Breast Cancer Biology for the Radiation Oncologist (Medical Radiology)

This is the first textbook of its kind devoted to describing the biological complexities of breast cancer in a way that is relevant to the radiation oncologist. Radiation Oncology has long treated breast cancer as a single biological entity, with all treatment decisions being based on clinical and pathologic risk factors. We are now beginning to understand that biological subtypes of breast cancer may have different risks of recurrence as well as different intrinsic sensitivity to radiotherapy. Multi-gene arrays that have for years been used to predict the risk of distant recurrence and the value of systemic chemotherapy may also have utility in predicting the risk of local recurrence. Additionally, the targeted agents used to treat breast cancer may interact with radiotherapy in ways that can be beneficial or undesirable. All of these emerging issues are extensively discussed in this book, and practical evidence-based treatment recommendations are presented whenever possible. Contents 5 Contributors 6 Biological Subtypes of Breast Cancer 7 Abstract 7 1 Molecular Subtypes of Breast Cancer 8 2 How Subtypes May Affect Response to Therapy? 9 3 How Subtypes May Impact Prognosis? 9 4 How Subtypes May Affect Patterns of Failure? 10 5 Summary 11 References 11 Gene Amplification of ErbB-2: From Gene to Therapy 13 Abstract 13 1 Gene Amplification: An Oncogenic Driver 13 2 Common Gene Amplifications in Breast Cancer 14 3 ErbB-2 Signaling Pathway (Fig. 1) 14 4 ErbB-2 Gene Amplification and Overexpression in Breast Cancer 14 5 Mechanisms of Action (Fig. 2) 15 6 Mechanisms of Resistance 15 6.1 Functional Redundancy Among ErbB Family Members 16 6.2 Role for Loss of Negative Regulators 17 6.3 Accumulation of Soluble p95-ErbB-2 17 6.4 Role for MUC4: Altered Receptor--Antibody Interaction 17 6.5 Crosstalk Between ErbB-2 and Notch Signaling Pathways 18 7 Alternative Treatment Options for ErbB-2-Overexpressing Breast Cancer 18 8 Conclusions 18 Further Reading 18 Current Clinical Role of Genetic Profiling in Breast Cancer 20 Abstract 20 1 Introduction 20 2 Gene Expression Profiling 21 3 21 Gene RT-PCR Assay (Oncotype DX) 21 4 70 Gene Signature (MammaPrint) 27 5 The HOXB13:IL17BR Ratio 30 6 Theros Breast Cancer Index 31 7 Rotterdam 76-Gene Signature 31 8 Mammostrat 31 9 PAM-50 32 10 EndoPredict---11 Genes 32 11 Genomic Grade Index--97 Genes 33 12 Wound-Response Gene Expression Signature 33 13 Comparison of Different Genetic Profiles 33 14 Limitations 35 15 Conclusion 35 References 36 Biology of DCIS and Progression to Invasive Disease 40 Abstract 40 1...What is Ductal Carcinoma In Situ? 41 2...The Biology of DCIS 42 2.1 The Genome and Transcriptome of Invasive Carcinoma 43 2.2 The Genome and Transcriptome of DCIS 43 2.3 Molecular Markers of DCIS 43 3...Progression of DCIS to Invasive Disease 46 3.1 Predictive Markers of DCIS Progression 46 3.2 Models of DCIS Progression 46 3.3 Role of the Microenvironment 48 4...Future Directions and Challenges 49 5...Summary 50 Acknowledgments 51 References 51 Cancer Stem Cells and Radiotherapy 54 Abstract 54 1...Introduction 54 2...CSC-Mediated Tumor Repopulation 55 3...Enhanced DNA Repair in CSC Radioresistance 56 4...Other Prosurvival Signaling Network in CSCs 57 5...NF kappa B-Initiated Pro-survival Network 57 6...HER2 and Breast Cancer Radioresistance 58 7...NF kappa B and HER2 Crosstalk in Signaling Breast Cancer Radioresistance 59 8...Conclusion 59 References 60 Genetic Basis of Normal Tissue Radiosensitivity and Late Toxicity in Breast Cancer 63 Abstract 63 1 Introduction 63 2 Cellular Studies Predictive of Radiation Sensitivity 64 3 BRCA1 and BRCA2 Mutations 64 4 Ataxia-Telangiectasia and the ATM Gene 65 5 XRCC1 Variants 66 6 TGFB1 67 7 Other Polymorphisms Implicated in DNA Repair and Radiation Toxicity 68 8 The RAPPER Trial: The End of Radiogenomics as We Know It 71 9 Outlook 71 References 72 Genetic Syndromes and Radiotherapy in Breast Cancer 75 Abstract 75 1 Introduction 75 1.1 BRCA-Associated Breast Cancer 76 2 Background of Breast-Conserving Surgery and Radiation 76 3 Breast Cancer and Second Malignancies in BRCA Carriers 77 4 Breast-Conserving Surgery and Radiation in BRCA Carriers 77 5 Comparison of Breast-Conserving Surgery and Mastectomy in BRCA Carriers 79 6 Breast-Conserving Surgery and Partial Breast Irradiation in BRCA Carriers 79 7 We Will Now Examine Some of the Intermediate to Low Penetrance Genes that Play a Role in Heritable Breast Cancer 79 7.1 Other Genetic Syndromes Associated with Breast Cancer 79 7.1.1 CHEK2 79 7.1.2 ATM 80 7.1.3 TP53 80 7.1.4 RAD50 81 7.1.5 PALB2 81 8 Conclusions 81 References 82 Experimental Therapies in Breast Cancer 85 Abstract 85 1 Introduction 85 2 Molecular Approaches 86 3 Intralesional 87 4 Nanomaterials 87 4.1 Organic-Based Nanomaterials 88 4.1.1 Liposomal, Micellar, and Polymeric Systems 88 4.1.2 Dendrimers 89 4.2 Inorganic-Based Nanomaterials 89 4.3 Hybrid Nanomaterials 90 5 Conclusions 91 References 91 Breast Cancer Biology for the Radiation Oncologist is the first textbook of its kind devoted to describing the biological complexities of breast cancer in a way that is relevant to the radiation oncologist. Radiation Oncology has long treated breast cancer as a single biological entity, with all treatment decisions being based on clinical and pathologic risk factors. We are now beginning to understand that biological subtypes of breast cancer may have different risks of recurrence as well as different intrinsic sensitivity to radiotherapy. Multi-gene arrays that have for years been used to predict the risk of distant recurrence and the value of systemic chemotherapy may also have utility in predicting the risk of local recurrence. Additionally, the targeted agents used to treat breast cancer may interact with radiotherapy in ways that can be beneficial or undesirable. All of these emerging issues of central importance to radiation oncologists are extensively discussed in this book, and practical treatment recommendations based on available clinical evidence are presented whenever possible Front Matter....Pages i-vii Biological Subtypes of Breast Cancer....Pages 1-6 Gene Amplification of ErbB-2: From Gene to Therapy....Pages 7-13 Current Clinical Role of Genetic Profiling in Breast Cancer....Pages 15-34 Biology of DCIS and Progression to Invasive Disease....Pages 35-48 Cancer Stem Cells and Radiotherapy....Pages 49-57 Genetic Basis of Normal Tissue Radiosensitivity and Late Toxicity in Breast Cancer....Pages 59-70 Genetic Syndromes and Radiotherapy in Breast Cancer....Pages 71-80 Experimental Therapies in Breast Cancer....Pages 81-90