Management of Breast Diseases (eBook)

Preface 5
Acknowledgements 6
Table of Contents 7
Contributors 10
1. Anatomy and Physiology of the Breast 15
List of Abbreviations 15
1.1 Gross Anatomy of the Breast 16
1.1.1 Relationships and Quadrants 16
1.1.2 Nerve Supply 16
1.1.3 Vascular Supply 18
1.1.4 Lymphatic Drainage 18
1.1.5 Gross Anatomical Changes Throughout the Lifespan 20
1.2 Histology 20
1.2.1 Overview 20
1.2.2 Nipple and Areola 21
1.2.3 Parenchyma 22
1.2.3.1 Luminal Epithelial Cells 22
1.2.3.2 Myoepithelial Cells 22
1.2.3.3 Stem Cells 22
1.2.4 Basement Membrane 24
1.2.5 Stroma 24
1.2.5.1 Cells in Breast Stroma 25
1.2.5.2 Extracellular Matrix 26
1.3 Synopsis of Hormones and Other Factors that Regulate Breast Structure and Function 26
1.3.1 Hormones 26
1.3.2 Other Regulators of Breast Development 28
1.4 Mammary Gland Structure and Function Throughout Life 29
1.4.1 Prenatal Development of the Breast 29
1.4.1.1 Events of Prenatal Breast Development 29
1.4.1.2 Hormonal Regulation of Prenatal Breast Development 30
1.4.1.3 Genes, Transcription Factorsand Growth Factors During Prenatal Breast Development 30
1.4.2 Breast Development from Birth to Puberty 31
1.4.2.1 Events in Breast Development from Birth to Puberty 31
1.4.2.2 Hormones in Breast Development from Birth to Puberty 31
1.4.2.3 Other Regulatory Factors in Breast Development from Birth to Puberty 31
1.4.3 Puberty 31
1.4.3.1 Events in the Breast During Puberty 31
1.4.3.2 Hormonal Regulation of the Breast During Puberty 32
1.4.3.3 Other Regulatory Factors in Breast Development During Puberty 33
1.4.4 The Adult Premenopausal Breast 33
1.4.4.1 Cyclic Events in the Premenopausal Adult Breast 33
1.4.4.2 Hormones Regulating the Adult Premenopausal Breast 34
1.4.4.3 Stat5 in the Adult Premenopausal Breast 34
1.4.5 Pregnancy 34
1.4.5.1 Events in the Breast During Pregnancy 34
1.4.5.2 Hormones in the Breast During Pregnancy (Fig. 1.15) 35
1.4.5.3 Other Regulatory Factors in Breast Development during Pregnancy 36
1.4.6 Lactation 36
1.4.6.1 Events in the Lactating Breast 36
1.4.6.2 The Process of Lactation 37
1.4.6.3 Hormones During Lactation and Nursing 38
1.4.6.4 Other Regulatory Factors During Lactation 38
1.4.6.5 Effects of Lactation on the Nursing Mother 39
1.4.6.6 Calcium Metabolism During Lactation 39
1.4.7 Postlactational Involution 39
1.4.8 Postmenopausal Involution 40
1.4.9 Concluding Comments 40
1.5 Appendix 41
1.5.1 A Brief Comparison of Murine and Human Breast 41
References 42
2. Congenital and Developmental Abnormalities of the Breast 51
2.1 Anatomy of the Breast 53
2.2 Premature Thelarche 53
2.3 Breast Masses 53
2.3.1 Gynecomastia 55
2.3.2 Accessory Breast Tissue:Polymastia/Polythelia 56
2.4 Congenital Breast Hypoplasia/Aplasia 57
2.4.1 Poland Syndrome 57
2.4.2 Tubular/Tuberous Breast 58
2.4.3 Idiopathic Asymmetry 59
2.4.4 Amastia/Athelia 59
2.5 Inverted Nipples 60
2.6 Gigantomastia 60
2.6.1 Juvenile Hypertrophy 60
2.6.2 Gravid-Induced Gigantomastia 61
2.6.3 Drug-Induced Gigantomastia 61
2.7 Deformational Breast Abnormalities: Iatrogenic,Traumatic 61
2.8 Conclusion 62
References 63
3. Nipple Discharge 66
3.1 Introduction 66
3.2 Anatomy and Physiology 66
3.3 Definition 66
3.4 Incidence 67
3.5 Characteristics and Etiology 68
3.6 Diagnostic Evaluation 72
3.7 Mammography 72
3.8 Ultrasound 73
3.9 MRI 73
3.10 Occult Blood 73
3.11 Cytology 74
3.12 Biochemical Markers 74
3.13 Ductal Imaging 75
3.14 Surgical Evaluation and Treatment 75
3.15 Mammary Ductoscopy 76
3.16 Follow Up 77
References 78
4. Mastalgia 81
4.1 Etiology 81
4.2 Classification 81
4.3 Cyclical Mastalgia 81
4.4 Noncyclical Mastalgia 82
4.5 Chest Wall Pain 82
4.6 Non-chest Wall Pain 83
4.7 Mastalgia and Breast Cancer 83
4.8 Psychosocial Factors 83
4.9 Clinical Assessment and Investigations 84
4.10 Treatment 84
4.10.1 Cyclical Mastalgia 84
4.10.2 Noncyclical Mastalgia 86
4.11 Management Algorithm 86
References 86
5. Management of Common Lactation and Breastfeeding Problems 89
5.1 Prenatal Period 89
5.1.1 Informed Choice 89
5.1.1.1 Benefits of Breastfeeding 89
5.1.1.2 The Hazards of Infant Formula 90
5.1.2 Prenatal Education 90
5.1.3 Prenatal Lactation Assessment 91
5.1.3.1 Screening for Risk Factors 91
5.1.3.2 Prenatal Breast Examination 92
5.1.3.3 Anticipatory Guidance 93
5.2 Intrapartum Period 93
5.2.1 Establishing Lactation 93
5.2.2 Factors that Help to Establish Lactation 94
5.2.3 Factors that Interfere with Lactation 94
5.2.3.1 Failure of Mammogenesis 94
5.2.3.2 Failure of Lactogenesis 95
5.2.3.3 Failure of Galactopoiesis 96
5.2.4 Milk Transfer 96
5.2.4.1 Factors that Help Milk Transfer 97
5.2.4.2 Factors Impeding Milk Transfer 98
5.2.5 Milk Intake 98
5.2.5.1 Frequency 98
5.2.5.2 Duration 99
5.2.5.3 Pattern of Breast Use 99
5.2.5.4 Factors that Help Milk Intake 99
5.2.5.5 Factors that Impair Milk Intake 99
5.2.6 Maternal Psychosocial Health 99
5.2.7 In-hospital Risk Assessment 99
5.2.8 Hospital Discharge Planning 100
5.3 Postpartum Period 100
5.3.1 Clinical Breastfeeding Assessment 100
5.3.2 Insufficient Milk Syndrome 101
5.3.3 Maternal Hyperlactation Syndrome 102
5.3.3.1 White Spot 103
5.3.3.2 Milk Stasis 103
5.3.3.3 Acute Mastitis 103
5.3.3.4 Chronic Mastitis 104
5.3.3.5 Breast Abscess 104
5.3.3.6 Management Goals 104
5.3.4 Sore Nipples 106
5.3.4.1 Nipple Trauma 106
5.3.4.2 Chapped Nipples 107
5.3.4.3 Bacterial Infection of the Nipple 107
5.3.4.4 Candidiasis 107
5.3.4.5 Dermatitis 108
5.3.4.6 Paget’s Disease 108
5.3.4.7 Vasospasm or Raynaud’s Phenomenon 108
5.3.4.8 Psoriasis 109
5.3.5 Induced Lactation and Relactation 109
5.3.6 Medicines and Breastfeeding 109
5.4 Conclusion 109
References 110
6. Evaluation of a Breast Mass 116
6.1 Introduction 116
6.2 Routes of Presentation 116
6.2.1 Symptomatic Breast Mass 116
6.2.2 Screening 117
6.2.3 Incidental Detection of the Breast Mass on Clinical Examination 117
6.3 History of Presentation 117
6.4 Clinical Examination 119
6.5 Investigation 121
6.6 Imaging 121
6.7 Breast Ultrasound 122
6.8 Mammography 123
6.9 Magnetic Resonance Imaging (MRI) 124
6.10 Other Imaging Techniques 125
6.11 Pathology Diagnosis 125
6.12 Patient Plan 127
6.13 Benign Breast Masses 127
6.13.1 Benign Nodularity 127
6.13.2 Changes Associated with Pregnancy and Lactation 128
6.13.3 Fibroadenoma 128
6.13.4 Phyllodes Tumour 128
6.13.5 Cysts 128
6.13.6 Breast Sepsis 128
6.13.7 Intraduct Papilloma 129
6.13.8 Skin Lesions 129
6.13.9 Fat Necrosis 129
6.13.10 Other Lesions 129
6.14 Summary 130
References 130
7. Breast Cancer Epidemiology 131
7.1 Descriptive Epidemiology 131
7.2 Aetiology 132
7.2.1 Inheritance 133
7.2.2 Tobacco 133
7.2.3 Diet 133
7.2.4 Alcohol 134
7.2.5 Reproductive Factors 134
7.2.6 Endogenous Sex Hormones and Hormone Intake 135
7.2.6.1 Endogenous Sex Hormones 135
7.2.6.2 Exogenous Sex Hormones 135
7.2.7 Body Mass Index 136
7.2.8 Height 137
7.2.9 Physical Activity 137
7.2.10 Ionising Radiation 137
7.3 Primary Prevention 138
7.4 Secondary Prevention/Screening 139
References 139
8. Breast Cancer Screening 141
8.1 Cancer Screening Principles 141
8.1.1 Lead-Time Bias 142
8.1.2 Length Bias 143
8.1.3 Selection Bias 143
8.2 Mammography Screening 143
8.2.1 Health Insurance Plan Trial 144
8.2.2 Swedish Trials 145
8.2.3 Edinburgh Trial 145
8.2.4 Canadian Trials 146
8.2.5 United Kingdom AgeTrial 146
8.3 Overview (Meta-Analyses) of the Mammographic Screening Trials 146
8.4 Effect of Age on Mammographic Screening 147
8.5 Screening Breast Ultrasound 149
8.6 Screening Breast MRI 149
8.7 Screening by Clinical Breast Examination 149
8.8 Screening by Breast Self-Examination 151
8.9 Potential Hazards of Screening 151
8.9.1 Lead Time 152
8.9.2 False Positives 152
8.9.3 Radiation Exposure 152
8.9.4 Over-Diagnosis 153
8.9.5 Cost 154
8.10 Conclusion 154
References 155
9. Breast Imaging 158
9.1 Introduction 158
9.2 Mammography 158
9.2.1 The Mammography Report 160
9.2.1.2 Breast Tissue Composition 160
9.2.1.3 Description of Findings 161
9.2.1.4 Final Assessment Categories 161
9.2.2 Describing the Location of an Abnormality 163
9.2.3 Masses 163
9.2.4 Calcifi cations 164
9.2.5 Indirect and Secondary Signs of Malignancy 165
9.2.6 Potential Adverse Consequences of Screening 166
9.2.7 False-negative Mammograms 168
9.3 Breast Ultrasound 168
9.3.1 Technical Advances 168
9.3.2 Normal Anatomy 168
9.3.3 Cystic Masses 169
9.3.4 Solid Masses 169
9.3.5 Screening Ultrasound 170
9.4 Core Needle Biopsy 171
9.4.1 Indications, Relative Contraindications and Complications 171
9.4.2 Appropriate Postcore Biopsy Follow-Up 172
9.5 Magnetic Resonance Imaging of the Breast 172
9.5.1 Contrast-Enhanced Breast MRI for Breast Cancer Screening 173
9.6 Radionuclide Imaging 173
References 174
10. Premalignant and MalignantBreast Pathology 177
10.1 Morphologic Variants of Invasive Breast Cancer 177
10.1.1 Ductal Carcinoma 177
10.1.2 Lobular Carcinoma 179
10.1.3 Malignant Tumors of Stroma Origin 180
10.2 Pathology of Invasion and Metastases 180
10.3 Proliferative and Preinvasive Breast Disease 181
10.4 Molecular Markersin Breast Cancer Management 183
References 186
11. Lobular Carcinoma in Situ 188
Abbreviations 188
11.1 Introduction 188
11.2 Historical Perspective 188
11.3 Epidemiology of LCIS 189
11.4 Natural History of LCIS 190
11.5 Histopathological Characteristics of LCIS 191
11.6 Differential Diagnoses of LCIS 194
11.7 Molecular Pathology of LCIS 194
11.7.1 Immunophenotype of LCIS 195
11.7.2 Role of E-Cadherin in LCIS 195
11.7.3 E-Cadherin Immunohistochemistry as a Diagnostic Tool 196
11.7.4 E-Cadherin as a Predisposition Gene for LCIS? 197
11.7.5 Molecular Genetic Analysis of LCIS 197
11.8 Detection and Clinical Managemenet of LCIS 199
11.8.1 Radiology 199
11.8.2 LCIS at Margins 199
11.8.3 Chemoprevention Therapy for LCIS Patients 199
11.8.4 Management of Patients Diagnosed with LCIS in Core-Needle Biopsy 199
11.9 Summary 200
References 201
12. Ductal Carcinoma in Situ 207
12.1 Introduction 207
12.2 Presentation 207
12.3 Diagnosis 209
12.4 Pathology 210
12.5 Natural History of DCIS 212
12.6 Treatment of the Breast 213
12.6.1 Mastectomy 213
12.6.2 Breast-Conserving Surgery and Radiation Therapy 214
12.6.3 Wide Local Excision Alone 217
12.7 Treatment of the Axilla 219
12.8 Endocrine Therapy 220
12.9 Treatment Selection 222
12.10 Follow-Up 224
12.11 Treatment of Recurrence 225
12.12 Conclusion 227
References 227
13. Surgical Considerationsin the Management of PrimaryInvasive Breast Cancer 232
13.1 Local Recurrences 234
13.2 Surgical Options 236
13.2.1 Breast Reconstructive Surgery 238
13.3 Management of the Axilla 239
13.3.1 Survival 240
13.3.2 Axillary Relapse 240
13.3.3 Staging 241
13.4 Sentinel Lymph Node Biopsy 242
13.5 Conclusion 243
References 243
14. Sentinel Node Concept 247
14.1 Introduction 247
14.2 Anatomy of the Axillary Lymph Nodes 248
14.3 Lymphatic System of the Breast 248
14.4 Axillary Lymph Node Dissection 251
14.4.1 Surgical Aspects 251
14.4.2 Overall Survival 252
14.4.3 Axillary Relapse 253
14.5 Methods for Axillary Node Sampling 254
14.5.1 Four Node Axillary Sampling 254
14.5.2 Blue Dye-assisted Node Sampling (BDANS) 254
14.6 Sentinel Lymph Node Biopsy 254
14.6.1 Technical Aspects 255
14.6.2 Completion Axillary Lymph Node Dissection 257
14.7 Indications for Sentinel Lymph Node Biopsy 258
14.7.1 Ductal Carcinoma in Situ 259
14.7.2 Multifocal and Multicentric Tumours 259
14.7.3 Neoadjuvant Chemotherapy 259
14.7.4 Pregnancy 260
14.8 Omission of Surgical Axillary Staging 260
14.9 Conclusion 261
References 261
15. Breast Reconstructive Surgery 265
15.1 Introduction 265
15.2 Indications for Reconstruction 265
15.3 Skin Sparing Mastectomy 266
15.4 Timing of Breast Reconstruction 266
15.5 Alloplastic vs. Autogenous Reconstruction 267
15.5.1 Alloplastic Reconstruction 267
15.5.2 Implant Types 268
15.5.3 Two Stage Expander/Implant Reconstruction 269
15.5.4 Single Stage Reconstruction with Implants 269
15.5.5 Permanent Tissue Expander/Implant Reconstruction 270
15.5.6 Complications of Implant Reconstruction 270
15.6 Autogenous Reconstruction 270
15.6.1 Pedicled TRAM Flap/Unipedicled Flap 271
15.6.2 Bipedicled TRAM Flap 273
15.6.3 Midabdominal TRAM Flap 273
15.6.4 Free TRAM Flaps 274
15.6.5 Latissimus Dorsi Musculocutaneous Flap 275
15.6.6 Gluteal Musculocutaneous and Perforator Flaps 276
15.7 Nipple-Areola Reconstruction 277
15.8 Contralateral Breast 277
15.9 Radiation and Breast Reconstruction 277
15.10 Chemotherapy 278
15.11 Conclusion 278
References 279
16. The Role of Radiotherapyin Breast Cancer Management 280
16.1 Introduction to Radiation Oncology 280
16.1.1 Physics of Radiation Therapy 280
16.1.2 Radiation, Surgery and Chemotherapy 282
16.1.3 Technical Aspects of Radiation Planning and Delivery 282
16.1.4 Adverse Effects of Radiation to the Breast 284
16.2 Radiation Therapy in the Early Stage Breast Cancer 286
16.2.1 Ductal Carcinoma in Situ 286
16.2.2 Invasive Breast Cancer 288
16.2.2.1 Breast Conservation 288
16.3 Locally Advanced Breast Cancer 294
16.4 Radiation as Palliation 295
16.5 Summary 295
References 295
17. Adjuvant Systemic Therapyfor Breast Cancer: An Overview 299
17.1 Role of Adjuvant Polychemotherapy 300
17.1.1 EBCTCG Systematic Reviewon Polychemotherapy (Oxford Overview) 300
17.1.1.1 Intergroup 9344 300
17.1.1.2 NSABP-28 301
17.1.1.3 ECOG 2197 301
17.1.1.4 PACS 01 301
17.1.1.5 GEICAM 9906 302
17.1.1.6 ECOG E1199 302
17.1.1.7 US Oncology 9735 302
17.1.1.8 BIG 02-98 302
17.1.1.9 TAXIT 216 303
17.1.1.10 MA21 303
17.1.1.11 HeCOG 10/97 303
17.1.2 European Cooperative Trial in Operable Breast Cancer (ECTO) 303
17.1.2.1 MD Anderson 94-002 304
17.1.2.2 BCIRG 001 304
17.1.3 Intergroup Trial C9741/CALGB Trial 9741 305
17.1.4 Metaanalysis of Taxane-Based Combination Trials 305
17.1.5 New Chemotherapy Combinations in EarlyStage Breast Cancer 306
17.1.6 Preoperative Chemotherapy 306
17.1.6.1 NSABP B-27 306
17.1.6.2 GEPAR-DUO Study 307
17.1.6.3 Aberdeen Study 307
17.1.6.4 MD Anderson Study 307
17.1.6.5 AngloCeltic Trial 308
17.1.6.6 High Dose Chemotherapy 308
17.1.7 Phase III Trials in Early Stage Breast Cancer 309
17.1.7.1 ECOGA 309
17.1.8 Trials with Allo-Transplantsin Breast Cancer 309
17.1.9 Conclusions 310
17.1.10 The Use of Genomics in Breast Cancer 310
17.1.11 70-Gene Assay (MammaPrint 310
17.1.11.1 76-Gene Assay 311
17.1.12 Clinical Data 311
17.1.12.1 Initial Studies 311
17.1.12.2 Response to Endocrine Therapy 312
17.1.12.3 Response to Chemotherapy 312
17.1.13 Analysis from the TransATAC Trial 314
17.1.13.1 Future Directions 314
17.2 Role of Adjuvant Endocrine Therapy 314
17.2.1 Aromatase Inhibitors 315
17.2.2 Arimidex, Tamoxifen and Combination (ATAC) Trial 315
17.2.2.1 BIG 1-98 Trial 316
17.2.2.2 ABCSG-8/ARNO 95 Trial 316
17.2.3 International Exemestane Study Group 031 (IES) Trial 317
17.2.4 National Cancer Instituteof Canada (NCIC) MA17 Trial 317
17.2.4.1 NSABP B33 318
17.2.5 Tamoxifen Exemestane Adjuvant Multinational (TEAM) Trial 318
17.2.6 Ovarian Ablation 319
17.2.6.1 FASG 06 319
17.2.6.2 ECOG 5188/INT-0101 320
17.2.6.3 INT0142 320
17.2.7 LHRH-Agonists in Early Breast Cancer Overview Group 320
17.3 Treatment of HER2-positive Tumors in the Adjuvant Setting 321
17.3.1 NSABP B31 and NCCTG 9831 Joint Analysis 321
17.3.2 HERceptin Adjuvant (HERA) Trial 322
17.3.3 Breast Cancer International Research Group (BCIRG) 006 323
17.3.3.1 FINher Trial 324
17.3.4 Ongoing and Future Trials 324
Reference 325
18. Endocrine Therapy 330
18.1 Introduction 330
18.2 Endocrine Therapyin Advanced Breast Cancer 330
18.2.1 Ovarian Ablation 330
18.2.2 Selective Oestrogen Receptor 332
18.2.2.1 Tamoxifen 332
18.2.2.2 Other Selective Oestrogen Receptor Modulators (SORMs) 332
18.2.2.3 “Tamoxifen-like” Triphenylethylene SERMs 333
18.2.2.4 “Fixed-Ring” SERMs 333
18.2.3 Fulvestrant (Faslodex ICI 182,780)334
18.2.3.1 Other Pure Oestrogen Antagonistsin Development 336
18.2.3.2 Aromatase Inhibitors 336
18.3 Oestrogens, Androgens and Progestins 337
18.3.1 Adjuvant Therapy 339
18.3.1.1 Tamoxifen 339
18.4 Ovarian Ablation (OA) and Ovarian Suppression (OS) 340
18.5 Aromatase Inhibitors 341
18.5.1 Monotherapy Comparisons Between Tamoxifen and AI 342
18.5.2 Switching/Sequencing Strategies 344
18.5.3 Extended Adjuvant Therapy 345
18.5.4 Neoadjuvant Endocrine Therapy 346
18.5.5 Toxicity of AIs and Tamoxifen 347
18.5.6 Concluding Remarks 348
References 348
19. Chemotherapeutic Agents 354
19.1 Cytotoxic Agents 354
19.1.1 Topoisomerase II Inhibitors: Anthracyclines 354
19.2 Taxanes (Tubulin Inhibitors) 356
19.2.1 Docetaxel and Paclitaxel 356
19.2.2 Ixabepilone 357
19.2.3 Vinorelbine 357
19.2.4 Alkylating Agents 359
19.2.4.1 Cyclophosphamide 359
19.2.4.2 Bendamustin 359
19.2.5 Antimetabolites 360
19.2.5.1 Methotrexate 360
19.2.5.2 Capecitabine 360
19.2.5.3 Gemcitabine 361
19.2.6 Platinum-containing Chemotherapy Agents 361
19.2.7 Targeted Agents 362
19.2.7.1 Agents Directed Against Human Epidermal Growth Factor Receptor (HER)2 362
19.2.7.2 Targeted Agents Affecting Tumor Angiogenesis and Other Targets 363
19.2.7.3 Selective Estrogen Receptor Modulators (SERMS) 365
19.2.7.4 Gonadotropin-Releasing Hormone (GnRH) Analogs 367
19.2.8 Bone-Targeted Agents 367
19.2.8.1 Bisphosphonates 367
19.2.8.2 Rank Ligand Inhibitors 370
References 370
20. HER2-Targeted Therapy 374
20.1 Introduction 374
20.2 Targeting the HER2 Receptor 374
20.2.1 Importance of Accurately Identifying HER2 375
20.3 Trastuzumab in the Metastatic Setting 375
20.3.1 Single-agent Therapy in Heavily Pretreated Patients 375
20.3.2 First-Line Single-Agent Therapy 375
20.3.3 Trastuzumab in Combination with Chemotherapy 375
20.3.3.1 Trastuzumab and Taxanes 375
20.3.3.2 Trastuzumab and Platinum Salts 376
20.3.3.3 Trastuzumab Plus Vinorelbine 376
20.3.3.4 Trastuzumab with Capecitabine 377
20.3.3.5 Trastuzumab Plus Gemcitabine 377
20.3.3.6 Trastuzumab with Poly-Chemotherapy 377
20.3.4 Trastuzumab in Combination with Hormonal Therapy 377
20.3.5 Trastuzumab after Disease Progression 378
20.4 Trastuzumab in the Adjuvant Setting 378
20.4.1 The Adjuvant Trials 378
20.4.1.1 HERA Trial 378
20.4.1.2 The Combined American NSABP-B31 and NCCTG-N9831 Trials 381
20.4.1.3 BCIRG 006 Trial 381
20.4.1.4 FinHer Trial 381
20.4.1.5 PACS-04 Trial 381
20.4.2 Trastuzumab Efficacy in the Adjuvant Trials 381
20.4.3 Trastuzumab Safety in the Adjuvant Trials 382
20.4.4 The Remaining Controversies with Adjuvant Trastuzumab 382
20.5 Beyond Trastuzumab: Other Anti-HER-2 Targeted Therapies 383
20.5.1 Trastuzumab Combined with EGFR Inhibitors 383
20.5.2 Lapatinib 384
20.5.3 HKI-272 384
20.5.4 Pertuzumab 385
20.5.5 Bevacizumab 385
20.5.6 Pazopanib 385
20.5.7 17-AAG (Anti-HSP-90) 385
20.5.8 Trastuzumab DM1 386
20.6 Conclusions 386
References 386
21. Inflammatory and Locally Advanced Breast Cancer 391
21.1 Epidemiology 391
21.2 Diagnosis and Staging 392
21.3 Management 393
21.4 Systemic Therapy 394
21.5 Local Therapy 400
21.6 Prognostic Factors of Locally Advanced Breast cancer 403
21.7 Molecular Biology of IBC 403
21.8 Survival 405
References 409
22. Preoperative (Neoadjuvant)Systemic Therapy 416
22.1 Introduction 416
22.2 Neoadjuvant Systemic Chemotherapy (NST) 416
22.3 Taxane-based Neoadjuvant Chemotherapy Regimens 417
22.4 Neoadjuvant Targeted Therapy 418
22.5 Infl uence of Histologic Subtypeson the Response of Neoadjuvant Systemic Treatment 418
22.6 Evaluation of Tumor Response after Neoadjuvant Systemic Treatment 418
22.7 Breast Conserving Surgery (BCS) 419
22.8 Evaluation of the Axilla in the Neoadjuvant Treatment Setting 419
22.9 Radiation Therapy after Neoadjuvant Systemic Therapy 420
22.10 Neoadjuvant Systemic Endocrine Therapy 420
22.11 Conclusions 421
References 421
23. Metastatic Breast Cancer 424
23.1 Hormonal Therapy 425
23.1.1 Premenopausal 426
23.1.2 Postmenopausal 427
23.2 Chemotherapy 428
23.3 Single: Agent Activity 429
23.3.1 Paclitaxel 429
23.3.2 Docetaxel 429
23.3.3 Nab-Paclitaxel 430
23.3.4 Which Taxane? 430
23.3.5 Anthracyclines 432
23.3.6 Ixabepilone 433
23.3.7 Capecitabine 433
23.4 Other Active Agents 434
23.4.1 Gemcitabine 434
23.4.2 Vinorelbine 434
23.4.3 Irinotecan 434
23.5 Combination Therapy 434
23.6 Taxane-based Combinations 434
23.6.1 Taxane and Doxorubicin 434
23.6.2 Taxane and Nonanthracycline Combination 436
23.6.2.1 Carboplatin/Paclitaxel 436
23.6.2.2 Gemcitabine/Paclitaxel 436
23.6.2.3 Capecitabine/Docetaxel 437
23.6.2.4 Gemcitabine/Docetaxel 437
23.6.2.5 Ixabepilone and Capecitabine 437
23.7 Biologic Agents 438
23.7.1 Trastuzumab 438
23.7.2 Lapatinib 439
23.7.3 CNS Metastases in HER2-positive Breast Cancer 440
23.7.4 Bevacizumab 440
23.8 Mechanisms of Drug Resistance 441
23.9 High-dose Chemotherapy with Stem Cell Rescue 441
23.10 Supportive Therpy 442
23.10.1 Bisphosphonates 442
23.11 Alternative Approaches 443
23.12 Surgery or Radiofrequency Ablation for Metastatic Disease- Oligometastases 443
23.13 Summary 443
References 444
24. Hormone Replacement Therapy:A Critical Review 449
24.1 Introduction 449
24.2 The Women’s Health Initiative (WHI) Hormone Replacement (HRT) Trials 449
24.3 The WHI HRT Trials: Background 450
24.3.1 The First WHI Trial 451
24.3.2 The Second WHI HRT Trial 452
24.4 Overview of the WHI HRT Trial 453
24.4.1 Analyses According to Age (Table 24.3) 453
24.4.2 Breast Cancers: Analyses According to Past Hormone Use 454
24.4.3 Impact of HRT and Duration of Follow-Up 454
24.5 Overview of the Second WHI HRT Trial 455
24.5.1 Analyses According to Age (24.5) 455
24.5.2 Analysis of Invasive Breast Cancer 455
24.6 HRT and Breast Cancer Incidence: Changing Trends after WHI Trial Reports? 456
24.7 Comments Regarding HRT Policy Shift and Reduced Breast Cancer Incidence Rates 457
24.8 Estrogen Breast Cancer Protective and Progestin A Breast Cancer Carcinogen? Identification of a New Paradigm 457
24.9 Summary 458
24.10 Concluding Remarks 458
24.11 Appendix I 459
24.11.1 Observational and Case–Control HRT Studies Prior to the Publications of the 2002 WHI HRT Trials. Breast Cancer 459
24.11.1.1 HRT and Carcinogenesis vs. Promotional Effect 459
24.11.2 Nononcological Aspects of HRT: Cardiac and Cardiovascular Events. Data Evaluation Before the 2002–2004 WHI HRT Trials 460
24.11.2.1 Estrogens and Lipids 460
24.11.2.2 Estrogen Effects on Vessels: Biochemical Effects 461
24.11.2.3 Direct Estrogen Effect on Vessel Wall 461
24.11.2.4 Epidemiological Data on Estrogen and Heart Disease: HRT and Primary Prevention of Cardiovascular Disease 461
24.11.2.5 Epidemiological Data on Estrogen and Heart Disease: Secondary Prevention 462
24.11.2.6 HRT and the “Timing” Hypothesis 463
24.11.3 Nononcological Aspects of HRT: Thrombo-Embolism (TE) 463
24.12 Appendix II 464
24.12.1 New HRT Agents 464
24.12.1.1 Clinical Equivalence of Intranasal and Oral 17b -Estradiol for Symptoms of Menopause [97] 464
24.12.1.2 A Prospective Randomized Comparative Study of the Effects of Intranasal and Transdermal17b -Estradiol on Postmenopausal Symptoms and Vaginal Cytology [98] 464
24.12.1.3 Efficacy and Acceptability of Intranasal 17b -Oestradiol for Menopausal Symptoms: Randomized Dose-Response Study.Aerodiol Study Group [99] 464
24.12.1.4 Efficacy and Tolerability of Pulsed Estrogen Therapy: A 12-Week Double-Blind Placebo-Controlled Study in Highly Symptomatic Postmenopausal Women [100] 465
24.12.1.5 Twice-Weekly Transdermal Estradiol and Vaginal Progesterone as Continuous Combined HRT in Postmenopausal Women: A 1-Year Prospective Study [101] 465
24.12.1.6 Vaginal Progesterone in Menopause: Crinone 4% in Cyclical and Constant Combined Regimens [102] 465
24.12.1.7 Relationship Between Long Durations and Different Regimens of Hormone Therapy and Risk of Breast Cancer [103] 465
References 465
25. Breast Diseases in Males 469
25.1 The Male Breast 469
25.2 Gynecomastia 469
25.3 Other Benign Breast Conditions 470
25.4 Breast Cancer in Males 471
25.4.1 Global Distribution 472
25.4.2 U.S. Incidence 472
25.4.3 Associated Factors and Conditions 472
25.4.4 Family History and Genetics 473
25.4.5 Histologies 474
25.4.6 Tumor Biology 475
25.4.7 Staging 475
25.4.8 Physical Findings 475
25.4.9 Imaging 475
25.5 Differential Diagnosis of Breast Masses in Males 476
25.5.1 Fine-Needle Aspiration-Based Evaluation of Breast Masses in Males 477
25.6 Breast Cancer in Males: Treatment and Outcomes 478
25.6.1 Surgery 478
25.6.2 Radiation 479
25.6.3 Adjuvant Chemotherapy 480
25.6.4 Hormone Therapy 480
25.6.5 Palliative Therapy 481
25.6.6 Prognostic Factors 481
25.6.7 Prognosis: Are BCM and BCF “Different” Diseases? A Critical Appraisal of the Literature 482
25.6.8 Similarities and Differences Between BCM and BCF: A Summary (Table 25.7) 484
25.7 Breast Cancer Survivorship Issues in Males 485
25.7.1 Follow-Up 485
25.7.2 Testing of Family Members 485
25.7.3 Tumor Registry 485
25.7.4 Psychological Issues/Resources/Support Groups 486
References 486
26. Breast Cancer in the Elderly 495
26.1 Introduction 495
26.2 Comorbidity in the Elderly Patient with Breast Cancer 496
26.3 Prevention 496
26.4 Screening 497
26.5 Treatment of Primary Breast Cancer 497
26.5.1 Surgery or Endocrine Therapy 497
26.5.2 Radiation 497
26.5.3 Management of the Axilla 498
26.6 Adjuvant Systemic Therapy 498
26.6.1 Treatment Benefit 498
26.6.2 Selecting Treatment 498
26.6.3 Treatment of Older Patients with Hormone Receptor Positive, HER-2 Negative Tumors 499
26.6.4 Treatment of Older Patients with HER-2 Positive Tumors 500
26.6.5 Treatment of Older Patients with ER- and PR-Negative and HER-2 Negative Tumors 500
26.7 Metastatic Disease 501
26.8 Clinical Trials 501
26.9 Conclusions 502
References 502
27. Breast Cancer in Younger Women 506
27.1 Introduction 506
27.2 Epidemiology 506
27.3 Risk Factors/Prognosis 506
27.4 Diagnosis 508
27.5 Tumor Characteristics 508
27.6 Management/Treatment of Early Breast Cancer 508
27.6.1 Surgery (Breast Conservingvs. Mastectomy) 508
27.6.2 Radiation 509
27.6.3 Chemotherapy 510
27.6.4 Endocrine Treatment 511
27.6.5 Targeted Treatment 512
27.7 Monoclonal Antibodies 512
27.8 Tyrosine Kinase Inhibitors 513
27.9 Vaccines 513
27.10 Side Effects of the Treatment 513
27.10.1 Surgery 513
27.10.2 Systemic Treatment 514
27.10.3 Radiation Therapy 514
27.11 Follow Up Recommendations and Survivors Care 515
27.12 Fertility Preservation 516
27.13 Breast Cancer Associated with Pregnancy (Lactation) 518
27.14 Fetal Exposure by Staging Procedures 520
27.15 Pregnancy After Breast Cancer 524
27.16 Psychosocial, Familial and Professional Aspects 525
27.17 In Conclusion 526
References 526
28. Psychological Support forthe Breast Cancer Patient 538
28.1 Diagnosis 538
28.2 Psychological Assessment 539
28.3 Effect of Hormonal Treatmenton Mood 539
28.4 Adherence to Hormonal Medications 539
28.5 Anxiety 540
28.6 Sleep 540
28.7 Cognitive Diffi culties 541
28.8 Overlap of Symptoms of Estrogen Deficiency and Depression 541
28.9 Fatigue 542
28.10 Prevalence of Major Depressive Disorder in Breast Cancer Patients 542
28.11 Treatment 542
28.12 Patients with Psychotic Illness 543
28.13 Conclusion 543
References 544
29. Management of the Patient with a GeneticPredisposition for Breast Cancer 547
29.1 Hereditary Breast Cancer 547
29.1.1 Somatic and Germline Genetics 547
29.2 Breast Cancer Syndromes 547
29.3 Identifi cation of High-risk Individuals 549
29.3.1 Family History 549
29.3.2 Personal Health History 550
29.4 Risk Assessment 550
29.4.1 Absolute Risk 551
29.4.2 Relative Risk 551
29.4.3 Predicting Development of Breast Cancer: Gail Modeland Claus Tables 551
29.4.4 Models for Predicting Presenceof a BRCA Gene Mutation: BRCAPro and BOADICEA 552
29.5 Genetic Testing 552
29.5.1 Genetic Education and Counseling 553
29.5.2 Interpretation of Test Results 554
29.6 Medical Management of High-Risk Individuals 554
29.6.1 Medical Management of a Woman with No Identifi able Mutation 555
29.6.2 Medical Management of Breast Cancer Predisposition Gene Mutation Carriers 555
29.6.3 Screening for Breast Cancerin Women 555
29.6.4 Screening for Breast Cancerin Men 556
29.6.5 Screening for Ovarian Cancer 556
29.6.6 Risk-reducing Mastectomy 556
29.6.7 Risk-Reducing Oophorectomy 557
29.6.8 Chemoprevention for Breast Cancer 558
29.6.9 Chemoprevention for Ovarian Cancer 559
29.6.10 Medical Management of Mutation Carriers Diagnosed with Breast Cancer 559
29.7 Information for Extended Family Members 559
29.8 Direct-to-Consumer Genetic testing 560
29.9 In summary 560
References 561
30. Chemoprevention of Breast Cancer 565
30.1 Introduction 565
30.2 Estrogen and Breast Cancer Risk 565
30.2.1 Estrogen in the Pathogenesis of Breast Cancer 565
30.2.2 Epidemiological Factors 565
30.2.3 Cohort Selection 566
30.3 Preclinical Models of Potential Chemopreventatives 566
30.3.1 Breast Cancer Xenografts 566
30.3.2 Carcinogen-induced Rat Mammary Tumors 566
30.4 SERMs in the Chemoprevention of Breast Cancer 567
30.4.1 Tamoxifen 567
30.4.1.1 Tamoxifen and Breast Cancer Risk Reduction 567
30.4.1.2 Tamoxifen Effects other than on the Breast 568
30.4.2 Raloxifene 569
30.4.2.1 Raloxifene and Breast Cancer Risk Reduction 569
30.4.2.2 Raloxifene Effects other than on the Breast 570
30.5 Other Possible Agents for Future Chemoprevention Trials 571
30.5.1 Pure Antiestrogens 571
30.5.2 Aromatase Inhibitors 571
30.5.3 Retinoids 572
30.5.4 Dietary Prevention 572
30.5.4.1 Flaxseed 573
30.5.4.2 Soya 573
30.5.4.3 Vitamin E 573
30.5.5 Oophorectomy 573
30.6 Considerations for Future Chemoprevention Trials 573
31. Design, Implementation,and Interpretation of Clinical Trials 580
31.1 Introduction 580
31.1.1 Highlights in the Evolution of Clinical Trials 580
31.1.2 History of Cancer Clinical Trial Cooperative Groups 582
31.2 Fundamental Features 583
31.2.1 Collaboration 583
31.2.2 Phases in Development and Testing of New Drugs 584
31.2.3 Explanatory and Pragmatic Considerations 586
31.2.4 Selection of the Primary Question for Investigation 588
31.3 Design Considerations 588
31.3.1 Assuring Precision and Eliminating Bias 588
31.3.2 Defining Study Outcomes 589
31.3.3 Choice of Control Group 590
31.3.4 Masking and Placebos 591
31.4 Sample Size and Study Power 592
31.4.1 Statistical Inference and Sample Size Considerations 592
31.4.2 Clinical Significance vs. Statistical Signifi cance 593
31.4.3 Statistical Significance and Study Power 594
31.4.4 Baseline Outcome Rates and Population Measures of Variability 594
31.4.5 Sample Sizes for Other Common Experimental Designs 594
31.4.6 Time-to-Event Outcomes 594
31.4.7 Sample Size Adjustments 595
31.5 Randomization Methods 595
31.5.1 An Example of Biased Coin Algorithm 598
31.6 Ethical and Related Considerations 599
31.6.1 Ethical Concerns Relatingto Randomization 600
31.6.2 Ethical Controversies in Randomization and NSABP Protocol B-06 601
31.6.3 Data Integrity 604
31.7 Conduct of the Clinical Trial 605
31.7.1 Interim Data Monitoring 605
31.8 General Analysis Considerations 608
31.8.1 Modeling Treatment Effects with Multivariable Models 611
31.8.2 Multiplicity Considerations 612
31.8.3 Analysis of Multiple Outcomes Under Competing Risks 613
31.8.3.1 One Sample Case 613
31.8.3.2 Comparing 1-KM Method and Nonparametric Cumulative Incidence Approach in NSABP B-04 Data 613
31.8.3.3 Two-Sample Comparison 614
31.8.3.4 Regression on Cumulative Incidence Function 614
31.8.3.5 Design Under Competing Risks Sample Size and Loss of Power614
31.8.4 Building and Validating Prediction Models 615
31.8.5 Interpretation 615
31.9 Reporting and Publication 616
31.10 Clinical Trial Overviews 616
References 617
32. Structure of Breast Care Center 621
32.1 Introduction 621
32.2 The National Accreditation Program for Breast Centers 621
32.3 NAPBC Standards 623
32.4 Center Leadership 623
32.4.1 Level of Responsibility and Accountability 623
32.4.2 Cancer Conference 624
32.4.3 Evaluation and Management Guidelines 625
32.5 Clinical Management 625
32.5.1 Interdisciplinary Patient Management 625
32.5.2 Patient Navigator 626
32.5.3 Breast Conservation 626
32.5.4 Sentinel Node Biopsy 627
32.5.5 Breast Cancer Surveillance 627
32.5.6 AJCC Staging 627
32.5.7 Pathology Reports 628
32.5.8 Diagnostic Imaging 628
32.5.9 Needle Biopsy 628
32.5.10 Ultrasonography 629
32.5.11 Stereotactic Core Needle Biopsy 629
32.5.12 Radiation Oncology 629
32.5.13 Medical Oncology 630
32.5.14 Nursing 630
32.5.15 Support and Rehabilitation 630
32.5.16 Genetic Counseling 631
32.5.17 Genetic Counseling for Breast Cancer 631
32.5.18 Genetic Testing for Breast Cancer 632
32.5.18.1 Breast Cancer Education for Women at Risk 632
32.5.19 Educational Resources 632
32.5.20 Reconstructive Surgery 632
32.5.21 Evaluation and Management of Benign Breast Disease 633
32.6 Research 633
32.6.1 Clinical Trial Information 633
32.6.2 Clinical Trial Accrual 634
32.7 Community Outreach 634
32.7.1 Prevention and Early Detection Programs 634
32.8 Professional Education 635
32.8.1 Breast Program Staff Education 635
32.9 Quality Improvement 635
32.9.1 Quality and Outcomes 636
32.10 Survey Process 637
32.11 Accreditation Awards 637
32.12 European Accreditation of Breast Units 637
32.13 Benefits of being a NAPBC Accredited Center 637
References 638
33. Medicolegal Pitfalls in Breast CancerDiagnosis and Management 639
33.1 Introduction 639
33.1.1 Magnitude of the Problem 639
33.1.2 Common Allegations in the Diagnosis or Management of Breast Cancer 640
33.2 Elements of Medical Malpractice 641
33.2.1 Malpractice Issues Related to Breast Cancer 642
33.3 The Litigation Process 647
33.3.1 What are the Common Questions that Lawyers Ask? 648
33.3.2 Patient-Physician and Physician-Physician Communication 648
33.3.3 Coping with a Lawsuit 649
33.3.4 What to do When You Are Sued 649
33.3.5 Summary 651
References 651
Index 653