Triple-negative Breast Cancer

Contents
Foreword by Zhi-Ming Shao
Foreword by Yibin Kang
About the Editors
List of Contributors
Abbreviations
Chapter ONE Overview of Triple-Negative Breast Cancer
	1.1 Introduction
	1.2 Classification of Breast Cancer
		1.2.1 Histopathological Classification
		1.2.2 Molecular Classification
			1.2.2.1 Molecular classification based on gene expression profiling
			1.2.2.2 Molecular classification based on immunohistochemistry
	1.3 Definition and Diagnosis of TNBC
	1.4 Similarities and Differences Between TNBC, Basal-Like Breast Cancer, and BRCA-Associated Breast Cancer
		1.4.1 TNBC vs. Basal-Like Breast Cancer (BLBC)
		1.4.2 TNBC vs. BRCA-Associated Breast Cancer
	1.5 Epidemiology and Risk Factors of TNBC
		1.5.1 Distribution of TNBC/BLBC by Race and Menopausal Status
		1.5.2 Distribution of TNBC/BLBC by Age and Sex
		1.5.3 Other Risk Factors of TNBC/BLBC
	1.6 Characteristics of TNBC
		1.6.1 General Clinical Features of TNBC
		1.6.2 Immunophenotypic and Molecular Characteristics of TNBC
		1.6.3 Histopathological Characteristics of TNBC
	References
Chapter TWO Heterogeneity and Subtyping of Triple-Negative Breast Cancer
	2.1 Introduction
	2.2 Clinical Heterogeneity of TNBC
	2.3 Histopathological Subtyping of TNBC
		2.3.1 Histopathological Subtypes of TNBC
		2.3.2 Major Histopathological Subtypes of TNBC
			2.3.2.1 High-grade invasive ductal carcinomas of no special type
			2.3.2.2 Metaplastic breast carcinomas
			2.3.2.3 Carcinomas with medullary features
			2.3.2.4 Carcinomas with apocrine features
			2.3.2.5 Low-grade TNBC
		2.3.3 The Underlying Pattern of Progression of TNBC
	2.4 Molecular Subtyping of TNBC
		2.4.1 Subtyping Based on Genomic Alterations
		2.4.2 Subtyping Based on Gene Expression Profiling
			2.4.2.1 Vanderbilt subtyping
			2.4.2.2 Baylor subtyping
			2.4.2.3 Fudan subtyping
		2.4.3 Subtyping Based on Immunohistochemistry
		2.4.4 Correlation Between Molecular and Histopathological Subtypes and Clinical Implications
	References
Chapter THREE Genetics and Signaling Events in Triple-Negative Breast Cancer
	3.1 Germline Mutations in TNBC
		3.1.1 BRCA1/2 Mutations and Homologous Recombination Defects
		3.1.2 Resemblance of Familial Breast Cancers with Germline BRCA1 Mutations with TNBC
			3.1.2.1 Association of BRCA1/2 germline mutations and tumorigenesis of TNBC
			3.1.2.2 Association of BRCA1/2 germline mutations and progression & prognosis of TNBC
			3.1.2.3 Association of BRCA1/2 germline mutations and therapy of TNBC
	3.2 Somatic Gene Mutations in TNBC
		3.2.1 Somatic Gene Mutations and Tumorigenesis of TNBC
		3.2.2 Somatic Gene Mutations and Progression & Prognosis of TNBC
		3.2.3 Somatic Gene Mutations and Therapy of TNBC
	3.3 Signaling Events in TNBC
		3.3.1 PI3K/Akt/mTOR Pathway
		3.3.2 Wnt Pathway
			3.3.2.1 Association of Wnt pathway and tumorigenesis of TNBC
			3.3.2.2 Association of Wnt pathway and progression & prognosis of TNBC
		3.3.3 MAPK Pathway
		3.3.4 Hedgehog Pathway
	References
Chapter FOUR Epigenetics in Triple-Negative Breast Cancer
	4.1 Alterations in DNA Methylation in TNBC
		4.1.1 Basics of DNA Methylation
		4.1.2 DNA Methylation Signatures in TNBC
	4.2 Alterations in Histone Modifications in TNBC
		4.2.1 Reversible Histone Acetylation/Deacetylation
		4.2.2 Histone Deacetylase Inhibitors and Their Potential Applications in TNBC
	4.3 Alterations in Phosphatidylcholine Metabolism in TNBC
		4.3.1 Reprogramming of Phosphatidylcholine Metabolism in TNBC
		4.3.2 Efforts to Target Phosphatidylcholine Metabolism in TNBC
	4.4 Roles of Non-coding RNAs in TNBC
		4.4.1 MicroRNAs
			4.4.1.1 MicroRNAs in TNBC
		4.4.2 Long Non-coding RNAs
			4.4.2.1 LncRNAs in TNBC
			4.4.2.2 Potential clinical applications of lncRNAs in TNBC
		4.4.3 Circular RNAs
		4.4.4 Interactions Between MicroRNAs and Other Epigenetic Mechanisms in TNBC
	References
Chapter FIVE Biomarkers of Triple-Negative Breast Cancer
	5.1 Circulating Tumor Cells in TNBC
	5.2 Circulating Tumor DNA in TNBC
	5.3 Molecular Biomarkers in TNBC
		5.3.1 Cytokeratins
		5.3.2 EGFR
		5.3.3 Ki67
		5.3.4 BRCA1/2
		5.3.5 PARPs
		5.3.6 Androgen Receptor
		5.3.7 VEGF
		5.3.8 p53
		5.3.9 Tyrosine Kinases
		5.3.10 mTOR
	References
Chapter SIX Clinical Aspects of Triple-Negative Breast Cancer
	6.1 Clinicopathological Features of TNBC
		6.1.1 General Clinical Features
		6.1.2 Pathological Features and Immunophenotypes
		6.1.3 Increased Risk of Pulmonary and Brain Metastasis in TNBC
	6.2 Diagnosis of TNBC
		6.2.1 Diagnosis Based on the Status of Receptors
		6.2.2 Medical Imaging as Complementary Diagnostic Methods
	6.3 Treatment of TNBC
		6.3.1 Surgery
		6.3.2 Chemotherapy
			6.3.2.1 Neoadjuvant chemotherapy
			6.3.2.2 Adjuvant chemotherapy
			6.3.2.3 Chemoresistance in TNBC
		6.3.3 Targeted Therapy Using PARP Inhibitors
		6.3.4 Radiotherapy
	6.4 Prognosis of TNBC
	6.5 Nursing Implications
	References
Chapter SEVEN Novel Therapeutic Strategies of Triple-Negative Breast Cancer
	7.1 Targeting Signaling Molecules in TNBC
		7.1.1 Tyrosine Kinase Inhibition
			7.1.1.1 EGFR inhibition
			7.1.1.2 Met inhibition
		7.1.2 PI3K/Akt/mTOR Pathway Inhibition
		7.1.3 MAPK Pathway Inhibition
		7.1.4 Androgen Receptor Inhibition
			7.1.4.1 Androgen receptor and its intracellular signaling
			7.1.4.2 Androgen receptor signaling inhibitors
			7.1.4.3 Androgen receptor inhibition combined with other targeted drugs
		7.1.5 VEGF/VEGFR Signaling Pathway Inhibition
	7.2 Targeting Epigenetic Modifications in TNBC
		7.2.1 DNMT Inhibition
		7.2.2 HDAC Inhibition
	7.3 Targeting Cancer Stem Cells in TNBC
		7.3.1 TNBC Cancer Stem Cell Markers
		7.3.2 Similarities Between TNBC and Breast Cancer Stem Cells
		7.3.3 Targeting Self-Renewal Capacity
			7.3.3.1 JAK/STAT3 signaling inhibition
			7.3.3.2 Src kinase inhibition
			7.3.3.3 Wnt/b-catenin signaling inhibition
		7.3.4 Targeting Metabolic Reprogramming
			7.3.4.1 Targeting anaerobic glycolysis
			7.3.4.2 Targeting OXPHOS
	7.4 Repurposing Old Drugs for TNBC
		7.4.1 Statins
			7.4.1.1 Preclinical evidence for the selective action of lipophilic statins in TNBC
			7.4.1.2 Clinical evidence supporting the use of statins as anti-TNBC agents
			7.4.1.3 Factors affecting statins’ use as anti-TNBC agents
		7.4.2 Metformin
		7.4.3 Mifepristone and Derivatives
	7.5 Summary
	References
Chapter EIGHT Immunotherapy of Triple-Negative Breast Cancer
	8.1 Cancer Immunotherapy
	8.2 Immune Checkpoints as an Important Target of Anti-cancer Therapy
	8.3 Promise of Immunotherapy in TNBC
	8.4 Targeting the PD1/PDL1 Pathway in TNBC
		8.4.1 Humanized Anti-PD1 Antibodies
			8.4.1.1 Pembrolizumab
			8.4.1.2 Nivolumab
		8.4.2 Humanized Anti-PDL1 Antibodies
			8.4.2.1 Atezolizumab
			8.4.2.2 Avelumab
			8.4.2.3 Durvalumab
	8.5 Targeting the CTLA4 Molecule in TNBC
		8.5.1 Preclinical Studies of CTLA4 Blockade
		8.5.2 Humanized Anti-CTLA4 Antibodies
		8.5.3 Clinical Trials of Anti-CTLA4 Antibody in TNBC
	References
Appendix: Online Resources
Afterword
Index