villava
- Department of Medical Oncology, INCLIVA Biomedical Research Institute, University of Valencia, 46010 Valencia, Spain; (M.H.); (S.R.); (A.F.); (N.T.); (D.R.); (V.G.); (A.C.)
- CIBERONC, Medical Oncology Unit, INCLIVA Biomedical Research Institute, University of Valencia, 46010 Valencia, Spain
- Correspondence: ; Tel.: +34-963-862-894
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