Circulating Tumor Cells in Breast Cancer Metastatic Disease (Advances in Experimental Medicine and Biology, 1220)

Contents
Contributors
List of Figures
List of Tables
1: Introduction – Biology of Breast Cancer Metastasis and Importance of the Analysis of CTCs
	1.1	 Breast Cancer Metastasis
		1.1.1	 Escape from Primary Tumor and Infiltration of Neighboring Tissue
		1.1.2	 Intravasation
		1.1.3	 Survival of CTCs in Circulation
		1.1.4	 Extravasation to a Secondary Site to form Micrometastasis
		1.1.5	 Breast Cancer Tropism and Dormancy
	1.2	 CTCs Analyses, a Tool to Understand Breast Cancer Progression
	References
2: Epithelial-Mesenchymal Plasticity in Circulating Tumor Cells, the Precursors of Metastasis
	2.1	 Defining Epithelial-Mesenchymal Plasticity
		2.1.1	 Epithelial-Mesenchymal Plasticity to Model the Early Steps of Metastasis
		2.1.2	 Inducers and Effectors of EMP
		2.1.3	 EMP in Cancer Stem Cells and Drug Resistance
		2.1.4	 Significance of EMP in Non-epithelial Cancers
		2.1.5	 Contribution of EMP to Genomic Instability and Genetic Diversity
		2.1.6	 Mouse Models of EMP
		2.1.7	 Detecting EMP in Clinical Samples
	2.2	 EMP in Circulating Tumor Cells
		2.2.1	 Hybrid-EMP and CTC Clusters
		2.2.2	 Role of EMP in CTCs During Progression and Therapeutic Response
		2.2.3	 The Influence of EMP on CTC Isolation Technologies
	2.3	 Clinical Correlates and Future Study
		2.3.1	 EMP as a Biomarker for Progression, Aggressiveness, and Drug Selection
		2.3.2	 Prevention or Reversal of EMP as a Therapeutic Target
	2.4	 Controversies
	2.5	 Remaining Questions
	References
3: Disseminated Tumor Cells and Dormancy in Breast Cancer Progression
	3.1	 Introduction
	3.2	 Cancer Dormancy
	3.3	 Potential Mechanisms and Clinical Relevance of Tumor Cell Dormancy
		3.3.1	 Microenvironment
		3.3.2	 Angiogenesis
		3.3.3	 Targeting Signaling Pathways
		3.3.4	 Immune System
	3.4	 Conclusions
	References
4: Methodology for the Isolation and Analysis of CTCs
	4.1	 Introduction
	4.2	 Isolation of CTCs: Enrichment
		4.2.1	 Strategies Based on Biological Properties
			4.2.1.1	 Positive Selection
			4.2.1.2	 Negative Selection
		4.2.2	 Strategies Based on Physical Properties
			4.2.2.1	 Density Centrifugation
			4.2.2.2	 Filtration
			4.2.2.3	 Microfluidics
			4.2.2.4	 Dielectrophoresis
		4.2.3	 Dual Combination Technologies
	4.3	 Single Cell CTC Isolation
	4.4	 Futures Perspectives in the Technologies Applied to CTCs Isolation and Their Clinical Application
	References
5: Advances in the Characterization of Circulating Tumor Cells in Metastatic Breast Cancer: Single Cell Analyses and Interactions, and Patient-Derived Models for Drug Testing
	5.1	 Introduction
	5.2	 Tumor Heterogeneity
	5.3	 Tumor Heterogeneity at Single-Cell Resolution
	5.4	 Single Cell Interactions
	5.5	 Reason for Propagating CTCs
	5.6	 In vitro Expansion
		5.6.1	 Short-Term Culture
		5.6.2	 Long-Term Culture
	5.7	 In vivo Expansion
	5.8	 Drug Testing Using CTC Models
	5.9	 Future Perspectives
	References
6: Circulating Tumor Cells (CTCs) Heterogeneity in Metastatic Breast Cancer: Different Approaches for Different Needs
	6.1	 Introduction
	6.2	 CTC Phenotypic Heterogeneity
	6.3	 CTC Molecular Characterization
	6.4	 Conclusions and Future Perspectives
	References
7: Relevance of CTC Clusters in Breast Cancer Metastasis
	7.1	 Introduction
	7.2	 Insights on the Existence of CTC Clusters
	7.3	 Challenging the Traditional View of the Dissemination Process
	7.4	 Origin of CTC Clusters
	7.5	 CTC Clusters Isolation Technologies
	7.6	 Metastatic Features of CTC Clusters
	7.7	 Survival and Proliferative Advantage of CTC Clusters
	7.8	 CTC Clusters, a Small Portion of Tumor Microenvironment
	7.9	 Prognostic Value of CTC Clusters in Metastatic Breast Cancer
	7.10	 Therapeutic Implications: Targeting CTC Clusters
	7.11	 Remaining Questions and Opportunities
	References
8: Epigenetics of Circulating Tumor Cells in Breast Cancer
	8.1	 Introduction
	8.2	 The Epigenetic Machinery: DNA Methylation and Non-coding RNAs
		8.2.1	 DNA Methylation
		8.2.2	 Noncoding RNAs
	8.3	 Methods for the Detection of Epigenetic Mechanisms in CTCs
	8.4	 Deregulation of Epigenetic Mechanisms in CTCs of Breast Cancer
		8.4.1	 DNA Methylation in CTCs
		8.4.2	 Non-coding RNAs in CTCs
	8.5	 Connection Between Epigenetic Alterations of CTCs and Circulating Nucleic Acids
	8.6	 Epigenetic Biomarkers in CTCs
	8.7	 Conclusions and Future Perspectives
	References
9: Circulating Tumor Cells: Applications for Early Breast Cancer
	9.1	 Introduction
	9.2	 CTCs Biology and Molecular Characterization in Early Breast Cancer
	9.3	 Prognostic Studies
		9.3.1	 Prognostic Studies of CTCs in Patients Who Did not Receive Adjuvant Chemotherapy
		9.3.2	 Prognostic Studies of CTCs in Patients Who Received Chemotherapy for Early Breast Cancer
		9.3.3	 Pooled Analysis of the Prognostic Value of CTCs in Early Breast Cancer
	9.4	 Other Prognostic Studies
		9.4.1	 CTCs and Late Recurrences in Early Breast Cancer
		9.4.2	 CTCs with EMT Phenotype and Prognosis
		9.4.3	 Dynamic Evolution of CTC During (Neo)adjuvant Treatment
	9.5	 Clinical Trials Based on CTCs
	9.6	 Conclusions and Future Directions
	References
10: Clinical Relevance and Therapeutic Application of CTCs in Advanced Breast Cancer
	10.1	 Introduction
	10.2	 Prognostic Value of CTCs
		10.2.1	 Pivotal Study
		10.2.2	 Other Studies
		10.2.3	 Clinical Value of the CTCs
	10.3	 Characterization and CTCs Heterogeneity
	10.4	 CTCs and Monitoring Treatment in Advanced Breast Cancer
		10.4.1	 Can Changes in the Quantification of CTCs Be Useful as Early Predictor of Treatment Efficacy?
		10.4.2	 Do Decisions Guided by the Use of CTCs Have an Impact on Treatment Efficacy Outcomes?
	10.5	 Precision Oncology and CTCs in Advanced Breast Cancer
		10.5.1	 Comparison of Primary Tumor Molecular Profile Versus CTCs
		10.5.2	 Circulating Stem Cells
		10.5.3	 CTCs, ESR1 and TK1: Importance in the Endocrine Treatment
		10.5.4	 Choice of Treatment According to CTCs in Advanced Breast Cancer
	10.6	 Discussion and Comments
	References
Index