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Breast Cancer - Translational Therapeutic Strategies - G. Lyman, H. Burstein (Informa, 2007) WW PDF

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Preview Breast Cancer - Translational Therapeutic Strategies - G. Lyman, H. Burstein (Informa, 2007) WW

Breast Cancer Translational Therapeutic Strategies Edited by Gary H. Lyman University of Rochester School of Medicine and Dentistry and James P. Wilmot Cancer Center University of Rochester Medical Center– Strong Memorial Hospital Rochester, New York, U.S.A. Harold J. Burstein Dana-Farber Cancer Institute Harvard Medical School Boston, Massachusetts, U.S.A. New York London DK7416_C000a.indd 3 12/19/06 7:50:18 AM Informa Healthcare USA, Inc. 270 Madison Avenue New York, NY 10016 © 2007 by Informa Healthcare USA, Inc. Informa Healthcare is an Informa business No claim to original U.S. Government works Printed in the United States of America on acid‑free paper 10 9 8 7 6 5 4 3 2 1 International Standard Book Number‑10: 0‑8493‑7416‑2 (Hardcover) International Standard Book Number‑13: 978‑0‑8493‑7416‑6 (Hardcover) This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with permission, and sources are indicated. A wide variety of references are listed. Reasonable efforts have been made to publish reliable data and information, but the author and the publisher cannot assume responsibility for the validity of all materials or for the consequences of their use. No part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, and recording, or in any information storage or retrieval system, without written permission from the publishers. For permission to photocopy or use material electronically from this work, please access www.copyright. com (http://www.copyright.com/) or contact the Copyright Clearance Center, Inc. (CCC) 222 Rosewood Drive, Danvers, MA 01923, 978‑750‑8400. CCC is a not‑for‑profit organization that provides licenses and registration for a variety of users. For organizations that have been granted a photocopy license by the CCC, a separate system of payment has been arranged. Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe. Library of Congress Cataloging‑in‑Publication Data Breast cancer : translational therapeutic strategies / edited by Gary H. Lyman, Harold J. Burstein. p. ; cm. ‑‑ (Translational medicine ; 2) Includes bibliographical references and index. ISBN‑13: 978‑0‑8493‑7416‑6 (hardcover : alk. paper) ISBN‑10: 0‑8493‑7416‑2 (hardcover : alk. paper) 1. Breast‑‑Cancer‑‑Treatment‑‑Technological innovations. I. Lyman, Gary H. II. Burstein, Harold J. III. Series. [DNLM: 1. Breast Neoplasms‑‑therapy. WP 870 D82425 2007] RC280.B8B6893 2007 616.99’44906‑‑dc22 2006051463 Visit the Informa Web site at www.informa.com and the Informa Healthcare Web site at www.informahealthcare.com DK7416_C000a.indd 4 12/19/06 7:50:18 AM To my wife, Nicole, and my sons, Stephen and Christopher. —G. H. L. To Mary. —H. J. B. B Foreword The past 30 years have seen considerable progress in the detection, diagnosis, treat- ment and prevention of breast cancer. Such progress followed developments on two parallel tracks: empirical observations and, increasingly, translational research. Empirical observations have been at the heart of medical progress for millennia and, until the middle of the 19th century, were largely responsible for all progress in medicine. The emerging fields of biology and genetics have achieved increasing importance, and over the past 30 years the explosion of knowledge about the process of malignant transformation has been dramatic. We now understand that all cancers, including all breast cancers, are ultimately the result of one or more molecular genetic anomalies that result in the loss of customary control processes for cell growth and communal organization. These molecular genetic anomalies can result from a variety of inherited conditions, or external or internal influences. Certainly exposure to environmental carcinogens is one obvious mechanism, but dysregulation of physiologic processes is another common pathway. Research in this area has revealed the central importance of steroid hormone physiology and, in its diseased state, pathophysiology in the development of premalignant and malignant changes of breast tissue. Further research has identified other critical growth hormone and receptor systems, including the type I tyrosine kinase receptor family. Other growth hormone families and the intricate network of intracellular signaling steps that govern cellular behavior and survival have acquired more prominent roles in our global understanding of breast cancer. All these pieces of the puzzle also serve to open opportunities for identifying therapeutic targets and lead to the development of molecularly targeted therapies. The past few years have witnessed the coming together of these various discoveries and led to a substantive paradigm change in our approach to breast cancer. Tamoxifen, as a targeted approach to the estrogen receptor signaling network, and trastuzumab, as a molecular modulator of HER2 signaling, became the prototypes of what many of us hope will be an increasing stream of smart drugs that will approach breast cancer treatment by identifying specific molecular targets that are critical to the survival of the malignant cell and cutting that lifeline. Recent years have also witnessed our increased understanding of the critical importance of stroma in the development and prospering of cancer cell colonies, whether primary or metastatic. Stromal cells mediate the progression from in situ to invasive breast cancer; normal vascular cells are the precursors of tumor neovas- cularity in an incestuous relationship with malignant cells. Stromal cells signal to malignant cells and provide the complement of growth factors and cytokines needed for tissue homing, invasion, and metastasis. Such developments opened avenues for entirely novel therapeutic strategies already shown to be clinically effective and relevant. It is important to understand that this process of discovery to clinical appli- cation is delicate, frail, and can be derailed by a variety of external influences. v Our understanding of basic biology, while markedly expanded compared to a few decades ago, is still woefully incomplete. The path from discovery of a potentially active compound in an in vitro system to a drug candidate depends on a series of economically motivated, and sometimes politically charged, influences within pharmaceutical companies, and on the uncertainties of peer-reviewed research support and the vagaries of health care reimbursement in academic centers. Strong credentials and sometimes luck are helpful for new drugs to succeed. A persistent champion that pushed the candidate drug through the existing system is often largely responsible for success or failure. The process of translating laboratory-based discoveries into practical clinical tools is convoluted and full of obstacles. Basic scientists are ill equipped to travel this road, and most clinical investigators are unskilled to initiate the process. The necessary bridge to make this process succeed is that rare breed of physician scientists labeled “translational investigators.” Few centers are equipped to train such individuals, and even fewer provide the support and career opportunities to ensure their success. Clinicians look at translational investigators as incomplete physicians, while basic scientists might consider them intruders with inadequate credentials. They compete, on a part-time basis, with full-time scientists of clinical investigators, and they are expected to not only succeed, but also to drag their skep- tical colleagues to follow their lead. And yet, if we don’t foster the development of well-trained, biologically oriented translational investigators, basic science discov- eries, as critical as they might be, will languish in someone’s desk drawer for lack of an effective “translator.” This volume brings together scientists and clinicians, laboratory investigators and clinical trialists. Ably led by the two editors, accomplished translational inves- tigators themselves, it brings to light the accomplishments and challenges of the paradigm shift mentioned previously. While our accomplishments to date are solidly anchored on the increased acceptance and use of the randomized clinical trial, it is clear that many of our new therapeutics will need novel clinical trial approaches for optimal effectiveness and to minimize the possibility of discarding new drugs with biological effects different from traditionally understood cytotox- icity. The development of high-throughput analytical methods have enhanced manifold our ability to analyze the genome, proteome, and metabolome, but also led to new challenges in the interpretation and analysis of massive amounts of data, often obtained from limited numbers of samples. Minimizing the probability of false discovery has become a major task of our statisticians, and maintaining a balance between discovery-led investigations and hypothesis-based research has become an important objective in itself. Technological advances now permit testing not only for overt molecular genetic abnormalities, but also for genetic poly- morphisms that are considered to be normal variants. This field will expand substantially in years to come, since it might explain the substantial variability in pharmacokinetics and, more importantly, pharmacodynamics of most drugs, and especially those that require metabolic activation or catabolism. This might lead to improved dosification of all our therapeutics, and perhaps a marked increase in the therapeutic ration of potentially toxic drugs. Clinical and biochemical markers of prognosis have emerged over the past few decades. Most provide reasonably accurate prognostic information for groups of patients but are seldom useful for prognostication of individuals. New molecular markers might provide individually accurate markers of prognosis or predictors of response or resistance to therapy. It is also possible that combinations of multiple markers, as in gene vi Foreword expression profiles, might provide the best prognostic models. The volume also summarizes evolving knowledge about multiple molecularly targeted therapeutic strategies and points out directions for future research. These are exciting times to be involved in oncology. The pace of discovery, the opportunities to improve our care for patients with breast cancer, and the increasing possibility of developing effective and nontoxic prevention strategies make this an invigorating and intellectually challenging field. How rapidly conceptual advances translate into applicable clinical tools will depend on the process of translation and the dedication and skills of our translational investigators, as well as the increasing involvement of the oncology community at large to effect the clinical validation of novel scientific concepts. I invite you to enjoy this excellent primer and hope it will provide useful, practical information and further provoke your intellectual curiosity. Gabriel N. Hortobagyi, MD, FACP Professor and Chair, Department of Breast Medical Oncology, and Nellie B. Connally Chair in Breast Cancer, The University of Texas M. D. Anderson Cancer Center Houston, Texas, U.S.A. Foreword vii B Preface Full fathom five thy father lies; Of his bones are coral made; Those are pearls that were his eyes: Nothing of him that doth fade But doth suffer a sea-change Into something rich and strange. —William Shakespeare, The Tempest We are living amidst a sea-change in our treatment of breast cancer. As Shakespeare imagined the sailor under the sea, so this medical transformation is both rich and strange. It was this richness, and a desire to make it less strange, that prompted this book, Breast Cancer: Translational Therapeutic Strategies. While the processes of the ocean are timeless, it is worth asking why the sea- change in breast cancer medicine is happening now. There are several major contri- butors to this transformation. The first has been the recent availability of novel targeted drugs. Breast cancer medicine had for decades depended on two systemic treatment options—chemotherapy and endocrine therapy; the latter representing the earliest successful effort to target therapies based on an improved under- standing of tumor biology and biomarker testing. The emergence of anti-HER2 targeted therapy with the humanized monoclonal antibody trastuzumab in the 1990s heralded a major new class of therapeutic modalities. Laboratory and clinical evidence indicated that trastuzumab would be effective only in tumors that were markedly HER2 overexpressing. This created a pressing need for diagnostic tests for HER2 overexpression so that tumors, and thus patients, could be appropriately selected for therapy. The impact of trastuzumab on HER2-positive metastatic breast cancer revised treatment algorithms such that therapy depended entirely on tumor HER2 status. In 2005, reports from several major adjuvant trials of trastuzumab demonstrated that this therapeutic impact extended into early stage breast cancer management as well. In addition to the apparent clinical benefits of targeted therapy, the focus on HER2 testing and targeted treatment fueled research into the second major trans- forming event in breast cancer medicine—the characterization of clinical subsets of breast cancer. It became obvious that not all breast cancers were the same. Indeed, several major clinical types of breast cancer could be characterized by marker analysis: estrogen receptor and/or progesterone receptor positive, HER2 positive, and “triple negative” (lacking estrogen receptor and/or progesterone receptor and HER2 expression) subsets. These subsets had immediate practical clinical implications in terms of selecting therapy for both early- and late-stage breast cancers. ix

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