Foreword I

Bombardieri · Bonadonna · Gianni

Breast Cancer Nuclear Medicine in Diagnosis and Therapeutic Options Foreword III

E. Bombardieri · G. Bonadonna · L. Gianni (Eds.) Breast Cancer Nuclear Medicine in Diagnosis and Therapeutic Options

With Contributions by

R. Agresti · A. Alessi · H. Bender · S. Bergomi · T. Beyer · H.-J. Biersack · E. Bombardieri A. K. Buck · E. Brugola · J. R. Buscombe · I. Butti · V. Cappelletti · A. Carbone M. L. Carcangiu · A. Coli · P. F. Conte · F. Crippa · M. G. Daidone · A. Fabbri · F. Fazio L. Florimonte · R. Fonti · O. Gentilini · A. Gerali · L. Gianni · L. Gianolli · M. Gion V. Guarneri · N. Harbeck · K. Hausegger · O. S. Hoekstra · I. Igerc · M. Intra · F. Iommelli N. C. Krak · J. M. H. de Klerk · M. G. E. H. Lam · A. A. Lammertsma · C. Landoni · P. Lind G. Lucignani · G. Madeddu · L. Maffi oli · C. Di Maggio · C. L. Maini · S. Manoukian P. Mariani · N. Mazzuca · C. Messa · A. J. Nordin · H. Palmedo · G. Paganelli · L. Pagani F. Pallotti · A. Paradiso · R. Pasqualoni · F. Piacentini · M. Picchio · P. Reinprecht · S. N. Reske P. P. van Rijk · I. Roca · M. Salvatore · O. Schillaci · M. Schmitt · R. Sciuto · E. Seregni G. Serfi ni · A. Spanu · L. Strigari · F. Sweep · L. Tagliabue · G. Trecate · G. Trifi rò S. Del Vecchio · D. Vernaghi · U. Veronesi · G. Viale · B. Zangheri · A. Zannetti

With 72 Figures in 156 Separate Illustrations, 56 in Color and 30 Tables

123 IV Foreword

Emilio Bombardieri, MD Division of Nuclear Medicine Department of Diagnostic Imaging and Radiotherapy Fondazione IRCCS Istituto Nazionale dei Tumori Via Venezian 1 20133 Milano Italy Luca Gianni, MD Division of Medical Oncology Fondazione IRCCS Istituto Nazionale dei Tumori Via Venezian 1 20133 Milano Italy Gianni Bonadonna, MD Chair, Perspective Clinical Trials Fondazione IRCCS Istituto Nazionale dei Tumori Via Venezian 1 20133 Milano Italy

Library of Congress Control Number: 2007933314

ISBN 978-3-540-36780-2 Springer Berlin Heidelberg New York

This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifi cally the rights of translation, reprinting, reuse of illustrations, recitations, broadcasting, reproduction on microfi lm or in any other way, and storage in data banks. Duplication of this publication or parts thereof is permit- ted only under the provisions of the German Copyright Law of September 9, 1965, in its current version, and permis- sion for use must always be obtained from Springer-Verlag. Violations are liable for prosecution under the German Copyright Law. Springer is part of Springer Science+Business Media http//www.springer.com © Springer-Verlag Berlin Heidelberg 2008 Printed in Germany The use of general descriptive names, trademarks, etc. in this publication does not imply, even in the absence of a specifi c statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. Product liability: The publishers cannot guarantee the accuracy of any information about dosage and application contained in this book. In every case the user must check such information by consulting the relevant literature. Medical Editor: Dr. Ute Heilmann, Heidelberg Desk Editor: Ursula N. Davis, Heidelberg Production Editor: Kurt Teichmann, Mauer Typesetting: Verlagsservice Teichmann, Mauer Cover-Design: Frido Steinen-Broo, eStudio Calamar, Spain Printed on acid-free paper – 21/3180xq – 5 4 3 2 1 0 Foreword V

Foreword

Breast cancer is the most common malignant disease among Western women and rep- resents a major public health problem, with more than 370,000 new cases and 130,000 deaths per year in women aged 35–64 years in Europe alone. It accounts for one third of the cancer-related deaths in women aged 35–55 years. The efforts of modern oncology to deal with this clinical problem are focused on reaching a diagnosis at the earliest stage, when the disease is still limited, the tumour is resectable and it is still possible to treat with curative intent. Another essential goal of modern research is to characterise the tumour cells in order to categorise patients into different risk groups, identify responders versus nonresponders to therapy, and design adequate targeted therapies that are effective also in the adjuvant setting to eradicate breast cancer cells that might have already spread to distant sites at the time of diagnosis. The great impact of nuclear medicine in oncology is due to its important progress in this fi eld in recent years, and the effect of such progress has been particularly noticeable in breast cancer. Research into molecular imaging has led to the development of several radiopharmaceuticals that can explore the cellular metabolism and visualise, at the molecular and subcellular level, pathological processes specifi c to cancer. Advances in diagnostic equipment have made high-technology instruments available such as PET, which is capable of producing high-quality tomographic images. Such imaging has become of major value to physicians because it often reveals alterations and lesions not demonstrated by conventional morphological techniques such as X-rays, US, CT or MRI. Research into image fusion techniques has led to the design of software pro- grammes capable of merging the molecular, functional and metabolic information of nuclear medicine with the morphological information provided by radiology into a single image. Hybrid instruments (PET/CT, SPECT/CT) are now available which allow the fusion of images of a patient in just one diagnostic session. All these impressive achievements are going to produce important results not only for the diagnosis but also the treatment of cancer. Nuclear medicine explores the func- tion and biology of cells and tissues, and can be considered an experimental area of drug development for individual tailored therapies. In fact, radiopharmaceuticals developed specifi cally to target and visualise malignant tumours can also be used, at high doses, for therapeutic purposes. Nuclear medicine therapeutics thus takes advan- tage of selective radiopharmaceuticals that have demonstrated anticancer effi cacy in many types of tumours. VI Foreword

This book on the diagnostic and therapeutic applications of nuclear medicine in breast cancer aims to describe the state of the art and the current position of nuclear medicine in the light of these recent developments and in comparison with conven- tional radiological and nonradiological modalities. Some basic concepts regarding breast cancer are treated and discussed with the aim of providing a general overview on a disease that is the subject of continuous stimulating proposals for research and clinical investigation. The text is therefore intended as an update also for non-nuclear- medicine specialists working in senology and oncology. The new defi nition of nuclear medicine is ‘molecular imaging’ and ‘targeted therapy’ and its clinical impact is becoming increasingly important. We have no doubt that the diagnosis and treatment of breast cancer will benefi t from the new horizons opened up by nuclear medicine.

Gianni Bonadonna Emilio Bombardieri Luca Gianni

Acknowledgements The editors are grateful to Ms Anna Luisa De Simone Sorrentino for her precious help in compiling this manuscript. Preface VII

Preface

The last three decades have witnessed tremendous advances in the understanding and treatment of breast cancer. As a result, starting shortly before the 1990s, a per- sistent decrease in breast cancer mortality has been documented, primarily in the United States and in several European countries. Breast cancer, however, remains an important health problem. In this book, which is mainly dedicated to nuclear medicine, experts have thoroughly reviewed the achievements made in the diagnosis, monitoring and treatment of this disease. There is no doubt that breast cancer has always been one of the most appealing areas of cancer research; the vast number of new clinical and preclinical studies published every day in the medical literature is an example. More recently, the development of molecular biology techniques has allowed the identifi cation and analysis of molecular factors that play an important role in normal cell growth and differentiation. Such factors have also been shown to infl uence the behavior of tumors in terms of cellular differentiation, growth rate, metastatic pat- tern and response to therapy. Furthermore, they will be instrumental in the develop- ment of new agents for targeted therapies. Using molecular tracers to characterize neoplastic tissues and to select, among the available effective regimens, the one with the highest probability of cure for the individual patient, is an appealing way to con- duct new research. The ability to predict who will need medical therapy and who will or will not respond to a given drug or drug regimen will serve to guide clinical deci- sion-making and treatment recommendations. Although predictive accuracy may not be an all-or-none phenomenon, patients can be spared treatments that are devoid of effi cacy but are associated with toxicity instead. Besides this, delivering treat- ments that have a more pronounced activity against tumors with specifi c molecular features will lead to improved benefi t for the patient, making the difference between cure and palliation. In this area nuclear medicine follows the new developments in oncology: the modern term “molecular imaging” means to visualize a biological phenomenon at the molecular level according to the specifi city and the specifi c biodistribution of a molecular probe. Cancer can be imaged through metabolic pathways (such as glucose and amino-acid transport, DNA precursor incorporation, hormone receptors, angio- genesis, hypoxia, antigen expression) targeted by radioactive tracers. This makes it possible to supplement the morphological description of a tumor with a considerable amount of biological information. Nuclear medicine images may provide prognostic VIII Preface

indications, predict the response to different treatments, and detect the presence and activity of viable cancer cells in already treated patients. The same radiophar- maceuticals that target neoplasia and are used in diagnostic imaging can carry high amounts of radioactivity to cancer cells and thus selectively deliver a lethal irradia- tion dose to a tumor. For all these reasons nuclear medicine techniques have acquired an important role in the study and management of breast cancer, and are becoming more and more integrated in the new developments of molecular biology, pharmacol- ogy, diagnostic imaging and therapy.

Gianni Bonadonna Contents IX

Contents

1 Introduction ...... 1

2 Histological Classifi cation of Breast Cancer Alessandra Fabbri, Maria Luisa Carcangiu, and Antonino Carbone . . . . . 3

3 Biomarkers for Breast Cancer: Towards the Proposition of Clinically Relevant Tools Maria Grazia Daidone, Vera Cappelletti, Angelo Paradiso, Massimo Gion, Nadia Harbeck, Fred Sweep, and Manfred Schmitt ...... 15

4 Circulating Tumour Markers in Breast Cancer Ettore Seregni, Antonio Coli, and Nicola Mazzuca ...... 33

5 Axillary Lymph Node Status Evaluation in Breast Cancer Patients: Role of SPECT and Pinhole SPECT with Cationic Lipophilic Radiotracers Giuseppe Madeddu and Angela Spanu ...... 43

6 Breast Imaging with Scintimammography Orazio Schillaci and John R. Buscombe ...... 57

7 99mTc-MIBI in the Evaluation of Breast Cancer Biology Silvana Del Vecchio, Antonella Zannetti, Rosa Fonti, Francesca Iommelli, and Marco Salvatore ...... 71

8 Sentinel Node Detection in Pre-Operative Axillary Staging Giovanni Paganelli, Giuseppe Trifi rò, Oreste Gentilini, Mattia Intra, Giuseppe Viale, and Umberto Veronesi ...... 83

9 State of the Art of Current Modalities for the Diagnosis of Breast Lesions Cosimo Di Maggio ...... 99

10 New Trends of MRI in Breast Cancer Diagnosis Daniele Vergnaghi, Giovanna Trecate, and Siranoush Manoukian ...... 127

11 PET Imaging of Breast Cancer Molecular Biomarkers Elisabetta Brugola, Andreas K. Buck, Lucia Tagliabue, Sven N. Reske, and Giovanni Lucignani ...... 145

12 The Role of FDG-PET for Axillary Lymph Node Staging in Primary Breast Cancer Flavio Crippa, Alberto Gerali, Alessandra Alessi, Roberto Agresti, and Emilio Bombardieri ...... 157

X Contents

13 Measuring Response to Chemotherapy in Locally Advanced Breast Cancer: Methodological Considerations Nanda C. Krak, Otto S. Hoekstra, and Adriaan A. Lammertsma ...... 169

14 FDG-PET in Monitoring Therapy of Breast Cancer Hans-Jürgen Biersack, Hans Bender, and Holger Palmedo ...... 181

15 FDG-PET and Tumour Marker Tests for the Diagnosis of Breast Cancer Emilio Bombardieri, Alessandra Alessi, Federica Pallotti, Gianluca Serafi ni, Nicola Mazzuca, Ettore Seregni, and Flavio Crippa ...... 189

16 Advantages and Limitations of FDG PET in the Follow-Up of Breast Cancer Peter Lind, Isabel Igerc, Thomas Beyer, Abdul Jalil Nordin, Peter Reinprecht, and Klaus Hausegger ...... 201

17 PET/CT and Breast Cancer Maria Picchio, Cristina Messa, Barbara Zangheri, Claudio Landoni, Lugio Gianolli, and Ferruccio Fazio ...... 217

18 Current Role of Bone Scan with Phosphonates in the Follow-Up of Breast Cancer Lorenzo Maffi oli, Luigia Florimonte, Luca Pagani, Ivana Butti, and Isabel Roca ...... 227

19 Progress in the Treatment of Early and Advanced Breast Cancer Valentina Guarneri, Frederico Piacentini, and PierFranco Conte ...... 239

20 186Re-HEDP for Metastatic Bone Pain in Breast Cancer Patients Marnix G. E. H. Lam, John M. H. de Klerk, and Peter P. van Rijk ...... 257

21 153Sm-EDTM for Bone Pain Treatment in Skeletal Metastases Carlo Ludovico Maini, Serenella Bergomi, Rosella Pasqualoni, Lidia Strigari, and Rosa Sciuto ...... 271

22 The Choice of the Correct Imaging Modality in Breast Cancer Management Paola Mariani and Luca Gianni ...... 281

Subject Index ...... 293 List of Contributors XI

List of Contributors

Roberto Agresti Ivana Butti Unit of Surgical Oncology Division of Health Physics Fondazione IRCCS Ospedale A. Manzoni Istituto Nazionale dei Tumori Lecco, Italy Milan, Italy Vera Cappelletti Alessandra Alessi Research Unit 10 PET Unit, Nuclear Medicine Division Department of Experimental Oncology Fondazione IRCCS Fondazione IRCCS Istituto Nazionale dei Tumori Istituto Nazionale dei Tumori Milan, Italy Milan, Italy Hans Bender Department of Nuclear Medicine Antonino Carbone University Hospital Bonn Department of Pathological Anatomy Bonn, Germany Fondazione IRCCS Istituto Nazionale dei Tumori Serenella Bergomi Milan, Italy Nuclear Medicine Department Regina Elena National Cancer Instiute Maria Luisa Carcangiu Rome, Italy Department of Pathological Anatomy Thomas Beyer Fondazione IRCCS Istituto Nazionale dei Tumori Department of Nuclear Medicine Milan, Italy University Hospital Essen, Germany Antonio Coli Hans-Jürgen Biersack Nuclear Medicine Unit Department of Nuclear Medicine Ospedale S. Andrea University Hospital Bonn La Spezia, Italy Bonn, Germany Pier Franco Conte Emilio Bombardieri Department of Oncology and Hematology Division of Nuclear Medicine University of Modena and Reggio Emilia Department of Diagnostic Imaging and Radiotherapy Modena, Italy Fondazione IRCCS Istituto Nazionale dei Tumori Flavio Crippa Milano, Italy PET Unit - Nuclear Medicine Division Andreas K. Buck Fondazione IRCCS Istituto Nazionale dei Tumori Department of Nuclear Medicine Milan, Italy University Hospital Ulm, Ulm, Germany Maria Grazia Daidone Elisabetta Brugola Research Unit 10 Institute of Radiological Sciences Department of Experimental Oncology University of Milan Fondazione IRCCS Unit of Nuclear Medicine Istituto Nazionale dei Tumori Hospital San Paolo Milan, Italy Milan, Italy Alessandra Fabbri John R. Buscombe Department of Pathological Anatomy Department of Nuclear Medicine Fondazione IRCCS Royal Free Hospital Istituto Nazionale dei Tumori London, United Kingdom Milan, Italy XII List of Contributors

Ferruccio Fazio Isabel Igerc Department of Nuclear Medicine Landeskrankenhaus-Klagenfurt Scientifi c Institute San Raffaele PET/CT Center Klagenfurt IBFM-CNR Klagenfurt, Austria University of Milano-Bicocca Milan, Italy Matti Intra Division of Senology Luigia Florimonte European Institute of Oncology Department of Nuclear Medicine Milan, Italy Fondazione IRCCS Ospedale Maggiore Policlinico Francesca Iommelli Mangiagalli Regina Elena Department of Biomorphological and Milan, Italy Functional Sciences Rosa Fonti Naples, Italy Institute of Biostructures and Bioimages Nanda C. Krak of the National Research Council (CNR) Naples, Italy Department of Nuclear Medicine and PET Research VU University Medical Centre Oreste Gentilini Amsterdam, The Netherlands Division of Senology European Institute of Oncology John M.H. de Klerk Milan, Italy Department of Nuclear Medicine University Medical Center Utrecht Alberto Gerali Utrecht, The Netherlands PET Unit – Nuclear Medicine Division Fondazione IRCCS Marnix G.E.H. Lam Istituto Nazionale dei Tumori Department of Nuclear Medicine Milan, Italy University Medical Center Utrecht Luca Gianni Utrecht, The Netherlands Division of Medical Oncology Adriaan A. Lammertsma Fondazione IRCCS Department of Nuclear Medicine and PET Research Istituto Nazionale dei Tumori VU University Medical Centre Milan, Italy Amsterdam, The Netherlands Luigi Gianolli Claudio Landoni Department of Nuclear Medicine Scientifi c Institute San Raffaele Department of Nuclear Medicine Milan, Italy Scientifi c Institute San Raffaele University of Milano Bicocca Massimo Gion Milan, Italy Centro Regionale Indicatori Biochimici di Tumore Ospedale Civile Peter Lind Venice, Italy Department of Nuclear Medicine and Endocrinology Landeskrankenhaus-Klagenfurt Valentina Guarneri PET/CT Center Department of Oncology and Haematology Klagenfurt, Austria University of Modena and Reggio Emilia Modena, Italy Giovanni Lucignani Institute of Radiological Sciences Nadia Harbeck University of Milan Clinical Research Unit Unit of Nuclear Medicine Department of Obstetrics and Gynecology Hospital San Paolo Technical University of Munich Milan, Italy Munich, Germany Giuseppe Madeddu Klaus Hausegger Department of Nuclear Medicine Department of Radiology University of Sassari Klagenfurt, Austria Sassari, Italy

Otto S. Hoekstra Lorenzo Maffi oli Department of Nuclear Medicine and PET Research Division of Nuclear Medicine VU University Medical Centre Ospedale Civile di Legnano Amsterdam, The Netherlands Legnano, Italy List of Contributors XIII

Cosimo Di Maggio Rosella Pasqualoni Diagnostic Breast Unit Nuclear Medicine Department University of Padua Regina Elena National Cancer Institute Padua, Italy Rome, Italy

Carlo L. Maini Frederico Piacentini Nuclear Medicine Department Department of Oncology and Hematology Regina Elena National Cancer Instiute University of Modena and Reggio Emilia Rome, Italy Modena, Italy Siranoush Manoukian Maria Picchio Department of Experiomental Oncology- Medical Gnetics Department of Nuclear Medicine Fondazione IRCCS Scientifi c Institute San Raffaele Istituto Nazionale dei Tumori Milan, Italy Milan, Italy Peter Reinprecht Paola Mariani Landeskrankenhaus-Klagenfurt Division of Medical Oncology Department of Radiology Fondazione IRCCS Klagenfurt, Austria Istituto Nazionale dei Tumori Milan, Italy Sven N. Reske Department of Nuclear Medicine Nicola Mazzuca University Hospital Ulm Nuclear Medicine Division Ulm, Germany Ospedale Misericordia Grosseto, Italy Peter P. van Rijk Cristina Messa Department of Nuclear Medicine University Medical Center Utrecht Department of Nuclear Medicine Utrecht, The Netherlands Scientifi c Institute San Raffaele IBFM-CNR Isabel Roca University of Milano Bicocca Milan, Italy Division of Nuclear Medicine Hospital Universitari Vall Hebron Abdul Jalil Nordin Barcelona, Spain Department of Radiology University Putra Marco Salvatore Putra, Malysia Department of Biomorphological and Functional Sciences Holger Palmedo University of Naples Department of Nuclear Medicine Naples, Italy University Hospital Bonn Bonn, Germany Orazio Schillaci Giovanni Paganelli Department of Biopathology and Diagnostic Imaging University Tor Vergata Division of Nuclear Medicine Rome, Italy European Institute of Oncology Milan, Italy Manfred Schmitt Luca Pagani Department of Chemical Endocrinology Division of Nuclear Medicine University Medical Center Nijmegen Ospedale A. Manzoni Nijmegen, The Netherlands Lecco, Italy Rosa Sciuto Frederica Pallotti Nuclear Medicine Department Nuclear Medicine Division Regina Elena National Cancer Instiute Fondazione IRCCS Rome, Italy Istituto Nazionale dei Tumori Milan, Italy Ettore Seregni Radioisotopes Laboratory Angelo Paradiso Nuclear Medicine Division Department of Experimental Oncology Fondazione IRCCS Istituto Oncologico Istituto Nazionale dei Tumori Bari, Italy Milan, Italy XIV List of Contributors

Gianluca Serafi ni Giuseppe Trifi rò Division of Nuclear Medicine Division of Nuclear Medicne Fondazione IRCCS European Institute of Oncology Istituto Nazionale dei Tumori Milan, Italy Milan, Italy Silvana Del Vecchio Angela Spanu Department of Biomorphological and Functional Sciences Department of Nuclear Medicine Naples, Italy University of Sassari Sassari, Italy Daniele Vernaghi Department of Diagnostic Imaging and Radiotherapy Lidia Strigari Unit of Diagnostic Radiology 1 Physical Department Fondazione IRCCS Regina Elena National Cancer Instiute Istituto Nazionale dei Tumori Rome, Italy Milan , Italy Umberto Veronesi Fred Sweep Scientifi c Direction Department of Chemical Endocrinology European Institute of Oncology University Medical Center Nijmegen Milan, Italy Nijmegen, The Netherlands Giuseppe Viale Luca Tagliabue Division of Pathology Institute of Radiological Sciences European Institute of Oncology University of Milan Milan, Italy Unit of Nuclear Medicine Hospital San Paolo Barbara Zangheri Milan, Italy Department of Nuclear Medicine Scientifi c Institute San Raffaele Giovanna Trecate Milan, Italy Department of Diagnostic Imaging and Radiotherapy Unit of Diagnostic Radiology 1 Antonella Zannetti Fondazione IRCCS Institute of Biostructures and Bioimages Istituto Nazionale dei Tumori of the National Research Council (CNR) Milan , Italy Naples, Italy