Breast Cancer, a Heterogeneous Disease Entity

Zsuzsanna Kahán€•Â€Tibor Tot Editors

Breast Cancer, a Heterogeneous Disease Entity The Very Early Stages

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Editors Dr. Zsuzsanna Kahán Department of Oncotherapy University of Szeged Korányi fasor 12 6720 Szeged Hungary [email protected]

Dr. Tibor Tot Department of Pathology Central Hospital Falun 79182 Falun Sweden [email protected]

ISBN 978-94-007-0488-6â•…â•…â•…â•… e-ISBN 978-94-007-0489-3 DOI 10.1007/978-94-007-0489-3 Springer Dordrecht Heidelberg London New York Library of Congress Control Number: 2011921320 © Springer Science+Business Media B.V. 2011 No part of this work may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, microfilming, recording or otherwise, without written permission from the Publisher, with the exception of any material supplied specifically for the purpose of being entered and executed on a computer system, for exclusive use by the purchaser of the work. Cover design: deblik, Berlin Printed on acid-free paper Springer is part of Springer Science+Business Media (www.springer.com)

The production of this volume has been inspired by the tireless activities and stimulating ideas of Professor László Tabár.

Contents

1  A  New Approach to Early Breast Cancer����������������������������������尓��������������   ╇ 1 Tibor Tot and Zsuzsanna Kahán 2  S  creening of Breast Cancer ����������������������������������尓������������������������������������尓 â•… 23 Per Skaane 3  M  agnetic Resonance Imaging (MRI) in the Screening of High-Risk Patients and in the Detection and Diagnosis of Early Breast Cancer ����������������������������������尓������������������������������������尓������������   45 Gábor Forrai 4  L  arge-Format Histology, a Prerequisite for Adequate Assessment of Early Breast Carcinomas����������������������������������尓��������������� â•… 57 Tibor Tot 5  T  he Molecular Evolution of Breast Cancer Precursors and Risk Indicators����������������������������������尓������������������������������������尓���������������������   89 Paul M. Wilkerson, Konstantin J. Dedes, Maria A. Lopez-Garcia, Felipe C. Geyer and Jorge S. Reis-Filho 6  I mmunohistochemistry and Molecular Biology of Breast Cancers: Old and New Prognostic Factors ����������������������������������尓����������� ╇ 119 Konstantin J. Dedes, Paul M. Wilkerson and Jorge S. Reis-Filho 7  S  entinel Node Biopsy and Nodal Staging ����������������������������������尓�������������� ╇ 149 Gábor Cserni  ailored Surgery: Limited Breast and Lymph Node Surgery��������������� ╇ 185 8  T György Lázár

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╇ 9  R  adiotherapy—A New Approach to Risk-Adapted Selective Radiotherapy����������������������������������尓������������������������������������尓���������������������� ╇ 211 Csaba Polgár 10  T  he Risks of Breast Radiotherapy and How to Avoid Them �������������� ╇ 241 Zsuzsanna Kahán, Katalin Hideghéty and Zoltán Varga 11  S  ystemic Adjuvant Therapy for Stage I Breast Cancer ����������������������� ╇ 269 Lajos Pusztai and Catherine M. Kelly 12  S  ystemic Therapy: Selection of Patients ����������������������������������尓������������� ╇ 283 Zsuzsanna Kahán Index ����������������������������������尓������������������������������������尓������������������������������������尓������� ╇ 305

Contributors

Gábor Cserni, MD, PhD╇ Bács-Kiskun County Teaching Hospital, Nyíri út 38, 6000 Kecskemet, Hungary, Tel.: +36-76-516700, Fax: +36-76-481219 e-mail: [email protected] Konstantin J. Dedes╇ Molecular Pathology Team, The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, 237 Fulham Road, SW3 6JB London, UK, Tel.: +44-20-71535167, Fax: +44-20-71535533 e-mail: [email protected] Gábor Forrai, MD, PhD╇ Department of Radiology, State Health Centre, Róbert Károly krt. 44, 1134 Budapest, Hungary, Tel: +36-20-9267067, Fax: +36-14-651873 e-mail: [email protected] Felipe C. Geyer╇ Molecular Pathology Team, The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, 237 Fulham Road, SW3 6JB London, UK, Tel.: +44-20-71535167, Fax: +44-20-71535533 Katalin Hideghéty, MD, PhD╇ Department of Oncotherapy, University of Szeged, Korányi fasor 12, 6720 Szeged, Hungary, Tel.: +36-62-545406, Fax: +36-62-545922 e-mail: [email protected] Zsuzsanna Kahán, MD, PhD╇ Department of Oncotherapy, University of Szeged, Korányi fasor 12, 6720 Szeged, Hungary, Tel.: +36-62-545406, Fax: +36-62-545922 e-mail: [email protected] Catherine M. Kelly, MD, MSc, (Clin Epi)╇ Department of Breast Medical Oncology, South East Cancer Center (SECC), Waterford Regional Hospital, Ireland e-mail: [email protected] György Lázár, MD, PhD╇ Department of Surgery, University of Szeged, Pécsi u. 6., 6720 Szeged, Hungary, Tel.: +36-62-545461, Fax: +36-62-545701 e-mail: [email protected]

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Maria A. Lopez-Garcia╇ Molecular Pathology Team, The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, 237 Fulham Road, SW3 6JB London, UK, Tel.: +44-20-71535167, Fax: +44-20-71535533 Csaba Polgár, MD, PhD╇ Department of Radiotherapy, National Institute of Oncology, Ráth Gy. u. 7–9, 1122 Budapest, Hungary, Tel.: +36-1-2248600, Fax: +36-1-2248680 e-mail: [email protected] Lajos Pusztai, MD, PhD╇ Department of Breast Medical Oncology, M.D Anderson Cancer Center, The University of Texas, PO Box 301439, Houston, TX 77230– 1439, USA, Tel.: +1-713-7922817, Fax: +1-713-7944385 e-mail: [email protected] Jorge S. Reis-Filho, MD, PhD, FRCPath╇ Molecular Pathology Team, The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, 237 Fulham Road, SW3 6JB London, UK, Tel.: +44-20-71535167, Fax: +44-20-71535533 e-mail: [email protected] Per Skaane, MD, PhD╇ Department of Radiology, Ullevaal University Hospital, Kirkeveien 166, 0407 Oslo, Norway, Tel.: +47-22-119411, Fax: +47-23-016535 e-mail: [email protected] Tibor Tot, MD, PhD╇ Department of Pathology, Central Hospital Falun, Uppsala University, 79182 Falun, Sweden, Tel.: +46-23-492696, Fax: +46-23-492389 e-mail: [email protected] Zoltán Varga, PhD╇ Department of Oncotherapy, University of Szeged, Korányi fasor 12, 6720 Szeged, Hungary, Tel.: +36-62-545406, Fax: +36-62-545922 e-mail: [email protected] Paul M. Wilkerson╇ Molecular Pathology Team, The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, 237 Fulham Road, SW3 6JB London, UK, Tel.: +44-20-71535167, Fax: +44-20-71535533 e-mail: [email protected]

Chapter 1

A New Approach to Early Breast Cancer Tibor Tot and Zsuzsanna Kahán

1.1  Introduction The incidence of early-stage breast cancer with a size of a few millimetres is constantly increasing. These tumours exhibit significantly more favourable pathological features and a far better outcome than their larger counterparts: most are lymph node-negative, display a low histology grade and hormone receptor positivity, and are free from vessel invasion (Molino et€al. 2000; Gill et€al. 2006; Anttinen et€al. 2006; Joensuu et€al. 2004; Bucchi et€al. 2005; Immonen-Raiha et€al. 2005; Klemi et€ al. 1992). They usually demand less extensive surgery and less radical radiotherapy (if any), and oncological treatment can often be omitted without affecting the excellent outcome. Although many of these cancers are easily cured by surgery, a minority of the cases are still fatal. Identification and appropriate therapy of these high-risk cases is mandatory. However, neither the first-generation prognostic factors (tumour size, lymph node status and histology grade), nor the usual additional parameters (receptor status and proliferation markers) are reliable enough to demonstrate the true nature of the prognostically different subgroups. We are facing a new era, in which a completely new approach to early breast cancer is needed. In this new era, each case should be characterized individually through the use of multimodality imaging and special pathological methods; a new classification system is required based on the knowledge acquired during decades of mammography screening (Tabár 2000). New therapeutic guidelines must be developed which are appropriately adapted to the heterogeneous nature of early breast cancers. One very important point is that the therapy should not follow the guidelines put forward in light of the trial results obtained on tumours traditionally called early, but which were in fact at a more advanced stage than most of the tumours we see today. Breast cancer is already heterogeneous in the very T. Tot () Department of Pathology, Central Hospital Falun, Uppsala University, 79182 Falun, Sweden Tel.: +46-23-492696 Fax: +46-23-492389 e-mail: [email protected] Z. Kahán, T. Tot (eds.), Breast Cancer, a Heterogeneous Disease Entity, DOI 10.1007/978-94-007-0489-3_1, ©Â€Springer Science+Business Media B.V. 2011

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early stages of its natural history, and this should be taken into consideration during the decision making concerning treatment.

1.2  Defining Criteria Traditionally, the term ‘early breast carcinoma’ has been used as a synonym of operable breast cancer. Thus, pT1N0M0, pT2N0M0 (Nealon et al. 1981), and even pT1N1M0 cancers (Rosen and Groshen 1990) have been reported to belong in this category. In general, while about 90% of all pT1N0 cases are relapse-free after a long follow-up period, only 50–80% of the patients in the pT1N1 or pT2N0 categories are long-term survivors (Ernst et€al. 2004; Moody-Ayers et€al. 2000; Gill et€al. 2004; Groenendijk et€al. 2002; Cortesi et€al. 2006; Tabár et€al. 2000; Smart et€al. 1997). This indicates that true early cancers and their more advanced counterparts were inappropriately grouped and studied together in the past. It is essential to distinguish between small, most often screen-detected cancers, and their symptomatic and large counterparts throughout their management, both mentally and in practice. The currently used TNM classification developed some time ago from experience with symptomatic breast cancers, now seems to be inadequate for the correct delineation of true ‘early’ breast cancer cases. Two of the routinely assessed morphologic prognostic parameters that have been traditionally used to characterize the ‘early’ stage of breast carcinoma are the presence or absence of invasion, and the size of the invasive component of the tumour. Gallagher (1976) applied the term ‘minimal breast cancer’, defined as in situ carcinomas and/or invasive cancers up to 5€mm in size. In the series he reported, the patients with these tumours had a 5-year overall survival rate of over 95%. A few years later, Hartmann extended the definition of the size of the invasive component up to 10€mm (Hartmann 1984). The prognosis of in situ and microinvasive carcinomas has been studied repeatedly. Patients with in situ carcinomas demonstrate a survival rate of about 98% after a follow-up time of 10€years (Ernster et€al. 2000). The prognosis of microinvasive carcinomas (defined as invasive tumours up to 1€ mm in size) is comparable to that of in situ tumours (Padmore et€al. 2000; Colleoni et€al. 2004). Recent studies also provided evidence of an excellent long-term prognosis in cases of invasive breast carcinomas measuring 10–14€mm (James et€al. 2003; Tabár et€al. 2004). Thus, we prefer to define the earliest stage of breast carcinoma as in situ carcinoma, microinvasive carcinoma (with an invasive component up to 1€ mm in size) and invasive tumours in the range of 1–14€mm. The tumours included in this category generally associated with a 5-year survival probability of >95% and a 10-year survival rate of >90%. Figure€1.1 demonstrates the excellent long-term breast cancer-specific survival rate in our own series of early breast carcinomas defined in this way. The 10-year survival rate for the overall population was 94.3%, and that for those with invasive carcinomas measuring 1–14€mm was 93.8%. Three patients among

Fig. 1.1↜渀 Cumulative breast cancer-specific survival rate data on 252 early breast carcinoma cases (pure in situ and invasive