Mastectomy - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

MASTECTOMY A M EDICAL D ICTIONARY , B IBLIOGRAPHY , AND A NNOTATED R ESEARCH G UIDE TO I NTERNET R E FERENCES

J AMES N. P ARKER , M.D. AND P HILIP M. P ARKER , P H .D., E DITORS

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ICON Health Publications ICON Group International, Inc. 4370 La Jolla Village Drive, 4th Floor San Diego, CA 92122 USA Copyright 2004 by ICON Group International, Inc. Copyright 2004 by ICON Group International, Inc. All rights reserved. This book is protected by copyright. No part of it may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without written permission from the publisher. Printed in the United States of America. Last digit indicates print number: 10 9 8 7 6 4 5 3 2 1

Publisher, Health Care: Philip Parker, Ph.D. Editor(s): James Parker, M.D., Philip Parker, Ph.D. Publisher's note: The ideas, procedures, and suggestions contained in this book are not intended for the diagnosis or treatment of a health problem. As new medical or scientific information becomes available from academic and clinical research, recommended treatments and drug therapies may undergo changes. The authors, editors, and publisher have attempted to make the information in this book up to date and accurate in accord with accepted standards at the time of publication. The authors, editors, and publisher are not responsible for errors or omissions or for consequences from application of the book, and make no warranty, expressed or implied, in regard to the contents of this book. Any practice described in this book should be applied by the reader in accordance with professional standards of care used in regard to the unique circumstances that may apply in each situation. The reader is advised to always check product information (package inserts) for changes and new information regarding dosage and contraindications before prescribing any drug or pharmacological product. Caution is especially urged when using new or infrequently ordered drugs, herbal remedies, vitamins and supplements, alternative therapies, complementary therapies and medicines, and integrative medical treatments. Cataloging-in-Publication Data Parker, James N., 1961Parker, Philip M., 1960Mastectomy: A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References / James N. Parker and Philip M. Parker, editors p. cm. Includes bibliographical references, glossary, and index. ISBN: 0-497-00707-X 1. Mastectomy-Popular works. I. Title.

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Disclaimer This publication is not intended to be used for the diagnosis or treatment of a health problem. It is sold with the understanding that the publisher, editors, and authors are not engaging in the rendering of medical, psychological, financial, legal, or other professional services. References to any entity, product, service, or source of information that may be contained in this publication should not be considered an endorsement, either direct or implied, by the publisher, editors, or authors. ICON Group International, Inc., the editors, and the authors are not responsible for the content of any Web pages or publications referenced in this publication.

Copyright Notice If a physician wishes to copy limited passages from this book for patient use, this right is automatically granted without written permission from ICON Group International, Inc. (ICON Group). However, all of ICON Group publications have copyrights. With exception to the above, copying our publications in whole or in part, for whatever reason, is a violation of copyright laws and can lead to penalties and fines. Should you want to copy tables, graphs, or other materials, please contact us to request permission (E-mail: [email protected]). ICON Group often grants permission for very limited reproduction of our publications for internal use, press releases, and academic research. Such reproduction requires confirmed permission from ICON Group International, Inc. The disclaimer above must accompany all reproductions, in whole or in part, of this book.

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Acknowledgements The collective knowledge generated from academic and applied research summarized in various references has been critical in the creation of this book which is best viewed as a comprehensive compilation and collection of information prepared by various official agencies which produce publications on mastectomy. Books in this series draw from various agencies and institutions associated with the United States Department of Health and Human Services, and in particular, the Office of the Secretary of Health and Human Services (OS), the Administration for Children and Families (ACF), the Administration on Aging (AOA), the Agency for Healthcare Research and Quality (AHRQ), the Agency for Toxic Substances and Disease Registry (ATSDR), the Centers for Disease Control and Prevention (CDC), the Food and Drug Administration (FDA), the Healthcare Financing Administration (HCFA), the Health Resources and Services Administration (HRSA), the Indian Health Service (IHS), the institutions of the National Institutes of Health (NIH), the Program Support Center (PSC), and the Substance Abuse and Mental Health Services Administration (SAMHSA). In addition to these sources, information gathered from the National Library of Medicine, the United States Patent Office, the European Union, and their related organizations has been invaluable in the creation of this book. Some of the work represented was financially supported by the Research and Development Committee at INSEAD. This support is gratefully acknowledged. Finally, special thanks are owed to Tiffany Freeman for her excellent editorial support.

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About the Editors James N. Parker, M.D. Dr. James N. Parker received his Bachelor of Science degree in Psychobiology from the University of California, Riverside and his M.D. from the University of California, San Diego. In addition to authoring numerous research publications, he has lectured at various academic institutions. Dr. Parker is the medical editor for health books by ICON Health Publications. Philip M. Parker, Ph.D. Philip M. Parker is the Eli Lilly Chair Professor of Innovation, Business and Society at INSEAD (Fontainebleau, France and Singapore). Dr. Parker has also been Professor at the University of California, San Diego and has taught courses at Harvard University, the Hong Kong University of Science and Technology, the Massachusetts Institute of Technology, Stanford University, and UCLA. Dr. Parker is the associate editor for ICON Health Publications.

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About ICON Health Publications To discover more about ICON Health Publications, simply check with your preferred online booksellers, including Barnes&Noble.com and Amazon.com which currently carry all of our titles. Or, feel free to contact us directly for bulk purchases or institutional discounts: ICON Group International, Inc. 4370 La Jolla Village Drive, Fourth Floor San Diego, CA 92122 USA Fax: 858-546-4341 Web site: www.icongrouponline.com/health

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Table of Contents FORWARD .......................................................................................................................................... 1 CHAPTER 1. STUDIES ON MASTECTOMY ........................................................................................... 3 Overview........................................................................................................................................ 3 Federally Funded Research on Mastectomy................................................................................... 3 E-Journals: PubMed Central ....................................................................................................... 25 The National Library of Medicine: PubMed ................................................................................ 26 CHAPTER 2. NUTRITION AND MASTECTOMY ................................................................................. 73 Overview...................................................................................................................................... 73 Finding Nutrition Studies on Mastectomy.................................................................................. 73 Federal Resources on Nutrition ................................................................................................... 74 Additional Web Resources ........................................................................................................... 74 CHAPTER 3. ALTERNATIVE MEDICINE AND MASTECTOMY ........................................................... 77 Overview...................................................................................................................................... 77 National Center for Complementary and Alternative Medicine.................................................. 77 Additional Web Resources ........................................................................................................... 83 General References ....................................................................................................................... 84 CHAPTER 4. DISSERTATIONS ON MASTECTOMY ............................................................................. 85 Overview...................................................................................................................................... 85 Dissertations on Mastectomy ...................................................................................................... 85 Keeping Current .......................................................................................................................... 86 CHAPTER 5. PATENTS ON MASTECTOMY........................................................................................ 87 Overview...................................................................................................................................... 87 Patents on Mastectomy................................................................................................................ 87 Patent Applications on Mastectomy .......................................................................................... 115 Keeping Current ........................................................................................................................ 118 CHAPTER 6. BOOKS ON MASTECTOMY ......................................................................................... 119 Overview.................................................................................................................................... 119 Book Summaries: Online Booksellers......................................................................................... 119 CHAPTER 7. PERIODICALS AND NEWS ON MASTECTOMY ........................................................... 121 Overview.................................................................................................................................... 121 News Services and Press Releases.............................................................................................. 121 Academic Periodicals covering Mastectomy .............................................................................. 123 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 127 Overview.................................................................................................................................... 127 NIH Guidelines.......................................................................................................................... 127 NIH Databases........................................................................................................................... 129 Other Commercial Databases..................................................................................................... 131 APPENDIX B. PATIENT RESOURCES ............................................................................................... 133 Overview.................................................................................................................................... 133 Patient Guideline Sources.......................................................................................................... 133 Finding Associations.................................................................................................................. 136 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 139 Overview.................................................................................................................................... 139 Preparation................................................................................................................................. 139 Finding a Local Medical Library................................................................................................ 139 Medical Libraries in the U.S. and Canada ................................................................................. 139 ONLINE GLOSSARIES................................................................................................................ 145 Online Dictionary Directories ................................................................................................... 146 MASTECTOMY DICTIONARY ................................................................................................. 147

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INDEX .............................................................................................................................................. 187

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FORWARD In March 2001, the National Institutes of Health issued the following warning: "The number of Web sites offering health-related resources grows every day. Many sites provide valuable information, while others may have information that is unreliable or misleading."1 Furthermore, because of the rapid increase in Internet-based information, many hours can be wasted searching, selecting, and printing. Since only the smallest fraction of information dealing with mastectomy is indexed in search engines, such as www.google.com or others, a non-systematic approach to Internet research can be not only time consuming, but also incomplete. This book was created for medical professionals, students, and members of the general public who want to know as much as possible about mastectomy, using the most advanced research tools available and spending the least amount of time doing so. In addition to offering a structured and comprehensive bibliography, the pages that follow will tell you where and how to find reliable information covering virtually all topics related to mastectomy, from the essentials to the most advanced areas of research. Public, academic, government, and peer-reviewed research studies are emphasized. Various abstracts are reproduced to give you some of the latest official information available to date on mastectomy. Abundant guidance is given on how to obtain free-of-charge primary research results via the Internet. While this book focuses on the field of medicine, when some sources provide access to non-medical information relating to mastectomy, these are noted in the text. E-book and electronic versions of this book are fully interactive with each of the Internet sites mentioned (clicking on a hyperlink automatically opens your browser to the site indicated). If you are using the hard copy version of this book, you can access a cited Web site by typing the provided Web address directly into your Internet browser. You may find it useful to refer to synonyms or related terms when accessing these Internet databases. NOTE: At the time of publication, the Web addresses were functional. However, some links may fail due to URL address changes, which is a common occurrence on the Internet. For readers unfamiliar with the Internet, detailed instructions are offered on how to access electronic resources. For readers unfamiliar with medical terminology, a comprehensive glossary is provided. For readers without access to Internet resources, a directory of medical libraries, that have or can locate references cited here, is given. We hope these resources will prove useful to the widest possible audience seeking information on mastectomy. The Editors

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the NIH, National Cancer Institute (NCI): http://www.cancer.gov/cancerinfo/ten-things-to-know.

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CHAPTER 1. STUDIES ON MASTECTOMY Overview In this chapter, we will show you how to locate peer-reviewed references and studies on mastectomy.

Federally Funded Research on Mastectomy The U.S. Government supports a variety of research studies relating to mastectomy. These studies are tracked by the Office of Extramural Research at the National Institutes of Health.2 CRISP (Computerized Retrieval of Information on Scientific Projects) is a searchable database of federally funded biomedical research projects conducted at universities, hospitals, and other institutions. Search the CRISP Web site at http://crisp.cit.nih.gov/crisp/crisp_query.generate_screen. You will have the option to perform targeted searches by various criteria, including geography, date, and topics related to mastectomy. For most of the studies, the agencies reporting into CRISP provide summaries or abstracts. As opposed to clinical trial research using patients, many federally funded studies use animals or simulated models to explore mastectomy. The following is typical of the type of information found when searching the CRISP database for mastectomy: •

Project Title: 3D BREAST MODELING USING PATIENT SPECIFIC 3D IMAGES Principal Investigator & Institution: Feng, Yuanming; Genex Technologies, Inc. 10605 Concord St, Ste 500 Kensington, Md 20895 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 29-SEP-2003 Description (provided by applicant): One in every 8 American women develops breast cancer at some point in their lifetime. With many advances in microsurgical technique

2 Healthcare projects are funded by the National Institutes of Health (NIH), Substance Abuse and Mental Health Services (SAMHSA), Health Resources and Services Administration (HRSA), Food and Drug Administration (FDA), Centers for Disease Control and Prevention (CDCP), Agency for Healthcare Research and Quality (AHRQ), and Office of Assistant Secretary of Health (OASH).

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and implantable prostheses, breast reconstruction can offer a nearly identical restoration of the breast while helping to diminish the emotional and psychological trauma breast cancer sufferer?s experience from the loss of a breast, thus enhancing the quality of life of cancer survivors. In current clinical practices of breast reconstruction, there exists no accurate and easy-to-perform method of measuring, quantifying or assessing breast shape or volume; There is no method available to accurately predict the surgical result of breast reconstruction based on volume to breast tissue added or removed. Genex Technologies, Inc. has recently developed a novel 3D camera that is able to acquire both 2D and 3D images of a breast with high precision and speed. Using the 3-D camera, we can accurately record the 3D shape and appearance of the breast to be removed by mastectomy or reduced by lumpectomy. We propose this SBIR program to demonstrate the feasibility of a breast modeling technique and software, dubbed as the 3DBREAST(TM) based on patient-specific 3D images. Phase 1 project will focus on developing the framework of the 3D-BREAST software and investigating breast deformation model. A prototype of the 3D-BREAST system will be demonstrated with limited verification tests using 3D breast image database we have collected in the past at Johns Hopkins Hospital. The Phase 2 project will demonstrate a fully functional 3DBREAST system. The Phase 2 system will be field-tested in multiple clinical sites to obtain feedback for improvement. Specifically, in the proposed 6-month Phase 1 program, we will investigate the following issues: 1. Develop 3D aboutBREASrM software framework and implement an interactive GUI. 2. Develop a geometric model of 3D breast deformation. 3. Verify the correctness and effectiveness of the breast deformation model using 3D pre- and post operative breast images. 4. Prepare Phase 2 work plan. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: A HER-2/NEU PULSED DC1 VACCINE FOR PATIENTS WITH DCIS Principal Investigator & Institution: Czerniecki, Brian J.; Assistant Professor of Surgery; Surgery; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2003; Project Start 19-JUN-2003; Project End 31-MAY-2006 Summary: (provided by applicant): The recently acquired ability to culture large numbers of human dendritic cells (DC), the most effective antigen-presenting cell for the sensitization of T lymphocytes, has provided an important resource for the formulation of active immunization strategies against cancer. The success of previous vaccine trials has probably been limited in part by the reliance on short synthetic peptide immunogens that cannot elicit CD4+ T cell help, the use of incorrectly cultured or administered DC that has failed to harness their full potential as APC, and the enrollment of patients who, because of their advanced metastatic disease and previous treatment with chemo- or radio-therapy make them inherently poor prospects for active immunotherapy. This proposed study is designed to circumvent these previous shortcomings by taking advantage of recent advances in our understanding of DC development, function, and administration, as well as the careful selection of both disease model and appropriate immunogen. High-grade ductal carcinoma in situ (DCIS) is a pre-invasive malignancy of the breast that often expresses the tumor-associated antigen her-2/neu. The proposed study will enroll her-2/neu-positive DCIS patients, who have localized disease and no previous experience with immunosuppressive therapies. These patients will receive a vaccine composed of autologous DC pulsed with multiple her-2/neu-derived peptides. These DC will be cultured in a manner proven to maximize their effectiveness in sensitizing tumor-recognizing T lymphocytes, and administered by the intra-nodal route, which has been demonstrated superior to other

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tested routes of delivery. The specific aims of this study are first to determine the feasibility and safety of administering an autologous DC1 vaccine pulsed with her2/neu peptides. Second, to determine the rate of sensitization of CD4+ and CD8+ T cells to her-2/neu after intra-nodal administration of the vaccine. Finally, the response in the peritumoral area following vaccination will be determined histopathologically and radiologically. The vaccine, if successful, will not only provide needed treatment options in addition to the current standard of care (mastectomy or lumpectomy) but may also prove useful for actually preventing invasive disease in patients judged at high risk for developing breast malignancies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ANATOMIC AND BIOLOGIC STAGING OF BREAST DISEASE WITH MRI Principal Investigator & Institution: Hylton, Nola M.; Professor; Radiology; University of California San Francisco 3333 California Street, Suite 315 San Francisco, Ca 941430962 Timing: Fiscal Year 2002; Project Start 15-JAN-1997; Project End 31-DEC-2005 Summary: Preoperative or neoadjuvant chemotherapy is now the standard of care for treatment of patients with locally advanced breast cancer and is being evaluated in patients with earlier stage disease. Neoadjuvant chemotherapy can achieve tumor downstaging and allow breast conservation in patients for whom initially, mastectomy was the only option. Response to chemotherapy is assessed clinically and clinical assessment of response of the primary tumor has been shown to be associated with improved disease-free survival. Nonetheless, clinical response does not accurately reflect pathologic response. MRI can accurately assess the extent of cancer in the breast and may be more effective than clinical exam at measuring changes in tumor size and distribution in response to neoadjuvant chemotherapy. Additionally, early tumor changes measured by MRI could be meaningful predictors of survival. More importantly, if MRI can identify those patients who are unlikely to respond to treatment, a change in management can be introduced at an earlier time. This study proposes to investigate these possibilities by using MRI to non-invasively measure tumor changes in patients with Stage III/IV breast cancer during neoadjuvant treatment. The goal is to design and validate MRI methods for measuring treatment response and predicting patient outcome. A high spatial resolution three time-point method was previously developed and evaluated for characterization of breast disease. This technique will be used to measure morphologic and enhancement properties of tumors and monitor their change over treatment. The effectiveness of MRI methods for measuring tumor response and predicting disease-free survival will be investigated in a group of 75 patients with locally-advanced breast cancer who are undergoing neoadjuvant chemotherapy. Clinical investigations will be supported by studies in model systems. Experimental models of breast cancer will be used to study the effects of tumor properties and treatment parameters on treatment response. These results will be used to guide the design of clinical studies. Experimental model studies will be used to study the anti-angiogenic properties of anti-VEGF and anti-FLKI, both being introduced into clinical trials for breast cancer. A third agent to be studied is an anti-body labeled immunoliposome agent containing doxorubicin and targeted against HER2, which has demonstrated superior therapeutic results to both free doxorubicin and non-targeted doxorubicincontaining liposomes. MRI methods will be developed using both standard gadoliniumDTPA and gadolinium-encapsulating immunoliposomes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: BREAST CANCER RISK MODIFIERS IN BRCA MUTATION CARRIERS Principal Investigator & Institution: Whittemore, Alice S.; Professor; Health Research and Policy; Stanford University Stanford, Ca 94305 Timing: Fiscal Year 2003; Project Start 20-SEP-2003; Project End 31-AUG-2005 Summary: (provided by applicant): Lifetime breast cancer risks among carriers of mutations of the genes BRCA1 and BRCA2 have been estimated at 40-80%. Thus some 20-60% of carriers live to advanced ages without developing the disease, which suggests that other genes or personal attributes may modify carriers' risks. At present however, title is known about such personal characteristics. There is urgent need to determine which, if any, modifiable lifestyle characteristics may alter a carrier's risk of developing breast cancer, to assist her in making rational, informed choices about such preventive options as prophylactic mastectomy. We propose to use uniformly collected data from young (aged < 50 years) case (N=425) and control (N=352) carriers of deleterious BRCA1 or BRCA2 mutations to evaluate associations between breast cancer risk and five modifiable characteristics. These are: history of oral contraceptive use, history of diagnostic or therapeutic chest irradiation prior to diagnosis, alcohol consumption, cigarette smoking, and physical activity patterns during puberty, young adulthood and middle age. We will focus on carriers under age 50 years at diagnosis (cases) or interview (controls) who have participated in an international Collaborative Family Registry for Breast Cancer Studies (CFRBCS) and in clinical studies in New York, Ontario and Australia. We will use unconditional logistic regression to estimate oddsratios relating these attributes to breast cancer risk while controlling for potential confounders, and use robust variance estimators to account for any correlation present in attributes of related carriers. These data on modifiable characteristics from a large group of young carriers of BRCA1 or BRCA2 mutations represent a unique resource for advancing our knowledge about breast cancer prevention in premenopausal women at high risk for the disease. The proposed analysis will provide new information on alternatives to mastectomy as a preventive strategy for these women. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: BREAST CANCER TREATMENT EFFECTIVENESS IN OLDER WOMEN Principal Investigator & Institution: Silliman, Rebecca A.; Professor; Boston Medical Center Gambro Bldg, 2Nd Fl, 660 Harrison Ave, Ste a Boston, Ma 02118 Timing: Fiscal Year 2003; Project Start 10-FEB-2003; Project End 31-DEC-2006 Summary: (provided by investigator): An estimated 192,200 women were diagnosed with breast cancer in 2001, more than half of whom were 60 years of age or older. Of concern is that while breast cancer-specific mortality rates have declined among women less than 70 years old, they are either stable (70-79 year olds) or are increasing (80+ year olds) among those 70 years or older. One explanation for this is that older women receive less than standard therapy more frequently than younger women. Neither efficacy nor effectiveness data to date justify this pattern of care. Taking advantage of the Health Maintenance Organization (HMO) Cancer Research Network, we propose to conduct a historical cohort study of an unselected group of older women (>65 years of age) newly diagnosed with early stage breast cancer (stages I-II) between 1990 and 1994. Specifically, we will (1) Compare the effectiveness of standard primary tumor therapy (breast conserving surgery, axillary dissection, and radiation therapy or modified radical mastectomy) versus other than standard therapy in preventing breast cancer

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recurrences and mortality, adjusting for co-morbidity, tumor characteristics, geographic site, and demographic characteristics; (2) Determine the extent to which the addition of systemic adjuvant therapy (chemotherapy, hormonal therapy, or the combination of chemotherapy and hormonal therapy) modifies the effectiveness of standard and other than standard primary tumor therapy in preventing breast cancer recurrences and mortality; (3) Describe patterns of surveillance testing for breast cancer recurrence and determine the extent to which surveillance testing is associated with a reduction in breast cancer-specific mortality; and (4) Identify provider, tumor, and patient characteristics associated with the receipt of standard primary tumor therapy and systemic adjuvant therapy in older women with newly diagnosed early stage disease in the HMO setting. Six sites from throughout the United States will together identify and follow 2180 women for ten years. Both electronic and medical record data sources will be used to collect information that will allow us to characterize the separate and joint effects of treatment, tumor, and patient characteristics on breast cancer recurrence and mortality. Findings from this study will inform clinical practice, particularly the care of older women with co-morbidities who are unlikely to participate in clinical trials. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CLINICAL/PATHOLOGIC PREDICTORS FOR RECURRENCE AFTER DCIS Principal Investigator & Institution: Habel, Laurel A.; Center for Health Studies Seattle, Wa 98101 Timing: Fiscal Year 2003; Project Start 03-JUN-2003; Project End 28-FEB-2007 Summary: Approximately 10-20% of women with ductal carcinoma in situ (DCIS) will have recurrent breast cancer, either in situ or invasive, within 5 years of their initial diagnosis. While every year in the U.S. more than 47,000 women are diagnosed with DClS, our ability to accurately predict which patients are most likely to have a recurrence is quite poor. Consequently, treatment decisions are difficult and up to 40% of DCIS patients will have a mastectomy. We propose to conduct a nested case-control study to identify clinical and pathologic factors that could be used to accurately identify DClS patients at high and low risk of a recurrence. The study population will come from the memberships of three Cancer Research Network (CRN) sites, Kaiser Permanente Northern California (KPNC), Kaiser Permanente Southern California (KPSC), and Harvard Pilgrim Health Care (HPHC). DCIS patients diagnosed between 1990 and 2001 and treated with breast-conserving surgery will be identified (N=3,700) and followed for recurrence. Diagnostic slides from patients with a recurrence (N=490) and from matched controls will be retrieved and reviewed by an expert DClS pathologist. One control will be selected for each recurrence (case), matched on health plan, calendar year of the initial diagnosis, age, and follow-up time. Pathology review will be conducted on the slides from the initial and recurrent tumors of cases and from the initial tumors of controls. Data on clinical factors will also be obtained. We aim to do the following: 1) Estimate and compare the risk of recurrence associated with several pathologic features (either alone or combined according to various classification systems) of the index DClS, and compare features of the index DCIS to those in recurrent lesions; 2) Estimate and compare the risk of recurrence associated with several clinical factors, such as age, menopausal status, obesity, and family history of breast cancer; and 3) Evaluate the relation between clinical and pathologic factors, and determine which combination of these factors best identifies subgroups of women at very high and low risk of recurrence. This will be the largest and most comprehensive study to date on prognostic factors for DClS. Our results will provide information on the natural history of this

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heterogeneous group of lesions, and in the future may help in the development of individually tailored treatment strategies for patients with DCIS. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: COMMUNITY CLINICAL ONCOLOGY PROGRAM Principal Investigator & Institution: Locker, Gershon Y.; Chief; Evanston Northwestern Healthcare Evanston, Il 60201 Timing: Fiscal Year 2002; Project Start 01-SEP-1983; Project End 31-MAY-2003 Summary: (Applicant's Description) Evanston Hospital Corporation which has been renamed as Evanston Northwestern Health care (ENH), has been a CCOP since 1093 and has participated in studies of the Eastern Cooperative Oncology Group (ECOG), the National Surgical Adjuvant Breast and Bowel Program (NSABP), and propose to accrue patients to the Gynecology Oncology Group (GOG). It accrued 259 patients with 272 credits to therapeutic trials between June of 1992 to May of 1997. ENH also contributed non-COP patients to NIH-sponsored studies on brain tumors. ENH investigators have chaired ECOG protocols in genitourinary, breast, and hematologic malignancies. They have also chaired steering committees and served in leadership roles in these groups. Currently, Dr. Ann Thor is on the Executive and directs the ECOG Pathology Coordination Office. Dr. David Calls chains the Health Behavior and Practices Committee and the Outcomes Subcommittee. The CCOP has participated in approved cancer control projects in the NSABP-sponsored breast cancer prevention trial with tamoxifen, the Prostate Cancer Prevention Trial, and other cancer control studies. During the 5 years, 279.5 cancer control credits were awarded. ENH investigators have been active in several cancer control projects outside the CCOP pertaining to epidemiology, diagnosis, "diagnostic marker" and dietary manipulation. These include a NCI funded study of low- fat diet in post-menopausal breast cancer, and the Women's Health Initiative, treatment of post-mastectomy arm lymphedema. The CCOP has been reorganized to increase accrual by: recruitment of new investigators, adding Swedish Covenant Hospital as an affiliate, and GOG as a research base. Efforts are underway to encompass minority enrollment. A 24-bed Clinical Pharmacology Unit sponsored by Searle is operation, with the PI on the advisory committee. We have expanded our education activities through Grand Rounds and lecture series. In the last 4 years, ENH investigators published 63 papers and 10 abstracts pertaining to clinical cancer treatment and control. A research effort in cellular and molecular biology has been developed with the establishment of a program in molecular genetics. Thus, a vertical integration, e.g., from laboratory studies to delivery of care in the local community is being sought. Support is asked for ENH's continued participation in the CCOP. Funding is sought for continued accrual of patients to cancer therapy and cancer control studies of the ECG, NSABP, and GOG. Thus, our participation in cancer control and therapeutic trials will promoter medical advances as well as stimulate better patient care. These in turn will impact favorably on the level of knowledge of staff and physicians within the community. Since 1983, we have successfully participated in the CCOP program, and our record and proposed changes promise continued success in the future. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: COST-EFFECTIVENESS--TREATMENTS--DUCTAL CARCINOMA IN SITU Principal Investigator & Institution: Dick, Andrew W.; Assistant Professor; Community and Prev Medicine; University of Rochester Orpa - Rc Box 270140 Rochester, Ny 14627

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Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2005 Summary: (provided by applicant): The incidence of ductal carcinoma in situ (DCIS) of the breast, a non-invasive form of breast cancer, has increased dramatically in the last 15 years. Its burden both on patients and on society has grown correspondingly. The optimal management of DCIS remains controversial because of the heterogeneity of the disease, the lack of randomized clinical trials comparing treatment strategies for women diagnosed with DCIS, the importance of patient preferences for possible outcomes and the uncertainty surrounding its natural history. Variations in the treatment of DCIS highlight the gaps in knowledge about the optimal management of the disease, gaps that have become increasingly important as the incidence of DCIS has increased. The cost implications of treatment variations also become substantial as DCIS is diagnosed more frequently. Ultimately, the variations in treatment result in differences in outcomes, including life expectancy, quality of life, and cost-effectiveness. We will examine the effects of various treatment strategies, including mastectomy with and without tamoxifen, and breast-conserving surgery with and without radiation and tamoxifen, on the following patient outcomes: DCIS recurrence rates, survival, costs, and quality of life. Decision analytic models will be used to estimate the costeffectiveness and cost-utility of the various treatment strategies. Models will include patient preferences for DCIS and associated treatments obtained from primary data collection. Transition probabilities for the decision analytic models wilt be estimated from primary data using duration models and supplemented from the literature as necessary. Potential endogeneity in treatment selection will be corrected using instrumental variable techniques. The linked Medicare-SEER data will be used to examine the generalizability of our estimated transition probabilities. DCIS treatment costs will be estimated using Medicare data. Sensitivity analyses will be used to test the robustness of our models. The ultimate goal of our project is to identify the most costeffective approaches to manage DCIS, taking into account a variety of clinical presentations and patient preferences, thus improving patient care and reducing the burden of the illness on society. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DEFINING SIGNATURES OF BREAST CANCER CELLS BY HRMAS MRS Principal Investigator & Institution: Cheng, Leo L.; Assistant Professor; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2003; Project Start 01-MAY-2003; Project End 30-APR-2007 Summary: (provided by applicant):Breast cancer is the most commonly diagnosed malignancy and second leading cause of cancer death among American women. Mammography has contributed to early detection, and thus new treatments, of breast tumors, but has also generated controversies. Many patients now diagnosed at very early, symptom free stages of the disease may be likely candidates for breast-conserving treatment (BCT), but some will experience a morbid disease course and die if not promptly treated with radical intervention (mastectomy, chemo- and radiation therapies). Morphology-based histopathology has to date served effectively in assessing breast cancer patients, particularly in the age dominated by mastectomy, but it is insensitive in guiding treatment plans with BCT. In addition to morphological evaluation, a method that directly evaluates the biological behavior of individual tumors and predicts potential aggressiveness is now needed for optimal breast cancer management. To achieve this, we will test the efficacy of an ex vivo spectroscopic method of identifying cellular metabolic signatures. By providing a new paradigm for

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the biochemical diagnosis of breast cancer, this method can assist in the diagnosis and prognostication of breast tumors in the era of BCT. We will quantify cellular metabolic changes in the development and progression of breast cancer with high-resolution magic angle spinning (HRMAS) proton magnetic resonance spectroscopy (1HMRS). HRMAS 1HMRS can measure cellular metabolites in intact human tissue specimens, while preserving histopathological structures. We will test the ability of HRMAS 1HMRS to quantify breast cancer metabolites, correlate metabolic concentrations obtained with histopathological features measured in the same intact tissue samples, define and evaluate metabolic signatures for breast cancer according to type, grade and histopathologic stage, perform molecular biology analyses of tumor signatures at the cellular level with laser capture microdissection (LCM), reverse transcription polymerase chain reaction (RT-PCR), and establish biochemical databases that help predict tumor pathologies and patient outcome, independently of pathology. Initially, we will quantify tissue metabolites of new surgical specimens, as well as stored frozen tissues, with HRMAS 1HMRS. Observed metabolites that correlate with histopathology will then be used to create a database of breast cancer metabolite signatures. These signatures should be useful in clinical care of women with breast cancer by identifying less aggressive tumors as candidates for breast-conserving treatment. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EPIGENETIC MODIFIERS OF BREAST CANCER RISK Principal Investigator & Institution: Swift-Scanlan, Theresa; None; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2003; Project Start 29-SEP-2003; Project End 28-SEP-2007 Summary: (provided by applicant): Breast cancer (BC) is a complex disease with both genetic and environmental causes, and is the second leading cause of cancer death in women. Most women who develop breast cancer (approximately 70%) have no known family history or obvious risk factors. The remaining 30% of cases tend to aggregate in families, and 5-7% of these are heritable through BRCA1 and BRCA2 mutations, the only gene tests currently available for breast cancer. Recent molecular studies of breast ductal epithelial cells and tumor tissue have demonstrated the presence of several DNA repair and tumor control genes whose expression into functional proteins is effectively shut down or silenced via DNA methylation. It is hypothesized that the presence of silenced tumor control genes in breast epithelial cells may presage the eventual development of BC in women with such molecular modifications. The specific aims of this research are: 1) to identify methylation suppressed tumor control genes in DNA isolated from breast tumor tissue and surrounding healthy breast tissue in a cohort of women at high risk for BC, as compared to a case-matched control cohort of women at average risk for BC, and 2) to determine the predictive contributions of family and personal factors on breast cancer outcome, such as a history of BC, age-of-onset, parity, age at menarche, previous breast biopsies, endogenous and exogenous hormone exposure, screening history, and BRCA mutation status. This research has implications for improving risk assessment, and may ultimately aid women in the decision-making process regarding screening and risk reduction prophylactic measures such as risk reduction mastectomy and chemoprevention. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: FASTING GLUCOSE IN LONG-TERM BREAST CANCER SURVIVAL Principal Investigator & Institution: Muti, Paola C.; Associate Professor; Social and Preventive Medicine; State University of New York at Buffalo Suite 211 Ub Commons Buffalo, Ny 14228 Timing: Fiscal Year 2004; Project Start 23-AUG-2004; Project End 30-JUN-2006 Summary: (provided by applicant): There is epidemiological evidence of a close association between major alteration in glucose metabolism and breast cancer risk. In three prospective studies there was a doubling of breast cancer risk for women who had a diagnosis of diabetes at baseline. In a recent prospective cohort study, we found a strong association of fasting glucose with risk of breast cancer. Overweight and obese women with breast cancer have poorer survival compared with thinner women. A recent study conducted at three Toronto hospitals observed that fasting insulin was associated with breast cancer outcomes in 512 women with early stages of the disease. The aim of the proposed study is to evaluate the long term prognostic significance of fasting glucose in primary breast cancer. The study will be conducted on 20,432 women admitted to the Istituto Nazionale per lo Studio e la Clara dei Tumori (Italian National Cancer Institute) in Milan, Lombardy Region, Italy between 1991 and 2002 for surgical treatment of a primary breast cancer. Women included in this study will be residents of the Lombardy Region (Northern Italy), who received complete resection of the neoplastic lesion (lumpectomy with margin clear of invasive cancer or mastectomy). We will derive information on pre-treatment serum fasting glucose levels from a computerized file of the Clinical Laboratory of the Italian National Cancer Institute in Milan. Personnel of the Lombardy Cancer Registry (LCR) will carry out the complete follow-up of the study participants for breast cancer recurrence and death. In addition to serum glucose, we will be able to collect individual information on total and HDLeholesterot, triglycerides, and serum uric acid from the same Clinical Laboratory file. These factors are, together with serum glucose, constituents of the Syndrome X, a condition defined by a cluster of metabolic factors and indicated to be a marker of insulin resistance and impaired glucose metabolism. Thus, we also propose to study the potential relation of individual pre-treatment baseline exposure to Syndrome X and breast cancer outcomes. Body weight and age, menopausal status, presence of diabetes at admission, traditional prognostic factors, such as tumor size, nodal stage, estrogenprogesterone receptor status and treatment related variables will also be available in the clinical chart and reported in the file together with the Clinical Laboratory data and they will be included in the analysis as potential confounders, or effect modifiers. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: FEASIBILITY OF CT IN HIGH RISK BREAST CANCER PATIENTS Principal Investigator & Institution: Boone, John M.; Professor; Radiology; University of California Davis Sponsored Programs, 118 Everson Hall Davis, Ca 956165200 Timing: Fiscal Year 2002; Project Start 01-JUL-2001; Project End 30-JUN-2004 Summary: Mammography is used to screen asymptomatic women for breast cancer, and typical breast cancer found using mammography is approximately 11 mm in diameter. At this small size, removal of lesion results in breast cancer cure in the majority of women. However, there is a small class of women (about 5% of all breast cancers) who are genetically predisposed to breast cancer (BRCA1 and BCRA2 genes), and in these women, more aggressive detection methods are needed. In addition to BRCA1 and BRCA2 carriers who are at extraordinary risk of breast cancer, women with extremely dense breasts are at higher risk from breast cancer (by virtue of their dense breasts with

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odds ratio from 4 to 6), and mammography is less sensitive in these women. For women in these high-risk categories, most of whom have dense breasts that are poorly imaged by mammography, an imaging modality with better lesion detectability performance (contrast resolution) is needed. While ultrasound rely on contrast mechanisms that are less reliable than X-ray contrast-that is why they are not used for screening. However, computed tomography (CT) does depend upon x-ray contrast mechanisms, but has about 10 times the contrast resolution as projection mammography. CT is very capable of identifying soft tissue lesions in the 3-5mm range- Such lesions are 10 to 50 times smaller in volume than the average 11mm lesion found by mammography. Therefore, CT has great potential for much earlier detection of breast cancer than mammography for high-risk patients. In this feasibility study, we propose to throughly investigate the potential of dedicated breast CT using computer simulation techniques coupled with CT of cadaver breasts and mastectomy specimens. Monte Carlo studies will be used to fully evaluate the glandular dose of breast CT, and imaging studies will be used to define the requirements of optimal CT acquisition. Using CT scans of breast lesions from about 10 mastectomy specimens, a breast tumor model will be developed. The tumor model will be used with a series of about 20 cadaver breast CT data sets to conduct extensive ROC studies. Computer observers will be used to define the Az versus tumor diameter curves for both CT and mammography. Human observers will be used to validate and calibrate the more extensive computer observer results. The results of this investigation should provide a clear understanding of the potential of breast CT as a tool to reduce breast cancer mortality in the population of women with dire risk of breast cancer. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: FEASIBILITY OF OPTOACOUSTIC TOMOGRAPHY IN BACKWARD MODE Principal Investigator & Institution: Oraevsky, Alexander A.; Vice President of Reserch Develoment; Ophthalmology and Visual Scis; University of Texas Medical Br Galveston 301 University Blvd Galveston, Tx 77555 Timing: Fiscal Year 2002; Project Start 14-DEC-2001; Project End 30-NOV-2002 Summary: (provided by applicant) Development of a novel optoacoustic imaging system for detection of early breast cancer is the main goal of the parent NIH grant. Comprehensive tests in phantoms resembling properties of the breast with tumors, extensive studies in mastectomy specimen surgically excised from the breast cancer patients and pilot clinical studies on breast cancer patients performed with laser optoacoustic imaging system (LOIS) developed at UTMB demonstrated high sensitivity of the system based on exceptional optical contrast between tumors and normal breast tissues combined with ultrawide-band detection of ultrasonic profiles induced by laser pulses in tumors. The resolution of LOIS matches the resolution of the state-of-the-art ultrasound systems (approximately 1-mm). Presently, two-dimensional optoacoustic images of the breast segments are being acquired with a system with optical fibers delivering laser pulses to one surface of the breast and an arc-shaped array of acoustic transducers receiving signals on the opposite surface of the breast (i.e. optoacoustic detection in so-called forward mode). The experience acquired with LOIS in the course of our project supported by NCI resulted in new ideas on the system modification in order to improve convenience for both, the operator and the patient. In particular, we propose a modification of LOIS to incorporate fiberoptic light delivery system and ultrasonic detectors in one compact hand-piece, with electronics allowing acquisition of breast images in real time and in a fusion similar to ultrasound imaging. Such a novel optoacoustic transducer (OAT) will operate in so-called backward detection mode. In

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order to perform feasibility studies of the LOIS in backward mode, we propose to enhance infrastructure at Moscow State University (MSU) enabling our collaborators to effectively participate in joint research and development projects on optoacoustic tomography, thereby enhancing the research of US Investigator. MSU group possesses a strong expertise in optoacoustics, nonlinear and ultrawide-band ultrasonics, and laser optics. Such a unique expertise will be very useful for expansion of the scope of the parent NIH grant. Specifically, the goals of the MSU group will be as follows: (1) to perform basic modeling and experimental studies of the optoacoustic tomography in backward mode using a single-element optoacoustic transducer, (2) design, fabricate and test in breast phantoms a hand-held optoacoustic transducer array with multiple optical fibers for illumination and multiple piezoelectric transducers for detection of ultrasonic waves at one and the same site on tissue surface. This project requires funding for equipment and supplies necessary for the MSU group to undertake proposed experiments. Joint feasibility studies in breast phantoms will be carried out at UTMB employing multi-element OAT to be developed at MSU and a multi-channel electronic data acquisition system developed at UTMB. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IMRT IN THE TREATMENT OF NODE-POSITIVE BREAST CANCER Principal Investigator & Institution: Pierce, Lori J.; Radiation Oncology; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2004; Project Start 01-SEP-2004; Project End 30-JUN-2007 Summary: (provided by applicant): Radiotherapy (RT) is an integral component in the management of early stage breast cancer following breast conservation and following mastectomy in high-risk patients. Previous reports have clearly documented, however, the potential for cardiac and pulmonary toxicity secondary to radiation injury, particularly in patients treated comprehensively to the regional nodes. Intensity modulated radiotherapy (IMRT) is a new treatment delivery technique that uses a variable intensity pattern determined with the aid of a computerized optimization algorithm. Preliminary results with IMRT in treatment of the breast only are promising with respect to improved target coverage and sparing of normal tissue. No studies to date, however, have prospectively compared the use of IMRT with the best standard three-dimensional (3-D) planning technique, with respect to cardiac and pulmonary exposure, in patients comprehensively treated to the breast/chest wall and regional nodes. Therefore, the long-term objective of the proposed research plan is to study comprehensive RT delivered using IMRT versus the best 3-D standard treatment technique (Partially Wide Tangential Fields (PWTF)). Quantitative indicators of potential cardiac and lung toxicity will be compared to determine the improvements that may be achieved with the new approach. Specific Aims: (1) Determine a static IMRT plan that significantly spares the heart and lung compared to the best static standard 3D plan PWTF; (2) Evaluate the effect of delivery-related issues, such as respiratory motion and setup uncertainty, on static PWTF and IMRT plans from Aim 1, and produce plans that compensate for motion. Determine the optimal motion corrected plan between delivery-optimized PWTF and delivery-optimized IMRT. (3) Compare the best delivery-optimized technique from Aim 2 with the best standard 3-D technique, PWTF, in a prospective trial. With the pilot data generated through this proposal, a randomized trial will ultimately be performed comparing these two treatment delivery techniques. Study Design: (1) Establish cost functions that drive the optimization to develop the IMRT plan using heart, lung, opposite breast, and spinal cord constraints while maximizing target coverage to the breast/chest wall and nodes. Optimize the best

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IMRT plan for 20 static cases and compare the static IMRT plan with PWTF using heart and lung metrics. (2) Measure the distribution of setup errors and motion of target volumes in a cohort of 20 patients. Determine the effect of motion on static IMRT and PWTF dose distributions, and then correct/adjust for motion to determine the best delivery-optimized plan. (3) Study 60 patients treated with either the best deliveryoptimized motion corrected plan from Aim 2 or PWTF and compare plans using heart and lung metrics. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INTERACTIVE DECISION AID FOR BRCA 1/2 MUTATION CARRIERS Principal Investigator & Institution: Schwartz, Marc D.; Associate Professor of Oncology / Co-Dir; Lombardi Comprehensive Cancer Center; Georgetown University Washington, Dc 20057 Timing: Fiscal Year 2002; Project Start 15-SEP-1999; Project End 30-JUN-2004 Summary: (adapted from investigator's abstract): Since the identification of the BRCA1 and BRCA2 breast cancer susceptibility genes, genetic testing has become increasingly widespread. Women who inherit a BRCA1/2 mutation have a 55-85 percent lifetime risk of breast cancer. The primary medical decision facing these women is whether to have a prophylactic mastectomy (breast removal) or to receive yearly mammograms. Because limited data favor one of these options or the other, women are informed about the benefits and limitations of each and counseled to select an option consistent with their personal preference and values. Although a specific recommendation for surgery versus surveillance is not generally made, BRCA1/2 carriers who do not elect surgery are advised to obtain annual mammograms. Given the lack of clear guidelines, it is not surprising that medical decision-making is reported to be one of the most challenging and stressful consequences of receiving a positive BRCA1/2 gene test result, and many carriers fail to adopt either option. The goal of this project is to develop and evaluate an interactive CD-ROM-based decision-aid for women who have recently received a positive BRCA1/2 gene test result. We propose a randomized trial among BRCA1 and BRCA2 mutation carriers in which we will compare standard genetic counseling (SGC) to an enhanced genetic counseling condition that consists of the individualized decisionaid (IDA) delivered in conjunction with standard genetic counseling. The IDA will be based, in part, on Subjective Expected Utility theory. Utility theory suggests that in making choices, people select the option that maximizes positive outcomes and minimizes negative outcomes. The value that an individual places on a particular health outcome is referred to as her preference or utility. Literature on decision-making in other medical contexts suggests that decision-aid interventions guided by Utility theory can promote informed decision-making and enhance psychological well being. If effective, the IDA can easily be disseminated to BRCA1/2 carriers across the country and adapted for use with other populations with inherited risk for cancer. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: LUTEAL ADJUVANT OOPHORECTOMY IN VIETNAMESE BREAST CANCER Principal Investigator & Institution: Love, Richard R.; Professor; Medicine; University of Wisconsin Madison 750 University Ave Madison, Wi 53706 Timing: Fiscal Year 2004; Project Start 01-MAY-2004; Project End 30-APR-2009

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Summary: (provided by applicant): In a randomized clinical trial of adjuvant oophorectomy and tamoxifen in 709 premenopausal Vietnamese and Chinese women with breast cancer, the proposers have demonstrated overall benefit (increased 5-year disease-free and overall survival) and specific benefit only to hormone receptor-positive tumor-bearing patients. Morbidity and symptomatic toxicity of this therapy were low; a cost-effectiveness analysis, assuming costs in Vietnam, shows a cost per life-year gained of $351. In detailed secondary analyses, benefit from adjuvant therapy was significantly greater in women undergoing simultaneous mastectomy and oophorectomy in the history-estimated luteal phases of their menstrual cycles. Analyses of axillary nodepositive and younger (