Breast Cancer Management and Molecular Medicine: Towards Tailored Approaches Book

Role of Modeling in Pharmacotherapeutics     3
Introduction     3
The Skipper-Schabel Model and its Relevance     4
Gompertzian Growth and the Norton-Simon Hypothesis     7
The Impact Of Sequential Chemotherapy     11
Dose Size     15
Scheduling: What about Dose Density?     16
Sequential Therapy and Dose Density in the Clinic     17
Some Cautions Regarding Dose Density     20
Gompertzian Growth is Biologically Driven     23
PET and Nuclear Medicine Imaging of the Breast     31
Introduction     31
[superscript 18]FDG-PET     31
Primary Breast Cancer Detection     32
Axillary Lymph Nodes     32
Metastatic Disease and Staging     33
Locally Advanced Breast Cancer: Response to Chemotherapy     34
Prognostic Assessment     34
Reimbursement     35
[superscript 99m]Tc-Sestamibi and [superscript 99m]Tc-Tetrofosmin     35
Dedicated Devices for Nuclear Medicine Breast Imaging     36
Summary     38
Functional Radiologic Imaging in Breast Cancer     43
Introduction     43
Magnetic Resonance Imaging     43
Nuclear Medicine     48
[superscript 18]F-Fluorodeoxyglucose     48
Amino Acid Metabolism     54
L-[1-[superscript 11]C]-Methionine     54
L-[1-[superscript 11]C]-Tyrosine     54
Matrix Metalloproteinase Inhibitor Radiotracer     55
[superscript 99m]Tc-rh-Annexin V Uptake as an Indicator of Apoptosis     55
Monitoring Resistance to Chemotherapy     55
Tumor Hypoxia     56
Conclusion     57
Prevention of Breast Cancer     63
Introduction     63
Surgery For Breast Cancer Risk Reduction     63
Prophylactic Mastectomy     63
Prophylactic Oophorectomy     66
Selection for Prophylactic Surgery     68
Chemoprevention of Breast Cancer     69
Scientific Basis for the Prevention of Estrogen-Receptor-Positive Breast Cancer     69
Clinical Prevention of Estrogen-Receptor-Positive Breast Cancer: Tamoxifen     70
The NSABP P1 Trial     70
The Royal Marsden Prevention Trial     74
The Italian Prevention Trial     74
The IBIS-I Trial     75
Overview of Studies     76
Identifying Candidates for Tamoxifen Chemoprevention      76
Clinical Prevention of ER-Positive Breast Cancer: Raloxifene     79
Clinical Prevention of ER-Positive Cancer: Aromatase Inhibitors     81
Prevention of ER-Negative Breast Cancer     83
Retinoids     83
Cyclooxyganase-2 Inhibitors     84
Epidermal Growth Factor Receptor Inhibitors     85
Current Progress and Future Challenges     86
DCIS: Pathology and Molecular Markers     99
Introduction     99
Histological Classification     101
Ductal Carcinoma In Situ     101
Intraductal Epithelial Proliferations     104
Genetic Alterations     104
Oncogenes     105
Amplification of the HER-2 Gene is Frequent in DCIS     106
Cyclin D1 Protein Overexpression in the Precursors of Invasive Breast Cancer     107
C-MYC Gene Amplification: Involved in the Progression of DCIS to Invasion?     107
Tumor Suppressor Genes     108
Inactivation of the p53 Gene in DCIS     108
E-Cadherin Gene Inactivation in LCIS but not in DCIS     109
Other Tumor Suppressor Genes?     109
Genetic Alterations Detected by LOH and CGH     110
A Multistep Model for Breast Carcinogenesis      112
Discussion and Future Prospects     113
Ductal Carcinoma In Situ: a Modern Approach to Patient Management     125
Introduction     125
Treatment Options     126
Local Treatment Options     126
Lumpectomy or Wide Excision Alone With or Without RT     126
Mastectomy     127
Treatment Options for Hormone-Responsive DCIS     127
Biomarkers of Disease and Outcome     128
Preventing Contralateral Breast Cancer     130
Decision-Making Tools for Treatment of Ipsilateral DCIS     131
Novel Therapies for Prevention     133
Conclusions     134
Ductal Carcinoma In Situ: Systemic Treatment     137
Introduction     137
Molecular Characteristics of DCIS     138
Systemic Treatment of HR-Positive DCIS     141
Tamoxifen Treatment for DCIS     141
ER status of DCIS in NSABP B-24     143
The United Kingdom, Australia, and New Zealand DCIS Trial     144
Aromatase Inhibitors as a Treatment for DCIS     146
Treatment of Hormone-Independent DCIS     148
Promising Novel Therapies for Hormone-Independent DCIS     149
Cyclooxygenase-2 Inhibitors      149
Inhibition of the EGFR Family in DCIS     150
Future Directions In Treating DCIS     151
Tailored Surgery for Early Breast Cancer: Surgical Techniques     161
Skin-Sparing Mastectomy     161
Anatomical Considerations     161
Oncological Considerations     163
Technical Considerations     163
Patient Selection     163
Types of Skin-Sparing Mastectomy     165
Skin-flap Elevation     166
Immediate Reconstruction     168
Complications     172
Oncoplastic Surgery of the Breast     172
Local Tissue     173
Breast Reshaping     176
Distant Flaps     177
Tailored Surgery for Early Breast Cancer: Biological Aspects     183
Introduction     183
Molecular Biology and Behavior of the Cancer in the Breast     184
Prediction of Lymph Node Involvement from the Primary Tumor     186
Predicting Further Lymph Node Involvement after SLN Biopsy     188
Molecular Biology and Tailored Surgery for the Individual Patient: Conclusion     193
Tailored Surgery for Early Breast Cancer: the Very Young Woman     199
Incidence and Prevalence     199
Risk Factors     199
Family History     200
Genetic Testing for Breast Cancers     200
Endogenous and Exogenous Hormonal Exposure     201
Racial Influence     202
Radiation Exposure     202
Presentation     203
Clinical Assessment and Diagnostic Procedure     203
Tumor Characteristics     204
Treatment     205
Breast-Conservation Therapy     205
Mastectomy     205
Prophylactic Mastectomy     206
Local and Distant Recurrence Rates and Prognosis     206
Late Effects of Treatment     209
Conclusions     210
Tailored Surgery for Older Women with Breast Cancer     215
Introduction     215
The Nature of Breast Cancer in Older Women     215
Burden of Other Illness     217
Early Diagnosis     217
Treatment of the Axilla     218
Mastectomy as a Treatment     220
The Role of Tamoxifen     221
The Role of Radiotherapy     223
Selection of Local Treatment     225
Tailored Radiotherapy for Breast Cancer Stages I and II: Technical Aspects     235
Introduction      235
Wide Excision Alone Trials     235
Studies Addressing the Benefit of a Tumor-Bed Boost after Whole-Breast RT     236
Tamoxifen as a Substitute for RT After Lumpectomy     238
Accelerated, Whole-Breast RT Fractionation Schedules     238
Accelerated, Partial-Breast Irradiation     239
Catheter-Based Interstitial Brachytherapy     239
MammoSite Balloon Catheter     241
Three-Dimensional Conformal External-Beam Irradiation     242
Three-Dimensional Conformal PBI Technique     243
Simulation and Treatment Planning     243
Dose-Volume Constraint Guidelines     244
Three-dimensional Treatment Planning and Intensity-Modulated RT     245
Virtual Simulation/3D Treatment Planning     245
Intensity-Modulated RT     246
Whole-Breast IMRT     246
Regional Nodal IMRT/Breath-Hold Techniques     249
Conclusions     252
Breast Cancer Management in the Era of Molecular Medicine: Tailored Radiotherapy - Clinical and Biological Aspects     257
Overview     257
Introduction     258
Hormone Receptors     259
Her2/neu Expression     261
P53 Expression      264
Proliferative Markers     266
Other Selected Molecular Markers     267
Genetic Factors and Local-Regional Management of Breast Cancer     268
Conclusion     273
Early Breast Cancer (Stage I and II): Tailored Radiotherapy for Very Young Women     279
Introduction     279
Age and Locoregional Recurrences     279
Clinical, Pathological, and Biological Features Associated with Breast Cancer in Very Young Patients     281
Respective Influence of Young Age and Other Associated Factors on the Risk of Breast Recurrence     283
Tailoring Radiotherapy in Young Patients     284
Prediction of Radiation Sensitivity and Curability     284
Modulation of Response to Radiotherapy     285
Radiation Dosage     285
Biological Response Modifiers and Radiotherapy     286
Conclusions     286
The Elderly and Breast Cancer Radiotherapy     291
Introduction     291
Effects of Age     291
Life Expectancy and Comorbidity     291
Biology     292
Psychology     293
Treatment     294
Breast-Conservation Therapy     294
Newer Techniques     295
Scheduling of Radiation Therapy and Other Adjuvant Treatment     297
Postmastectomy Radiotherapy     298
Palliative Radiotherapy     299
Summary     300
Early Breast Cancer (Stage I and Stage II): Tailored Systemic Therapy for Endocrine-Resistant Breast Cancer     309
Introduction     309
The Use of Molecular Markers to Identify Low-Risk Endocrine-Resistant Disease     309
Cellular Markers of Metastatic Potential     312
Tumor Grade     312
S-Phase Fraction     313
[[superscript 3]H]-Thymidine Labeling Index     313
Molecular Markers of Metastatic Potential     314
HER-2     314
Cyclin E     314
Other Cell Cycle Regulators     315
Urokinase-Type Plasminogen Activator and Plasminogen Activator Inhibitor-1     315
Genetic Markers of Metastatic Potential     315
The "Amsterdam" Profile     315
Discussion     316
The Use of Molecular Markers to Select Adjuvant Chemotherapy     316
HER-2, Topoisomerase-II[alpha] and Anthracyclines     318
Thymidylate Synthase and 5-Fluorouracil     319
Tubulin Polymorphisms and Taxanes     319
Discussion     320
Early Breast Cancer (Stage I and Stage II): Tailored Systemic Therapy for Endocrine-Responsive Breast Cancer     327
Introduction     327
Tailored Endocrine Therapy     327
Predictive and Prognostic Factors for Endocrine Therapy     328
Tailored Chemotherapy     333
Treatment Summary     339
Future Directions     342
Tailored Therapy for Breast Cancer in Very Young Women     349
Introduction     349
Incidence and Prevalence     349
Age as a Prognostic Factor in Breast Cancer     350
Breast Cancer Outcomes by Age: Population Studies     350
The American Experience     350
The European Experience     351
Breast Cancer Outcomes by Age: Institutional Data     351
The American Experience     351
The European Experience     352
Breast Cancer Outcomes by Age: Cooperative Group Studies/Tumor Banks     352
Prognostic Factors in the Young     354
Stage at Presentation     354
Tumor Size     354
Nodal Status     355
Grade     355
HER2-neu (c-erbB-2) Expression     355
Overexpression of p53     355
Hormone Receptor Status      356
S-phase and Ki67 Expression     356
Lymphovascular Invasion     356
Novel Prognostics: Gene Expression Profiling     356
Age as an Independent Prognostic Factor     357
Treatment of Breast Cancer in Young Women     359
Consensus Guidelines     359
Chemotherapy     359
Endocrine Therapy     361
Chemoendocrine Therapy     362
Radiation Therapy     362
Special Considerations in the Young     363
Genetic Predisposition     363
Quality of Life     364
Premature Menopause     364
Breast Cancer Diagnosed during Pregnancy     365
Breast Cancer and Subsequent Fertility     365
Conclusions and Caveats Regarding Tailored Therapy in Younger Women     366
Tailored Systemic Therapy for the Elderly Woman     375
Epidemiology     375
Tumor Biology     375
Life Expectancy for Older Women     376
Comorbidities-Prevalence and Impact on Decision Making     377
HER-2/neu Testing in Older Women with Early Stage Breast Cancer     379
Adjuvant Systemic Therapy     380
Hormonal Therapy     380
Tamoxifen      380
Aromatase Inhibitors: Arimidex, Letrozole, and Exemestane     382
Primary Endocrine Management     384
Chemotherapy     384
Chemotherapy in Addition to Endocrine Therapy in the Adjuvant Setting     386
Neoadjuvant Therapy in Early Stage Disease     388
Integrating the Data for Older Women into an Individualized Approach to Adjuvant Systemic Therapy     389
Older Patients and Clinical Trials     393
Locoregional Therapy Following Neoadjuvant Chemotherapy: an Evolving Paradigm of Treatment Individualization     401
Introduction     401
Appropriate Tumor Assessment Before, During, and After Neoadjuvant Chemotherapy and its Effects on Locoregional Management     402
Use of Core Needle Biopsy vs Fine-Needle Aspiration for Initial Diagnosis and Biomarker Assessment     402
Clinical Assessment of the Extent of Primary Breast Tumor Before, During, and After Neoadjuvant Chemotherapy     403
Identifying the Exact Location of the Tumor Bed in Cases of Clinical and/or Pathologic Complete Response     405
Clinical and Radiologic Assessment of Axillary Nodal Status Before Neoadjuvant Chemotherapy     406
Locoregional Therapy Considerations Following Neoadjuvant Chemotherapy     407
Surgical Management of the Primary Breast Tumor      407
Ipsilateral Breast Tumor Recurrence Following Neoadjuvant Chemotherapy and Breast-Conserving Surgery     408
Breast Reconstruction after Neoadjuvant Chemotherapy and Mastectomy     409
Surgical Management of Axillary Nodes     409
Issues Regarding Locoregional Radiotherapy Following Neoadjuvant Chemotherapy and Surgery     414
Future Directions in Locoregional Therapy after Neoadjuvant Chemotherapy     415
Medical Therapy of Locally Advanced Breast Cancer     427
Introduction     427
Diagnosis     427
Prognostic and Predictive Factors     428
Therapy     429
Local Therapy     429
Medical Therapy     430
Inflammatory Breast Cancer     439
Therapy for Inflammatory Breast Cancer     439
Conclusion     440
Metastatic Breast Cancer: Tailored Endocrine Therapy for Premenopausal Women     451
Introduction     451
Ovarian Ablation for Treatment of Metastatic Breast Cancer     451
Background     451
Methods of Ovarian Ablation     452
Oophorectomy     452
Ovarian Irradiation     452
Ovarian Suppression with LHRH Agonists     452
Comparison of Methods of Ovarian Ablation     453
Tamoxifen for Treatment of Metastatic Breast Cancer     454
Background     454
Tamoxifen Withdrawal     455
Tamoxifen Compared to Ovarian Ablation or Suppression     455
Combined Endocrine Therapy with Ovarian Suppression and Tamoxifen     456
Aromatase Inhibitors for Treatment of Metastatic Breast Cancer     457
Background     457
Combined Endocrine Therapy with Selective Aromatase Inhibitors and LHRH Agonists     458
Sex Steroids for Treatment of Metastatic Breast Cancer     458
Future Considerations     459
Use of HER2/neu Status to Select Therapy     459
Conclusion     459
Metastatic Breast Cancer: Tailored Endocrine Therapy for Postmenopausal Women     465
Introduction     465
Tailored Treatment Approaches to Endocrine Therapy for Breast Cancer     465
Efficacy Issues in Tailored Endocrine Therapy for Advanced Disease     466
Selective Estrogen-Receptor Downregulators     469
High-Dose Estrogen     470
The Use of HER2 to Tailor Endocrine Therapy for Advanced Disease?     470
Combination Therapies with Signal Transduction Inhibitors     471
New Technologies to Assess the Endocrine Therapy Resistance Problem     472
Oncotype DX     472
Conclusion     474
Metastatic Breast Cancer: Tailored Chemotherapy for the Elderly Woman     479
Introduction     479
Clinical Definition of Age     479
Assessment of the Elderly Patient with Cancer     481
Cancer Chemotherapy in the Elderly Patient     484
Pharmacokinetics     484
Absorption     484
Distribution     485
Metabolism     485
Excretion     485
Pharmacodynamics in the Elderly Patient     489
Myelotoxicity     489
Mucositis     490
Cardiotoxicity     490
Neurotoxicity     491
Chemotherapy Regimens in the Elderly     491
The Anthracyclines     491
The Taxanes     493
Vinorelbine     494
Capecitabine     495
Gemcitabine     495
Clinical Trials     496
Conclusion     496
Treatment of Brain Metastases from Breast Cancer     505
Clinical Features     505
Radiosurgery: Definition     507
Treatment Algorithm     508
Radiobiological and Technical Principles for Radiation Treatment     510
LINAC     510
Gamma Knife Radiosurgery     511
Proton-Beam Therapy     512
Toxicity     513
Institutional Experience     514
Patient and Brain Metastasis Characteristics     514
Treatment Characteristics     515
Results     515
Control of Brain Metastases     515
Survival     515
Discussion     518
Local Recurrence     518
Survival     518
Conclusions     521
Surgical Management of Breast Cancer Liver Metastases     525
Introduction     525
Surgical Management of Breast Cancer Liver Metastases: Rationale     525
Metastases from Breast Cancer are Frequently Isolated to the Liver     525
Metastatic Deposits in the Liver may Give Rise to Further Dissemination to Other Organs     526
Cure of Metastatic Breast Cancer is Unusual Using Chemotherapy Alone     526
Liver Metastases are Particularly Resistant to Most Hormonal and Chemotherapeutic Agents     527
One Alternative is High-Dose Chemotherapy, which has Considerable Attendant Morbidity and Mortality     527
Hepatic Resection can be Performed with Mortality Rates Well Below 2%     528
New Models of the Development of Breast Cancer Metastases Suggest that Achievement of a Complete Response is Most Critical for Long-Term Control of the Disease     528
Surgical Management of Breast Cancer Liver Metastases: Options     529
Resection of Breast Cancer Liver Metastases: the Concept of "Adjuvant Surgery"     529
Radio