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Rusnáková DŠ, Aziri R, Dubovan P, Jurík M, Mego M, Pinďák D. Detection, significance and potential utility of circulating tumor cells in clinical practice in breast cancer (Review). Oncol Lett 2025; 29:10. [PMID: 39492933 PMCID: PMC11526295 DOI: 10.3892/ol.2024.14756] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Accepted: 08/15/2024] [Indexed: 11/05/2024] Open
Abstract
Although advances in diagnostic techniques, new therapeutic strategies and personalization of breast cancer (BC) care have improved the survival for a number of patients, BC remains a major cause of morbidity and mortality for women. The study of circulating tumor cells (CTCs) has significant potential in translational oncology since these cells represent promising biomarkers throughout the entire course of BC in patients. CTCs also have notable prognostic value in early BC as well as metastatic BC. Based on current knowledge, it seems that the dynamics of CTCs that change during therapy reflect therapy response, and CTCs could serve as a tool for risk stratification and real-time monitoring of treatment in patients with BC. The question of how to use this information in everyday clinical practice and how this information can guide or change therapy to affect the clinical outcome of patients with BC remains unanswered. The present review aims to discuss current completed and ongoing trials that have been designed to demonstrate the clinical significance of CTCs, offer insights into treatment efficacy and assess CTC utility, facilitating their implementation in the routine management of patients with BC.
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Affiliation(s)
- Dominika Šmičková Rusnáková
- Department of Surgical Oncology, Faculty of Medicine, Slovak Medical University and National Cancer Institute, 833 10 Bratislava, Slovak Republic
| | - Ramadan Aziri
- Department of Surgical Oncology, Faculty of Medicine, Slovak Medical University and National Cancer Institute, 833 10 Bratislava, Slovak Republic
| | - Peter Dubovan
- Department of Surgical Oncology, Faculty of Medicine, Slovak Medical University and National Cancer Institute, 833 10 Bratislava, Slovak Republic
| | - Miroslav Jurík
- Department of Surgical Oncology, Faculty of Medicine, Slovak Medical University and National Cancer Institute, 833 10 Bratislava, Slovak Republic
| | - Michal Mego
- Second Department of Oncology, Faculty of Medicine, Comenius University and National Cancer Institute, 833 10 Bratislava, Slovak Republic
| | - Daniel Pinďák
- Department of Surgical Oncology, Faculty of Medicine, Slovak Medical University and National Cancer Institute, 833 10 Bratislava, Slovak Republic
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Pearce H, Chang YC, Javitt MC, Datta J, Pimentel A, Bialick S, Hosein PJ, Alessandrino F. ctDNA in the reading room: A guide for radiologists. Eur J Radiol 2024; 181:111796. [PMID: 39461058 DOI: 10.1016/j.ejrad.2024.111796] [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: 08/22/2024] [Revised: 10/02/2024] [Accepted: 10/17/2024] [Indexed: 10/29/2024]
Abstract
Liquid biopsy with sequencing of circulating tumor DNA (ctDNA) is a minimally invasive method for sampling body fluids and offers a promising alternative to tissue biopsies that involve greater risks, costs, and time. ctDNA not only identifies actionable targets by revealing unique molecular signatures in cancer, but also may assess treatment response, treatment resistance and progression, and recurrence. Imaging correlates of these applications are already being identified and utilized for various solid tumors. Radiologists have new challenges in interpreting oncologic imaging. Given their integral role in cancer surveillance, they must become familiar with the importance of ctDNA in detecting recurrence and minimal residual disease, measuring treatment response, predicting survival and metastatic patterns, and identifying new molecular therapeutic targets. In this review, we provide an overview of ctDNA testing, and a snapshot of current clinical guidelines from the National Comprehensive Cancer Network and the European Society of Molecular Oncology on the use of ctDNA in lung, breast, colorectal, pancreatic, and hepatobiliary cancers. For each cancer type, we also highlight current research applications of ctDNA that are relevant to the field of diagnostic radiology.
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Affiliation(s)
- Hayes Pearce
- University of Miami Leonard M. Miller School of Medicine, 1600 NW 10th Ave, Miami, FL, USA
| | - Yu-Cherng Chang
- Department of Radiology, University of Miami Leonard M. Miller School of Medicine, 1600 NW 10th Ave, Miami, FL, USA.
| | - Marcia C Javitt
- Division of Abdominal Imaging, Department of Radiology, University of Miami Leonard M. Miller School of Medicine, 1600 NW 10th Ave, Miami, FL, USA
| | - Jashodeep Datta
- Division of Surgical Oncology, Department of Surgery, University of Miami Leonard M. Miller School of Medicine, 1600 NW 10th Ave, Miami, FL, USA; Sylvester Comprehensive Cancer Center, University of Miami Leonard M. Miller School of Medicine, 1600 NW 10th Ave, Miami, FL, USA
| | - Agustin Pimentel
- Sylvester Comprehensive Cancer Center, University of Miami Leonard M. Miller School of Medicine, 1600 NW 10th Ave, Miami, FL, USA; Division of Medical Oncology, Department of Medicine, University of Miami Leonard M. Miller School of Medicine, 1600 NW 10th Ave, Miami, FL, USA
| | - Steven Bialick
- Sylvester Comprehensive Cancer Center, University of Miami Leonard M. Miller School of Medicine, 1600 NW 10th Ave, Miami, FL, USA; Division of Medical Oncology, Department of Medicine, University of Miami Leonard M. Miller School of Medicine, 1600 NW 10th Ave, Miami, FL, USA
| | - Peter J Hosein
- Sylvester Comprehensive Cancer Center, University of Miami Leonard M. Miller School of Medicine, 1600 NW 10th Ave, Miami, FL, USA; Division of Medical Oncology, Department of Medicine, University of Miami Leonard M. Miller School of Medicine, 1600 NW 10th Ave, Miami, FL, USA
| | - Francesco Alessandrino
- Division of Abdominal Imaging, Department of Radiology, University of Miami Leonard M. Miller School of Medicine, 1600 NW 10th Ave, Miami, FL, USA; Sylvester Comprehensive Cancer Center, University of Miami Leonard M. Miller School of Medicine, 1600 NW 10th Ave, Miami, FL, USA
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Li D, Heffernan K, Koch FC, Peake DA, Pascovici D, David M, Kehelpannala C, Mann GB, Speakman D, Hurrell J, Preston S, Vafaee F, Batarseh A. Discovery of Plasma Lipids as Potential Biomarkers Distinguishing Breast Cancer Patients from Healthy Controls. Int J Mol Sci 2024; 25:11559. [PMID: 39519111 PMCID: PMC11546708 DOI: 10.3390/ijms252111559] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2024] [Revised: 10/09/2024] [Accepted: 10/14/2024] [Indexed: 11/16/2024] Open
Abstract
The development of a sensitive and specific blood test for the early detection of breast cancer is crucial to improve screening and patient outcomes. Existing methods, such as mammography, have limitations, necessitating the exploration of alternative approaches, including circulating factors. Using 598 prospectively collected blood samples, a multivariate plasma-derived lipid biomarker signature was developed that can distinguish healthy control individuals from those with breast cancer. Liquid chromatography with high-resolution and tandem mass spectrometry (LC-MS/MS) was employed to identify lipids for both extracellular vesicle-derived and plasma-derived signatures. For each dataset, we identified a signature of 20 lipids using a robust, statistically rigorous feature selection algorithm based on random forest feature importance applied to cross-validated training samples. Using an ensemble of machine learning models, the plasma 20-lipid signature generated an area under the curve (AUC) of 0.95, sensitivity of 0.91, and specificity of 0.79. The results from this study indicate that lipids extracted from plasma can be used as target analytes in the development of assays to detect the presence of early-stage breast cancer.
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Affiliation(s)
- Desmond Li
- BCAL Diagnostics Ltd., Sydney, NSW 2000, Australia
| | | | | | | | | | - Mark David
- BCAL Diagnostics Ltd., Sydney, NSW 2000, Australia
| | | | - G. Bruce Mann
- Department of Surgery, The Royal Melbourne Hospital, Parkville, VIC 3050, Australia
| | - David Speakman
- The Peter MacCallum Cancer Centre, Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC 3010, Australia
- BreastScreen Victoria, Carlton, VIC 3053, Australia
| | - John Hurrell
- BCAL Diagnostics Ltd., Sydney, NSW 2000, Australia
| | | | - Fatemeh Vafaee
- OmniOmics.ai Pty Ltd., Pagewood, NSW 2035, Australia
- School of Biotechnology and Biomolecular Sciences, University of New South Wales (UNSW), Sydney, NSW 2052, Australia
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Shi J, Duan Y. Knowledge-map and research trends of circulating tumor cells in breast cancer: a scientometric analysis. Discov Oncol 2024; 15:506. [PMID: 39340703 PMCID: PMC11438760 DOI: 10.1007/s12672-024-01385-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Accepted: 09/23/2024] [Indexed: 09/30/2024] Open
Abstract
Assessing circulating tumor cells (CTCs) in early-stage breast cancer patients can help identify relapse risk for timely interventions. Molecular analysis of CTCs can reveal vulnerabilities for personalized treatment options in metastatic breast cancer. This study aims to summarize CTCs in breast cancer research understanding and evaluate research trends. Extracted from the Web of Science Core Collection, publications on CTCs in breast cancer studies spanning from January 1, 2008, to December 21, 2023, were included. Co-authorships, references, and keywords were analyzed using Bibliometrix R packages and VOSviewer software. References and keywords burst detection were conducted with CiteSpace, and BICOMB was utilized to generate high-frequency keyword layouts. Biclustering analysis of the binary co-keyword matrix was performed using gCLUTO. 1747 articles focusing on CTCs in breast cancer were identified. The USA and the University of Texas MD Anderson Cancer Center demonstrated the highest productivity at the national and institutional levels, respectively. The journal "CANCERS" had the highest publication outputs on this subject. Pantel K emerged as the foremost author with the highest publication and co-citation counts. Analysis of co-keywords unveiled five prominent research areas concerning CTCs in breast cancer. The prognostic and predictive roles of CTCs in breast cancer have substantial implications for clinical practice. Nevertheless, precise assessment of CTCs, encompassing its quantities and attributes through advanced technologies, and its role in detecting minimal residual disease in breast cancer, continue to pose notable challenges. In conclusion, recent advancements and trends in CTCs research in breast cancer are examined through scientometric analysis in this study. The results provide valuable insights for the formulation of novel approaches in CTCs research, emphasizing the current research frontiers.
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Affiliation(s)
- Jinan Shi
- Department of Medical Oncology, Zhejiang Hospital, Hangzhou, Zhejiang, China
| | - Yin Duan
- Department of Breast Surgery, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang, China.
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Chen JH, Addanki S, Roy D, Bassett R, Kalashnikova E, Spickard E, Kuerer HM, Meas S, Sarli VN, Korkut A, White JB, Rauch GM, Tripathy D, Arun BK, Barcenas CH, Yam C, Sethi H, Rodriguez AA, Liu MC, Moulder SL, Lucci A. Monitoring response to neoadjuvant chemotherapy in triple negative breast cancer using circulating tumor DNA. BMC Cancer 2024; 24:1016. [PMID: 39148033 PMCID: PMC11328413 DOI: 10.1186/s12885-024-12689-6] [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: 03/15/2024] [Accepted: 07/24/2024] [Indexed: 08/17/2024] Open
Abstract
BACKGROUND Triple negative breast cancer (TNBC) is an aggressive subtype with poor prognosis. We aimed to determine whether circulating tumor DNA (ctDNA) and circulating tumor cell (CTC) could predict response and long-term outcomes to neoadjuvant chemotherapy (NAC). METHODS Patients with TNBC were enrolled between 2017-2021 at The University of Texas MD Anderson Cancer Center (Houston, TX). Serial plasma samples were collected at four timepoints: pre-NAC (baseline), 12-weeks after NAC (mid-NAC), after NAC/prior to surgery (post-NAC), and one-year after surgery. ctDNA was quantified using a tumor-informed ctDNA assay (SignateraTM, Natera, Inc.) and CTC enumeration using CellSearch. Wilcoxon and Fisher's exact tests were used for comparisons between groups and Kaplan-Meier analysis used for survival outcomes. RESULTS In total, 37 patients were enrolled. The mean age was 50 and majority of patients had invasive ductal carcinoma (34, 91.9%) with clinical T2, (25, 67.6%) node-negative disease (21, 56.8%). Baseline ctDNA was detected in 90% (27/30) of patients, of whom 70.4% (19/27) achieved ctDNA clearance by mid-NAC. ctDNA clearance at mid-NAC was significantly associated with pathologic complete response (p = 0.02), whereas CTC clearance was not (p = 0.52). There were no differences in overall survival (OS) and recurrence-free survival (RFS) with positive baseline ctDNA and CTC. However, positive ctDNA at mid-NAC was significantly associated with worse OS and RFS (p = 0.0002 and p = 0.0034, respectively). CONCLUSIONS Early clearance of ctDNA served as a predictive and prognostic marker in TNBC. Personalized ctDNA monitoring during NAC may help predict response and guide treatment.
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Affiliation(s)
- Jennifer H Chen
- Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, 1400 Pressler Street, FCT 7.6000, Unit 1484,, Houston, TX, 77030, US
| | - Sridevi Addanki
- Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, 1400 Pressler Street, FCT 7.6000, Unit 1484,, Houston, TX, 77030, US
| | - Dhruvajyoti Roy
- Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, 1400 Pressler Street, FCT 7.6000, Unit 1484,, Houston, TX, 77030, US
| | - Roland Bassett
- Department of Biostatistics, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
| | | | | | - Henry M Kuerer
- Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, 1400 Pressler Street, FCT 7.6000, Unit 1484,, Houston, TX, 77030, US
| | - Salyna Meas
- Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, 1400 Pressler Street, FCT 7.6000, Unit 1484,, Houston, TX, 77030, US
| | - Vanessa N Sarli
- Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, 1400 Pressler Street, FCT 7.6000, Unit 1484,, Houston, TX, 77030, US
| | - Anil Korkut
- Department of Bioinformatics and Computational Biology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
| | - Jason B White
- Breast Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
| | - Gaiane M Rauch
- Abdominal Imaging Department, MD Anderson Cancer Center, Houston, TX, USA
| | - Debu Tripathy
- Breast Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
| | - Banu K Arun
- Breast Medical Oncology and Clinical Cancer Genetics, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
| | - Carlos H Barcenas
- Breast Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
| | - Clinton Yam
- Breast Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
| | | | | | | | - Stacy L Moulder
- Medical Oncology, Eli Lilly and Company, Indianapolis, IN, USA
| | - Anthony Lucci
- Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, 1400 Pressler Street, FCT 7.6000, Unit 1484,, Houston, TX, 77030, US.
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Alba-Bernal A, Godoy-Ortiz A, Domínguez-Recio ME, López-López E, Quirós-Ortega ME, Sánchez-Martín V, Roldán-Díaz MD, Jiménez-Rodríguez B, Peralta-Linero J, Bellagarza-García E, Troyano-Ramos L, Garrido-Ruiz G, Hierro-Martín MI, Vicioso L, González-Ortiz Á, Linares-Valencia N, Velasco-Suelto J, Carbajosa G, Garrido-Aranda A, Lavado-Valenzuela R, Álvarez M, Pascual J, Comino-Méndez I, Alba E. Increased blood draws for ultrasensitive ctDNA and CTCs detection in early breast cancer patients. NPJ Breast Cancer 2024; 10:36. [PMID: 38750090 PMCID: PMC11096188 DOI: 10.1038/s41523-024-00642-6] [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: 11/04/2023] [Accepted: 05/01/2024] [Indexed: 05/18/2024] Open
Abstract
Early breast cancer patients often experience relapse due to residual disease after treatment. Liquid biopsy is a methodology capable of detecting tumor components in blood, but low concentrations at early stages pose challenges. To detect them, next-generation sequencing has promise but entails complex processes. Exploring larger blood volumes could overcome detection limitations. Herein, a total of 282 high-volume plasma and blood-cell samples were collected for dual ctDNA/CTCs detection using a single droplet-digital PCR assay per patient. ctDNA and/or CTCs were detected in 100% of pre-treatment samples. On the other hand, post-treatment positive samples exhibited a minimum variant allele frequency of 0.003% for ctDNA and minimum cell number of 0.069 CTCs/mL of blood, surpassing previous investigations. Accurate prediction of residual disease before surgery was achieved in patients without a complete pathological response. A model utilizing ctDNA dynamics achieved an area under the ROC curve of 0.92 for predicting response. We detected disease recurrence in blood in the three patients who experienced a relapse, anticipating clinical relapse by 34.61, 9.10, and 7.59 months. This methodology provides an easily implemented alternative for ultrasensitive residual disease detection in early breast cancer patients.
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Affiliation(s)
- Alfonso Alba-Bernal
- Unidad de Gestion Clinica Intercentros de Oncologia Medica, Hospitales Universitarios Regional y Virgen de la Victoria, 29010, Malaga, Spain
- The Biomedical Research Institute of Málaga (IBIMA-CIMES-UMA), 29010, Malaga, Spain
- Andalusia-Roche Network in Precision Medical Oncology, 41092, Sevilla, Spain
| | - Ana Godoy-Ortiz
- Unidad de Gestion Clinica Intercentros de Oncologia Medica, Hospitales Universitarios Regional y Virgen de la Victoria, 29010, Malaga, Spain
- The Biomedical Research Institute of Málaga (IBIMA-CIMES-UMA), 29010, Malaga, Spain
- Centro de Investigacion Biomedica en Red de Cancer (CIBERONC - CB16/12/00481), 28029, Madrid, Spain
| | - María Emilia Domínguez-Recio
- Unidad de Gestion Clinica Intercentros de Oncologia Medica, Hospitales Universitarios Regional y Virgen de la Victoria, 29010, Malaga, Spain
- The Biomedical Research Institute of Málaga (IBIMA-CIMES-UMA), 29010, Malaga, Spain
| | - Esperanza López-López
- Unidad de Gestion Clinica Intercentros de Oncologia Medica, Hospitales Universitarios Regional y Virgen de la Victoria, 29010, Malaga, Spain
- The Biomedical Research Institute of Málaga (IBIMA-CIMES-UMA), 29010, Malaga, Spain
| | - María Elena Quirós-Ortega
- Unidad de Gestion Clinica Intercentros de Oncologia Medica, Hospitales Universitarios Regional y Virgen de la Victoria, 29010, Malaga, Spain
- The Biomedical Research Institute of Málaga (IBIMA-CIMES-UMA), 29010, Malaga, Spain
- Andalusia-Roche Network in Precision Medical Oncology, 41092, Sevilla, Spain
| | - Victoria Sánchez-Martín
- Unidad de Gestion Clinica Intercentros de Oncologia Medica, Hospitales Universitarios Regional y Virgen de la Victoria, 29010, Malaga, Spain
- Centro de Investigacion Biomedica en Red de Cancer (CIBERONC - CB16/12/00481), 28029, Madrid, Spain
| | - María Dunia Roldán-Díaz
- Unidad de Gestion Clinica Intercentros de Oncologia Medica, Hospitales Universitarios Regional y Virgen de la Victoria, 29010, Malaga, Spain
- The Biomedical Research Institute of Málaga (IBIMA-CIMES-UMA), 29010, Malaga, Spain
| | - Begoña Jiménez-Rodríguez
- Unidad de Gestion Clinica Intercentros de Oncologia Medica, Hospitales Universitarios Regional y Virgen de la Victoria, 29010, Malaga, Spain
- The Biomedical Research Institute of Málaga (IBIMA-CIMES-UMA), 29010, Malaga, Spain
- Centro de Investigacion Biomedica en Red de Cancer (CIBERONC - CB16/12/00481), 28029, Madrid, Spain
| | - Jesús Peralta-Linero
- Unidad de Gestion Clinica Intercentros de Oncologia Medica, Hospitales Universitarios Regional y Virgen de la Victoria, 29010, Malaga, Spain
- The Biomedical Research Institute of Málaga (IBIMA-CIMES-UMA), 29010, Malaga, Spain
| | - Estefanía Bellagarza-García
- Unidad de Gestion Clinica Intercentros de Oncologia Medica, Hospitales Universitarios Regional y Virgen de la Victoria, 29010, Malaga, Spain
| | - Laura Troyano-Ramos
- Unidad de Gestion Clinica Intercentros de Oncologia Medica, Hospitales Universitarios Regional y Virgen de la Victoria, 29010, Malaga, Spain
| | - Guadalupe Garrido-Ruiz
- Radiology Department, Hospital Clinico Universitario Virgen de la Victoria de Malaga, 29010, Malaga, Spain
| | - M Isabel Hierro-Martín
- The Biomedical Research Institute of Málaga (IBIMA-CIMES-UMA), 29010, Malaga, Spain
- Unidad de Gestion Clinica Provincial de Anatomia Patologica de Malaga, Hospital Clinico Universitario Virgen de la Victoria de Malaga, 29010, Malaga, Spain
- University of Málaga, Faculty of Medicine, 29010, Malaga, Spain
| | - Luis Vicioso
- The Biomedical Research Institute of Málaga (IBIMA-CIMES-UMA), 29010, Malaga, Spain
- Unidad de Gestion Clinica Provincial de Anatomia Patologica de Malaga, Hospital Clinico Universitario Virgen de la Victoria de Malaga, 29010, Malaga, Spain
- University of Málaga, Faculty of Medicine, 29010, Malaga, Spain
| | - Álvaro González-Ortiz
- Unidad de Gestion Clinica Intercentros de Oncologia Medica, Hospitales Universitarios Regional y Virgen de la Victoria, 29010, Malaga, Spain
| | - Noelia Linares-Valencia
- Unidad de Gestion Clinica Intercentros de Oncologia Medica, Hospitales Universitarios Regional y Virgen de la Victoria, 29010, Malaga, Spain
- The Biomedical Research Institute of Málaga (IBIMA-CIMES-UMA), 29010, Malaga, Spain
| | - Jesús Velasco-Suelto
- Unidad de Gestion Clinica Intercentros de Oncologia Medica, Hospitales Universitarios Regional y Virgen de la Victoria, 29010, Malaga, Spain
- The Biomedical Research Institute of Málaga (IBIMA-CIMES-UMA), 29010, Malaga, Spain
| | - Guillermo Carbajosa
- Unidad de Gestion Clinica Intercentros de Oncologia Medica, Hospitales Universitarios Regional y Virgen de la Victoria, 29010, Malaga, Spain
- University of Málaga, Faculty of Medicine, 29010, Malaga, Spain
| | - Alicia Garrido-Aranda
- Unidad de Gestion Clinica Intercentros de Oncologia Medica, Hospitales Universitarios Regional y Virgen de la Victoria, 29010, Malaga, Spain
- The Biomedical Research Institute of Málaga (IBIMA-CIMES-UMA), 29010, Malaga, Spain
- Andalusia-Roche Network in Precision Medical Oncology, 41092, Sevilla, Spain
- Laboratorio de biologia molecular del cancer (LBMC), Centro de investigaciones medico-sanitarias (CIMES-UMA), 29010, Malaga, Spain
| | - Rocío Lavado-Valenzuela
- Unidad de Gestion Clinica Intercentros de Oncologia Medica, Hospitales Universitarios Regional y Virgen de la Victoria, 29010, Malaga, Spain
- The Biomedical Research Institute of Málaga (IBIMA-CIMES-UMA), 29010, Malaga, Spain
- Andalusia-Roche Network in Precision Medical Oncology, 41092, Sevilla, Spain
- Centro de Investigacion Biomedica en Red de Cancer (CIBERONC - CB16/12/00481), 28029, Madrid, Spain
- Laboratorio de biologia molecular del cancer (LBMC), Centro de investigaciones medico-sanitarias (CIMES-UMA), 29010, Malaga, Spain
| | - Martina Álvarez
- The Biomedical Research Institute of Málaga (IBIMA-CIMES-UMA), 29010, Malaga, Spain
- Andalusia-Roche Network in Precision Medical Oncology, 41092, Sevilla, Spain
- Centro de Investigacion Biomedica en Red de Cancer (CIBERONC - CB16/12/00481), 28029, Madrid, Spain
- University of Málaga, Faculty of Medicine, 29010, Malaga, Spain
- Laboratorio de biologia molecular del cancer (LBMC), Centro de investigaciones medico-sanitarias (CIMES-UMA), 29010, Malaga, Spain
| | - Javier Pascual
- Unidad de Gestion Clinica Intercentros de Oncologia Medica, Hospitales Universitarios Regional y Virgen de la Victoria, 29010, Malaga, Spain
- The Biomedical Research Institute of Málaga (IBIMA-CIMES-UMA), 29010, Malaga, Spain
- Andalusia-Roche Network in Precision Medical Oncology, 41092, Sevilla, Spain
- Centro de Investigacion Biomedica en Red de Cancer (CIBERONC - CB16/12/00481), 28029, Madrid, Spain
| | - Iñaki Comino-Méndez
- Unidad de Gestion Clinica Intercentros de Oncologia Medica, Hospitales Universitarios Regional y Virgen de la Victoria, 29010, Malaga, Spain.
- The Biomedical Research Institute of Málaga (IBIMA-CIMES-UMA), 29010, Malaga, Spain.
- Andalusia-Roche Network in Precision Medical Oncology, 41092, Sevilla, Spain.
- Centro de Investigacion Biomedica en Red de Cancer (CIBERONC - CB16/12/00481), 28029, Madrid, Spain.
| | - Emilio Alba
- Unidad de Gestion Clinica Intercentros de Oncologia Medica, Hospitales Universitarios Regional y Virgen de la Victoria, 29010, Malaga, Spain
- The Biomedical Research Institute of Málaga (IBIMA-CIMES-UMA), 29010, Malaga, Spain
- Andalusia-Roche Network in Precision Medical Oncology, 41092, Sevilla, Spain
- Centro de Investigacion Biomedica en Red de Cancer (CIBERONC - CB16/12/00481), 28029, Madrid, Spain
- University of Málaga, Faculty of Medicine, 29010, Malaga, Spain
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7
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Zeng Q, Zhong H, Rao H, Wang Y. Diagnostic value of circulating tumor cells in patients with thyroid cancer: a retrospective study of 1478 patients. Discov Oncol 2024; 15:114. [PMID: 38607590 PMCID: PMC11014821 DOI: 10.1007/s12672-024-00976-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Accepted: 04/09/2024] [Indexed: 04/13/2024] Open
Abstract
BACKGROUND Circulating tumor cell (CTC) detection is one form of liquid biopsy. It is a novel technique that is beginning to be applied in the field of thyroid cancer. The present study was designed to evaluate the diagnostic value of CTCs in patients with thyroid cancer. METHODS A total of 1478 patients were retrospectively analyzed and divided into malignant group (n = 747) and benign group (n = 731). Peripheral blood was collected, and CTCs were enriched and quantified before surgery. The baseline data of the two groups were matched by Propensity Score Matching (PSM). Receiver operating characteristic (ROC) curves were used to evaluate the diagnostic efficiency of different indicators for thyroid cancer. The malignant group before PSM was further divided into subgroups according to the BRAF V600E mutation and lymphatic metastasis (N stage), and the number of CTCs in different subgroups was compared. RESULTS After 1:1 PSM, baseline characteristics of the malignant group and benign group were matched and assigned 315 cases in each group. The number of CTCs and the TPOAb values were comparable in the two groups (p > 0.05). The TgAb values [1.890 (1.110 - 16.010) vs 1.645 (1.030 - 7.073) IU/mL, p = 0.049] were significantly higher in the malignant group than in the benign group. After PSM, ROC analyses showed that the areas under the curve (AUCs) of CTC, TgAb and ultrasound were 0.537 (sensitivity 65.6%, specificity 45.8%), 0.546 (sensitivity 40.0%, specificity 70.8%) and 0.705 (sensitivity 77.1%, specificity 63.2%), respectively. The AUCs of the combined detection of 'CTC + ultrasound' (combine 1) and the combined detection of 'CTC + TgAb + ultrasound' (combine 2) were 0.718 (sensitivity 79.3%, specificity 61.7%) and 0.724 (sensitivity 78.0%, specificity 63.3%), respectively. The AUC of ultrasound was significantly higher than CTC (p < 0.001). There was no statistically significant difference in AUC between combination 1 and ultrasound, and between combination 2 and ultrasound (p > 0.05). The number of CTCs between the N0 and N1 subgroups, and between the BRAF mutant and BRAF wild subgroups was comparable (p > 0.05). CONCLUSIONS As an emerging and noninvasive testing tool, the efficacy of CTCs in diagnosing thyroid cancer is limited.
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Affiliation(s)
- Qingxin Zeng
- Department of Thyroid Surgery, Meizhou People's Hospital (Huangtang Hospital)/Meizhou Academy of Medical Sciences, No. 63, Huangtang Road, Meijiang District, Meizhou, 514031, China
| | - Haifeng Zhong
- Department of Thyroid Surgery, Meizhou People's Hospital (Huangtang Hospital)/Meizhou Academy of Medical Sciences, No. 63, Huangtang Road, Meijiang District, Meizhou, 514031, China
| | - Hui Rao
- Department of Laboratory Medicine, Meizhou People's Hospital (Huangtang Hospital)/Meizhou Academy of Medical Sciences, Meizhou, China
| | - Yuedong Wang
- Department of Thyroid Surgery, Meizhou People's Hospital (Huangtang Hospital)/Meizhou Academy of Medical Sciences, No. 63, Huangtang Road, Meijiang District, Meizhou, 514031, China.
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Abbasi AB, Wu V, Lang JE, Esserman LJ. Precision Oncology in Breast Cancer Surgery. Surg Oncol Clin N Am 2024; 33:293-310. [PMID: 38401911 DOI: 10.1016/j.soc.2023.12.011] [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] [Indexed: 02/26/2024]
Abstract
Outcomes for patients with breast cancer have improved over time due to increased screening and the availability of more effective therapies. It is important to recognize that breast cancer is a heterogeneous disease that requires treatment based on molecular characteristics. Early endpoints such as pathologic complete response correlate with event-free survival, allowing the opportunity to consider de-escalation of certain cancer treatments to avoid overtreatment. This article discusses clinical trials of tailoring treatment (eg, I-SPY2) and screening (eg, WISDOM) to individual patients based on their unique risk features.
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Affiliation(s)
- Ali Benjamin Abbasi
- Department of Surgery, San Francisco Breast Care Center, University of California, Box 1710, UCSF, San Francisco, CA 94143, USA
| | - Vincent Wu
- Department of Surgery, Cleveland Clinic Breast Services, 9500 Euclid Avenue, A80, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Julie E Lang
- Department of Surgery, Cleveland Clinic Breast Services, 9500 Euclid Avenue, A80, Cleveland Clinic, Cleveland, OH 44195, USA.
| | - Laura J Esserman
- Department of Surgery, San Francisco Breast Care Center, University of California, Box 1710, UCSF, San Francisco, CA 94143, USA
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Xie Q, Liu S, Zhang S, Liao L, Xiao Z, Wang S, Zhang P. Research progress on the multi-omics and survival status of circulating tumor cells. Clin Exp Med 2024; 24:49. [PMID: 38427120 PMCID: PMC10907490 DOI: 10.1007/s10238-024-01309-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: 11/22/2023] [Accepted: 02/08/2024] [Indexed: 03/02/2024]
Abstract
In the dynamic process of metastasis, circulating tumor cells (CTCs) emanate from the primary solid tumor and subsequently acquire the capacity to disengage from the basement membrane, facilitating their infiltration into the vascular system via the interstitial tissue. Given the pivotal role of CTCs in the intricate hematogenous metastasis, they have emerged as an essential resource for a deeper comprehension of cancer metastasis while also serving as a cornerstone for the development of new indicators for early cancer screening and new therapeutic targets. In the epoch of precision medicine, as CTC enrichment and separation technologies continually advance and reach full fruition, the domain of CTC research has transcended the mere straightforward detection and quantification. The rapid advancement of CTC analysis platforms has presented a compelling opportunity for in-depth exploration of CTCs within the bloodstream. Here, we provide an overview of the current status and research significance of multi-omics studies on CTCs, including genomics, transcriptomics, proteomics, and metabolomics. These studies have contributed to uncovering the unique heterogeneity of CTCs and identifying potential metastatic targets as well as specific recognition sites. We also review the impact of various states of CTCs in the bloodstream on their metastatic potential, such as clustered CTCs, interactions with other blood components, and the phenotypic states of CTCs after undergoing epithelial-mesenchymal transition (EMT). Within this context, we also discuss the therapeutic implications and potential of CTCs.
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Affiliation(s)
- Qingming Xie
- NHC Key Laboratory of Cancer Proteomics, Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People's Republic of China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People's Republic of China
| | - Shilei Liu
- NHC Key Laboratory of Cancer Proteomics, Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People's Republic of China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People's Republic of China
| | - Sai Zhang
- NHC Key Laboratory of Cancer Proteomics, Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People's Republic of China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People's Republic of China
| | - Liqiu Liao
- Department of Breast Surgery, Hunan Clinical Meditech Research Center for Breast Cancer, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People's Republic of China
| | - Zhi Xiao
- Department of Breast Surgery, Hunan Clinical Meditech Research Center for Breast Cancer, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People's Republic of China
| | - Shouman Wang
- Department of Breast Surgery, Hunan Clinical Meditech Research Center for Breast Cancer, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People's Republic of China.
| | - Pengfei Zhang
- NHC Key Laboratory of Cancer Proteomics, Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People's Republic of China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People's Republic of China.
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10
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Jia S, Yang Y, Zhu Y, Yang W, Ling L, Wei Y, Fang X, Lin Q, Hamaï A, Mehrpour M, Gao J, Tan W, Xia Y, Chen J, Jiang W, Gong C. Association of FTH1-Expressing Circulating Tumor Cells With Efficacy of Neoadjuvant Chemotherapy for Patients With Breast Cancer: A Prospective Cohort Study. Oncologist 2024; 29:e25-e37. [PMID: 37390841 PMCID: PMC10769790 DOI: 10.1093/oncolo/oyad195] [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: 12/22/2022] [Accepted: 05/23/2023] [Indexed: 07/02/2023] Open
Abstract
BACKGROUND The association between different phenotypes and genotypes of circulating tumor cells (CTCs) and efficacy of neoadjuvant chemotherapy (NAC) remains uncertain. This study was conducted to evaluate the relationship of FTH1 gene-associated CTCs (F-CTC) with/without epithelial-mesenchymal transition (EMT) markers, or their dynamic changes with the efficacy of NAC in patients with non-metastatic breast cancer. PATIENTS AND METHODS This study enrolled 120 patients with non-metastatic breast cancer who planned to undergo NAC. The FTH1 gene and EMT markers in CTCs were detected before NAC (T0), after 2 cycles of chemotherapy (T1), and before surgery (T2). The associations of these different types of CTCs with rates of pathological complete response (pCR) and breast-conserving surgery (BCS) were evaluated using the binary logistic regression analysis. RESULTS F-CTC in peripheral blood ≥1 at T0 was an independent factor for pCR rate in patients with HER2-positive (odds ratio [OR]=0.08, 95% confidence interval [CI], 0.01-0.98, P = .048). The reduction in the number of F-CTC at T2 was an independent factor for BCS rate (OR = 4.54, 95% CI, 1.14-18.08, P = .03). CONCLUSIONS The number of F-CTC prior to NAC was related to poor response to NAC. Monitoring of F-CTC may help clinicians formulate personalized NAC regimens and implement BCS for patients with non-metastatic breast cancer.
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Affiliation(s)
- Shijie Jia
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China
- Department of Breast Surgery, Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China
| | - Yaping Yang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China
- Department of Breast Surgery, Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China
| | - Yingying Zhu
- Division of Clinical Research Design, Clinical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China
| | - Wenqian Yang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China
- Department of Breast Surgery, Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China
| | - Li Ling
- Department of Medical Statistics, School of Public Health, Sun Yat-sen University, Guangzhou, People’s Republic of China
| | - Yanghui Wei
- The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, People’s Republic of China
| | - Xiaolin Fang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China
- Department of Breast Surgery, Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China
| | - Qun Lin
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China
- Department of Breast Surgery, Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China
| | - Ahmed Hamaï
- Institut Necker-Enfants Malades (INEM), Inserm U1151-CNRS UMR 8253, Université de Paris, Paris, France
| | - Maryam Mehrpour
- Institut Necker-Enfants Malades (INEM), Inserm U1151-CNRS UMR 8253, Université de Paris, Paris, France
| | - Jingbo Gao
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China
- Department of Breast Surgery, Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China
| | - Weige Tan
- Department of Breast Surgery, The First Affiliated Hospital, Guangzhou Medical University, Guangzhou, People’s Republic of China
| | - Yuan Xia
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China
- Department of Breast Surgery, Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China
| | - Jiayi Chen
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China
- Department of Breast Surgery, Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China
| | - Wenguo Jiang
- Cardiff China Medical Research Collaborative, Cardiff University School of Medicine, Cardiff University, Heath Park, Cardiff, UK
| | - Chang Gong
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China
- Department of Breast Surgery, Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China
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Cani AK, Hayes DF. Breast Cancer Circulating Tumor Cells: Current Clinical Applications and Future Prospects. Clin Chem 2024; 70:68-80. [PMID: 38175590 DOI: 10.1093/clinchem/hvad191] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Accepted: 10/19/2023] [Indexed: 01/05/2024]
Abstract
BACKGROUND Identification and characterization of circulating tumor markers, designated as "liquid biopsies," have greatly impacted the care of cancer patients. Although more recently referring to circulating tumor DNA (ctDNA), the term liquid biopsy initially was coined to refer to any blood-borne biomarker related to malignancy, including circulating tumor cells (CTCs) in blood. In this manuscript, we review the specific state of the art of CTCs in breast cancer. CONTENT Liquid biopsies might play a clinical role across the entire spectrum of breast cancer, from risk assessment, prevention, screening, and treatment. CTC counts have been shown to carry clear, independent prognostic information in the latter situation. However, the clinical utility of CTCs in breast cancer remains to be determined. Nonetheless, in addition to CTC enumeration, analyses of CTCs provide tumor molecular information representing the entire, often-heterogeneous disease, relatively noninvasively and longitudinally. Technological advances have allowed the interrogation of CTC-derived information, providing renewed hope for a clinical role in disease monitoring and precision oncology. SUMMARY This narrative review examines CTCs, their clinical validity, and current prospects of clinical utility in breast cancer with the goal of improving patient outcomes.
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Affiliation(s)
- Andi K Cani
- Division of Hematology and Oncology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, United States
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI, United States
| | - Daniel F Hayes
- Division of Hematology and Oncology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, United States
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI, United States
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Affiliation(s)
- Catherine Alix-Panabières
- Laboratory of Rare Circulating Human Cells (LCCRH), University Medical Center of Montpellier, Montpellier, France.
- CREEC/CANECEV, MIVEGEC (CREES), Université de Montpellier, CNRS, IRD, Montpellier, France.
- European Liquid Biopsy Society (ELBS), Hamburg, Germany.
- Institut Universitaire de Recherche Clinique (IURC), 641, avenue du Doyen Gaston Giraud, 34093, Montpellier Cedex 5, France.
| | - Dario Marchetti
- Departments of Internal Medicine and Pathology, The University of New Mexico Health Sciences Center, UNM Comprehensive Cancer Center, MSC07 4025, 1 University of New Mexico, Albuquerque, NM, 87131, USA
| | - Julie E Lang
- Breast Surgery and Cancer Biology, Cleveland Clinic, 9500 Euclid Ave, A80, Cleveland, OH, 44195, USA
- Case Comprehensive Cancer Center, Cleveland Clinic, 9500 Euclid Ave, A80, Cleveland, OH, 44195, USA
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Nicolò E, Serafini MS, Munoz-Arcos L, Pontolillo L, Molteni E, Bayou N, Andreopoulou E, Curigliano G, Reduzzi C, Cristofanilli M. Real-time assessment of HER2 status in circulating tumor cells of breast cancer patients: Methods of detection and clinical implications. THE JOURNAL OF LIQUID BIOPSY 2023; 2:100117. [PMID: 40028485 PMCID: PMC11863949 DOI: 10.1016/j.jlb.2023.100117] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/06/2023] [Accepted: 10/01/2023] [Indexed: 03/05/2025]
Abstract
The human epidermal growth factor receptor 2 (HER2) plays a central role in breast cancer (BC). Therefore, it is critical to develop a method that can capture its spatial and temporal heterogeneity. Nowadays, therapeutic decisions for BC patients relies on evaluation of HER2 status from tissue biopsies using immunohistochemistry and in situ hybridization. Nevertheless, considering the technical and logistical challenges associated with tissue biopsies, there is an unmet need for a non-invasive and accurate approach to obtain real-time assessment of HER2 status. In this context, circulating biomarkers, particularly circulating tumor cells (CTCs), emerged as promising candidates. HER2 assessment on CTCs can be performed at genomic, transcriptomic, and protein levels on both bulk CTCs and at the single-cell resolution. However, the main limitation of the literature to date is the lack of a consistent definition of HER2-positive CTCs, which poses a major challenge for both, future research and clinical applications. Several studies revealed discordance in HER2 status between the primary tumor and corresponding CTCs. For instance, HER2-positive CTCs have been detected among patients with HER2-negative BC and vice versa. As a result, researchers have evaluated the prognostic and predictive value of HER2 status in CTCs, both in the early and metastatic settings, to increase the possibility of using anti-HER2 therapy also for these patients and to dissect mechanisms of treatment resistance. This review aims to provide an overview of the methods to determine HER2 status in CTCs and to summarize the evidence and future perspective on how CTCs-HER2 assessment can be integrated into the clinical management of BC patients.
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Affiliation(s)
- Eleonora Nicolò
- Division of New Drugs and Early Drug Development, European Institute of Oncology IRCCS, Milan, Italy
- Department of Oncology and Hematology-Oncology, University of Milan, Milan, Italy
- Department of Medicine, Division of Hematology-Oncology, Weill Cornell Medicine, New York, NY, USA
| | - Mara Serena Serafini
- Department of Medicine, Division of Hematology-Oncology, Weill Cornell Medicine, New York, NY, USA
| | - Laura Munoz-Arcos
- Department of Medicine, Division of Hematology-Oncology, Weill Cornell Medicine, New York, NY, USA
| | - Letizia Pontolillo
- Department of Medicine, Division of Hematology-Oncology, Weill Cornell Medicine, New York, NY, USA
- Medical Oncology Department, Catholic University of Sacred Heart, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Elisabetta Molteni
- Department of Medicine, Division of Hematology-Oncology, Weill Cornell Medicine, New York, NY, USA
- Department of Medicine, University of Udine, Via Chiusaforte, Udine, Italy
| | - Nadia Bayou
- Department of Medicine, Division of Hematology-Oncology, Weill Cornell Medicine, New York, NY, USA
- Human Genetics Laboratory (LR99ES10), Faculty of Medicine of Tunis, University of Tunis El Manar, Tunis, 2092, Tunisia
| | - Eleni Andreopoulou
- Department of Medicine, Division of Hematology-Oncology, Weill Cornell Medicine, New York, NY, USA
| | - Giuseppe Curigliano
- Division of New Drugs and Early Drug Development, European Institute of Oncology IRCCS, Milan, Italy
- Department of Oncology and Hematology-Oncology, University of Milan, Milan, Italy
| | - Carolina Reduzzi
- Department of Medicine, Division of Hematology-Oncology, Weill Cornell Medicine, New York, NY, USA
| | - Massimo Cristofanilli
- Department of Medicine, Division of Hematology-Oncology, Weill Cornell Medicine, New York, NY, USA
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Cai S, Deng Y, Wang Z, Zhu J, Huang C, Du L, Wang C, Yu X, Liu W, Yang C, Wang Z, Wang L, Ma K, Huang R, Zhou X, Zou H, Zhang W, Huang Y, Li Z, Qin T, Xu T, Guo X, Yu Z. Development and clinical validation of a microfluidic-based platform for CTC enrichment and downstream molecular analysis. Front Oncol 2023; 13:1238332. [PMID: 37849806 PMCID: PMC10578963 DOI: 10.3389/fonc.2023.1238332] [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: 06/11/2023] [Accepted: 08/29/2023] [Indexed: 10/19/2023] Open
Abstract
Background Although many CTC isolation and detection methods can provide information on cancer cell counts, downstream gene and protein analysis remain incomplete. Therefore, it is crucial to develop a technology that can provide comprehensive information on both the number and profile of CTC. Methods In this study, we developed a novel microfluidics-based CTC separation and enrichment platform that provided detailed information about CTC. Results This platform exhibits exceptional functionality, achieving high rates of CTC recovery (87.1%) and purification (∼4 log depletion of WBCs), as well as accurate detection (95.10%), providing intact and viable CTCs for downstream analysis. This platform enables successful separation and enrichment of CTCs from a 4 mL whole-blood sample within 15 minutes. Additionally, CTC subtypes, selected protein expression levels on the CTC surface, and target mutations in selected genes can be directly analyzed for clinical utility using immunofluorescence and real-time polymerase chain reaction, and the detected PD-L1 expression in CTCs is consistent with immunohistochemical assay results. Conclusion The microfluidic-based CTC enrichment platform and downstream molecular analysis together provide a possible alternative to tissue biopsy for precision cancer management, especially for patients whose tissue biopsies are unavailable.
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Affiliation(s)
- Songhua Cai
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital and Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China
| | - Youjun Deng
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital and Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China
| | - Zhe Wang
- Department of Oncology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Junyu Zhu
- Institute of Cancer Control, Cancer Hospital of Xinjiang Medical University, Urumqi, China
| | - Chujian Huang
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital and Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China
| | - Longde Du
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital and Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China
| | - Chunguang Wang
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital and Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China
| | - Xiangyang Yu
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital and Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China
| | - Wenyi Liu
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital and Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China
| | - Chenglin Yang
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital and Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China
| | - Zhe Wang
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital and Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China
| | - Lixu Wang
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital and Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China
| | - Kai Ma
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital and Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China
| | - Rui Huang
- Shenzhen Futian Research Institute, City University of Hong Kong, Shenzhen, China
| | - Xiaoyu Zhou
- Department of Medical Affairs, Cellomics (ShenZhen) Limited, Shenzhen, China
| | - Heng Zou
- Department of Medical Affairs, Cellomics (ShenZhen) Limited, Shenzhen, China
| | - Wenchong Zhang
- Department of Medical Affairs, Cellomics (ShenZhen) Limited, Shenzhen, China
| | - Yan Huang
- Department of Medical Affairs, Cellomics (ShenZhen) Limited, Shenzhen, China
| | - Zhi Li
- Department of Medical Affairs, Cellomics (ShenZhen) Limited, Shenzhen, China
| | - Tiaoping Qin
- Department of Medical Affairs, Cellomics (ShenZhen) Limited, Shenzhen, China
| | - Tao Xu
- Department of Medical Affairs, Cellomics (ShenZhen) Limited, Shenzhen, China
| | - Xiaotong Guo
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital and Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China
| | - Zhentao Yu
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital and Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China
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Du WQ, Zhu ZM, Jiang X, Kang MJ, Pei DS. COPS6 promotes tumor progression and reduces CD8 + T cell infiltration by repressing IL-6 production to facilitate tumor immune evasion in breast cancer. Acta Pharmacol Sin 2023; 44:1890-1905. [PMID: 37095198 PMCID: PMC10462724 DOI: 10.1038/s41401-023-01085-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Accepted: 03/28/2023] [Indexed: 04/26/2023]
Abstract
Due to poor T cell infiltration, tumors evade immune surveillance. Increased CD8+ T cell infiltration in breast cancer suggests a satisfactory response to immunotherapy. COPS6 has been identified as an oncogene, but its role in regulating antitumor immune responses has not been defined. In this study, we investigated the impact of COPS6 on tumor immune evasion in vivo. Tumor transplantation models were established in C57BL/6 J mice and BALB/c nude mice. Flow cytometry was conducted to identify the role of COPS6 on tumor-infiltrating CD8+ T cells. By analyzing the TCGA and GTEx cohort, we found that COPS6 expression was significantly up-regulated in a variety of cancers. In human osteosarcoma cell line U2OS and non-small cell lung cancer cell line H1299, we showed that p53 negatively regulated COPS6 promoter activity. In human breast cancer MCF-7 cells, COPS6 overexpression stimulated p-AKT expression as well as the proliferation and malignant transformation of tumor cells, whereas knockdown of COPS6 caused opposite effects. Knockdown of COPS6 also significantly suppressed the growth of mouse mammary cancer EMT6 xenografts in BALB/c nude mice. Bioinformatics analysis suggested that COPS6 was a mediator of IL-6 production in the tumor microenvironment and a negative regulator of CD8+ T cell tumor infiltration in breast cancer. In C57BL6 mice bearing EMT6 xenografts, COPS6 knockdown in the EMT6 cells increased the number of tumor-infiltrating CD8+ T cells, while knockdown of IL-6 in COPS6KD EMT6 cells diminished tumor infiltrating CD8+ T cells. We conclude that COPS6 promotes breast cancer progression by reducing CD8+ T cell infiltration and function via the regulation of IL-6 secretion. This study clarifies the role of p53/COPS6/IL-6/CD8+ tumor infiltrating lymphocytes signaling in breast cancer progression and immune evasion, opening a new path for development of COPS6-targeting therapies to enhance tumor immunogenicity and treat immunologically "cold" breast cancer.
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Affiliation(s)
- Wen-Qi Du
- Department of Pathology, Xuzhou Medical University, Xuzhou, 221004, China
- Department of Human Anatomy, Xuzhou Medical University, Xuzhou, 221004, China
| | - Zhi-Man Zhu
- Department of Pathology, Xuzhou Medical University, Xuzhou, 221004, China
| | - Xin Jiang
- Department of Pathology, Xuzhou Medical University, Xuzhou, 221004, China
| | - Meng-Jie Kang
- Department of Pathology, Xuzhou Medical University, Xuzhou, 221004, China
| | - Dong-Sheng Pei
- Department of Pathology, Xuzhou Medical University, Xuzhou, 221004, China.
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16
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Orsini A, Diquigiovanni C, Bonora E. Omics Technologies Improving Breast Cancer Research and Diagnostics. Int J Mol Sci 2023; 24:12690. [PMID: 37628869 PMCID: PMC10454385 DOI: 10.3390/ijms241612690] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Revised: 08/09/2023] [Accepted: 08/10/2023] [Indexed: 08/27/2023] Open
Abstract
Breast cancer (BC) has yielded approximately 2.26 million new cases and has caused nearly 685,000 deaths worldwide in the last two years, making it the most common diagnosed cancer type in the world. BC is an intricate ecosystem formed by both the tumor microenvironment and malignant cells, and its heterogeneity impacts the response to treatment. Biomedical research has entered the era of massive omics data thanks to the high-throughput sequencing revolution, quick progress and widespread adoption. These technologies-liquid biopsy, transcriptomics, epigenomics, proteomics, metabolomics, pharmaco-omics and artificial intelligence imaging-could help researchers and clinicians to better understand the formation and evolution of BC. This review focuses on the findings of recent multi-omics-based research that has been applied to BC research, with an introduction to every omics technique and their applications for the different BC phenotypes, biomarkers, target therapies, diagnosis, treatment and prognosis, to provide a comprehensive overview of the possibilities of BC research.
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Affiliation(s)
| | - Chiara Diquigiovanni
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, 40131 Bologna, Italy; (A.O.); (E.B.)
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Temilola DO, Wium M, Paccez J, Salukazana AS, Otu HH, Carbone GM, Kaestner L, Cacciatore S, Zerbini LF. Potential of miRNAs in Plasma Extracellular Vesicle for the Stratification of Prostate Cancer in a South African Population. Cancers (Basel) 2023; 15:3968. [PMID: 37568783 PMCID: PMC10417259 DOI: 10.3390/cancers15153968] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Revised: 07/29/2023] [Accepted: 08/01/2023] [Indexed: 08/13/2023] Open
Abstract
Prostate cancer (PCa) is the most common cause of cancer death among African men. The analysis of microRNAs (miRNAs) in plasma extracellular vesicles (EVs) can be utilized as a non-invasive tool for the diagnosis of PCa. In this study, we used small RNA sequencing to profile miRNAs cargo in plasma EVs from South African PCa patients. We evaluated the differential expression of miRNAs between low and high Gleason scores in the plasma EVs of South African patients and in the prostatic tissue from data available in the Cancer Genome Atlas (TCGA) Data Portal. We identified 7 miRNAs differently expressed in both EVs and prostatic tissues. We evaluated their expression using qPCR in a larger cohort of 10 patients with benign prostatic hyperplasia (BPH) and 24 patients with PCa. Here, we reported that the ratio between two of these miRNAs (i.e., miR-194-5p/miR-16-5p) showed a higher concentration in PCa compared to BPH and in metastatic PCa compared to localized PCa. We explored for the first time the profiling of miRNAs cargo in plasma EVs as a tool for the identification of putative markers in the South African population. Our finding indicated the ratio miR-194-5p/miR-16-5p as a non-invasive marker for the evaluation of PCa aggressiveness in this population.
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Affiliation(s)
- Dada Oluwaseyi Temilola
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town 7925, South Africa
- Integrative Biomedical Sciences Division, Faculty of Health Sciences, University of Cape Town, Cape Town 7925, South Africa
| | - Martha Wium
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town 7925, South Africa
| | - Juliano Paccez
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town 7925, South Africa
| | - Azola Samkele Salukazana
- Division of Urology, University of Cape Town, Groote Schuur Hospital, Cape Town 7925, South Africa
| | - Hasan H. Otu
- Department of Electrical and Computer Engineering, University of Nebraska-Lincoln, Lincoln, NE 68588, USA
| | - Giuseppina M. Carbone
- Institute of Oncology Research (IOR), Università della Svizzera italiana, 6900 Bellinzona, Switzerland
| | - Lisa Kaestner
- Division of Urology, University of Cape Town, Groote Schuur Hospital, Cape Town 7925, South Africa
| | - Stefano Cacciatore
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town 7925, South Africa
| | - Luiz Fernando Zerbini
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town 7925, South Africa
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18
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Wang DQ, Wang YY, Shi YL, Zeng B, Lin ZJ, Deng Q, Ming J. Correlation between connexin 43 expression in circulating tumor cells and biological characteristics of breast cancer. Heliyon 2023; 9:e18697. [PMID: 37583757 PMCID: PMC10424078 DOI: 10.1016/j.heliyon.2023.e18697] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Revised: 07/20/2023] [Accepted: 07/25/2023] [Indexed: 08/17/2023] Open
Abstract
Background Connexin 43 (Cx43) has been closely linked to the occurrence and progression of breast cancer. Distant metastasis of breast cancer is aided by the epithelial-mesenchymal transition of circulating tumor cells (CTCs). However, the impact of Cx43 expression on CTCs and the extent of its role in the disease remain unclear. Methods We determined CTCs in 156 patients, who had breast cancer with a disease course of two or more years. We also measured the expression of Cx43 in the CTCs. The CTCs were detected in the blood of 139 of these patients. These 139 patients were divided into two groups: the Cx43 group and the non-Cx43 group based on their Cx43 expression. Results Overall, Cx43 expression was found in 83 of the 139 patients (59.7%, 83/139 cases). The two groups significantly differed in terms of the number of mixed biphenotypic type CTCs and the total number of CTCs (P < 0.05). There were significant correlations between Cx43 expression and Ki67 expression, tumor size, lymph node metastasis, and TNM stage (P < 0.05 for all). The data suggested that patients with Cx43 expression had a higher risk of distant metastasis and had later-stage disease. The difference in Cx43 expression between patients with and without epidermal growth factor receptor 2 (Her2) overexpression was statistically significant (P < 0.05). The difference in disease-free survival (DFS) between the two groups was statistically significant (P = 0.03), and the Cx43 group had a shorter duration of DFS. Univariate Cox regression analysis revealed that Cx43 expression, Her2 expression, and tumor size were significantly correlated with DFS (P = 0.03, 0.0023, and 0.01, respectively). Conclusion Cx43 expression in the CTCs of patients with breast cancer is a cancer-promoting factor.
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Affiliation(s)
- Dan-Qing Wang
- Department of Breast and Thyroid Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, People's Republic of China
| | - Yuan-Yuan Wang
- Department of Emergency, Xi'an Central Hospital, Xi'an 710003, People's Republic of China
| | - Yan-Ling Shi
- Department of Breast and Thyroid Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, People's Republic of China
| | - Bin Zeng
- Department of Breast and Thyroid Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, People's Republic of China
| | - Zi-Jing Lin
- Department of Breast and Thyroid Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, People's Republic of China
| | - Qin Deng
- Department of Breast and Thyroid Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, People's Republic of China
| | - Jia Ming
- Department of Breast and Thyroid Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, People's Republic of China
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Farhang Ghahremani M, Seto KKY, Cho W, Miller MC, Smith P, Englert DF. Novel method for highly multiplexed gene expression profiling of circulating tumor cells (CTCs) captured from the blood of women with metastatic breast cancer. J Transl Med 2023; 21:414. [PMID: 37365600 DOI: 10.1186/s12967-023-04242-z] [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: 11/23/2022] [Accepted: 06/02/2023] [Indexed: 06/28/2023] Open
Abstract
BACKGROUND Enumeration of circulating tumor cells (CTCs) has proven clinical significance for monitoring patients with metastatic cancers. Multiplexed gene expression profiling of CTCs is a potential tool for assessing disease status and monitoring treatment response. The Parsortix® technology enables the capture and harvest of CTCs from blood based on cell size and deformability. The HyCEAD™ (Hybrid Capture Enrichment Amplification and Detection) assay enables simultaneous amplification of short amplicons for up to 100 mRNA targets, and the Ziplex™ instrument quantifies the amplicons for highly sensitive gene expression profiling down to single cell levels. The aim of the study was to functionally assess this system. METHODS The HyCEAD/Ziplex platform was used to quantify the expression levels for 72 genes using as little as 20 pg of total RNA or a single cultured tumor cell. Assay performance was evaluated using cells or total RNA spiked into Parsortix harvests of healthy donor blood. The assay was also evaluated using total RNA obtained from Parsortix harvests of blood from metastatic breast cancer (MBC) patients or healthy volunteers (HVs). RESULTS Using genes with low expression in WBC RNA and/or in unspiked Parsortix harvests from HVs, the assay distinguished between the different breast cancer and ovarian cancer cell lines with as little as 20 pg of total RNA (equivalent to a single cell) in the presence of 1 ng of WBC RNA. Single cultured cells spiked into Parsortix harvests from 10 mL of HV blood were also detected and distinguished from each other. CVs from repeatability experiments were less than 20%. Hierarchical clustering of clinical samples differentiated most MBC patients from HVs. CONCLUSION HyCEAD/Ziplex provided sensitive quantification of expression of 72 genes from 20 pg of total RNA from cultured tumor cell lines or from single cultured tumor cells spiked into lysates from Parsortix harvests of HV blood. The HyCEAD/Ziplex platform enables the quantification of selected genes in the presence of residual nucleated blood cells in Parsortix harvests. The HyCEAD/Ziplex platform is an effective tool for multiplexed molecular characterization of mRNA in small numbers of tumor cells harvested from blood.
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Affiliation(s)
| | | | | | - Michael Craig Miller
- Clinical Development, ANGLE North America, Inc., Plymouth Meeting, Pennsylvania, USA
| | - Paul Smith
- ANGLE Biosciences Inc., Toronto, ON, Canada
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Kurniali PC, Storandt MH, Jin Z. Utilization of Circulating Tumor Cells in the Management of Solid Tumors. J Pers Med 2023; 13:jpm13040694. [PMID: 37109080 PMCID: PMC10145886 DOI: 10.3390/jpm13040694] [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: 03/16/2023] [Revised: 04/18/2023] [Accepted: 04/18/2023] [Indexed: 04/29/2023] Open
Abstract
Circulating tumor cells (CTCs) are tumor cells shed from the primary tumor into circulation, with clusters of CTCs responsible for cancer metastases. CTC detection and isolation from the bloodstream are based on properties distinguishing CTCs from normal blood cells. Current CTC detection techniques can be divided into two main categories: label dependent, which depends upon antibodies that selectively bind cell surface antigens present on CTCs, or label-independent detection, which is detection based on the size, deformability, and biophysical properties of CTCs. CTCs may play significant roles in cancer screening, diagnosis, treatment navigation, including prognostication and precision medicine, and surveillance. In cancer screening, capturing and evaluating CTCs from peripheral blood could be a strategy to detect cancer at its earliest stage. Cancer diagnosis using liquid biopsy could also have tremendous benefits. Full utilization of CTCs in the clinical management of malignancies may be feasible in the near future; however, several challenges still exist. CTC assays currently lack adequate sensitivity, especially in early-stage solid malignancies, due to low numbers of detectable CTCs. As assays improve and more trials evaluate the clinical utility of CTC detection in guiding therapies, we anticipate increased use in cancer management.
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Affiliation(s)
- Peter C Kurniali
- Sanford Cancer Center, 701 E Rosser Ave, Bismarck, ND 58501, USA
- Department of Internal Medicine, Division of Hematology/Oncology, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND 58203, USA
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Yang Y, Liu H, Chen Y, Xiao N, Zheng Z, Liu H, Wan J. Liquid biopsy on the horizon in immunotherapy of non-small cell lung cancer: current status, challenges, and perspectives. Cell Death Dis 2023; 14:230. [PMID: 37002211 PMCID: PMC10066332 DOI: 10.1038/s41419-023-05757-5] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 03/14/2023] [Accepted: 03/17/2023] [Indexed: 04/03/2023]
Abstract
Non-small cell lung cancer (NSCLC) is one of the most threatening malignancies to human health and life. In most cases, patients with NSCLC are already at an advanced stage when they are diagnosed. In recent years, lung cancer has made great progress in precision therapy, but the efficacy of immunotherapy is unstable, and its response rate varies from patient to patient. Several biomarkers have been proposed to predict the outcomes of immunotherapy, such as programmed cell death-ligand 1 (PD-L1) expression and tumor mutational burden (TMB). Nevertheless, the detection assays are invasive and demanding on tumor tissue. To effectively predict the outcomes of immunotherapy, novel biomarkers are needed to improve the performance of conventional biomarkers. Liquid biopsy is to capture and detect circulating tumor cells (CTCs), circulating tumor DNA (ctDNA) and exosomes in body fluids, such as blood, saliva, urine, pleural fluid and cerebrospinal fluid as samples from patients, so as to make analysis and diagnosis of cancer and other diseases. The application of liquid biopsy provides a new possible solution, as it has several advantages such as non-invasive, real-time dynamic monitoring, and overcoming tumor heterogeneity. Liquid biopsy has shown predictive value in immunotherapy, significantly improving the precision treatment of lung cancer patients. Herein, we review the application of liquid biopsy in predicting the outcomes of immunotherapy in NSCLC patients, and discuss the challenges and future directions in this field.
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Affiliation(s)
- Ying Yang
- Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Hongyang Liu
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Youming Chen
- Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Nan Xiao
- Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Zhaoyang Zheng
- Department of Clinical Laboratory, The Second Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou, Henan, China
| | - Hongchun Liu
- Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
| | - Junhu Wan
- Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
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Circulating Tumor Cells Predict Response of Neoadjuvant Chemotherapy in Patients with Bladder Cancer: A Preliminary Study. Diagnostics (Basel) 2023; 13:diagnostics13061032. [PMID: 36980339 PMCID: PMC10047015 DOI: 10.3390/diagnostics13061032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Revised: 02/23/2023] [Accepted: 03/07/2023] [Indexed: 03/11/2023] Open
Abstract
This study aimed to explore the existence of circulating tumor cells (CTCs) in patients with muscle-invasive bladder cancer (MIBC) and their predictive potential for response to neoadjuvant chemotherapy (NAC). From 33 blood samples of MIBC patients, CTCs were isolated by cell surface markers and enriched by the IsoFlux™ device, followed by morphological and immunofluorescent identification. CTCs were detected at baseline in all samples. Immunofluorescence confirmed the tumor origin. MIBC patients were stratified by NAC response into the disease control (DC) and progressive disease (PD) groups. In the DC group, the number of CTCs decreased significantly after four courses of NAC (p < 0.0001). CTC counts in 7.5 mL after four NAC cycles were highly correlated with postoperative pathological T stage (p < 0.0001). Our study demonstrated that CTCs might represent a valuable predictive marker for NAC response in MIBC. CTC detection in MIBC patients could allow early arrangement of radical cystectomy for NAC non-responders to prevent disease progression while receiving the NAC courses.
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Gupta A, Kurzrock R, Adashek JJ. Evolution of the Targeted Therapy Landscape for Cholangiocarcinoma: Is Cholangiocarcinoma the 'NSCLC' of GI Oncology? Cancers (Basel) 2023; 15:1578. [PMID: 36900367 PMCID: PMC10000383 DOI: 10.3390/cancers15051578] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2023] [Revised: 02/27/2023] [Accepted: 03/02/2023] [Indexed: 03/06/2023] Open
Abstract
In the past two decades, molecular targeted therapy has revolutionized the treatment landscape of several malignancies. Lethal malignancies such as non-small cell lung cancer (NSCLC) have become a model for precision-matched immune- and gene-targeted therapies. Multiple small subgroups of NSCLC defined by their genomic aberrations are now recognized; remarkably, taken together, almost 70% of NSCLCs now have a druggable anomaly. Cholangiocarcinoma (CCA) is a rare tumor with a poor prognosis. Novel molecular alterations have been recently identified in patients with CCA, and the potential for targeted therapy is being realized. In 2019, a fibroblast growth factor receptor 2 (FGFR2) inhibitor, pemigatinib, was the first approved targeted therapy for patients with locally advanced or metastatic intrahepatic CCA who had FGFR2 gene fusions or rearrangement. More regulatory approvals for matched targeted therapies as second-line or subsequent treatments in advanced CCA followed, including additional drugs that target FGFR2 gene fusion/rearrangement. Recent tumor-agnostic approvals include (but are not limited to) drugs that target mutations/rearrangements in the following genes and are hence applicable to CCA: isocitrate dehydrogenase 1 (IDH1); neurotrophic tropomyosin-receptor kinase (NTRK); the V600E mutation of the BRAF gene (BRAFV600E); and high tumor mutational burden, high microsatellite instability, and gene mismatch repair-deficient (TMB-H/MSI-H/dMMR) tumors. Ongoing trials investigate HER2, RET, and non-BRAFV600E mutations in CCA and improvements in the efficacy and safety of new targeted treatments. This review aims to present the current status of molecularly matched targeted therapy for advanced CCA.
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Affiliation(s)
- Amol Gupta
- Department of Medicine, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins Hospital, Baltimore, MD 21287, USA
| | - Razelle Kurzrock
- WIN Consortium, San Diego, CA 92093, USA
- Division of Hematology and Oncology, Medical College of Wisconsin Cancer Center, Milwaukee, WI 53226, USA
- Division of Hematology and Oncology, University of Nebraska, Omaha, NE 68182, USA
| | - Jacob J. Adashek
- Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins Hospital, Baltimore, MD 21287, USA
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Armakolas A, Kotsari M, Koskinas J. Liquid Biopsies, Novel Approaches and Future Directions. Cancers (Basel) 2023; 15:1579. [PMID: 36900369 PMCID: PMC10000663 DOI: 10.3390/cancers15051579] [Citation(s) in RCA: 42] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Revised: 02/22/2023] [Accepted: 03/01/2023] [Indexed: 03/06/2023] Open
Abstract
Cancer is among the leading causes of death worldwide. Early diagnosis and prognosis are vital to improve patients' outcomes. The gold standard of tumor characterization leading to tumor diagnosis and prognosis is tissue biopsy. Amongst the constraints of tissue biopsy collection is the sampling frequency and the incomplete representation of the entire tumor bulk. Liquid biopsy approaches, including the analysis of circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), circulating miRNAs, and tumor-derived extracellular vesicles (EVs), as well as certain protein signatures that are released in the circulation from primary tumors and their metastatic sites, present a promising and more potent candidate for patient diagnosis and follow up monitoring. The minimally invasive nature of liquid biopsies, allowing frequent collection, can be used in the monitoring of therapy response in real time, allowing the development of novel approaches in the therapeutic management of cancer patients. In this review we will describe recent advances in the field of liquid biopsy markers focusing on their advantages and disadvantages.
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Affiliation(s)
- Athanasios Armakolas
- Physiology Laboratory, Medical School, National and Kapodistrian University of Athens, 115 27 Athens, Greece
- B' Department of Medicine, Hippokration Hospital, National and Kapodistrian University of Athens, 115 27 Athens, Greece
| | - Maria Kotsari
- Physiology Laboratory, Medical School, National and Kapodistrian University of Athens, 115 27 Athens, Greece
| | - John Koskinas
- B' Department of Medicine, Hippokration Hospital, National and Kapodistrian University of Athens, 115 27 Athens, Greece
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Liquid biopsy for monitoring of tumor dormancy and early detection of disease recurrence in solid tumors. Cancer Metastasis Rev 2023; 42:161-182. [PMID: 36607507 PMCID: PMC10014694 DOI: 10.1007/s10555-022-10075-x] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Accepted: 12/22/2022] [Indexed: 01/07/2023]
Abstract
Cancer is one of the three leading causes of death worldwide. Even after successful therapy and achieving remission, the risk of relapse often remains. In this context, dormant residual cancer cells in secondary organs such as the bone marrow constitute the cellular reservoir from which late tumor recurrences arise. This dilemma leads the term of minimal residual disease, which reflects the presence of tumor cells disseminated from the primary lesion to distant organs in patients who lack any clinical or radiological signs of metastasis or residual tumor cells left behind after therapy that eventually lead to local recurrence. Disseminated tumor cells have the ability to survive in a dormant state following treatment and linger unrecognized for more than a decade before emerging as recurrent disease. They are able to breakup their dormant state and to readopt their proliferation under certain circumstances, which can finally lead to distant relapse and cancer-associated death. In recent years, extensive molecular and genetic characterization of disseminated tumor cells and blood-based biomarker has contributed significantly to our understanding of the frequency and prevalence of tumor dormancy. In this article, we describe the clinical relevance of disseminated tumor cells and highlight how latest advances in different liquid biopsy approaches can be used to detect, characterize, and monitor minimal residual disease in breast cancer, prostate cancer, and melanoma patients.
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Circulating Tumor Cell Detection by Liquid Biopsy during Early-Stage Endometrial Cancer Surgery: A Pilot Study. Biomolecules 2023; 13:biom13030428. [PMID: 36979364 PMCID: PMC10046537 DOI: 10.3390/biom13030428] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 02/16/2023] [Accepted: 02/21/2023] [Indexed: 03/02/2023] Open
Abstract
The recurrence of non-metastatic endometrial carcinoma (EC) (6 to 21%) might be due to disseminated tumor cells. This feasibility study investigated whether circulating tumor cells (CTCs) were detectable in blood samples from the peripheral and ovarian veins of 10 patients undergoing laparoscopic resection of stage I-II EC between July 2019 and September 2021. CTCs were detected using the CellSearch® system (i) preoperatively (T0) in peripheral blood, (ii) after ovary suspensory ligament pediculation in ovarian vein blood (T1), and (iii) before colpotomy in peripheral blood (T2). CTCs were detected only in ovarian vein samples in 8/10 patients. The CTC median number did not differ with patient age (37 (min-max: 0–91) in <70-year-old vs. 11 (0–65) in ≥70 year-old women, p = 0.59), tumor grade (15 (0–72) for grade 1 vs. 15 (0–91) for grade 2, p = 0.97), FIGO stage (72 (27–91) vs. 2 (0–65) vs. 3 (0–6]) for stage IA, B, and II, respectively; p = 0.08), and tumor size (40 (2–72) for size < 30 mm vs. 4 (0–91) for size ≥ 30 mm, p = 0.39). Estrogen receptor-positive CTCs and CTC clusters were identified. The prognostic and therapeutic values of CTCs released during EC surgery need to be determined.
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Guo S, Chen J, Hu P, Li C, Wang X, Chen N, Sun J, Wang Y, Wang J, Gu W, Wu S. The Value of Circulating Tumor Cells and Tumor Markers Detection in Lung Cancer Diagnosis. Technol Cancer Res Treat 2023; 22:15330338231166754. [PMID: 37093867 PMCID: PMC10134176 DOI: 10.1177/15330338231166754] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/25/2023] Open
Abstract
OBJECTIVE Circulating tumor cells are complete tumor cells with multi-scale analysis values that present a high potential for lung cancer diagnosis. To enhance the accuracy of lung cancer diagnosis, we detected circulating tumor cells by the innovated conical micro filter integrated microfluidic system. METHODS We recruited 45 subjects of study, including 22 lung cancer patients, 2 precancerous patients, the control group including 14 healthy participants, and 7 patients with lung benign lesions in this prospective study. We calculated the area under the receiver operating characteristic curve of circulating tumor cells, cytokeratin19 fragment, carcinoma embryonic antigen, squamous cell carcinoma, neuron-specific enolase, and their combination, respectively, while compared the circulating tumor cells levels between vein blood and arterial blood. A conical shape filter embedded in a microfluidic chip was used to improve the detection capability of circulating tumor cells. RESULTS The study indicated that the sensitivity, specificity, positive predictive value, and negative predictive value of circulating tumor cells detection were 81.8%, 90.5%, 90.0%, and 82.6%, respectively. The circulating tumor cells level of lung cancer patient was significantly higher than that of the control group (P < .05). The area under the curve of circulating tumor cells, cytokeratin19 fragment, carcinoma embryonic antigen, squamous cell carcinoma, and neuron-specific enolase alone was 0.838, 0.760, 0.705, 0.614, and 0.636, respectively. The combination area under the curve of the 4 tumor markers (cytokeratin19 fragment, carcinoma embryonic antigen, squamous cell carcinoma, and neuron-specific enolase) was 0.805 less than that of circulating tumor cells alone. Together, the total area under the curve of circulating tumor cell and the 4 tumor markers were 0.847, showing the highest area under the curve value among all biomarkers. In addition, this study found that there was no significant difference in positive rate of circulating tumor cell between arterial and venous blood samples. CONCLUSION The circulating tumor cells detection technology by conical micro filter integrated microfluidic could be used for lung cancer diagnosis with high sensitivity and specificity. Complementary combination of circulating tumor cells and conventional 4 lung cancer markers could enhance the clinical application accuracy. Venous blood should be used as a routine sample for circulating tumor cells detections.
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Affiliation(s)
- Sumin Guo
- Department of Internal Medicine, Hebei Medical University, Shijiazhuang, Hebei, People's Republic of China
| | - Jingyu Chen
- Department of Chinese Medicine Internal Medicine, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, People's Republic of China
| | - Po Hu
- Department of Oncology, Hebei Chest Hospital, Lung Cancer Prevention and Research Center of Hebei Province, Shijiazhuang, Hebei, People's Republic of China
| | - Chen Li
- Department of Oncology, Hebei Chest Hospital, Lung Cancer Prevention and Research Center of Hebei Province, Shijiazhuang, Hebei, People's Republic of China
| | - Xiang Wang
- Department of Oncology, Hebei Chest Hospital, Lung Cancer Prevention and Research Center of Hebei Province, Shijiazhuang, Hebei, People's Republic of China
| | - Ning Chen
- Department of Pathology, Hebei Chest Hospital, Lung Cancer Prevention and Research Center of Hebei Province, Shijiazhuang, Hebei, People's Republic of China
| | - Jiale Sun
- College of Lab Medicine, Hebei North University, Zhangjiakou, Hebei, People's Republic of China
| | - Yongfeng Wang
- Department of Oncology, Hebei Chest Hospital, Lung Cancer Prevention and Research Center of Hebei Province, Shijiazhuang, Hebei, People's Republic of China
| | - Jianling Wang
- Department of Oncology, Hebei Chest Hospital, Lung Cancer Prevention and Research Center of Hebei Province, Shijiazhuang, Hebei, People's Republic of China
| | - Weikuan Gu
- Department of Orthopedic Surgery and BME-Campbell Clinic, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Shucai Wu
- Department of Internal Medicine, Hebei Medical University, Shijiazhuang, Hebei, People's Republic of China
- Department of Internal Medicine, Hebei Chest Hospital, Lung Cancer Prevention and Research Center of Hebei Province, Shijiazhuang, Hebei, People's Republic of China
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Wei Y, Yang W, Huang Q, Chen Y, Zeng K, Chen J, Chen J. Clinical significance of circulating tumor cell (CTC)-specific microRNA (miRNA) in breast cancer. PROGRESS IN BIOPHYSICS AND MOLECULAR BIOLOGY 2023; 177:229-234. [PMID: 36574883 DOI: 10.1016/j.pbiomolbio.2022.12.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/17/2022] [Revised: 10/05/2022] [Accepted: 12/22/2022] [Indexed: 12/25/2022]
Abstract
As a noninvasive method, circulating tumor cell (CTC) provides ideal liquid biopsy specimens for early cancer screening and diagnosis. CTCs detection in breast cancer is correlated with patient prognosis such as disease-free survival (DFS) and overall survival (OS). Besides, accumulating evidence supported that CTCs count may be indicator for chemotherapy response as well. The functional roles of microRNA (miRNA) in breast cancer have been well-recognized for the last few years. Due to its stability in circulation, numerous studies have proven that circulating miRNA may serve as promising diagnostic and prognostic biomarkers in breast cancer. The potential ability of miRNAs in disease screening, staging or even molecular subtype classification makes them valuable tools for early breast cancer patients. It would be of great significance to characterize the miRNA expression profile in CTCs, which could provide reliable biological information originated from tumor. However, some issues need to be addressed before the utility of CTC-specific miRNAs in clinical setting. Taken together, we believe that CTC-specific miRNA detection will be trend for early breast cancer screening, diagnosis and treatment monitor in near future.
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Affiliation(s)
- Yanghui Wei
- Department of Surgery, The Eighth Affiliated Hospital, Sun Yat-Sen University, Hong Kong, China.
| | - Weiqin Yang
- School of Biomedical Sciences, The Chinese, University of Hong Kong, Hong Kong, China.
| | - Qingnan Huang
- Department of Surgery, The Eighth Affiliated Hospital, Sun Yat-Sen University, Hong Kong, China.
| | - Yong Chen
- Department of Surgery, The Eighth Affiliated Hospital, Sun Yat-Sen University, Hong Kong, China.
| | - Kai Zeng
- Department of Surgery, The Eighth Affiliated Hospital, Sun Yat-Sen University, Hong Kong, China.
| | - Juan Chen
- Department of Medicine & Rehabilitation, Tung Wah Eastern Hospital, Hong Kong, China.
| | - Jiawei Chen
- Department of Surgery, The Eighth Affiliated Hospital, Sun Yat-Sen University, Hong Kong, China.
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29
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Gianni C, Palleschi M, Merloni F, Bleve S, Casadei C, Sirico M, Di Menna G, Sarti S, Cecconetto L, Mariotti M, De Giorgi U. Potential Impact of Preoperative Circulating Biomarkers on Individual Escalating/de-Escalating Strategies in Early Breast Cancer. Cancers (Basel) 2022; 15:96. [PMID: 36612091 PMCID: PMC9817806 DOI: 10.3390/cancers15010096] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 12/18/2022] [Accepted: 12/20/2022] [Indexed: 12/28/2022] Open
Abstract
The research on non-invasive circulating biomarkers to guide clinical decision is in wide expansion, including the earliest disease settings. Several new intensification/de-intensification strategies are approaching clinical practice, personalizing the treatment for each patient. Moreover, liquid biopsy is revealing its potential with multiple techniques and studies available on circulating biomarkers in the preoperative phase. Inflammatory circulating cells, circulating tumor cells (CTCs), cell-free DNA (cfDNA), circulating tumor DNA (ctDNA), and other biological biomarkers are improving the armamentarium for treatment selection. Defining the escalation and de-escalation of treatments is a mainstay of personalized medicine in early breast cancer. In this review, we delineate the studies investigating the possible application of these non-invasive tools to give a more enlightened approach to escalating/de-escalating strategies in early breast cancer.
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Affiliation(s)
- Caterina Gianni
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy
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Yang L, Rivandi M, Franken A, Hieltjes M, van der Zaag PJ, Nelep C, Eberhardt J, Peter S, Niederacher D, Fehm T, Neubauer H. Implementing microwell slides for detection and isolation of single circulating tumor cells from complex cell suspensions. Cytometry A 2022; 101:1057-1067. [PMID: 35698878 DOI: 10.1002/cyto.a.24660] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Revised: 04/12/2022] [Accepted: 05/23/2022] [Indexed: 01/27/2023]
Abstract
Cell loss during detection and isolation of circulating tumor cells (CTCs) is a challenge especially when label-free pre-enrichment technologies are used without the aid of magnetic particles. Although microfluidic systems can remove the majority of "contaminating" white blood cells (WBCs), their remaining numbers are still impeding single CTC isolation, thus making additional separation steps needed. This study aimed to develop a workflow from blood-to-single CTC for complex cell suspensions by testing two microwell formats. In the first step, different cell lines were used to compare the performances of Sievewell™ 370 K (TOK, Japan) and CellCelector™ Nanowell U25 (ALS Automated Lab Solutions, Germany) slides for cell labelling and single-cell micromanipulation. Confounding levels of auto-fluorescence inherent to different plastic materials used to cast the microwells, staining recovery rates, and cell isolation rates were determined. In the second step, three different blood preservation tubes were tested for RNA analysis. Lastly, the established workflow was applied to isolate CTCs from peripheral blood samples obtained from metastasized breast cancer (mBC) patients for single-cell DNA and RNA analysis. The detection of CTCs in Sievewell slides profit from better signal-to-noise ratios in the fluorescence channels mainly used for CTC detection. In addition, due to its design, Sievewell supports direct in situ CTC labelling, which minimizes cell loss and leads to single-cell recovery rates after staining of approx. 94%. Detection of PIK3CA mutations in single CTCs verified the applicability of the workflow for the analysis of genomic DNA of CTCs. Furthermore, combined with blood preservation up to 48 h at room temperature in LBguard tubes, panel RT-PCR transcript analysis was successful for single cell line cells and CTCs, respectively. The combined use of Sievewell microwell slides and CellCelector™ automated micromanipulation system improves single CTC detection, labelling and isolation from complex cell suspensions. This approach is especially valuable when samples of high cellular content are processed.
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Affiliation(s)
- Liwen Yang
- Department of Obstetrics and Gynecology, University Hospital and Medical Faculty of the Heinrich-Heine University Düsseldorf, Düsseldorf, Germany
| | - Mahdi Rivandi
- Department of Obstetrics and Gynecology, University Hospital and Medical Faculty of the Heinrich-Heine University Düsseldorf, Düsseldorf, Germany
| | - André Franken
- Department of Obstetrics and Gynecology, University Hospital and Medical Faculty of the Heinrich-Heine University Düsseldorf, Düsseldorf, Germany
| | - Maarten Hieltjes
- Philips Research Laboratories, Eindhoven, The Netherlands.,Plasmacure b.v., Eindhoven, The Netherlands
| | - Pieter Jan van der Zaag
- Philips Research Laboratories, Eindhoven, The Netherlands.,Molecular Biophysics, Zernike Institute, University of Groningen, Groningen, The Netherlands.,Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | | | | | | | - Dieter Niederacher
- Department of Obstetrics and Gynecology, University Hospital and Medical Faculty of the Heinrich-Heine University Düsseldorf, Düsseldorf, Germany
| | - Tanja Fehm
- Department of Obstetrics and Gynecology, University Hospital and Medical Faculty of the Heinrich-Heine University Düsseldorf, Düsseldorf, Germany
| | - Hans Neubauer
- Department of Obstetrics and Gynecology, University Hospital and Medical Faculty of the Heinrich-Heine University Düsseldorf, Düsseldorf, Germany
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Signatures of Breast Cancer Progression in the Blood: What Could Be Learned from Circulating Tumor Cell Transcriptomes. Cancers (Basel) 2022; 14:cancers14225668. [PMID: 36428760 PMCID: PMC9688726 DOI: 10.3390/cancers14225668] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Revised: 11/03/2022] [Accepted: 11/08/2022] [Indexed: 11/19/2022] Open
Abstract
Gene expression profiling has revolutionized our understanding of cancer biology, showing an unprecedented ability to impact patient management especially in breast cancer. The vast majority of breast cancer gene expression signatures derive from the analysis of the tumor bulk, an experimental approach that limits the possibility to dissect breast cancer heterogeneity thoroughly and might miss the message hidden in biologically and clinically relevant cell populations. During disease progression or upon selective pressures, cancer cells undergo continuous transcriptional changes, which inevitably affect tumor heterogeneity, response to therapy and tendency to disseminate. Therefore, metastasis-associated signatures and transcriptome-wide gene expression measurement at single-cell resolution hold great promise for the future of breast cancer clinical care. Seen from this perspective, transcriptomics of circulating tumor cells (CTCs) represent an attractive opportunity to bridge the knowledge gap and develop novel biomarkers. This review summarizes the current state-of-the-science on CTC gene expression analysis in breast cancer, addresses technical and clinical issues related to the application of CTC-derived signatures, and discusses potential research directions.
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32
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Fridrichova I, Kalinkova L, Ciernikova S. Clinical Relevancy of Circulating Tumor Cells in Breast Cancer: Epithelial or Mesenchymal Characteristics, Single Cells or Clusters? Int J Mol Sci 2022; 23:12141. [PMID: 36292996 PMCID: PMC9603393 DOI: 10.3390/ijms232012141] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 10/05/2022] [Accepted: 10/07/2022] [Indexed: 07/30/2023] Open
Abstract
Metastatic breast cancer (MBC) is typically an incurable disease with high mortality rates; thus, early identification of metastatic features and disease recurrence through precise biomarkers is crucial. Circulating tumor cells (CTCs) consisting of heterogeneous subpopulations with different morphology and genetic, epigenetic, and gene expression profiles represent promising candidate biomarkers for metastatic potential. The experimentally verified role of epithelial-to-mesenchymal transition in cancer dissemination has not been clearly described in BC patients, but the stemness features of CTCs strongly contributes to metastatic potency. Single CTCs have been shown to be protected in the bloodstream against recognition by the immune system through impaired interactions with T lymphocytes and NK cells, while associations of heterotypic CTC clusters with platelets, leucocytes, neutrophils, tumor-associated macrophages, and fibroblasts improve their tumorigenic behavior. In addition to single CTC and CTC cluster characteristics, we reviewed CTC evaluation methods and clinical studies in early and metastatic BCs. The variable CTC tests were developed based on specific principles and strategies. However, CTC count and the presence of CTC clusters were shown to be most clinically relevant in existing clinical trials. Despite the known progress in CTC research and sampling of BC patients, implementation of CTCs and CTC clusters in routine diagnostic and treatment strategies still requires improvement in detection sensitivity and precise molecular characterizations, focused predominantly on the role of CTC clusters for their higher metastatic potency.
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33
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Wang Z, Xu W, Yang Y, Gao G, Teng C, Ge Z, Zhang H, Yuan Z, Ding G, Wang Y, Li P, Xu Y, Li P, Hu Z, Zhang Z, Qu X. Impact of changing treatment strategy based on circulating tumor cells on postoperative survival of breast cancer. Front Oncol 2022; 12:1006909. [PMID: 36263206 PMCID: PMC9573986 DOI: 10.3389/fonc.2022.1006909] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Accepted: 09/15/2022] [Indexed: 11/13/2022] Open
Abstract
Background We sought to explore the impact of changing treatment strategy based on circulating tumor cells (CTC) on postoperative survival of breast cancer. Methods We retrospectively analyzed records of patients who underwent surgery for early-stage breast cancer at Beijing Friendship Hospital from January 2016 to January 2018 and regularly underwent CTC examination after surgery. During the regular examination and CTC monitoring, the patients with positive CTC results and without distant metastasis had their treatment regimen changed. Results Of 109 patients who received CTC examination regularly after surgery, 61 (56.0%) were CTC-positive during postoperative follow-up, including 33 ER or PR-positive, and 28 ER and PR-negative patients. Of the 33 ER or PR-positive patients, 20 changed endocrine therapy drugs. Compared with those without replacement, those with changed endocrine therapy strategy had higher CTC clearance rates (90.0% vs. 53.8%, p=0.04) and significantly lower CTC-positive values (1.70 ± 1.72 vs. 0.62 ± 0.65, p = 0.04). Among the 28 patients who were CTC positive and ER and PR-negative, 11 used capecitabine. Compared with non-users, the capecitabine users had higher CTC clearance rates (100.0% vs. 52.9%, p=0.01) and more significant decrease in CTC-positive values (2.09 ± 1.14 vs. 0.82 ± 1.67, p=0.04). Disease-free survival (DFS) at 1, 3, and 5 years was significantly longer in those who changed treatment than in those who did not (respectively, 96.6% vs. 89.6%, 92.8% vs. 56.9%, 69.0% vs. 47.8%, p<0.01). By changing the treatment strategy, CTC-positive patients achieved DFS that was not significantly different from CTC-negative patients (95.0% vs. 97.7%, 77.5% vs. 82.9%, 57.6% vs. 59.9%, p=0.20). Conclusion Timely change of treatment strategy for breast cancer patients with positive CTC results after surgery may improve CTC clearance rate and DFS.
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Affiliation(s)
- Zihan Wang
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Wei Xu
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Yanlian Yang
- Chinese Academy of Sciences (CAS) Key Laboratory of Biological Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Guoxuan Gao
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Changsheng Teng
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Zhicheng Ge
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Huiming Zhang
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Zhu Yuan
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Guoqian Ding
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Yang Wang
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Peixin Li
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Yaqian Xu
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Ping Li
- Chinese Academy of Sciences (CAS) Key Laboratory of Biological Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology, Beijing, China
| | - Zhiyuan Hu
- Chinese Academy of Sciences (CAS) Key Laboratory of Biological Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Zhongtao Zhang
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- *Correspondence: Zhongtao Zhang, ; Xiang Qu,
| | - Xiang Qu
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- *Correspondence: Zhongtao Zhang, ; Xiang Qu,
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Shah UJ, Alsulimani A, Ahmad F, Mathkor DM, Alsaieedi A, Harakeh S, Nasiruddin M, Haque S. Bioplatforms in liquid biopsy: advances in the techniques for isolation, characterization and clinical applications. Biotechnol Genet Eng Rev 2022; 38:339-383. [PMID: 35968863 DOI: 10.1080/02648725.2022.2108994] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Tissue biopsy analysis has conventionally been the gold standard for cancer prognosis, diagnosis and prediction of responses/resistances to treatments. The existing biopsy procedures used in clinical practice are, however, invasive, painful and often associated with pitfalls like poor recovery of tumor cells and infeasibility for repetition in single patients. To circumvent these limitations, alternative non-invasive, rapid and economical, yet sturdy, consistent and dependable, biopsy techniques are required. Liquid biopsy is an emerging technology that fulfills these criteria and potentially much more in terms of subject-specific real-time monitoring of cancer progression, determination of tumor heterogeneity and treatment responses, and specific identification of the type and stages of cancers. The present review first briefly revisits the state-of-the-art technique of liquid biopsy and then proceeds to address in detail, the advances in the potential clinical applications of four major biological agencies present in liquid biopsy samples (circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), exosomes and tumor-educated platelets (TEPs)). Finally, the authors conclude with the limitations that need to be addressed in order for liquid biopsy to effectively replace the conventional invasive biopsy methods in the clinical settings.
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Affiliation(s)
- Ushma Jaykamal Shah
- MedGenome Labs Ltd, Kailash Cancer Hospital and Research Center, Vadodara, India
| | - Ahmad Alsulimani
- Medical Laboratory Technology Department, College of Applied Medical Sciences, Jazan University, Jazan, Saudi Arabia
| | - Faraz Ahmad
- Department of Biotechnology, School of Bio Sciences and Technology (SBST), Vellore Institute of Technology, Vellore, India
| | - Darin Mansor Mathkor
- Research and Scientific Studies Unit, College of Nursing and Allied Health Sciences, Jazan University, Jazan, Saudi Arabia
| | - Ahdab Alsaieedi
- Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia.,Vaccines and Immunotherapy Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Steve Harakeh
- King Fahd Medical Research Center, and Yousef Abdullatif Jameel Chair of Prophetic Medicine Application, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Mohammad Nasiruddin
- MedGenome Labs Ltd, Narayana Health City, Bangalore, India.,Genomics Lab, Orbito Asia Diagnostics, Coimbatore, India
| | - Shafiul Haque
- Research and Scientific Studies Unit, College of Nursing and Allied Health Sciences, Jazan University, Jazan, Saudi Arabia
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35
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Wang M, Liu Y, Shao B, Liu X, Hu Z, Wang C, Li H, Zhu L, Li P, Yang Y. HER2 status of CTCs by peptide-functionalized nanoparticles as the diagnostic biomarker of breast cancer and predicting the efficacy of anti-HER2 treatment. Front Bioeng Biotechnol 2022; 10:1015295. [PMID: 36246381 PMCID: PMC9554095 DOI: 10.3389/fbioe.2022.1015295] [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: 08/09/2022] [Accepted: 08/29/2022] [Indexed: 11/22/2022] Open
Abstract
Efficacy of anti-human epidermal growth factor receptor 2 (HER2) treatment is impacted by tissue-based evaluation bias due to tumor heterogeneity and dynamic changes of HER2 in breast cancer. Circulating tumor cell (CTC)-based HER2 phenotyping provides integral and real-time assessment, benefiting accurate HER2 diagnosis. This study developed a semi-quantitative fluorescent evaluation system of HER2 immunostaining on CTCs by peptide-functionalized magnetic nanoparticles (Pep@MNPs) and immunocytochemistry (ICC). 52 newly-diagnosed advanced breast cancer patients were enrolled for blood samples before and/or after first-line treatment, including 24 patients who were diagnosed with HER2+ tumors and treated with anti-HER2 drugs. We enumerated CTCs and assessed levels of HER2 expression on CTCs in 2.0 ml whole blood. Enumerating CTCs at baseline could distinguish cancer patients (sensitivity, 69.2%; specificity, 100%). 80.8% (42/52) of patients had at least one CTCs before therapy. Patients with <3 CTCs at baseline had significantly longer progression-free survival (medians, 19.4 vs. 9.2 months; log-rank p = 0.046) and overall survival (medians, not yet reached; log-rank p = 0.049) than those with ≥3 CTCs. Both HER2+ and HER2-low patients could be detected with HER2 overexpression on CTCs (CTC-HER2+) (52.6%, 44.4%, respectively), whereas all the HER2-negative patients had no CTC-HER2+ phenotype. Among HER2+ patients with ≥3 CTCs at baseline, objective response only appeared in pretherapeutic CTC-HER2+ cohort (60.0%), rather than in CTC-HER2- cohort (0.0%) (p = 0.034). In conclusion, we demonstrate the significance of CTC enumeration in diagnosis and prognosis of first-line advanced breast cancer, and highlight the value of CTC-HER2 status in predicting efficacy of anti-HER2 treatment.
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Affiliation(s)
- Mengting Wang
- CAS Key Laboratory of Standardization and Measurement for Nanotechnology, CAS Key Laboratory of Biological Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Yaxin Liu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Breast Oncology, Peking University Cancer Hospital & Institute, Beijing, China
| | - Bin Shao
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Breast Oncology, Peking University Cancer Hospital & Institute, Beijing, China
| | - Xiaoran Liu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Breast Oncology, Peking University Cancer Hospital & Institute, Beijing, China
| | - Zhiyuan Hu
- CAS Key Laboratory of Standardization and Measurement for Nanotechnology, CAS Key Laboratory of Biological Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Chen Wang
- CAS Key Laboratory of Standardization and Measurement for Nanotechnology, CAS Key Laboratory of Biological Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Huiping Li
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Breast Oncology, Peking University Cancer Hospital & Institute, Beijing, China
| | - Ling Zhu
- CAS Key Laboratory of Standardization and Measurement for Nanotechnology, CAS Key Laboratory of Biological Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Ping Li
- CAS Key Laboratory of Standardization and Measurement for Nanotechnology, CAS Key Laboratory of Biological Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Yanlian Yang
- CAS Key Laboratory of Standardization and Measurement for Nanotechnology, CAS Key Laboratory of Biological Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
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36
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Setayesh SM, Hart O, Naghdloo A, Higa N, Nieva J, Lu J, Hwang S, Wilkinson K, Kidd M, Anderson A, Velasco CR, Kolatkar A, Matsumoto N, Nevarez R, Hicks JB, Mason J, Shishido SN, Kuhn P. Multianalyte liquid biopsy to aid the diagnostic workup of breast cancer. NPJ Breast Cancer 2022; 8:112. [PMID: 36167819 PMCID: PMC9515081 DOI: 10.1038/s41523-022-00480-4] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Accepted: 09/16/2022] [Indexed: 11/19/2022] Open
Abstract
Breast cancer (BC) affects 1 in every 8 women in the United States and is currently the most prevalent cancer worldwide. Precise staging at diagnosis and prognosis are essential components for the clinical management of BC patients. In this study, we set out to evaluate the feasibility of the high-definition single cell (HDSCA) liquid biopsy (LBx) platform to stratify late-stage BC, early-stage BC, and normal donors using peripheral blood samples. Utilizing 5 biomarkers, we identified rare circulating events with epithelial, mesenchymal, endothelial and hematological origin. We detected a higher level of CTCs in late-stage patients, compared to the early-stage and normal donors. Additionally, we observed more tumor-associated large extracellular vesicles (LEVs) in the early-stage, compared to late-stage and the normal donor groups. Overall, we were able to detect reproducible patterns in the enumeration of rare cells and LEVs of cancer vs. normal donors and early-stage vs. late-stage BC with high accuracy, allowing for robust stratification. Our findings illustrate the feasibility of the LBx assay to provide robust detection of rare circulating events in peripheral blood draws and to stratify late-stage BC, early-stage BC, and normal donor samples.
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Affiliation(s)
- Sonia Maryam Setayesh
- Convergent Science Institute in Cancer, Michelson Center for Convergent Bioscience, Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, CA, 90089, USA
| | - Olivia Hart
- Convergent Science Institute in Cancer, Michelson Center for Convergent Bioscience, Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, CA, 90089, USA
| | - Amin Naghdloo
- Convergent Science Institute in Cancer, Michelson Center for Convergent Bioscience, Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, CA, 90089, USA
| | - Nikki Higa
- Convergent Science Institute in Cancer, Michelson Center for Convergent Bioscience, Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, CA, 90089, USA
| | - Jorge Nieva
- Norris Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA
| | - Janice Lu
- Norris Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA
| | - Shelley Hwang
- Department of Surgery, Duke University School of Medicine, Durham, NC, 27710, USA
| | | | | | | | - Carmen Ruiz Velasco
- Convergent Science Institute in Cancer, Michelson Center for Convergent Bioscience, Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, CA, 90089, USA
| | - Anand Kolatkar
- Convergent Science Institute in Cancer, Michelson Center for Convergent Bioscience, Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, CA, 90089, USA
| | - Nicholas Matsumoto
- Convergent Science Institute in Cancer, Michelson Center for Convergent Bioscience, Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, CA, 90089, USA
| | - Rafael Nevarez
- Convergent Science Institute in Cancer, Michelson Center for Convergent Bioscience, Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, CA, 90089, USA
| | - James B Hicks
- Convergent Science Institute in Cancer, Michelson Center for Convergent Bioscience, Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, CA, 90089, USA
| | - Jeremy Mason
- Convergent Science Institute in Cancer, Michelson Center for Convergent Bioscience, Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, CA, 90089, USA
| | - Stephanie N Shishido
- Convergent Science Institute in Cancer, Michelson Center for Convergent Bioscience, Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, CA, 90089, USA
| | - Peter Kuhn
- Convergent Science Institute in Cancer, Michelson Center for Convergent Bioscience, Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, CA, 90089, USA.
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37
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Grigoryeva ES, Tashireva LA, Alifanov VV, Savelieva OE, Vtorushin SV, Zavyalova MV, Cherdyntseva NV, Perelmuter VM. The Novel Association of Early Apoptotic Circulating Tumor Cells with Treatment Outcomes in Breast Cancer Patients. Int J Mol Sci 2022; 23:ijms23169475. [PMID: 36012742 PMCID: PMC9408919 DOI: 10.3390/ijms23169475] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2022] [Revised: 08/18/2022] [Accepted: 08/19/2022] [Indexed: 11/16/2022] Open
Abstract
Stemness and epithelial-mesenchymal plasticity are widely studied in the circulating tumor cells of breast cancer patients because the roles of both processes in tumor progression are well established. An important property that should be taken into account is the ability of CTCs to disseminate, particularly the viability and apoptotic states of circulating tumor cells (CTCs). Recent data demonstrate that apoptosis reversal promotes the formation of stem-like tumor cells with pronounced potential for dissemination. Our study focused on the association between different apoptotic states of CTCs with short- and long-term treatment outcomes. We evaluated the association of viable CTCs, CTCs with early features of apoptosis, and end-stage apoptosis/necrosis CTCs with clinicopathological parameters of breast cancer patients. We found that the proportion of circulating tumor cells with features of early apoptosis is a perspective prognosticator of metastasis-free survival, which also correlates with the neoadjuvant chemotherapy response in breast cancer patients. Moreover, we establish that apoptotic CTCs are associated with the poor response to neoadjuvant chemotherapy, and metastasis-free survival expressed at least two stemness markers, CD44 and CD133.
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Affiliation(s)
- Evgeniya S. Grigoryeva
- The Laboratory of Molecular Oncology and Immunology, Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, 634050 Tomsk, Russia
- Correspondence:
| | - Liubov A. Tashireva
- The Department of General and Molecular Pathology, Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, 634050 Tomsk, Russia
| | - Vladimir V. Alifanov
- The Department of General and Molecular Pathology, Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, 634050 Tomsk, Russia
| | - Olga E. Savelieva
- The Department of General and Molecular Pathology, Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, 634050 Tomsk, Russia
| | - Sergey V. Vtorushin
- The Department of General and Molecular Pathology, Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, 634050 Tomsk, Russia
| | - Marina V. Zavyalova
- The Department of General and Molecular Pathology, Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, 634050 Tomsk, Russia
| | - Nadezhda V. Cherdyntseva
- The Laboratory of Molecular Oncology and Immunology, Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, 634050 Tomsk, Russia
| | - Vladimir M. Perelmuter
- The Department of General and Molecular Pathology, Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, 634050 Tomsk, Russia
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Sutton TL, Patel RK, Anderson AN, Bowden SG, Whalen R, Giske NR, Wong MH. Circulating Cells with Macrophage-like Characteristics in Cancer: The Importance of Circulating Neoplastic-Immune Hybrid Cells in Cancer. Cancers (Basel) 2022; 14:cancers14163871. [PMID: 36010865 PMCID: PMC9405966 DOI: 10.3390/cancers14163871] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Revised: 08/08/2022] [Accepted: 08/09/2022] [Indexed: 12/14/2022] Open
Abstract
Simple Summary In cancer, disseminated neoplastic cells circulating in blood are a source of tumor DNA, RNA, and protein, which can be harnessed to diagnose, monitor, and better understand the biology of the tumor from which they are derived. Historically, circulating tumor cells (CTCs) have dominated this field of study. While CTCs are shed directly into circulation from a primary tumor, they remain relatively rare, particularly in early stages of disease, and thus are difficult to utilize as a reliable cancer biomarker. Neoplastic-immune hybrid cells represent a novel subpopulation of circulating cells that are more reliably attainable as compared to their CTC counterparts. Here, we review two recently identified circulating cell populations in cancer—cancer-associated macrophage-like cells and circulating hybrid cells—and discuss the future impact for the exciting area of disseminated hybrid cells. Abstract Cancer remains a significant cause of mortality in developed countries, due in part to difficulties in early detection, understanding disease biology, and assessing treatment response. If effectively harnessed, circulating biomarkers promise to fulfill these needs through non-invasive “liquid” biopsy. While tumors disseminate genetic material and cellular debris into circulation, identifying clinically relevant information from these analytes has proven difficult. In contrast, cell-based circulating biomarkers have multiple advantages, including a source for tumor DNA and protein, and as a cellular reflection of the evolving tumor. While circulating tumor cells (CTCs) have dominated the circulating cell biomarker field, their clinical utility beyond that of prognostication has remained elusive, due to their rarity. Recently, two novel populations of circulating tumor-immune hybrid cells in cancer have been characterized: cancer-associated macrophage-like cells (CAMLs) and circulating hybrid cells (CHCs). CAMLs are macrophage-like cells containing phagocytosed tumor material, while CHCs can result from cell fusion between cancer and immune cells and play a role in the metastatic cascade. Both are detected in higher numbers than CTCs in peripheral blood and demonstrate utility in prognostication and assessing treatment response. Additionally, both cell populations are heterogeneous in their genetic, transcriptomic, and proteomic signatures, and thus have the potential to inform on heterogeneity within tumors. Herein, we review the advances in this exciting field.
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Affiliation(s)
- Thomas L. Sutton
- Department of Surgery, Oregon Health & Science University, Portland, OR 97239, USA
| | - Ranish K. Patel
- Department of Surgery, Oregon Health & Science University, Portland, OR 97239, USA
| | - Ashley N. Anderson
- Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, Portland, OR 97201, USA
| | - Stephen G. Bowden
- Department of Neurological Surgery, Oregon Health & Science University, Portland, OR 97239, USA
| | - Riley Whalen
- Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, Portland, OR 97201, USA
| | - Nicole R. Giske
- Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, Portland, OR 97201, USA
| | - Melissa H. Wong
- Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, Portland, OR 97201, USA
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97201, USA
- Correspondence: ; Tel.: +1-503-494-8749; Fax: +1-503-494-4253
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Powering single-cell genomics to unravel circulating tumour cell subpopulations in non-small cell lung cancer patients. J Cancer Res Clin Oncol 2022; 149:1941-1950. [PMID: 35896898 PMCID: PMC10097753 DOI: 10.1007/s00432-022-04202-y] [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: 04/05/2022] [Accepted: 07/09/2022] [Indexed: 10/16/2022]
Abstract
BACKGROUND Circulating tumour cells (CTCs) are attractive "liquid biopsy" candidates that could provide insights into the different phenotypes of tumours present within a patient. The epithelial-to-mesenchymal transition (EMT) of CTCs is considered a critical step in tumour metastasis; however, it may confound traditional epithelial feature-based CTC isolation and detection. We applied single-cell copy number alteration (CNA) analysis for the identification of genomic alterations to confirm the neoplastic nature of circulating cells with only mesenchymal phenotypes. METHODS We isolated CTCs from blood samples collected from 46 NSCLC patients using the Parsortix system. Enriched cells were subjected to immunofluorescent staining for CTC identification using a multi-marker panel comprising both epithelial and mesenchymal markers. A subset of isolated CTCs was subjected to whole genome amplification (WGA) and low-pass whole-genome sequencing (LP-WGS) for the analysis of copy number alterations (CNAs). RESULTS CTCs were detected in 16/46 (34.8%) patients, inclusive of CK+/EpCAM+ CTCs (3/46, 6.5%) and Vim+ CTCs (13/46, 28.3%). Clusters of Vim+ cells were detected in 8 samples, which constitutes 50% of the total number of NSCLC patients with CTCs. No patients had detectable hybrid CK+/EpCAM+/Vim+ cells. All of the tested CK+/EpCAM+ CTCs and 7/8 Vim+ CTCs or CTC clusters carried CNAs confirming their neoplastic nature. Notably, the Vim+ cluster with no CNAs was characterised by spindle morphology and, therefore, defined as normal mesenchymal circulating cells. CONCLUSION Our results revealed that CK-negative, vimentin-expressing cells represent a large proportion of CTCs detected in NSCLC patients, which are likely missed by standard epithelial-marker-dependent CTC categorisation.
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Addanki S, Meas S, Sarli VN, Singh B, Lucci A. Applications of Circulating Tumor Cells and Circulating Tumor DNA in Precision Oncology for Breast Cancers. Int J Mol Sci 2022; 23:ijms23147843. [PMID: 35887191 PMCID: PMC9315812 DOI: 10.3390/ijms23147843] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Revised: 07/14/2022] [Accepted: 07/15/2022] [Indexed: 11/25/2022] Open
Abstract
Liquid biopsies allow for the detection of cancer biomarkers such as circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA). Elevated levels of these biomarkers during cancer treatment could potentially serve as indicators of cancer progression and shed light on the mechanisms of metastasis and therapy resistance. Thus, liquid biopsies serve as tools for cancer detection and monitoring through a simple, non-invasive blood draw, allowing multiple longitudinal sampling. These circulating markers have significant prospects for use in assessing patients’ prognosis, monitoring response to therapy, and developing precision medicine. In addition, single-cell omics of these liquid biopsy markers can be potential tools for identifying tumor heterogeneity and plasticity as well as novel therapeutic targets. In this review, we focus on our current understanding of circulating tumor biomarkers, especially in breast cancer, and the scope of novel sequencing technologies and diagnostic methods for better prognostication and patient stratification to improve patient outcomes.
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Affiliation(s)
- Sridevi Addanki
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;
- Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (S.M.); (V.N.S.); (B.S.)
| | - Salyna Meas
- Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (S.M.); (V.N.S.); (B.S.)
- Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Vanessa Nicole Sarli
- Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (S.M.); (V.N.S.); (B.S.)
- Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Balraj Singh
- Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (S.M.); (V.N.S.); (B.S.)
- Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Anthony Lucci
- Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (S.M.); (V.N.S.); (B.S.)
- Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Correspondence:
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Yu E, Allan AL, Sanatani M, Lewis D, Warner A, Dar AR, Yaremko BP, Lowes LE, Palma DA, Raphael J, Vincent MD, Rodrigues GB, Fortin D, Inculet RI, Frechette E, Bierer J, Law J, Younus J, Malthaner RA. Circulating tumor cells detected in follow-up predict survival outcomes in tri-modality management of advanced non-metastatic esophageal cancer: a secondary analysis of the QUINTETT randomized trial. BMC Cancer 2022; 22:746. [PMID: 35804307 PMCID: PMC9264673 DOI: 10.1186/s12885-022-09846-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Accepted: 06/30/2022] [Indexed: 11/27/2022] Open
Abstract
Background Our aim was to establish if presence of circulating tumor cells (CTCs) predicted worse outcome in patients with non-metastatic esophageal cancer undergoing tri-modality therapy. Methods We prospectively collected CTC data from patients with operable non-metastatic esophageal cancer from April 2009 to November 2016 enrolled in our QUINTETT esophageal cancer randomized trial (NCT00907543). Patients were randomized to receive either neoadjuvant cisplatin and 5-fluorouracil (5-FU) plus radiotherapy followed by surgical resection (Neoadjuvant) or adjuvant cisplatin, 5-FU, and epirubicin chemotherapy with concurrent extended volume radiotherapy following surgical resection (Adjuvant). CTCs were identified with the CellSearch® system before the initiation of any treatment (surgery or chemoradiotherapy) as well as at 6-, 12-, and 24-months post-treatment. The threshold for CTC positivity was one and the findings were correlated with patient prognosis. Results CTC data were available for 74 of 96 patients and identified in 27 patients (36.5%) at a median follow-up of 13.1months (interquartile range:6.8-24.1 months). Detection of CTCs at any follow-up visit was significantly predictive of worse disease-free survival (DFS;hazard ratio [HR]: 2.44; 95% confidence interval [CI]: 1.41-4.24; p=0.002), regional control (HR: 6.18; 95% CI: 1.18-32.35; p=0.031), distant control (HR: 2.93; 95% CI: 1.52-5.65;p=0.001) and overall survival (OS;HR: 2.02; 95% CI: 1.16-3.51; p=0.013). After adjusting for receiving neoadjuvant vs. adjuvant chemoradiotherapy, the presence of CTCs at any follow-up visit remained significantly predictive of worse OS ([HR]:2.02;95% [Cl]:1.16-3.51; p=0.013) and DFS (HR: 2.49;95% Cl: 1.43-4.33; p=0.001). Similarly, any observed increase in CTCs was significantly predictive of worse OS (HR: 3.14; 95% CI: 1.56-6.34; p=0.001) and DFS (HR: 3.34; 95% CI: 1.67-6.69; p<0.001). Conclusion The presence of CTCs in patients during follow-up after tri-modality therapy was associated with significantly poorer DFS and OS regardless of timing of chemoradiotherapy.
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Affiliation(s)
- Edward Yu
- Department of Oncology, Divisions of Radiation Oncology, Western University, 1151 Richmond Street, London, Ontario, N6A3K7, Canada.
| | | | | | - Debra Lewis
- Thoracic Surgery and Surgical Oncology, London, Ontario, Canada
| | - Andrew Warner
- Department of Oncology, Divisions of Radiation Oncology, Western University, 1151 Richmond Street, London, Ontario, N6A3K7, Canada
| | - A Rashid Dar
- Department of Oncology, Divisions of Radiation Oncology, Western University, 1151 Richmond Street, London, Ontario, N6A3K7, Canada
| | - Brian P Yaremko
- Department of Oncology, Divisions of Radiation Oncology, Western University, 1151 Richmond Street, London, Ontario, N6A3K7, Canada
| | - Lori E Lowes
- Pathology & laboratory medicine, London Health Science Centre, London, Ontario, Canada
| | - David A Palma
- Department of Oncology, Divisions of Radiation Oncology, Western University, 1151 Richmond Street, London, Ontario, N6A3K7, Canada
| | | | | | - George B Rodrigues
- Department of Oncology, Divisions of Radiation Oncology, Western University, 1151 Richmond Street, London, Ontario, N6A3K7, Canada
| | - Dalilah Fortin
- Thoracic Surgery and Surgical Oncology, London, Ontario, Canada
| | | | - Eric Frechette
- Department of Thoracic Surgery and Surgical Oncology, Sherbrooke University, Sherbrooke, Quebec, Canada
| | - Joel Bierer
- Department of Medicine, Western University, London, Ontario, Canada
| | - Jeffery Law
- Department of Medicine, Western University, London, Ontario, Canada
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Guo Q, Spasic M, Maynard AG, Goreczny GJ, Bizuayehu A, Olive JF, van Galen P, McAllister SS. Clonal barcoding with qPCR detection enables live cell functional analyses for cancer research. Nat Commun 2022; 13:3837. [PMID: 35788590 PMCID: PMC9252988 DOI: 10.1038/s41467-022-31536-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Accepted: 06/21/2022] [Indexed: 11/27/2022] Open
Abstract
Single-cell analysis methods are valuable tools; however, current approaches do not easily enable live cell retrieval. That is a particular issue when further study of cells that were eliminated during experimentation could provide critical information. We report a clonal molecular barcoding method, called SunCatcher, that enables longitudinal tracking and live cell functional analysis. From complex cell populations, we generate single cell-derived clonal populations, infect each with a unique molecular barcode, and retain stocks of individual barcoded clones (BCs). We develop quantitative PCR-based and next-generation sequencing methods that we employ to identify and quantify BCs in vitro and in vivo. We apply SunCatcher to various breast cancer cell lines and combine respective BCs to create versions of the original cell lines. While the heterogeneous BC pools reproduce their original parental cell line proliferation and tumor progression rates, individual BCs are phenotypically and functionally diverse. Early spontaneous metastases can also be identified and quantified. SunCatcher thus provides a rapid and sensitive approach for studying live single-cell clones and clonal evolution, and performing functional analyses.
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Affiliation(s)
- Qiuchen Guo
- Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA
- Department of Medicine, Harvard Medical School, Boston, MA, 02115, USA
| | - Milos Spasic
- Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA
- Department of Medicine, Harvard Medical School, Boston, MA, 02115, USA
| | - Adam G Maynard
- Department of Medicine, Harvard Medical School, Boston, MA, 02115, USA
| | - Gregory J Goreczny
- Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA
- Department of Medicine, Harvard Medical School, Boston, MA, 02115, USA
| | - Amanuel Bizuayehu
- Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA
| | - Jessica F Olive
- Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA
- Department of Medicine, Harvard Medical School, Boston, MA, 02115, USA
| | - Peter van Galen
- Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA
- Department of Medicine, Harvard Medical School, Boston, MA, 02115, USA
- Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA
- Harvard Stem Cell Institute, Cambridge, MA, 02138, USA
| | - Sandra S McAllister
- Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA.
- Department of Medicine, Harvard Medical School, Boston, MA, 02115, USA.
- Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA.
- Harvard Stem Cell Institute, Cambridge, MA, 02138, USA.
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Cardinali B, De Luca G, Tasso R, Coco S, Garuti A, Buzzatti G, Sciutto A, Arecco L, Villa F, Carli F, Reverberi D, Quarto R, Dono M, Del Mastro L. Targeting PIK3CA Actionable Mutations in the Circulome: A Proof of Concept in Metastatic Breast Cancer. Int J Mol Sci 2022; 23:ijms23116320. [PMID: 35682999 PMCID: PMC9181240 DOI: 10.3390/ijms23116320] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Revised: 05/27/2022] [Accepted: 05/30/2022] [Indexed: 11/21/2022] Open
Abstract
The study of circulating cancer-derived components (circulome) is considered the new frontier of liquid biopsy. Despite the recognized role of circulome biomarkers, their comparative molecular profiling is not yet routine. In advanced breast cancer (BC), approximately 40% of hormone-receptor-positive, HER2-negative BC cases harbor druggable PIK3CA mutations suitable for combined alpelisib/fulvestrant treatment. This pilot study investigates PIK3CA mutations in circulating tumor DNA (ctDNA), tumor cells (CTCs), and extracellular vesicles (EVs) with the aim of determining which information on molecular targetable profiling could be recollected in each of them. The in-depth molecular analysis of four BC patients demonstrated, as a proof-of-concept study, that it is possible to retrieve mutational information in the three components. Patient-specific PIK3CA mutations were found in both tissue and ctDNA and in 3/4 cases, as well as in CTCs, in the classical population (large-sized CD45−/EpCAM+/− cells), and/or in the “non-conventional” sub-population (smaller-sized CD44+/EpCAM−/CD45− cells). Consistent mutational profiles of EVs with CTCs suggest that they may have been released by CTCs. This preliminary evidence on the molecular content of the different circulating biomaterials suggests their possible function as a mirror of the intrinsic heterogeneity of BC. Moreover, this study demonstrates, through mutational assessment, the tumor origin of the different CTC sub-populations sustaining the translational value of the circulome for a more comprehensive picture of the disease.
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Affiliation(s)
- Barbara Cardinali
- Clinica di Oncologia Medica, IRCCS Ospedale Policlinico San Martino, 10-16132 Genova, Italy; (A.S.); (L.A.); (L.D.M.)
- Correspondence: (B.C.); (G.D.L.); Tel.: +39-0105558101 (B.C.); +39-0105558940 (G.D.L.)
| | - Giuseppa De Luca
- Molecular Diagnostic Unit, IRCCS Ospedale Policlinico San Martino, 10-16132 Genova, Italy;
- Correspondence: (B.C.); (G.D.L.); Tel.: +39-0105558101 (B.C.); +39-0105558940 (G.D.L.)
| | - Roberta Tasso
- Department of Experimental Medicine (DIMES), University of Genova, 5-16126 Genova, Italy; (R.T.); (R.Q.)
| | - Simona Coco
- Lung Cancer Unit, IRCCS Ospedale Policlinico San Martino, 10-16132 Genova, Italy;
| | - Anna Garuti
- Clinica Oncologia Medica ad Indirizzo Oncologico, IRCCS Ospedale Policlinico San Martino, 10-16132 Genova, Italy;
| | - Giulia Buzzatti
- Oncologia Medica 2, IRCCS Ospedale Policlinico San Martino, 10-16132 Genova, Italy;
| | - Andrea Sciutto
- Clinica di Oncologia Medica, IRCCS Ospedale Policlinico San Martino, 10-16132 Genova, Italy; (A.S.); (L.A.); (L.D.M.)
| | - Luca Arecco
- Clinica di Oncologia Medica, IRCCS Ospedale Policlinico San Martino, 10-16132 Genova, Italy; (A.S.); (L.A.); (L.D.M.)
| | - Federico Villa
- Molecular Oncology and Angiogenesis Unit, IRCCS Ospedale Policlinico San Martino, 10-16132 Genova, Italy;
| | - Franca Carli
- Surgical Pathology Unit, IRCCS Ospedale Policlinico San Martino, 10-16132 Genova, Italy;
| | - Daniele Reverberi
- Molecular Pathology Unit, IRCCS Ospedale Policlinico San Martino, 10-16132 Genova, Italy;
| | - Rodolfo Quarto
- Department of Experimental Medicine (DIMES), University of Genova, 5-16126 Genova, Italy; (R.T.); (R.Q.)
- Cellular Oncology Unit, IRCCS Ospedale Policlinico San Martino, 10-16132 Genova, Italy
| | - Mariella Dono
- Molecular Diagnostic Unit, IRCCS Ospedale Policlinico San Martino, 10-16132 Genova, Italy;
| | - Lucia Del Mastro
- Clinica di Oncologia Medica, IRCCS Ospedale Policlinico San Martino, 10-16132 Genova, Italy; (A.S.); (L.A.); (L.D.M.)
- Department of Internal Medicine and Medical Specialties (DIMI), University of Genova, 5-16126 Genova, Italy
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Beyond Genetics: Metastasis as an Adaptive Response in Breast Cancer. Int J Mol Sci 2022; 23:ijms23116271. [PMID: 35682953 PMCID: PMC9181003 DOI: 10.3390/ijms23116271] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 05/26/2022] [Accepted: 06/01/2022] [Indexed: 01/27/2023] Open
Abstract
Metastatic disease represents the primary cause of breast cancer (BC) mortality, yet it is still one of the most enigmatic processes in the biology of this tumor. Metastatic progression includes distinct phases: invasion, intravasation, hematogenous dissemination, extravasation and seeding at distant sites, micro-metastasis formation and metastatic outgrowth. Whole-genome sequencing analyses of primary BC and metastases revealed that BC metastatization is a non-genetically selected trait, rather the result of transcriptional and metabolic adaptation to the unfavorable microenvironmental conditions which cancer cells are exposed to (e.g., hypoxia, low nutrients, endoplasmic reticulum stress and chemotherapy administration). In this regard, the latest multi-omics analyses unveiled intra-tumor phenotypic heterogeneity, which determines the polyclonal nature of breast tumors and constitutes a challenge for clinicians, correlating with patient poor prognosis. The present work reviews BC classification and epidemiology, focusing on the impact of metastatic disease on patient prognosis and survival, while describing general principles and current in vitro/in vivo models of the BC metastatic cascade. The authors address here both genetic and phenotypic intrinsic heterogeneity of breast tumors, reporting the latest studies that support the role of the latter in metastatic spreading. Finally, the review illustrates the mechanisms underlying adaptive stress responses during BC metastatic progression.
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Kwak SB, Kim SJ, Kim J, Kang YL, Ko CW, Kim I, Park JW. Tumor regionalization after surgery: Roles of the tumor microenvironment and neutrophil extracellular traps. EXPERIMENTAL & MOLECULAR MEDICINE 2022; 54:720-729. [PMID: 35764882 PMCID: PMC9256747 DOI: 10.1038/s12276-022-00784-2] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/16/2022] [Revised: 03/20/2022] [Accepted: 03/30/2022] [Indexed: 11/09/2022]
Abstract
Surgery is unanimously regarded as the primary strategy to cure solid tumors in the early stages but is not always used in advanced cases. However, tumor surgery must be carefully considered because the risk of metastasis could be increased by the surgical procedure. Tumor surgery may result in a deep wound, which induces many biological responses favoring tumor metastasis. In particular, NETosis, which is the process of forming neutrophil extracellular traps (NETs), has received attention as a risk factor for surgery-induced metastasis. To reduce cancer mortality, researchers have made efforts to prevent secondary metastasis after resection of the primary tumor. From this point of view, a better understanding of surgery-induced metastasis might provide new strategies for more effective and safer surgical approaches. In this paper, recent insights into the surgical effects on metastasis will be reviewed. Moreover, in-depth opinions about the effects of NETs on metastasis will be discussed. Therapies that limit the formation of web-like structures formed by white cells known as neutrophils may lower the risk of cancer spread (metastasis) following surgical tumor removal. Removing solid tumors remains a key cancer treatment, but in some cases surgery itself increases the risk of metastasis. Jong-Wan Park at Seoul National University, South Korea, and co-workers reviewed current understanding of metastasis following surgery. Surgical removal destroys the architecture supporting cancer cells but this can release tumor cells into blood vessels. The stress of deep wounds also affects immune responses, most notably neutrophil extracellular traps (NETs), web-like structures formed by neutrophils to trap and kill pathogens. NETs have previously been implicated in metastasis. In a post-surgical environment enriched in neutrophils and pro-inflammatory cytokines, NET formation may help cancer cells thrive, promoting metastasis.
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Affiliation(s)
- Su-Bin Kwak
- Department of Pharmacology, Seoul National University College of Medicine, Daehak-ro, Jongno-gu, Seoul, 03080, Korea.,Department of Biomedical Science, BK21-plus Education Program, Seoul National University College of Medicine, Daehak-ro, Jongno-gu, Seoul, 03080, Korea
| | - Sang Jin Kim
- Department of Pharmacology, Seoul National University College of Medicine, Daehak-ro, Jongno-gu, Seoul, 03080, Korea.,Cancer Research Institute and Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Daehak-ro, Jongno-gu, Seoul, 03080, Korea
| | - Jiyoung Kim
- Department of Pharmacology, Seoul National University College of Medicine, Daehak-ro, Jongno-gu, Seoul, 03080, Korea
| | - Ye-Lim Kang
- Department of Pharmacology, Seoul National University College of Medicine, Daehak-ro, Jongno-gu, Seoul, 03080, Korea.,Department of Biomedical Science, BK21-plus Education Program, Seoul National University College of Medicine, Daehak-ro, Jongno-gu, Seoul, 03080, Korea
| | - Chang Woo Ko
- Department of Pharmacology, Seoul National University College of Medicine, Daehak-ro, Jongno-gu, Seoul, 03080, Korea.,Department of Biomedical Science, BK21-plus Education Program, Seoul National University College of Medicine, Daehak-ro, Jongno-gu, Seoul, 03080, Korea
| | - Iljin Kim
- Department of Pharmacology, Inha University College of Medicine, Inha-ro, Michuhol-gu, Incheon, 22212, Korea
| | - Jong-Wan Park
- Department of Pharmacology, Seoul National University College of Medicine, Daehak-ro, Jongno-gu, Seoul, 03080, Korea. .,Department of Biomedical Science, BK21-plus Education Program, Seoul National University College of Medicine, Daehak-ro, Jongno-gu, Seoul, 03080, Korea. .,Cancer Research Institute and Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Daehak-ro, Jongno-gu, Seoul, 03080, Korea.
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Singh AK, Malviya R. Coagulation and inflammation in cancer: Limitations and prospects for treatment. Biochim Biophys Acta Rev Cancer 2022; 1877:188727. [PMID: 35378243 DOI: 10.1016/j.bbcan.2022.188727] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Revised: 03/26/2022] [Accepted: 03/29/2022] [Indexed: 02/08/2023]
Abstract
The development of so-called immune checkpoint inhibitors (ICIs), which target specific molecular processes of tumour growth, has had a transformative effect on cancer treatment. Widespread use of antibody-based medicines to inhibit tumour cell immune evasion by modulating T cell responses is becoming more common. Despite this, response rates are still low, and secondary resistance is an issue that arises often. In addition, a wide range of serious adverse effects is triggered by enhancing the immunological response. As a result of an increased mortality rate, a higher prevalence of thrombotic complications is connected with an increased incidence of immunological reactions, complement activation, and skin toxicity. This suggests that the tumour microenvironment's interaction between coagulation and inflammation is important at every stage of the tumour's life cycle. The coagulation system's function in tumour formation is the topic of this review. By better understanding the molecular mechanisms in which tumour cells circulate, plasmatic coagulation and immune system cells are engaged, new therapy options for cancer sufferers may be discovered.
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Affiliation(s)
- Arun Kumar Singh
- Department of Pharmacy, School of Medical and Allied Sciences, Galgotias University, Greater Noida, Uttar Pradesh, India
| | - Rishabha Malviya
- Department of Pharmacy, School of Medical and Allied Sciences, Galgotias University, Greater Noida, Uttar Pradesh, India.
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Andre F, Ismaila N, Allison KH, Barlow WE, Collyar DE, Damodaran S, Henry NL, Jhaveri K, Kalinsky K, Kuderer NM, Litvak A, Mayer EL, Pusztai L, Raab R, Wolff AC, Stearns V. Biomarkers for Adjuvant Endocrine and Chemotherapy in Early-Stage Breast Cancer: ASCO Guideline Update. J Clin Oncol 2022; 40:1816-1837. [PMID: 35439025 DOI: 10.1200/jco.22.00069] [Citation(s) in RCA: 186] [Impact Index Per Article: 62.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
PURPOSE To update recommendations on appropriate use of breast cancer biomarker assay results to guide adjuvant endocrine and chemotherapy decisions in early-stage breast cancer. METHODS An updated literature search identified randomized clinical trials and prospective-retrospective studies published from January 2016 to October 2021. Outcomes of interest included overall survival and disease-free or recurrence-free survival. Expert Panel members used informal consensus to develop evidence-based recommendations. RESULTS The search identified 24 studies informing the evidence base. RECOMMENDATIONS Clinicians may use Oncotype DX, MammaPrint, Breast Cancer Index (BCI), and EndoPredict to guide adjuvant endocrine and chemotherapy in patients who are postmenopausal or age > 50 years with early-stage estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative (ER+ and HER2-) breast cancer that is node-negative or with 1-3 positive nodes. Prosigna and BCI may be used in postmenopausal patients with node-negative ER+ and HER2- breast cancer. In premenopausal patients, clinicians may use Oncotype in patients with node-negative ER+ and HER2- breast cancer. Current data suggest that premenopausal patients with 1-3 positive nodes benefit from chemotherapy regardless of genomic assay result. There are no data on use of genomic tests to guide adjuvant chemotherapy in patients with ≥ 4 positive nodes. Ki67 combined with other parameters or immunohistochemistry 4 score may be used in postmenopausal patients without access to genomic tests to guide adjuvant therapy decisions. BCI may be offered to patients with 0-3 positive nodes who received 5 years of endocrine therapy without evidence of recurrence to guide decisions about extended endocrine therapy. None of the assays are recommended for treatment guidance in individuals with HER2-positive or triple-negative breast cancer. Treatment decisions should also consider disease stage, comorbidities, and patient preferences.Additional information is available at www.asco.org/breast-cancer-guidelines.
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Affiliation(s)
| | | | | | | | | | | | - N Lynn Henry
- University of Michigan Rogel Cancer Center, Ann Arbor, MI
| | - Komal Jhaveri
- Memorial Sloan Kettering Cancer Center, New York, NY.,Weill Cornell Medical College, New York, NY
| | - Kevin Kalinsky
- Winship Cancer Institute at Emory University, Atlanta, GA
| | | | - Anya Litvak
- Cancer Center at Saint Barnabas Medical Center, Livingston, NJ
| | | | | | - Rachel Raab
- Messino Cancer Centers-A Division of American Oncology Partners, Asheville, NC
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The potential of liquid biopsy in the management of cancer patients. Semin Cancer Biol 2022; 84:69-79. [PMID: 35331850 DOI: 10.1016/j.semcancer.2022.03.013] [Citation(s) in RCA: 75] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2021] [Revised: 03/06/2022] [Accepted: 03/17/2022] [Indexed: 02/07/2023]
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50
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Gwark S, Ahn HS, Yeom J, Yu J, Oh Y, Jeong JH, Ahn JH, Jung KH, Kim SB, Lee HJ, Gong G, Lee SB, Chung IY, Kim HJ, Ko BS, Lee JW, Son BH, Ahn SH, Kim K, Kim J. Plasma Proteome Signature to Predict the Outcome of Breast Cancer Patients Receiving Neoadjuvant Chemotherapy. Cancers (Basel) 2021; 13:6267. [PMID: 34944885 PMCID: PMC8699627 DOI: 10.3390/cancers13246267] [Citation(s) in RCA: 5] [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: 11/05/2021] [Revised: 12/07/2021] [Accepted: 12/10/2021] [Indexed: 12/31/2022] Open
Abstract
The plasma proteome of 51 non-metastatic breast cancer patients receiving neoadjuvant chemotherapy (NCT) was prospectively analyzed by high-resolution mass spectrometry coupled with nano-flow liquid chromatography using blood drawn at the time of diagnosis. Plasma proteins were identified as potential biomarkers, and their correlation with clinicopathological variables and survival outcomes was analyzed. Of 51 patients, 20 (39.2%) were HR+/HER2-, five (9.8%) were HR+/HER2+, five (9.8%) were HER2+, and 21 (41.2%) were triple-negative subtype. During a median follow-up of 52.0 months, there were 15 relapses (29.4%) and eight deaths (15.7%). Four potential biomarkers were identified among differentially expressed proteins: APOC3 had higher plasma concentrations in the pathological complete response (pCR) group, whereas MBL2, ENG, and P4HB were higher in the non-pCR group. Proteins statistically significantly associated with survival and capable of differentiating low- and high-risk groups were MBL2 and P4HB for disease-free survival, P4HB for overall survival, and MBL2 for distant metastasis-free survival (DMFS). In the multivariate analysis, only MBL2 was a consistent risk factor for DMFS (HR: 9.65, 95% CI 2.10-44.31). The results demonstrate that the proteomes from non-invasive sampling correlate with pCR and survival in breast cancer patients receiving NCT. Further investigation may clarify the role of these proteins in predicting prognosis and thus their therapeutic potential for the prevention of recurrence.
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Affiliation(s)
- Sungchan Gwark
- Department of Surgery, Ewha Womans University Mokdong Hospital, Ewha Womans University College of Medicine, Seoul 07985, Korea;
| | - Hee-Sung Ahn
- Asan Institute for Life Sciences, Asan Medical Center, Seoul 05505, Korea; (H.-S.A.); (J.Y.); (Y.O.)
- Convergence Medicine Research Center, Asan Institute for Life Sciences, Asan Medical Center, Seoul 05505, Korea;
| | - Jeonghun Yeom
- Convergence Medicine Research Center, Asan Institute for Life Sciences, Asan Medical Center, Seoul 05505, Korea;
| | - Jiyoung Yu
- Asan Institute for Life Sciences, Asan Medical Center, Seoul 05505, Korea; (H.-S.A.); (J.Y.); (Y.O.)
| | - Yumi Oh
- Asan Institute for Life Sciences, Asan Medical Center, Seoul 05505, Korea; (H.-S.A.); (J.Y.); (Y.O.)
- Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul 05505, Korea
| | - Jae Ho Jeong
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea; (J.H.J.); (J.-H.A.); (K.H.J.); (S.-B.K.)
| | - Jin-Hee Ahn
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea; (J.H.J.); (J.-H.A.); (K.H.J.); (S.-B.K.)
| | - Kyung Hae Jung
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea; (J.H.J.); (J.-H.A.); (K.H.J.); (S.-B.K.)
| | - Sung-Bae Kim
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea; (J.H.J.); (J.-H.A.); (K.H.J.); (S.-B.K.)
| | - Hee Jin Lee
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea; (H.J.L.); (G.G.)
| | - Gyungyub Gong
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea; (H.J.L.); (G.G.)
| | - Sae Byul Lee
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea; (S.B.L.); (I.Y.C.); (H.J.K.); (B.S.K.); (J.W.L.); (B.H.S.); (S.H.A.)
| | - Il Yong Chung
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea; (S.B.L.); (I.Y.C.); (H.J.K.); (B.S.K.); (J.W.L.); (B.H.S.); (S.H.A.)
| | - Hee Jeong Kim
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea; (S.B.L.); (I.Y.C.); (H.J.K.); (B.S.K.); (J.W.L.); (B.H.S.); (S.H.A.)
| | - Beom Seok Ko
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea; (S.B.L.); (I.Y.C.); (H.J.K.); (B.S.K.); (J.W.L.); (B.H.S.); (S.H.A.)
| | - Jong Won Lee
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea; (S.B.L.); (I.Y.C.); (H.J.K.); (B.S.K.); (J.W.L.); (B.H.S.); (S.H.A.)
| | - Byung Ho Son
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea; (S.B.L.); (I.Y.C.); (H.J.K.); (B.S.K.); (J.W.L.); (B.H.S.); (S.H.A.)
| | - Sei Hyun Ahn
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea; (S.B.L.); (I.Y.C.); (H.J.K.); (B.S.K.); (J.W.L.); (B.H.S.); (S.H.A.)
| | - Kyunggon Kim
- Asan Institute for Life Sciences, Asan Medical Center, Seoul 05505, Korea; (H.-S.A.); (J.Y.); (Y.O.)
- Convergence Medicine Research Center, Asan Institute for Life Sciences, Asan Medical Center, Seoul 05505, Korea;
- Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul 05505, Korea
- Clinical Proteomics Core Laboratory, Convergence Medicine Research Center, Asan Medical Center, Seoul 05505, Korea
- Bio-Medical Institute of Technology, Asan Medical Center, Seoul 05505, Korea
| | - Jisun Kim
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea; (S.B.L.); (I.Y.C.); (H.J.K.); (B.S.K.); (J.W.L.); (B.H.S.); (S.H.A.)
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