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Book Details
Abstract
Get a quick, expert overview of clinically-focused topics and guidelines that are relevant to testing for HER2, which contributes to approximately 25% of breast cancers today. This concise resource by Drs. Sara Hurvitz, and Kelly McCann consolidates today’s available information on this growing topic into one convenient resource, making it an ideal, easy-to-digest reference for practicing and trainee oncologists.
Table of Contents
| Section Title | Page | Action | Price |
|---|---|---|---|
| Front Cover | Cover | ||
| HER2-Positive Breast Cancer | i | ||
| HER2-Positive Breast Cancer | iii | ||
| Copyright | iv | ||
| Dedication | v | ||
| List of Contributors | vii | ||
| Preface | xi | ||
| Acknowledgements | xiii | ||
| Contents | xv | ||
| I - BACKGROUND/TESTING | 1 | ||
| 1 - The Molecular Biology of HER2 and HER2-Targeted Therapies | 1 | ||
| DISCOVERY OF THE ONCOGENE ERBB | 1 | ||
| ERBB2/HER2/NEU GENE AMPLIFICATION IN HUMAN BREAST CANCER | 1 | ||
| HER2 IS A TYROSINE KINASE RECEPTOR | 2 | ||
| DRUGS TARGETING PATHOLOGIC HER2 SIGNALING | 4 | ||
| MECHANISMS OF RESISTANCE TO HER2-TARGETED THERAPIES | 9 | ||
| REFERENCES | 9 | ||
| 2 - HER2 Testing in the Era of Changing Guidelines | 13 | ||
| BACKGROUND | 13 | ||
| COMPANION DIAGNOSTICS AND US FOOD AND DRUG ADMINISTRATION DIAGNOSTIC CRITERIA | 13 | ||
| INFORM HER2 FISH Assay | 15 | ||
| HercepTest and Other IHC Companion Diagnostic Assays | 15 | ||
| PathVysion HER2 FISH Assay | 17 | ||
| In Situ HER2 Assays Using Bright-Field Microscopy | 20 | ||
| NGS and Foundation One CDx | 20 | ||
| 2007 ASCO-CAP GUIDELINES FOR HER2 TESTING | 20 | ||
| IHC Changes From the FDA-Approved Requirements | 21 | ||
| FISH Changes From FDA-Approved Requirements | 21 | ||
| Challenges With the 2007 ASCO-CAP Guidelines | 23 | ||
| 2013/2014 ASCO-CAP GUIDELINES FOR HER2 TESTING | 25 | ||
| IHC Testing | 25 | ||
| ISH Testing | 26 | ||
| Problems With ISH Testing according to the 2013/2014 Guidelines | 26 | ||
| USC/BCIRG-TRIO CENTRAL LABORATORY | 27 | ||
| Association of Each ASCO-CAP FISH Group With HER2 Protein Expression Level | 28 | ||
| Association of Each ASCO-CAP FISH Group With Clinical Outcomes | 28 | ||
| EXPECTATIONS | 29 | ||
| CONCLUSION | 31 | ||
| REFERENCES | 34 | ||
| II - ADVANCED DISEASE | 41 | ||
| 3 - Optimal First-Line Treatment of Advanced HER2-Positive Breast Cancer | 41 | ||
| INTRODUCTION | 41 | ||
| TRASTUZUMAB | 41 | ||
| THE ADDITION OF TRASTUZUMAB TO CHEMOTHERAPY | 41 | ||
| THE ADDITION OF OTHER DRUGS TO THE TRASTUZUMAB AND TAXANE BACKBONE | 43 | ||
| TRASTUZUMAB WITH OTHER CHEMOTHERAPY AGENTS | 45 | ||
| TRASTUZUMAB AS A SINGLE AGENT | 46 | ||
| PERTUZUMAB | 47 | ||
| TRASTUZUMAB EMTANSINE | 50 | ||
| LAPATINIB | 50 | ||
| NERATINIB | 52 | ||
| TRASTUZUMAB BIOSIMILARS | 52 | ||
| ENDOCRINE THERAPY WITH HER2 THERAPY | 53 | ||
| AMERICAN SOCIETY OF CLINICAL ONCOLOGY GUIDELINES | 55 | ||
| NATIONAL COMPREHENSIVE CANCER NETWORK GUIDELINES | 56 | ||
| TOXICITIES | 56 | ||
| ONGOING PHASE III TRIALS IN THE FIRST-LINE SETTING | 58 | ||
| LIMITATIONS OF CURRENT STUDIES AND FUTURE DIRECTIONS | 59 | ||
| REFERENCES | 60 | ||
| 4 - HER2-Positive Breast Cancer: Second Line and Beyond | 63 | ||
| INTRODUCTION | 63 | ||
| CONTINUING HER2-DIRECTED THERAPY BEYOND PROGRESSION ON TRASTUZUMAB | 64 | ||
| TRASTUZUMAB EMTANSINE IN HER2-POSITIVE METASTATIC BREAST CANCER | 66 | ||
| Trastuzumab Emtansine for Second-Line Therapy | 66 | ||
| Trastuzumab Emtansine Beyond Second Line | 66 | ||
| LAPATINIB COMBINATIONS IN HER2-POSITIVE METASTATIC BREAST CANCER | 66 | ||
| Lapatinib Plus Capecitabine | 67 | ||
| Lapatinib Plus Trastuzumab | 67 | ||
| Lapatinib Plus Vinorelbine | 68 | ||
| TRASTUZUMAB AND CHEMOTHERAPY COMBINATIONS IN HER2-POSITIVE METASTATIC BREAST CANCER | 68 | ||
| Trastuzumab Plus Vinorelbine | 70 | ||
| Trastuzumab Plus Capecitabine | 70 | ||
| Trastuzumab/Pertuzumab Plus Capecitabine | 70 | ||
| Trastuzumab Plus Gemcitabine | 71 | ||
| HORMONE RECEPTOR POSITIVE, HER2-POSITIVE METASTATIC BREAST CANCER | 71 | ||
| CONCLUSIONS | 72 | ||
| REFERENCES | 72 | ||
| 5 - Central Nervous System Metastases in HER2-Positive Breast Cancer | 75 | ||
| BACKGROUND | 75 | ||
| DIAGNOSIS | 75 | ||
| PROGNOSTIC FACTORS | 76 | ||
| TREATMENT | 76 | ||
| SURGICAL RESECTION | 76 | ||
| RADIATION THERAPY | 77 | ||
| Whole Brain Radiation | 77 | ||
| Brain-Directed Stereotactic Radiation | 78 | ||
| WBRT Versus Stereotactic Radiation | 80 | ||
| Stereotactic Radiation in Patients With More Than Four Brain Metastases | 80 | ||
| SYSTEMIC THERAPIES | 82 | ||
| Trastuzumab | 82 | ||
| Pertuzumab | 82 | ||
| Trastuzumab Emtansine | 83 | ||
| Lapatinib | 83 | ||
| Cytotoxic Chemotherapy | 83 | ||
| INVESTIGATIONAL APPROACHES AND FUTURE DIRECTIONS | 83 | ||
| HER2-Targeted Tyrosine-Kinase Inhibitors | 84 | ||
| Cell Cycle Inhibitors | 84 | ||
| Immunotherapy-Based Approaches | 85 | ||
| Targeting of the PI3K/Mammalian Target of Rapamycin Pathway | 85 | ||
| Cytotoxic Agents | 85 | ||
| Alternative Dosing Schedules | 85 | ||
| TREATMENT APPROACH | 86 | ||
| Initial Presentation | 86 | ||
| Subsequent Central Nervous System Progression After Initial Local Therapy | 86 | ||
| Isolated Central Nervous System Progression in the Absence of Extracranial Disease | 87 | ||
| CONCLUSIONS | 88 | ||
| REFERENCES | 88 | ||
| 6 - Neoadjuvant Treatment of HER2-Positive Breast Cancer—A Review | 95 | ||
| INTRODUCTION AND RATIONALE FOR NEOADJUVANT THERAPY IN HER2-POSITIVE PATIENTS | 95 | ||
| CLINICAL STUDIES FOR NEOADJUVANT ANTI-HER2 TREATMENT | 95 | ||
| Introduction of Trastuzumab Into the Neoadjuvant Therapy Setting | 95 | ||
| Lapatinib and Trastuzumab in the Neoadjuvant Treatment | 100 | ||
| Pertuzumab and Trastuzumab | 100 | ||
| Trastuzumab Emtansine (T-DM1) | 100 | ||
| CDK4/6 Inhibitors | 101 | ||
| Optimizing Neoadjuvant Chemotherapy | 101 | ||
| PCR AND PROGNOSIS: IMPLICATIONS FOR CLINICAL USE | 101 | ||
| EVALUATION OF MOLECULAR PREDICTORS OF RESPONSE | 101 | ||
| Genomic Instability | 101 | ||
| Gene Expression | 102 | ||
| Activating Mutations in Phosphatidylinositol 3-Kinase | 102 | ||
| Immune Responsiveness | 103 | ||
| CONCLUSIONS | 103 | ||
| REFERENCES | 103 | ||
| FURTHER READING | 105 | ||
| 7 - Adjuvant Therapy | 107 | ||
| INTRODUCTION | 107 | ||
| TRASTUZUMAB | 107 | ||
| Large Randomized Trials of Adjuvant Trastuzumab | 107 | ||
| Herceptin Adjuvant | 107 | ||
| North Central Cancer Treatment Group N9831 and National Surgical Adjuvant Breast and Bowel Project B-31 (Combined Analyses) | 108 | ||
| Breast Cancer International Research Group 006 | 110 | ||
| Small Randomized trials | 110 | ||
| Finland Herceptin Trial | 110 | ||
| Federation Nationale des Centres de Lutte Contre le Cancer-Programe Adjuvant Cancer Sein (FNCLCC-PACS04) Trial | 111 | ||
| Concurrent Versus Sequential Trastuzumab | 111 | ||
| Optimal Length of Therapy With Trastuzumab | 111 | ||
| Protocol of Herceptin Adjuvant with Reduced Exposure | 111 | ||
| The Hellenic Cooperative Oncology Research Group Study | 112 | ||
| The Persephone Trial | 112 | ||
| ShortHER | 112 | ||
| The Synergism or Long Duration | 112 | ||
| Anthracycline Versus Nonanthracycline Regimens | 112 | ||
| DUAL HER2 BLOCKADE | 112 | ||
| PERTUZUMAB | 113 | ||
| Adjuvant Pertuzuamb and Herceptin in Initial Therapy of Breast Cancer | 113 | ||
| Adjuvant Lapatinib | 114 | ||
| Tykerb Evaluation After Chemotherapy Trial | 114 | ||
| The Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization Trial | 114 | ||
| NERATINIB | 114 | ||
| ExteNET Trial | 114 | ||
| BEVACIZUMAB | 115 | ||
| BETH Trial | 115 | ||
| ONGOING STUDIES | 115 | ||
| Ado-Trastuzumab Emtansine | 115 | ||
| Katherine Trial | 115 | ||
| ATEMPT Trial | 115 | ||
| Trial of Adjuvant T-DM1 for Older Patients With HER2-Positive BC | 115 | ||
| NSABP-B47 | 116 | ||
| CONCLUSIONS | 116 | ||
| REFERENCES | 116 | ||
| 8 - Hormone Receptor and Human Epidermal Growth Factor Receptor 2 Co-expressing Tumors: Overview of Clinical Practi ... | 119 | ||
| INTRODUCTION | 119 | ||
| PROGNOSTIC IMPLICATIONS OF PATHOLOGIC COMPLETE RESPONSE AMONG PATIENTS WITH HR+/HER2+ BREAST CANCER | 120 | ||
| CORRELATION BETWEEN IMMUNOHISTOCHEMISTRY AND BC MOLECULAR SUBTYPES AMONG HR+/HER2+ TUMORS | 120 | ||
| EFFICACY OF ANTI–HER2-BASED NEOADJUVANT THERAPY IN HR+/HER2+ PATIENTS | 122 | ||
| NOVEL THERAPIES ON THE HORIZON FOR HR/HER2 CO-EXPRESSING TUMORS | 128 | ||
| CONCLUSION | 130 | ||
| REFERENCES | 130 | ||
| 9 - Deescalating Treatment in the Adjuvant Setting in Low-Risk HER2-Positive Breast Cancer | 135 | ||
| INTRODUCTION | 135 | ||
| DEESCALATING THERAPY FOR SMALL TUMORS | 135 | ||
| USING BIOMARKERS TO DEESCALATE THERAPY | 138 | ||
| Intrinsic Breast Cancer Molecular Subtypes | 138 | ||
| PI3K-AKT Pathway Alterations | 138 | ||
| Immune Biomarkers | 139 | ||
| NEW CLINICAL TRIAL DESIGNS: USING RESPONSE TO PREOPERATIVE THERAPY TO DEESCALATE THERAPY | 139 | ||
| CONCLUSION | 140 | ||
| REFERENCES | 140 | ||
| III - TOXICITY CONSIDERATIONS | 143 | ||
| 10 - Cardiac Toxicity of HER-2 Targeted Regimens | 143 | ||
| INTRODUCTION | 143 | ||
| PROPOSED MECHANISM OF HER2 CARDIOTOXICITY | 143 | ||
| CLINICAL TRIALS AND INCIDENCE OF HER2 CARDIOTOXICITY | 145 | ||
| Clinical Incidence | 145 | ||
| Risk Factors | 147 | ||
| Cardiac Recovery | 148 | ||
| CARDIOTOXICITY OF OTHER HER2 BLOCKING AGENTS | 149 | ||
| Monoclonal Antibodies: Trastuzumab Emtansine and Pertuzumab | 149 | ||
| Tyrosine Kinase Inhibitors: Lapatinib, Afatinib, and Neratinib | 150 | ||
| DETECTION OF CARDIOTOXICITY | 150 | ||
| Multigated Cardiac Blood Pool Acquisition | 150 | ||
| Cardiac Magnetic Resonance Imaging | 150 | ||
| Transthoracic Echocardiography | 152 | ||
| DETECTION OF SUBCLINICAL CARDIOTOXICITY | 153 | ||
| Strain Imaging | 153 | ||
| Cardiac Biomarkers | 156 | ||
| SURVEILLANCE OF TRASTUZUMAB CARDIOTOXICITY | 156 | ||
| Prechemotherapy Surveillance | 156 | ||
| Surveillance During Chemotherapy | 158 | ||
| Postchemotherapy Surveillance | 158 | ||
| Surveillance With Biomarkers and Strain Imaging | 158 | ||
| PREVENTION AND TREATMENT STRATEGIES | 159 | ||
| Primary Prevention | 159 | ||
| Secondary Prevention | 162 | ||
| FUTURE AVENUES | 162 | ||
| REFERENCES | 167 | ||
| 11 - Noncardiac Toxicity of HER2-Targeted Therapy | 171 | ||
| INTRODUCTION | 171 | ||
| TRASTUZUMAB | 171 | ||
| LAPATINIB | 172 | ||
| PERTUZUMAB | 173 | ||
| TRASTZUMAB EMTANSINE | 175 | ||
| NERATINIB | 175 | ||
| CONCLUSIONS | 176 | ||
| REFERENCES | 176 | ||
| IV - THERAPIES ON THE HORIZON | 179 | ||
| 12 - Novel Non–HER2-targeted Therapies in HER2+ Breast Cancer | 179 | ||
| INTRODUCTION | 179 | ||
| CDK4/6 INHIBITORS | 179 | ||
| Preclinical Data for Targeting CDKs in HER2+ Breast Cancer | 180 | ||
| Clinical Studies of CDK Inhibitors in HER2+ Breast Cancer | 181 | ||
| Side Effect Profile | 181 | ||
| PI3K PATHWAY INHIBITORS | 181 | ||
| Preclinical Data for Targeting the PI3K/mTOR Pathway in HER2+ Breast Cancer | 181 | ||
| PI3K Pathway Activation and Resistance to HER2-Directed Therapies in the Clinic | 184 | ||
| Clinical Studies of PI3K Pathway Inhibitors | 184 | ||
| mTOR and dual inhibitors | 184 | ||
| AKT inhibitors | 185 | ||
| PI3K inhibitors | 185 | ||
| Side Effect Profile | 187 | ||
| ANTIANGIOGENIC AGENTS | 187 | ||
| Preclinical Data Supporting the Use of Antiangiogenic Agents in HER2+ Breast Cancer | 188 | ||
| Clinical Studies of Antiangiogenic Agents in HER2+ Breast Cancer | 188 | ||
| Bevacizumab in advanced disease | 188 | ||
| Ziv-aflibercept and ramucirumab | 189 | ||
| Antiangiogenic Tyrosine Kinase Inhibitors | 189 | ||
| Adjuvant/Neoadjuvant Trials | 190 | ||
| Side Effect Profile | 191 | ||
| DUAL HER2/EGFR INHIBITORS | 191 | ||
| Preclinical Data Supporting Dual/Pan HER Family Inhibitors | 191 | ||
| Multi-HER Inhibitors in Advanced Disease | 191 | ||
| Multi-HER Inhibitors in Adjuvant/Neoadjuvant Therapy | 197 | ||
| Side Effect Profile | 199 | ||
| OTHER GROWTH FACTOR PATHWAYS | 199 | ||
| PreClinical Data for IGF-1R, FGFR, and c-MET in Anti-HER2 Inhibitor Resistance | 199 | ||
| Clinical Trials | 200 | ||
| Side Effect Profile | 202 | ||
| IMMUNOTHERAPY | 202 | ||
| Preclinical Data Supporting Immunotherapy in HER2+ Disease | 203 | ||
| Clinical Trials with Immunomodulatory Agents | 203 | ||
| Side Effect Profile | 203 | ||
| PARP INHIBITORS | 205 | ||
| CONCLUSION | 205 | ||
| REFERENCES | 206 | ||
| 13 - Harnessing the Immune System in HER2+ Disease | 213 | ||
| INTRODUCTION | 213 | ||
| THE IMMUNE MILIEU OF HER2+ TUMORS | 213 | ||
| The Adaptive Immune System: T Lymphocytes and B Lymphocytes | 213 | ||
| Tumor-infiltrating lymphocytes predict response to chemotherapy and HER2-targeted therapy in HER2+ disease | 214 | ||
| A type 1 (antitumor) immune environment is progressively lost during HER2 oncogenesis and replaced with a type 2 (tumor-tol ... | 216 | ||
| The Innate Immune System in HER2+ Breast Cancer; Dendritic Cells, Natural Killer Cells, and Macrophages | 217 | ||
| Dendritic cells in HER2+ breast cancer | 217 | ||
| Natural killer cells are decreased and their function altered in HER2+ breast cancer | 218 | ||
| Macrophages and mast cells are immunosuppressive and associated with worse clinical outcome, whereas γδ T cells are associa ... | 219 | ||
| IMMUNOMODULATING EFFECTS OF HER2-TARGETED ANTIBODIES | 219 | ||
| HER2-Specific Monoclonal Antibody Therapy: Trastuzumab | 220 | ||
| Trastuzumab response and TILs | 220 | ||
| Trastuzumab therapy increases HER2-specific Th1 immunity in HER2+ breast cancer | 220 | ||
| Trastuzumab mediates anticancer activity principally through antibody-dependent cellular cytotoxicity involving NK cells | 220 | ||
| HER2-Specific Monoclonal Antibody Therapy: Pertuzumab | 222 | ||
| Pertuzumab mediates ADCC similar to trastuzumab and may augment ADCC when used in combination with trastuzumab | 222 | ||
| IMMUNE MODULATION WITH CYTOTOXIC THERAPY | 222 | ||
| Taxanes and Immune Modulation in HER2+ Breast Cancer | 222 | ||
| Cyclophosphamide | 223 | ||
| HER2 VACCINES | 223 | ||
| IMMUNE CHECKPOINT BLOCKADE | 224 | ||
| CONCLUSION | 225 | ||
| REFERENCES | 225 | ||
| 14 - Biosimilars for HER2-Positive Breast Cancer | 231 | ||
| INTRODUCTION | 231 | ||
| REQUIREMENTS FOR BIOSIMILARITY | 231 | ||
| ANALYTIC ASSESSMENT OF BIOSIMILARS | 232 | ||
| CLINICAL STUDIES | 232 | ||
| CLINICAL TRIALS | 233 | ||
| PHARMACOVIGILANCE | 235 | ||
| EXTRAPOLATION AND INTERCHANGEABILITY | 236 | ||
| Naming | 236 | ||
| FUTURE STEPS | 236 | ||
| REFERENCES | 236 | ||
| Index | 239 | ||
| A | 239 | ||
| B | 240 | ||
| C | 240 | ||
| D | 241 | ||
| E | 241 | ||
| F | 242 | ||
| G | 242 | ||
| H | 242 | ||
| I | 243 | ||
| K | 243 | ||
| L | 244 | ||
| M | 244 | ||
| N | 244 | ||
| O | 245 | ||
| P | 245 | ||
| Q | 246 | ||
| R | 246 | ||
| S | 246 | ||
| T | 246 | ||
| U | 247 | ||
| V | 247 | ||
| W | 247 | ||
| Z | 247 |