Martine J. Piccart – William C. Wood Chie-Mien Hung – Lawrence J. Solin Fatima Cardoso (Eds.) Breast Cancer and Molecular Medicine With 134 Figures and 118 Tables 123 Martine J. Piccart, MD, PhD Mien-Chie Hung, PhD Lawrence J Solin, MD Dept. of Medical Oncology The University of Texas MD Dept. of Radiation Oncology Jules Bordet Institute Anderson Cancer Center Hospital of the University of Boulevard de Waterloo, 215 1515 Holcombe Blvd Pennsylvania 1000 Brussels Houston, TX 77030-4095 3400 Spruce Street Belgium USA Philadelphia, Pennsylvania [email protected] [email protected] 19104-4283 USA [email protected] Fatima Cardoso, MD William Wood, MD Dept. of Medical Oncology Dept. of Surgery Jules Bordet Institute Emory University Hospital Boulevard de Waterloo, 125 1364 Clifton Road NE B206 1000 Brussels Atlanta, Georgia 30322-1059 Belgium USA [email protected] [email protected] Library of Congress Control Number: 2006925084 ISBN 10 3-540-28265-3 Springer Berlin Heidelberg New York ISBN 13 978-3-540-28265-5 Springer Berlin Heidelberg New York This work is subject to copyright. 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Productliability: The publisher cannot guarantee the accuracy of any information about dosage and application contained in this book. In every individual case the user must check such information by consulting there levant literature. Editor: Dr. Ute Heilmann, Heidelberg Deskeditor: Meike Stoeck, Heidelberg Coverdesign: design & production GmbH, Heidelberg Production & Typesetting: LE-TeX Jelonek, Schmidt & Vöckler GbR, Leipzig Printed on acid-freepaper SPIN 10938713 21/3100/YL – 5 4 3 2 1 0 Foreword Lawrence J. Solin, William Wood, Fatima Cardoso, Mien-Chie Hung, and Martine Piccart Why should you buy another book on breast cancer? Don’t you already have enough breast cancer books on your shelf? As edi- tors, we have attempted to create a different kind of breast can- cer book. Although the typical breast cancer book is written as a compendium of diagnoses and treatments, the focus of this book is on the present and future of breast cancer research and treatment, with an emphasis on translational research. Breast cancer treatment is moving increasingly toward laboratory- based, targeted therapies that are tailored to the individual pa- tient. The treatment of breast cancer, and probably all cancers, will likely soon be practiced in this radically different fashion. The tsunami wave of laboratory and translational research that is already under way will soon alter the management of breast cancer in fundamental ways, and in fact, is already influencing the way in which we think about treating breast cancer patients and performing research. Research into clinical, laboratory, and translational aspects of breast cancer has improved enormously our ability to treat and cure patients with this disease. Population-based data (for exam- ple, from the USA and the UK) document a substantial decrease in the mortality from breast cancer in the last decade, notwith- standing an increase in the incidence of breast cancer detection, attesting to the benefit in human terms from this research. We believe that this downward trend in mortality is only the begin- ning. What makes this book unique is that it considers a wide range of relevant and exciting areas of clinical, translational, and basic research for their potential for clinical application today as well as for transforming future breast cancer treatment. If the history of scientific discovery is any guide, then some, but not all, of these research areas will prove valuable for patient care, and the remainder will fall by the wayside. However, no one can predict today which of these research areas will have the most impact on treating patients in the years to come. VI Foreword The last 25years of clinical research have been characterized by large, randomized trials that have led to improved outcomes for populations of women. Some of these trials have addressed differing treatment concepts, and others, different regimens of similar therapy. Overviews and meta-analyses have uncovered major trends. However, for any given trial, only some of the pa- tients will derive the benefit from treatment that is nevertheless applied to the overall group of patients. A limitation of compar- ing large populations of patients is that some subgroups may be too small to be properly evaluated. While such large clinical trials have improved demonstrably the outcome for the overall group, this approach may do so by overtreating some patients while undertreating others. With the growing recognition of the large heterogeneity of breast cancer patients, breast cancer treatment is becoming in- creasingly individualized. The observation that each patient is unique, recognized clinically for decades, is now being con- firmed by the genetic analysis of individual tumor DNA speci- mens. The genetic individuality of tumors strongly supports the clinical trend toward increasingly individualized treatment for each patient. Today, laboratory-based research is expanding, with the po- tential to translate into clinically valuable improvements. The most basic and elemental processes are understanding cancer genes, how these genes work, the products and mechanisms of altered cellular functions, and the relationship between cancer cells and normal cells. Laboratory research is fueling our under- standing of cancer cell biology. With this research come insights into potential targets to exploit and new targeted therapies to employ. Individually designed combinations of therapies will soon become the norm, and currently available antineoplastic treatments (chemotherapeutic, hormonal, biologic, radiothera- peutic, and surgical) will be used more strategically. Today’s translational research presages a new era in which therapies may ultimately be tailored to the most elemental basis of the indi- vidual tumor in the individual patient. Historically, classifying patients into broad groups has fa- cilitated the development of treatment guidelines. “Lumping” patients into broad categories of disease (for example, based on nodal positivity, stage, or hormone receptor status) and “split- ting” patients based on individual patient and tumor character- istics both play an important role in the conceptual framework for managing breast cancer patients. For example, lumping pa- tients into so-called early-stage disease guides local-regional management of breast-conservation treatment versus mastec- Foreword VII tomy, whereas lumping patients into so-called locally advanced breast cancer guides the treatment decision toward neoadjuvant chemotherapy. Nonetheless, the paradigm of broadly grouping patients to guide treatment decisions may soon undergo radical change. Our increasingly sophisticated understanding of breast cancer is forcing us to recognize substantial clinical heterogeneity, even within predefined patient groups, and to reevaluate our concepts of patient management strategies. Thus, splitting or separating the patients into smaller subgroups of patients has become a widely accepted practice, and tailoring treatment in this fashion has emerged as a rational treatment strategy. Translational re- search has become the driving factor for much of this change in our approach toward treatment strategies. Furthermore, as the basic principles of cancer biology drive translational efforts into more effective clinical treatment strategies, clinical problems are also driving laboratory-based research to solve these problems. Many examples could be given to demonstrate translational research findings that have already altered clinical practice to- day. The use of tamoxifen as a hormonal agent represents a ma- jor shift in the systemic management of breast cancer patients, and innumerable women have been cured through the use of this very well tolerated drug. However, the most effective clinical use of tamoxifen takes into account the heterogeneity of patient presentations. After research studies demonstrated the impor- tance of estrogen and progesterone receptors, clinicians were able to determine the appropriate subgroup of tumors (hormone receptor positive) that should be treated with adjuvant tamoxi- fen. In this way, tamoxifen became the first systemic agent used for targeted breast cancer treatment. Although uncommon, the clinically observed side effects of tamoxifen can potentially be severe, even life-threatening, and have consequently stimulated laboratory research into devel- oping more specific agents with fewer side effects. Two major groups of new agents have been developed: (1) the selective es- trogen receptor modulators (SERMs), and (2) the aromatase in- hibitors (AIs). SERMs and AIs may have the same, or an even higher, benefit as tamoxifen for preventing recurrence of disease, but with a lower risk of side effects. These agents are also not without side effects, and so even newer agents continue to be developed for clinical testing. The AIs have been evaluated in several studies and are chal- lenging tamoxifen as the gold standard both for metastatic dis- ease and in the adjuvant setting. The Arimidex, Tamoxifen Alone or in Combination (ATAC) trial demonstrated an improved dis- VIII Foreword ease-free survival (DFS) and toxicity profile for women treated with anastrozole. The National Cancer Institute of Canada MA 17 trial reported an improved DFS for women receiving 5years of letrozole after completing a 5-year course of tamoxifen, raising the hypothesis that a prolonged duration of more than 5years of adjuvant hormonal therapy may be beneficial. In the Intergroup Exemestane Study, an improved DFS was found for the combi- nation of tamoxifen followed by exemestane for a total of 5years compared to tamoxifen alone for 5years. The hereditary breast cancer story is another example of a clinical observation driving translational research. In the not too distant past, it was commonly observed that “breast cancer runs in families.” The power of this clinical observation was channeled into the laboratory finding of specific breast cancer genes asso- ciated with hereditary breast cancer. To date, two major genes (BRCA1 and BRCA2), as well as other genes, have been associ- ated with an increased risk of developing breast cancer. Several hereditary breast cancer syndromes have been identified, and the potential exists for identifying additional genes responsible for these breast cancer syndromes. The ability to use rapid and reliable testing to identify women with specific BRCA mutations has promoted the development of improved management strategies for these patients. The avail- able options today for such patients include a number of tailored strategies, such as prophylactic surgery (for example, bilateral oophorectomies or bilateral mastectomies), systemic agents for breast cancer prevention (for example, tamoxifen), or height- ened surveillance (for example, breast cancer screening using magnetic resonance imaging, MRI, in addition to conventional mammography). The impact of research on clinical practice is not limited to systemic therapies. Many research developments have in- fluenced local-regional treatments and their integration with systemic therapies. For example, improved imaging allows for more accurate surgery. MRI has become part of routine clinical practice, as it is complementary to conventional imaging stud- ies. MRI of the breast may have a role in any number of clinical scenarios, such as improving the definition of the tumor volume, monitoring the response to neoadjuvant chemotherapy for lo- cally advanced breast cancer, more accurate staging of the breast for potential candidates for breast-conservation treatment with early stage disease, and differentiating scar from local recurrence in follow-up after breast-conservation treatment. The integration of computed tomography (CT) and MRI into radiation oncology treatment planning has become routine in Foreword IX clinical practice. Furthermore, the integration of high-speed computers has facilitated the delivery of targeted radiation treat- ment that can increase the radiation dose to the tumor (or tar- get) and decrease the dose to normal tissues, with a correspond- ing reduction in toxicity. The ability to cover the target volume (for example, the intact breast) while omitting critical normal tissues (for example, the heart and coronary vessels) maintains tumor control, but without the late toxicities that were seen in older studies. One can easily envision even further refinements in local-regional treatment that incorporate the ongoing devel- opments in radiologic imaging. The future of translational research cannot be predicted. Many, but not all, of the promising strategies explored in this textbook will prove clinically valuable in the years to come. While some of these approaches have already reached the clinic and have made a tremendous impact on patient management today, many strat- egies, although highly promising, remain to show clinical utility. “Bench to bedside” and “bedside to bench” research for breast cancer is an exciting dynamic that has only just begun to yield valuable results. Contents 1 Role of Modeling in Pharmacotherapeutics ... 3 1.1 Introduction ................................... 3 1.2 The Skipper-Schabel Model and its Relevance ..... 4 1.3 Gompertzian Growth and the Norton-Simon Hypothesis ..................................... 7 1.4 The Impact Of Sequential Chemotherapy ....... 11 1.5 Dose Size .................................... 15 1.6 Scheduling: What about Dose Density? ......... 16 1.7 Sequential Therapy and Dose Density in the Clinic .................................. 17 1.8 Some Cautions Regarding Dose Density ........ 20 1.9 Gompertzian Growth is Biologically Driven ..... 23 2 PET and Nuclear Medicine Imaging of the Breast ................................ 31 2.1 Introduction ................................. 31 2.2 18FDG-PET .................................. 31 2.3 Primary Breast Cancer Detection .............. 32 2.4 Axillary Lymph Nodes ........................ 32 2.5 Metastatic Disease and Staging ................. 33 2.6 Locally Advanced Breast Cancer: Response to Chemotherapy ............................. 34 2.7 Prognostic Assessment ........................ 34 2.8 Reimbursement .............................. 35 2.9 99mTc-Sestamibi and 99mTc-Tetrofosmin ......... 35 2.10 Dedicated Devices for Nuclear Medicine Breast Imaging ...................................... 36 2.11 Summary .................................... 38 XII Contents 3 Functional Radiologic Imaging in Breast Cancer ............................. 43 3.1 Introduction ................................. 43 3.2 Magnetic Resonance Imaging .................. 43 3.3 Nuclear Medicine ............................. 48 3.3.1 18F-Fluorodeoxyglucose ....................... 48 3.3.2 Amino Acid Metabolism ...................... 54 3.3.2.1 L-[1-11C]-Methionine ......................... 54 3.3.2.2 L-[1-11C]-Tyrosine ............................ 54 3.3.3 Matrix Metalloproteinase Inhibitor Radiotracer 55 3.3.4 99mTc-rh-Annexin V Uptake as an Indicator of Apoptosis .................................. 55 3.4 Monitoring Resistance to Chemotherapy ....... 55 3.5 Tumor Hypoxia ............................... 56 3.6 Conclusion ................................... 57 4 Prevention of Breast Cancer ................. 63 4.1 Introduction ................................. 63 4.2 Surgery For Breast Cancer Risk Reduction ...... 63 4.2.1 Prophylactic Mastectomy ...................... 63 4.2.2 Prophylactic Oophorectomy ................... 66 4.2.3 Selection for Prophylactic Surgery .............. 68 4.3 Chemoprevention of Breast Cancer ............. 69 4.3.1 Scientific Basis for the Prevention of Estrogen- Receptor-Positive Breast Cancer ............... 69 4.3.2 Clinical Prevention of Estrogen-Receptor- Positive Breast Cancer: Tamoxifen .............. 70 4.3.2.1 The NSABP P1 Trial .......................... 70 4.3.2.2 The Royal Marsden Prevention Trial ............ 74 4.3.2.3 The Italian Prevention Trial .................... 74 4.3.2.4 The IBIS-I Trial ............................... 75 4.3.2.5 Overview of Studies ........................... 76 4.3.2.6 Identifying Candidates for Tamoxifen Chemoprevention ............................ 76 4.3.3 Clinical Prevention of ER-Positive Breast Cancer: Raloxifene ............................ 79 4.3.4 Clinical Prevention of ER-Positive Cancer: Aromatase Inhibitors .......................... 81 4.4 Prevention of ER-Negative Breast Cancer ....... 83 4.4.1 Retinoids .................................... 83 4.4.2 Cyclooxyganase-2 Inhibitors ................... 84 4.4.3 Epidermal Growth Factor Receptor Inhibitors ... 85 Contents XIII 4.5 Current Progress and Future Challenges ........ 86 5 DCIS: Pathology and Molecular Markers .... 99 5.1 Introduction ................................. 99 5.2 Histological Classification .................... 101 5.2.1 Ductal Carcinoma In Situ .................... 101 5.2.2 Intraductal Epithelial Proliferations ........... 104 5.3 Genetic Alterations .......................... 104 5.3.1 Oncogenes .................................. 105 5.3.1.1 Amplification of the HER-2 Gene is Frequent in DCIS ..................................... 106 5.3.1.2 Cyclin D1 Protein Overexpression in the Precursors of Invasive Breast Cancer .......... 107 5.3.1.3 C-MYC Gene Amplification: Involved in the Progression of DCIS to Invasion? ........ 107 5.3.2 Tumor Suppressor Genes ..................... 108 5.3.2.1 Inactivation of the p53 Gene in DCIS .......... 108 5.3.2.2 E-Cadherin Gene Inactivation in LCIS but not in DCIS ............................. 109 5.3.2.3 Other Tumor Suppressor Genes? .............. 109 5.3.3 Genetic Alterations Detected by LOH and CGH 110 5.4 A Multistep Model for Breast Carcinogenesis ... 112 5.5 Discussion and Future Prospects .............. 113 6 Ductal Carcinoma In Situ: a Modern Approach to Patient Management ......... 125 6.1 Introduction ................................ 125 6.2 Treatment Options ........................... 126 6.2.1 Local Treatment Options ..................... 126 6.2.1.1 Lumpectomy or Wide Excision Alone With or Without RT ............................... 126 6.2.1.2 Mastectomy ................................. 127 6.2.2 Treatment Options for Hormone-Responsive DCIS ....................................... 127 6.3 Biomarkers of Disease and Outcome .......... 128 6.4 Preventing Contralateral Breast Cancer ........ 130 6.5 Decision-Making Tools for Treatment of Ipsilateral DCIS ........................... 131 6.6 Novel Therapies for Prevention ............... 133 6.7 Conclusions ................................. 134