Report in English with a Dutch summary (KCE reports 63A)

Wetenschappelijke
ondersteuning van het
College voor Oncologie: een
nationale praktijkrichtlijn voor
de aanpak van borstkanker
KCE reports vol. 63A
Federaal Kenniscentrum voor de Gezondheidszorg
Centre fédéral dÊexpertise des soins de santé
2007

Het Federaal Kenniscentrum voor de Gezondheidszorg
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parastatale, opgericht door de programma-wet van 24 december 2002
(artikelen 262 tot 266) die onder de bevoegdheid valt van de Minister
van Volksgezondheid en Sociale Zaken. Het Centrum is belast met het
realiseren van beleidsondersteunende studies binnen de sector van de
gezondheidszorg en de ziekteverzekering.
Raad van Bestuur
Effectieve leden : Gillet Pierre (Voorzitter), Cuypers Dirk (Ondervoorzitter),
Avontroodt Yolande, De Cock Jo (Ondervoorzitter), De Meyere
Frank, De Ridder Henri, Gillet Jean-Bernard, Godin Jean-Noël, Goyens
Floris, Kesteloot Katrien, Maes Jef, Mertens Pascal, Mertens Raf,
Moens Marc, Perl François, Smiets Pierre, Van Massenhove Frank,
Vandermeeren Philippe, Verertbruggen Patrick, Vermeyen Karel.
Plaatsvervangers : Annemans Lieven, Boonen Carine, Collin Benoît, Cuypers Rita, Dercq
Jean-Paul, Désir Daniel, Lemye Roland, Palsterman Paul, Ponce Annick,
Pirlot Viviane, Praet Jean-Claude, Remacle Anne, Schoonjans Chris,
Schrooten Renaat, Vanderstappen Anne.
Regeringscommissaris : Roger Yves
Directie
Algemeen Directeur : Dirk Ramaekers
Algemeen Directeur adjunct : Jean-Pierre Closon
Contact
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Wetstraat 62
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Wetenschappelijke
ondersteuning van het
College voor Oncologie: een
nationale praktijkrichtlijn voor
de aanpak van borstkanker
KCE reports vol. 63A
M.-R. CHRISTIAENS, J. VLAYEN, J. GAILLY , P. NEVEN, B. CARLY,
J.-C. SCHOBBENS, R. DRIJKONINGEN, E. LIFRANGE,
V. COCQUYT, C. BOURGAIN, G. VILLEIRS, D. LARSIMONT,
S. D’HAESE, J. DE GRÈVE
Federaal Kenniscentrum voor de Gezondheidszorg
Centre fédéral d’expertise des soins de santé
2007

KCE reports vol. 63A
Titel : Wetenschappelijke ondersteuning van het College voor Oncologie: een
nationale praktijkrichtlijn voor de aanpak van borstkanker
Auteurs : Marie-Rose Christiaens (UZ Leuven), Joan Vlayen (KCE), Jeannine Gailly
(KCE), Patrick Neven (UZ Leuven), Birgit Carly (UMC Sint-Pieter,
Brussel), Jean Christophe Schobbens (Jules Bordet Instituut), Ria
Drijkoningen (UZ Leuven), Eric Lifrange (CHU Liège), Véronique Cocquyt
(UZ Gent), Claire Bourgain (UZ Brussel), Geert Villeirs (UZ Gent), Denis
Larsimont (Jules Bordet Instituut - ULB), Svan D’Haese (College
Oncologie), Jacques De Grève (Voorzitter Working Party Manual and
Guidelines College Oncologie)
Externe experten : Fatima Cardoso (Belgian Society of Medical Oncology), Thierry
Defechereux (Belgian Section of Breast Surgery of the Belgian Royal
Society of Surgery), Jan Lamote (Belgian Section of Breast Surgery of the
Belgian Royal Society of Surgery), Amin Makar (Belgian Society of Surgical
Oncology), Jean-Pierre Nolens (Vlaamse Vereniging voor Obstetrie en
Gynaecologie), Robert Paridaens (Belgian Society of Medical Oncology),
Philippe Simon (Groupement de Gynécologues et Obstétriciens de la
Langue Française de Belgique), Rudy Van Den Broecke (Vlaamse
Vereniging voor Obstetrie en Gynaecologie), Joseph Weerts (Belgian
Society of Surgical Oncology)
Externe validatoren : Martine Berlière (UCL), Geert Page (Jan Yperman Ziekenhuis), Maarten F.
von Meyenfeldt (University Hospital Maastricht)
Belangenconflict : De meeste auteurs, externe experten en validatoren werken in een
borstcentrum. Sommige experten ontvingen betalingen om te spreken,
opleidingsvergoedingen, reisondersteuning of betaling voor deelname aan
een symposium (M. Berlière, M.-R. Christiaens, V. Cocquyt, J. De Grève, J.
Lamote, E. Lifrange, P. Neven, P. Simon). M. Berlière ontving honoraria
voor het deelnemen aan de ontwikkeling van een publicatie over
trastuzumab. V. Cocquyt krijgt een beurs voor wetenschappelijk
onderzoek aan de Universiteit van Gent. E. Lifrange ontving honoraria
voor consultancy bij Astra Zeneca, Pfizer and Novartis. P. Simon nam deel
aan de FACE trial en de IBIS trial.
Disclaimer De experts en validatoren werkten mee aan het wetenschappelijk rapport
maar werden niet betrokken in de aanbevelingen voor het beleid. Deze
aanbevelingen vallen onder de volledige verantwoordelijkheid van het
KCE.
Layout: Ine Verhulst
Brussel, 20 augustus 2007 (2nd print; 1st print, 26 juli 2007)
Studie nr.: 2006-03-2
Domein: Good Clinical Practice (GCP)
MeSH : Breast Neoplasms ; Breast Diseases ; Carcinoma, Ductal, Breast
NLM classification : WP 870
Taal: Nederlands, Engels
Format: Adobe® PDF (A4)
Wettelijk depot D2007/10.273/35

Elke gedeeltelijke reproductie van dit document is toegestaan mits bronvermelding.
Dit document is beschikbaar van op de website van het Federaal Kenniscentrum voor de
gezondheidszorg.
Hoe refereren naar dit document?
Christiaens M-R, Vlayen J, Gailly J, Neven P, Carly B, Schobbens J-C, et al. Wetenschappelijke
ondersteuning van het College voor Oncologie: een nationale praktijkrichtlijn voor de aanpak van
borstkanker. Good Clinical Practice (GCP). Brussel: Federaal Kenniscentrum voor de
Gezondheidszorg (KCE); 2007. KCE reports 63A (D2007/10.273/35)

KCE Reports 63A Nationale praktijkrichtlijn voor de aanpak van borstkanker i
Voorwoord
Borstkanker laat niemand onberoerd. Ongeveer één vrouw op negen wordt vroeg of laat met
deze diagnose geconfronteerd, jaarlijks naar schatting een 9 000 tal nieuwe gevallen. Ook een 90tal
mannen wordt jaarlijks met borstkanker geconfronteerd. De afgelopen jaren waren er
meerdere mediacampagnes die sensibiliseerden voor borstkankerscreening. Borstkanker staat dit
jaar ook centraal in het ‘Kom op tegen Kanker ‘ initiatief.
Dat er veel wetenschappelijk onderzoek gebeurt naar de opsporing, diagnose en behandeling van
borstkanker is voor de hand liggend. Minder voor de hand liggend is hoe zorgverleners volledig
op de hoogte kunnen blijven van de massa aan informatie en kaf van koren kunnen scheiden.
Evidence-based praktijkrichtlijnen kunnen gezien worden als een samenvatting of vertaling naar de
praktijk van deze wetenschappelijke literatuur, en vormen op die manier een belangrijk
hulpmiddel bij het nemen van klinische beslissingen. De behandeling van borstkanker is immers
vaak een traject van lange adem waarin arts en patiënt keuzes moeten maken. Voorwaarde is
uiteraard dat dergelijke richtlijnen up-to-date gehouden worden.
Voorliggende richtlijn over de aanpak van borstkanker kwam opnieuw tot stand dankzij een
vruchtbare samenwerking tussen het College voor Oncologie en het KCE. Waar experten van
het KCE de wetenschappelijke literatuur samenvatten, werd de vertaalslag naar de praktijk
gemaakt door een multidisciplinair team van experten. We danken alle betrokkenen voor hun
inhoudelijke bijdrage en belangrijke inzet, uiteindelijk een illustratie van een groot engagement
van de medische professie om de kwaliteit van borstkankerzorg verder te verbeteren.
Het werk stopt hier echter niet. Waar het tot stand komen van een richtlijn grote inspanningen
vraagt, is de implementatie ervan een nog grotere uitdaging. Het online ter beschikking stellen
van de richtlijn via de website van het College voor Oncologie is een eerste stap in dit proces.
Meten hoe de kwaliteit van de kankerzorg evolueert in België een volgende.
Jean-Pierre Closon Dirk Ramaekers
Adjunct Algemeen Directeur Algemeen Directeur

ii Nationale praktijkrichtlijn voor de aanpak van borstkanker KCE Reports 63A
INLEIDING
EXECUTIVE SUMMARY
Onlangs ontwikkelde het College voor Oncologie samen met het KCE een model voor een
oncologisch kwaliteitshandboek. Aansluitend werden 2 nationale praktijkrichtlijnen ontwikkeld,
één voor colorectale kanker en één voor testiskanker. In het kader van deze samenwerking werd
nu een praktijkrichtlijn voor borstkanker ontwikkeld die een breed spectrum aan onderwerpen
dekt, gaande van screening tot follow-up. The richtlijn is voornamelijk van toepassing op vrouwen
met borstkanker, en is gericht naar alle zorgverleners die betrokken zijn in de zorg voor deze
vrouwen.
METHODOLOGIE
Voor de ontwikkeling van deze richtlijn werd de ADAPTE methodologie gebruikt. In eerste
instantie werden met behulp van klinische experten de belangrijkste klinische zoekvragen
geformuleerd. Bestaande (inter)nationale richtlijnen werden gezocht in Medline, Embase, Cinahl,
National Guideline Clearinghouse en websites van richtlijnorganisaties en oncologische
organisaties. De 40 gevonden richtlijnen werden door middel van het AGREE instrument
beoordeeld op hun kwaliteit door twee onafhankelijke reviewers en al dan niet geselecteerd op
basis van een algemeen kwaliteitsoordeel. Vervolgens werden de 21 geselecteerde richtlijnen
geupdated voor elke klinische vraag, door bijkomende evidentie te zoeken in Medline en de
Cochrane Database of Systematic Reviews. Een level of evidence werd toegekend aan elke
originele aanbeveling en bijkomende studie door gebruik te maken van het GRADE systeem.
Gebaseerd op de gevonden evidentie werden aanbevelingen geformuleerd door een
multidisciplinaire richtlijnontwikkelingsgroep. Deze aanbevelingen werden op een formele manier
beoordeeld door vertegenwoordigers van de Professionele Verenigingen. Belangenconflicten
werden genoteerd.

KCE Reports 63A Nationale praktijkrichtlijn voor de aanpak van borstkanker iii
FINALE AANBEVELINGEN
De details van de richtlijn kunnen teruggevonden worden in het scientific report onmiddellijk na
deze samenvatting. Hieronder is het algemene algoritme van de richtlijn weergegeven.

iv Nationale praktijkrichtlijn voor de aanpak van borstkanker KCE Reports 63A
POPULATIE SCREENING
Het huidige borstkankerscreeningsprogramma met mammografie voor vrouwen van 50 tot 69
jaar blijft verantwoord. Er is onvoldoende evidence om andere screeningsmethoden dan
mammografie (met dubbele lezing) aan te raden.
OPPORTUNISTISCHE SCREENING
Voor vrouwen met een hoog risico om borstkanker te ontwikkelen is een multidisciplinaire
benadering nodig om een geïndividualiseerd opvolgingsschema uit te werken en de indicatie voor
profylactische behandeling te stellen.
DIAGNOSE EN STADIËRING VAN BORSTKANKER
De diagnose van borstkanker dient gebaseerd te zijn op de zogenaamde ‘triple assessment’
(klinisch onderzoek, beeldvorming en weefselonderzoek). Er is onvoldoende evidence om
routinematig MRI of 99mTc-MIBI scintimammografie te gebruiken voor de diagnose en stadiëring
van borstkanker.
Er is geen evidence om vóór het starten van behandeling routinematig een botscintigrafie,
leverechografie en thoraxradiografie te doen voor asymptomatische patiënten met een negatief
klinisch onderzoek, tenzij er minstens een klinisch stadium II vastgesteld wordt en/of
neoadjuvante behandeling overwogen wordt. Er is eveneens onvoldoende evidence om
tumormarkers te gebruiken bij de stadiëring van borstkanker.
Echografie van de oksel met fijne naald aspiratie cytologie van verdachte okselklieren kan
aanbevolen worden. Er is evidence die het gebruik van de sentinelprocedure (SLNB) ondersteunt
voor invasieve tumoren kleiner dan 3 cm. Ook voor hoge graad ductaal carcinoma in situ (DCIS)
wanneer mastectomie met of zonder onmiddellijke reconstructie gepland is, is er dergelijke
evidence.
PET scan is niet geïndiceerd voor de diagnose van borstkanker of okselstadiëring. PET scan kan
nuttig zijn indien er bij de klinische stadiëring aanwijzingen zijn voor metastasen.
BEHANDELING VAN NIET-INVASIEVE BORSTKANKER
Vroege precursor en hoog-risico letsels
Behandeling van precursor letsels, zoals atypische lobulaire hyperplasie, atypische ductale
hyperplasie en (kleincellig) lobulair carcinoma in situ, wordt bij voorkeur bediscussieerd in
multidisciplinair verband.
Ductaal carcinoma in situ
Ziekte van Paget
Vrouwen met een hoge graad en/of palpabel en/of groot DCIS die kandidaat zijn voor
borstsparende chirurgie moeten de keuze krijgen tussen locale wijde excisie (niet in het geval van
multicentriciteit) of totale mastectomie, nadat de patiënt correct geïnformeerd is. Voor vrouwen
met DCIS blijft mastectomie met of zonder onmiddellijke reconstructie een aanvaardbare keuze
indien ze een maximale lokale controle wensen of om radiotherapie te vermijden. Indien er een
lokale wijde excisie gebeurd bij vrouwen met DCIs, dan moet de ziekte volledige verwijderd
worden. Okselklieruitruiming is niet aanbevolen bij vrouwen met DCIS, maar SLNB kan
overwogen worden bij grote of graad III DCIS. Radiotherapie maakt meestal deel uit van een
borstsparende behandeling van DCIS. Adjuvante hormonale therapie kan overwogen worden bij
patiënten met oestrogeen-receptor positieve DCIS.
Patiënten met de ziekte van Paget zonder onderliggende invasieve borstkanker kunnen behandeld
worden met een conus excisie van het tepelareolair complex, gevolgd door radiotherapie.

KCE Reports 63A Nationale praktijkrichtlijn voor de aanpak van borstkanker v
BEHANDELING VAN INVASIEVE NIET-GEMETASTASEERDE
BORSTKANKER
Chirurgie
Radiotherapie
Systemische therapie
Alle patiënten met een T3-4 en/of N2-3 tumor dienen op individuele basis besproken te worden
op het multidisciplinaire teamoverleg vooraleer behandeling gestart wordt.
Borstsparende chirurgie geeft dezelfde overlevingsvoordelen als gemodificeerde radicale
mastectomie voor vrouwen met een stadium I of II borstkanker die kandidaat zijn voor
borstsparende chirurgie. De keuze van ingreep moet individueel bepaald worden voor deze
patiënten, die volledig geïnformeerd dienen te zijn over de opties. Bij vrouwen met primaire
borstkanker kleiner dan 3 cm en klinische en echografische negatieve klieren moet een SLNB
gebeuren. Als de sentinelklier positief is (>0.2 mm) is een okselklieruitruiming level I en II
geïndiceerd. Ook als een SLNB onmogelijk is, is een okselklieruitruiming level I en II geïndiceerd.
Voor tumoren groter dan 3 cm of bij klinisch positieve klieren is een okselklieruitruiming level I
en II noodzakelijk.
Bij patiënten met invasieve borstkanker is adjuvante radiotherapie aangewezen na borstsparende
chirurgie. Radiotherapie van de thoraxwand na mastectomie is aangewezen voor pT3 tumoren,
pN+ tumoren (wat het aantal positieve klieren ook is) en lymfovasculaire invasie. Bestraling van
de interne mammaire klierketen en van de oksel dienen besproken te worden tijdens het
multidisciplinaire teamoverleg. Als adjuvante chemotherapie en radiotherapie aangewezen zijn,
dient de chemotherapie eerst gegeven te worden.
De keuze voor adjuvante chemotherapie en/of hormonale therapie voor invasieve borstkanker
dient gebaseerd te zijn op de hormonale gevoeligheid en risicoprofiel van de tumor, en de leeftijd
van de patiënt.
Te verkiezen chemotherapie schemata zijn standaard antracycline-gebaseerde schemata met of
zonder een taxaan. Aan patiënten met unifocale operabele tumoren die te groot zijn voor
borstsparende chirurgie kan down-stadiëring met neoadjuvante chemotherapie aangeboden
worden.
Premenopauzale patiënten met hormoonreceptor positieve borstkanker moeten adjuvante
endocriene behandeling krijgen met tamoxifen gedurende 5 jaar met of zonder een LHRH
agonist. Postmenopauzale patiënten met hormoonreceptor positieve borstkanker moeten
adjuvante endocriene behandeling krijgen met hetzij tamoxifen gedurende 5 jaar, tamoxifen
gedurende 2 – 3 jaar gevolgd door een aromatase inhibitor gedurende 3 – 2 jaar, of een
aromatase inhibitor. Postmenopauzale vrouwen met een hormoonreceptor positieve tumor die
een adjuvante tamoxifen-behandeling gedurende 5 jaar (dagelijks 20 mg) beëindigd hebben,
komen in aanmerking voor een verlengde behandeling met een aromatase inhibitor indien ze
positieve klieren hebben of indien ze een hoog-risico kliernegatieve tumor hebben (pT2 of graad
III).
Een behandeling met adjuvante trastuzumab gedurende 1 jaar is aangewezen voor vrouwen met
HER2 FISH positieve borstkanker, een linkerventrikel ejectiefractie ≥ 55% en zonder
cardiovasculaire exclusie criteria. Gedurende de behandeling met trastuzumab moet de
hartfunctie gevolgd worden.

vi Nationale praktijkrichtlijn voor de aanpak van borstkanker KCE Reports 63A
BEHANDELING VAN GEMETASTASEERDE BORSTKANKER
Systemische behandeling
Bij premenopauzale patiënten met hormoonreceptor positieve metastatische borstkanker of met
metastatische borstkanker met onbekende hormoonreceptor status is de eerstelijns hormonale
behandeling ovariële suppressietherapie (bvb. met LHRH agonisten, oöforectomie, bestraling van
de ovaria) in combinatie met tamoxifen. Bij postmenopauzale patiënten met hormoonreceptor
positieve metastatische borstkanker of met metastatische borstkanker met onbekende
hormoonreceptor status zijn aromatase inhibitoren de eerstelijns hormonale behandeling.
Tamoxifen blijft een aanvaardbaar alternatief als eerstelijns behandeling. Als tweedelijns
behandeling worden anastrozole, letrozole of exemestane aanbevolen.
Chemotherapie is aangewezen voor patiënten met metastatische borstkanker in geval van
hormoonrefractaire of –negatieve tumoren, snel progressieve ziekte en invasie van vitale
organen. Het te verkiezen chemotherapie schema dient besproken te worden door het
multidisciplinaire team.
Trastuzumab dient voorbehouden te worden voor die patiënten waarvan de tumor HER2-gen
amplificatie vertoont. Combinatietherapie van trastuzumab met een taxaan is aanbevolen voor
vrouwen met metastatische borstkanker met HER2-gen amplificatie.
Behandeling van botmetastasen
Bisfosfonaten dienen routinematig gebruikt te worden in combinatie met andere systemische
therapie bij patiënten met metastatische borstkanker met multipele en lytische botmetastasen.
Voor patiënten met pijnlijke botmetastasen is radiotherapie een optie.
OPVOLGING VAN PATIËNTEN MET BORSTKANKER
Een jaarlijkse mammo/echografie dient gebruikt te worden om een recidief of een tweede
primaire tumor op te sporen bij patiënten die voordien een behandeling voor borstkanker
ondergingen. Routine diagnostische testen om te screenen naar metastasen op afstand zijn niet
aangewezen bij asymptomatische vrouwen. Follow-up consultaties kunnen voorzien worden elke
3 maanden tijdens het eerste jaar na diagnose, elke 6 maanden tot 5 jaar na diagnose, en jaarlijks
vanaf 5 jaar na diagnose.
MULTIDISCIPLINAIRE AANPAK VAN PATIËNTEN MET BORSTKANKER
Patiënten dienen gezien te worden in een multidisciplinair centrum met borstclinici, radiologen en
pathologen. Alle vrouwen met een potentiële of gekende diagnose van borstkanker moeten
tijdens elk stadium van diagnose of behandeling toegang hebben tot een borstverpleegkundige
voor informatie en ondersteuning.

KCE Reports 63A Nationale praktijkrichtlijn voor de aanpak van borstkanker vii
CONCLUSIES
• De implementatie van deze richtlijn dient bevorderd te worden door middel van een
online implementatie instrument dat gebaseerd is op het algemene algoritme van de
richtlijn. Dit instrument dient beschikbaar gesteld te worden op de website van het
College voor Oncologie.
• Er dienen geschikte kwaliteitsindicatoren ontwikkeld te worden op basis van de
belangrijkste aanbevelingen van deze richtlijn.
• Gezien de evidence evolueert, zal een update van deze richtlijn – na een preassessment
van de literatuur – vermoedelijk noodzakelijk zijn over 3 tot 5 jaar.

KCE reports 63 Breast Cancer 1
ABBREVIATIONS
95% CI 95 percent confidence interval
ADH Atypical ductal hyperplasia
ALH Atypical lobular hyperplasia
ASCO American Society of Clinical Oncology
BRCA Breast cancer gene
CBO Dutch Institute for Healthcare Improvement
CDSR Cochrane database of systematic reviews
CEA Carcinoembryonic antigen
CMF Cyclophosphamide, methotrexate, fluorouracil
CPG Clinical practice guideline
CT Computed tomography
DCIS Ductal carcinoma in situ
ER Estrogen receptor
FAC Cyclophosphamide, doxorubicin, fluorouracil
FEA Flat epithelial atypia
FEC Cyclophosphamide, epirubicin, fluorouracil
FNAC Fine needle aspiration cytology
FNCLCC Fédération Nationale des Centres de Lutte Contre le Cancer
GRADE Grading of Recommendations Assessment, Development and Evaluation
HER2 Human epidermal growth factor receptor 2
HR Hazard ratio
HRT Hormone replacement therapy
LCIS Lobular carcinoma in situ
LHRH Luteinising-hormone releasing hormone
LVI Lymphovascular invasion
MCA Mucin like carcinoma associated antigen
MDT Multidisciplinary team
MeSH Medical Subject Headings
MRI Magnetic resonance imaging
NICE National Institute for Health and Clinical Excellence
PET Positron-emission tomography
PgR Progesterone receptor
PLCIS Pleomorphic lobular carcinoma in situ
RCT Randomised controlled trial
RR Risk ratio
SIGN Scottish Intercollegiate Guidelines Network
SLNB Sentinel lymph node biopsy
SMM Scintimammography

2 Breast Cancer KCE reports 63
SR Systematic review
TPA Tissue polypeptide antigen
TPS Tissue polypeptide specific antigen
US Ultrasonography

KCE reports 63 Breast Cancer 3
Table of contents
Scientific summary
1 INTRODUCTION............................................................................................. 5
2 METHODOLOGY............................................................................................. 6
2.1 GENERAL APPROACH................................................................................................................6
2.2 CLINICAL QUESTIONS ..............................................................................................................6
2.3 SEARCH FOR EVIDENCE ...........................................................................................................7
2.3.1 Clinical practice guidelines................................................................................................7
2.3.2 Additional evidence............................................................................................................9
2.4 QUALITY APPRAISAL..................................................................................................................9
2.4.1 Clinical practice guidelines................................................................................................9
2.4.2 Additional evidence............................................................................................................9
2.5 DATA EXTRACTION AND SUMMARY ................................................................................9
2.6 FORMULATION OF RECOMMENDATIONS.......................................................................9
2.7 EXTERNAL REVIEW.....................................................................................................................9
3 FINAL RECOMMENDATIONS..................................................................... 11
3.1 GENERAL ALGORITHM .......................................................................................................... 11
3.2 POPULATION SCREENING ................................................................................................... 12
3.3 MANAGEMENT OF HIGH-RISK WOMEN......................................................................... 13
3.3.1 Definition of high-risk ..................................................................................................... 13
3.3.2 Breast cancer susceptibility gene testing.................................................................... 13
3.3.3 Surveillance of women with a high risk for developing breast cancer................ 14
3.3.4 Treatment of women with a high risk for developing breast cancer.................. 14
3.4 DIAGNOSIS OF BREAST CANCER ...................................................................................... 17
3.4.1 Triple assessment ............................................................................................................ 17
3.4.2 Magnetic resonance imaging (MRI).............................................................................. 18
3.4.3 99mTc-MIBI scintimammography (SMM)................................................................... 18
3.5 STAGING OF BREAST CANCER .......................................................................................... 19
3.5.1 Routine staging tests ....................................................................................................... 19
3.5.2 Tumour markers.............................................................................................................. 19

4 Breast Cancer KCE reports 63
3.5.3 Axillary ultrasonography ................................................................................................ 19
3.5.4 Sentinel lymph node biopsy........................................................................................... 20
3.5.5 PET scan............................................................................................................................. 20
3.6 TREATMENT OF NON-INVASIVE BREAST TUMORS ................................................... 21
3.6.1 Early precursor and high-risk lesions.......................................................................... 21
3.6.2 Ductal carcinoma in situ................................................................................................. 22
3.6.3 Paget’s disease .................................................................................................................. 23
3.7 TREATMENT OF INVASIVE NON-METASTATIC BREAST CANCER ....................... 24
3.7.1 Surgery ............................................................................................................................... 24
3.7.2 Radiotherapy..................................................................................................................... 24
3.7.3 Systemic therapy.............................................................................................................. 25
3.8 TREATMENT OF METASTATIC BREAST CANCER........................................................ 29
3.8.1 Systemic treatment.......................................................................................................... 29
3.8.2 Treatment of bone metastases..................................................................................... 30
3.9 TREATMENT OF LOCOREGIONAL RELAPSE ................................................................. 31
3.10 SUPPORTIVE CARE FOR PATIENTS WITH BREAST CANCER .................................. 31
3.11 SURVEILLANCE OF PATIENTS WITH BREAST CANCER ............................................ 32
3.12 MULTIDISCIPLINARY APPROACH OF PATIENTS WITH BREAST CANCER........ 32
3.13 BREAST CANCER AND PREGNANCY............................................................................... 33
3.14 PARTICIPATION IN CLINICAL TRIALS.............................................................................. 33
4 IMPLEMENTATION AND UPDATING OF THE BREAST CANCER
GUIDELINE..................................................................................................... 34
4.1 IMPLEMENTATION ................................................................................................................... 34
4.2 QUALITY CONTROL............................................................................................................... 34
4.3 GUIDELINE UPDATE ................................................................................................................34
5 REFERENCES.................................................................................................. 35
6 APPENDICES.................................................................................................. 50

KCE reports 63 Breast Cancer 5
1 INTRODUCTION
Recently, the College of Physicians for Oncology and the KCE collaborated for the
elaboration of a model of a quality handbook and the development of clinical practice
guidelines for colorectal cancer and testicular cancer [1]. Within this collaboration, it
was decided to develop a clinical practice guideline for breast cancer. This clinical
practice guideline will cover a broad range of topics: screening, diagnosis, staging,
treatment, supportive therapy, follow-up, reconstructive surgery, and organisational
issues. The guideline primarily concerns women with breast cancer, and is intended to
be used by all care providers involved in the care for these women.

6 Breast Cancer KCE reports 63
2 METHODOLOGY
2.1 GENERAL APPROACH
As for the clinical practice guidelines (CPGs) for colorectal cancer and testicular cancer,
the present CPG was developed by adapting (inter)national CPGs to the Belgian context
[1]. This approach is currently being structured in a formal methodology by the
ADAPTE group, an international group of guideline developers and researchers [2]. The
ADAPTE methodology generally consists of three major phases:
Set-up Phase: Outlines the necessary tasks to be completed prior to beginning the
adaptation process (e.g., identifying necessary skills and resources).
Adaptation Phase: Assists guideline developers in moving from selection of a topic
to identification of specific clinical questions; searching for and retrieving guidelines;
assessing the consistency of the evidence therein, their quality, currency, content and
applicability; decision making around adaptation; and preparing the draft adapted
guideline.
Finalization Phase: Guides guideline developers through getting feedback on the
document from stakeholders who will be impacted by the guideline, consulting with the
source developers of guidelines used in the adaptation process, establishing a process
for review and updating of the adapted guideline and the process of creating a final
document.
This stepwise approach is currently being validated in an evaluation study using the
(qualitative and quantitative) information from multiple case studies.
2.2 CLINICAL QUESTIONS
The clinical practice guideline addresses the following clinical questions:
1. Which screening strategy is the most effective for the early detection of
breast cancer?
a. < 50 years
b. 50 – 69 years
c. > 70 years
2. What is the ideal follow-up (and treatment) of women with a high familial
and/or genetic risk of developing breast cancer?
3. What diagnostic tests are the most effective to confirm the diagnosis of
breast cancer?
a. Triple test approach: clinical examination / mammography / pathology
b. MRI?
c. MIBI?
4. What diagnostic tests are necessary to investigate the extent of the breast
cancer?
a. Sentinel biopsy
b. X-ray heart/lungs
c. Ultrasonography of the liver
d. Bone scintigraphy
e. Biochemical and tumormarkers; genetic tests
f. CAT scan of the thorax
g. PET scan

KCE reports 63 Breast Cancer 7
5. What is the most effective treatment strategy for:
a. Non-invasive breast cancer (carcinoma in situ, Paget)
b. Early-stage invasive breast cancer
c. Locally-advanced invasive breast cancer
d. Metastatic breast cancer
e. Locoregional recurrence of breast cancer?
6. What is the place of supportive treatment of breast cancer, such as
hormonal substitution?
7. What is the place of reconstructive surgery in the treatment of breast
cancer?
8. How does the treatment strategy change in the following circumstance:
a. Pre-menopause
b. Desire to have children (e.g. ovarian protection)
c. Pregnancy
9. What is the most effective strategy for the follow-up of patients with breast
cancer?
10. What organisational issues need to be considered in the treatment of breast
cancer?
a. Multidisciplinary team (breast clinic)
b. Nurse specialists
2.3 SEARCH FOR EVIDENCE
2.3.1 Clinical practice guidelines
2.3.1.1 Sources
A broad search of electronic databases (Medline, Cinahl, EMBASE), specific guideline
websites and websites of oncologic organisations (Table 1) was conducted.

8 Breast Cancer KCE reports 63
Table 1: Searched guideline websites and websites of oncologic
organisations.
Alberta Heritage Foundation For Medical
Research (AHFMR)
http://www.ahfmr.ab.ca/
American Society of Clinical Oncology (ASCO) http://www.asco.org/
American College of Surgeons (ACS) http://www.facs.org/cancer/coc/
CMA Infobase http://mdm.ca/cpgsnew/cpgs/index.asp
Guidelines International Network (GIN) http://www.g-i-n.net/
National Comprehensive Cancer Network
(NCCN)
http://www.nccn.org/
National Guideline Clearinghouse http://www.guideline.gov/
Haute Autorité de Santé (HAS) http://bfes.hassante.fr/HTML/indexBFES_HAS.html
BC Cancer Agency http://www.bccancer.bc.ca/default.htm
Institute for Clinical Systems Improvement (ICSI) http://www.icsi.org/index.asp
National Health and Medical Research Council
(NHMRC)
http://www.nhmrc.gov.au/
Scottish Intercollegiate Guidelines Network
(SIGN)
http://www.sign.ac.uk/
New Zealand Guidelines Group (NZGG) http://www.nzgg.org.nz/
Fédération Nationale des Centres de Lutte http://www.fnclcc.fr/sor/structure/index-
Contre le Cancer (FNCLCC)
sorspecialistes.html
National Institute for Health and Clinical
Excellence (NICE)
http://www.nice.org.uk/
2.3.1.2 Search terms
For Medline and Cinahl the following MeSH terms were used in combination: breast,
breast diseases, neoplasms, breast neoplasms. For EMBASE the Emtree term ‘breast
tumor’ was used. These MeSH and Emtree terms were combined with a standardised
search strategy to identify CPGs (Table 2).
Table 2: Standardised search strategy for CPGs.
Database Search strategy
Medline guideline [pt] OR practice guideline [pt] OR
recommendation* [ti] OR standard* [ti] OR
guideline* [ti]
Cinahl practice guidelines/ OR recommendation* [ti]
OR standard* [ti] OR guideline* [ti]
EMBASE practice guideline
2.3.1.3 In- and exclusion criteria
Both national and international CPGs on breast cancer were searched. A language
(English, Dutch, French) and date restriction (2003 – 2006) were used. CPGs without
references were excluded, as were CPGs without clear recommendations.

KCE reports 63 Breast Cancer 9
2.3.2 Additional evidence
For each clinical question, the evidence – identified through the included CPGs – was
updated by searching Medline and the Cochrane Database of Systematic Reviews
(CDSR) from the search date of the CPG on. A combination of appropriate MeSH
terms and free text words was used for the Medline search (see evidence tables). For
the search in CDSR, the search term ‘breast’ was used. In addition the publications of
the Cochrane Breast Cancer Group were scrolled.
For therapeutic interventions, only systematic reviews and randomized controlled trials
(RCT) were included. However, for diagnostic interventions we also searched for
observational studies in case no systematic review or RCT was found. The identified
studies were selected based on title and abstract. For all eligible studies, the full-text
was retrieved. In case no full-text was available, the study was not taken into account
for the final recommendations.
2.4 QUALITY APPRAISAL
2.4.1 Clinical practice guidelines
In total, 40 CPGs were identified. All were quality appraised by two independent
reviewers (JV, JG) using the AGREE instrument. Disagreement was discussed face-toface.
At the end, agreement was reached for all CPGs, and 21 CPGs were included. In
appendix, an overview is provided of all dimensions scores of the identified CPGs.
2.4.2 Additional evidence
The quality of the retrieved systematic reviews and RCTs was assessed using the
checklists of the Dutch Cochrane Centre (www.cochrane.nl).
2.5 DATA EXTRACTION AND SUMMARY
For each included CPG the following data were extracted: used search databases and
search terms, search date, publication year, used in- and exclusion criteria, quality
appraisal, availability of evidence tables, the consistency between the evidence and its
interpretation, and the consistency between the interpretation of the evidence and the
recommendations.
For each systematic review, the search date, publication year, included studies and main
results were extracted. For RCTs, the following data were extracted: publication year,
study population, study intervention, and outcomes.
For each clinical question, the recommendations from the identified CPGs and the
additional evidence were summarized in evidence tables. A level of evidence was
assigned to each recommendation and additional study using the GRADE system (see
appendix).
2.6 FORMULATION OF RECOMMENDATIONS
Based on the retrieved evidence, a first draft of recommendations was prepared by a
small working group (JV, JG, MRC). This first draft together with the evidence tables
was circulated to the guideline development group 4 weeks prior to the first face-toface
meeting. The guideline development group met on 2 occasions (March 9 th and
March 21 st 2007) to discuss the first draft. Recommendations were changed if important
evidence supported this change. Based on the discussion meetings a second draft of
recommendations was prepared. A grade of recommendation was assigned to each
recommendation using the GRADE system (see appendix). The second draft was once
more circulated to the guideline development group for final approval.
2.7 EXTERNAL REVIEW
The recommendations prepared by the guideline development group were circulated to
the Professional Associations (Table 3). Each association was asked to assign 2 key

10 Breast Cancer KCE reports 63
persons to discuss the recommendations during an open meeting. These panellists
received the recommendations one week prior to this open meeting. As a preparation
of the meeting all invited panellists were asked to score each recommendation on a 5point
Likert-scale to indicate their agreement with the recommendation, with a score of
‘1’ indicating ‘completely disagree’, ‘2’ indicating ‘somewhat disagree’, ‘3’ indicating
‘unsure’, ‘4’ indicating ‘somewhat agree’, and ‘5’ indicating ‘completely agree’ (the
panellists were also able to answer ‘not applicable’ in case they were not familiar with
the underlying evidence). In case a panellist disagreed with the recommendation (score
‘1’ or ‘2’), (s)he was asked to provide appropriate evidence. All scores were than
anonymized and summarized into a mean score, standard deviation and % of ‘agree’scores
(score ‘4’ and ‘5’) to allow a targeted discussion (see appendix). The
recommendations were then discussed during a face-to-face meeting on April 19 th 2007.
Based on this discussion a final draft of the recommendations was prepared. In
appendix, an overview is provided of the comments of the experts, and how these were
taken into account.
Table 3: List of Professional Associations to which the draft
recommendations were communicated.
Belgian Society of Pathology
Belgian Society of Medical Oncology
Belgian Society for Radiotherapy – Oncology
Royal Belgian Radiological Society
Belgian Association for Nuclear Medicine
Belgian Society of Surgical Oncology
Vlaamse Vereniging voor Obstetrie en Gynecologie
Groupement de Gynécologues et Obstétriciens de la Langue Française de Belgique
Royal Belgian Society of Surgery
Belgian Section of Breast Surgery of the Belgian Royal Society of Surgery
Belgian Society of Senology

KCE reports 63 Breast Cancer 11
3 FINAL RECOMMENDATIONS
3.1 GENERAL ALGORITHM

12 Breast Cancer KCE reports 63
3.2 POPULATION SCREENING
A previous KCE report already formulated recommendations on mass screening for
breast cancer [3]. This report was taken as a starting point for the present literature
search. The report concluded that there were insufficient arguments against the present
breast cancer screening programme by mammography for women aged 50 – 69 years
[3]. However, the advantages of extension of the programme to women aged < 50
years or > 69 years were found to be unsure. Above this, no hard evidence was found
to recommend other screening methods than two-view mammography, such as
ultrasonography, MRI or self-examination [3].
Our search did not identify good-quality CPGs on population screening published after
2003. However, 3 systematic reviews and 1 pooled analysis of 3 RCTs were identified
[4-7] (see evidence tables). In a recent systematic review of Gotzsche et al. 7 RCTs
were identified, of which one was excluded because of bias [4]. The authors calculated a
relative risk (RR) for breast cancer mortality of 0.80 (95% confidence interval [CI] 0.73
– 0.88) in favour of screening, and a number-needed-to-screen of 2000 women to
throughout 10 years to prevent 1 death. However, the authors also pointed at the
inevitable overdiagnosis associated with screening [4]. Indeed, it was calculated that for
every 2000 women invited for screening throughout 10 years, 10 healthy women who
would not have been diagnosed if there had not been screening, would be diagnosed as
breast cancer patients and would be treated unnecessarily.
In a pooled analysis of 3 RCTs, a shift to earlier stages was found in breast cancers
detected by screening mammography [7]. Patients with interval cancers were found to
have a 53% (95%CI 17% – 100%) greater hazard of death from breast cancer than
patients with screen-detected cancers, and patients with cancer in the control groups
had a 36% (95%CI 10% – 68%) greater hazard of death than patients with screendetected
cancer.
Kösters et al. identified 2 population-based studies that compared breast selfexamination
with no intervention in more than 388.000 women [6]. No statistically
significant difference was found in breast cancer mortality (RR 1.05, 95%CI 0.90 – 1.24).
Finally, Irwig et al. reported on a systematic review of the accuracy of ultrasonography
(US), magnetic resonance imaging (MRI), full-field digital mammography and computeraided
detection for breast cancer screening [5]. All identified studies had an
observational design. No hard data were found to support the use of these imaging
techniques for population breast cancer screening.
The recommendations formulated in the present guideline are in line with the recent
European guidelines on breast cancer screening and diagnosis [8], which were not
identified through our literature search.
1. Based on the literature, the present breast cancer screening programme by
mammography for women aged 50 – 69 years remains justified (2A
evidence) [3, 4, 7].
2. There is no hard evidence to recommend other screening methods (e.g.
ultrasonography, MRI, self-examination) than two-view mammography (1C
evidence) [3, 5, 6].

KCE reports 63 Breast Cancer 13
3.3 MANAGEMENT OF HIGH-RISK WOMEN
3.3.1 Definition of high-risk
A distinction should be made between genetic and familial risk for developing breast
cancer:
• Women with a proven mutation of the BRCA1, BRCA2 or TP53 gene
are considered to be at genetic risk.
• For the calculation of the familial risk, several models are available.
Recently, Amir et al. compared four of these models [9], and
concluded the Tyrer-Cuzick model to be the most consistently
accurate model for the prediction of breast cancer (rate of expected to
observed number of breast cancers = 0.81). This model incorporates
the BRCA genes, a low penetrance gene and personal risk factors, such
as age at menarche, parity, height, etc [10]. The model has been
computerised and an interactive program is available from the authors
on request [10]. Women with a lifetime risk of 20% or greater of
developing breast cancer are considered to be at high risk.
3.3.2 Breast cancer susceptibility gene testing
Two CPGs of good quality were found on breast cancer susceptibility gene testing [11,
12]. No additional evidence was identified. The recommendations from these CPGs
were only slightly rephrased and adapted to the local Belgian context. We refer to the
original CPGs for the evidence base.
3. Routine referral for genetic counselling or routine breast cancer
susceptibility gene (BRCA) testing for women whose family or personal
history is not associated with an increased risk for deleterious mutations in
breast cancer susceptibility gene 1 (BRCA1) or breast cancer susceptibility
gene 2 (BRCA2) is not recommended (1B evidence) [12].
4. Women whose family or personal history is associated with an increased
risk for:
• deleterious mutations in BRCA 1 or BRCA 2 gene (early-age-onset breast cancer,
two primary breast cancers and/or breast and ovarian cancers in the same
individual or close relatives on the same side of the family, known mutation in a
family member, Ashkenazi Jewish decent with breast cancer in women < 50 years
or ovarian cancer, male breast cancer, more than one ovarian cancer on the
same side of the family);
• Li-Fraumeni and Cowden Syndrome (thyroid cancer, sarcoma, adrenocortical
cancer, endometrium cancer, pancreatic cancer, brain tumors, dermatologic
manifestations, leukemia/lymphoma)
should be referred for genetic counselling (1B evidence) [11, 12].
5. All high-risk women should have access to information on genetic tests
aimed at mutation finding (1C evidence) [11].
6. Pre-test counselling (preferably two sessions) should be undertaken (1A
evidence) [11].
7. Discussion of genetic testing (predictive and mutation finding) should be
undertaken by someone with appropriate training (1A evidence) [11].
8. High-risk women and their affected relatives should be informed about the
likely informativeness of the test (the meaning of a positive and a negative
test) and the likely timescale of being given the results (1A evidence) [11].

14 Breast Cancer KCE reports 63
9. Women from families with a 20% or greater chance of carrying a mutation
such as BRCA1, BRCA2 or TP53 should have access to testing (1C
evidence) [11].
10. The development of a genetic test for a family should usually start with the
testing of an affected individual (mutation searching/screening) to try to
identify a mutation in the appropriate gene (such as BRCA1, BRCA2 or
TP53) (1C evidence) [11].
11. A search/screen for a mutation in a gene (such as BRCA1, BRCA2 or TP53)
should aim for as close to 100% sensitivity as possible for detecting coding
alterations and the whole gene(s) should be searched (1C evidence) [11].
3.3.3 Surveillance of women with a high risk for developing breast cancer
Again, the NICE guideline on the management of high-risk women was taken as the
basis for our recommendations [11]. However, some recommendations were adapted
according to new evidence. In fact, the recommendation on the use of MRI was recently
adapted by NICE in their partially updated CPG (published after our literature search)
[13], and is in line with our recommendation.
Surveillance of high-risk women with a lifetime risk of 30% or higher should start at the
age of 35 years, or 5 years earlier than the age at which a relative was diagnosed with
breast or ovarian cancer if < 35 years. In high-risk women with a lifetime risk of

KCE reports 63 Breast Cancer 15
3.3.4.1 Prophylactic mastectomy
Our literature search identified 2 systematic reviews [14, 17] not included in the NICE
guideline [11]. The Cochrane review of Lostumbo et al. identified 23 observational
studies, no RCTs or non-randomized controlled trials were found [17]. All identified
studies reporting on incidence of breast cancer and disease-specific mortality reported
reductions after prophylactic mastectomy [17].
Also Calderon-Margalit et al. only identified observational studies [14]. A significant
reduction in breast cancer risk of 89.5 – 100% in favour of prophylactic mastectomy was
found.
17. Bilateral risk-reducing mastectomy is appropriate only for a small
proportion of women who are from high-risk families and should be
managed by a multidisciplinary team (1C evidence) [11].
18. Bilateral mastectomy should be raised as a risk-reducing strategy option
with all women at high risk (1C evidence) [11, 14, 17].
19. High-risk women considering bilateral risk-reducing mastectomy should
have genetic counselling in a specialist cancer genetics clinic, before a
decision is made (1C evidence) [11].
20. Discussion of individual breast cancer risk and its potential reduction by
surgery should take place and take into account individual risk factors,
including the woman's current age (especially at extremes of age ranges)
(1C evidence) [11].
21. When bilateral mastectomy is considered but no mutation has been
identified, family history should be taken into account before a decision is
made (1C evidence) [11].
22. Where no family history verification is possible, agreement by a
multidisciplinary team (surgeon and genetic specialist) must be sought
before proceeding with bilateral risk-reducing mastectomy (1C evidence)
[11].
23. Pre-operative counselling about psychosocial and sexual consequences of
bilateral risk-reducing mastectomy should be undertaken (1C evidence)
[11].
24. The possibility of breast cancer being diagnosed histologically following a
risk-reducing mastectomy should be discussed pre-operatively (1C
evidence) [11].
25. All women considering bilateral risk-reducing mastectomy should be able to
discuss their breast reconstruction options (immediate and delayed) with a
member of a surgical team with specialist oncoplastic or breast
reconstructive skills (1C evidence) [11].
26. A surgical team with specialist oncoplastic/breast reconstructive skills
should carry out risk-reducing mastectomy and/or reconstruction (1C
evidence) [11].
27. Women considering bilateral risk-reducing mastectomy should be offered
access to support groups and/or women who have undergone the procedure
(1C evidence) [11].
3.3.4.2 Prophylactic salpingo-oophorectomy
Although the present guideline is on breast cancer, the risk of ovarian cancer is too high
in genetic high-risk patients to be ignored. As for prophylactic mastectomy, these
recommendations are mainly based on the NICE guideline [11]. In their systematic
review, Calderon-Margalit et al. identified 2 observational studies examining the efficacy
of salpingo-oophorectomy in the prevention of breast cancer [14]. Prophylactic
salpingo-oophorectomy was found to be associated with hazard ratios for breast cancer
of 0.47 (95%CI 0.29 – 0.77) and 0.32 (95%CI 0.08 –1.20) respectively. A very recent

16 Breast Cancer KCE reports 63
systematic review – published after our literature search – confirmed the risk-reducing
potential of prophylactic salpingo-oophorectomy, but highlighted the poor quality of the
underlying evidence [18]. For example, the authors of this systematic review identified
only one case-control study showing the possible protective effect of fallopian tube
ligation, which in fact was limited to women carrying a BRCA1 gene mutation [18].
Information about bilateral salpingo-oophorectomy as a potential risk-reducing strategy
should be made available to high-risk women [11]. These women should also be
informed about the negative consequences (early menopause, possible impact on
sexuality, small risk of developing peritoneal cancer, …).
28. Risk-reducing bilateral salpingo-oophorectomy is appropriate only for a
small proportion of women who are from high risk families and should be
managed by a multidisciplinary team (1C evidence) [11].
29. Information about bilateral salpingo-oophorectomy as a potential riskreducing
strategy should be made available to women who are classified as
high risk (1C evidence) [11, 14].
30. When bilateral salpingo-oophorectomy is considered but no mutation has
been identified, family history should be taken into account before a
decision is made (1C evidence) [11].
31. Where no family history verification is possible, agreement by a
multidisciplinary team (surgeon and genetic specialist) must be sought
before proceeding with bilateral risk-reducing salpingo-oophorectomy (1C
evidence) [11].
32. Any discussion of bilateral salpingo-oophorectomy as a risk-reducing
strategy should take fully into account factors such as anxiety levels on the
part of the woman concerned (1C evidence) [11].
33. Healthcare professionals should be aware that women being offered riskreducing
bilateral salpingo-oophorectomy may not have been aware of their
risks of ovarian cancer as well as breast cancer and should be able to discuss
this (1C evidence) [11].
34. The effects of early menopause should be discussed with any woman
considering risk-reducing bilateral salpingo-oophorectomy (1C evidence)
[11].
35. Options for management of early menopause should be discussed with any
woman considering risk-reducing bilateral salpingo-oophorectomy,
including the advantages, disadvantages and risk impact of hormonal
replacement therapy (1C evidence) [11].
36. Women considering risk-reducing bilateral salpingo-oophorectomy should
have access to support groups and/or women who have undergone the
procedure (1C evidence) [11].
37. Women considering risk-reducing bilateral salpingo-oophorectomy should
be informed of possible psychosocial and sexual consequences of the
procedure and have the opportunity to discuss these issues (1C evidence)
[11].
38. Women not at high risk who raise the possibility of risk-reducing bilateral
salpingo-oophorectomy should be offered appropriate information, and if
seriously considering this option should be offered referral to the team that
deals with women at high risk (1C evidence) [11].
39. Women undergoing bilateral risk-reducing salpingo-oophorectomy should
have their fallopian tubes removed as well (1C evidence) [11].

KCE reports 63 Breast Cancer 17
3.3.4.3 Chemoprevention with tamoxifen
Fisher et al. randomized 13.338 high-risk women to either tamoxifen 20 mg/day for 5
years or placebo [19]. After 7 years of follow-up, a RR of 0.57 (95%CI 0.46 – 0.70) for
invasive breast cancer was found in favour of chemoprevention with tamoxifen.
However, an important flaw of this trial was the unblinded design.
In this RCT, 19 of the 288 incident breast cancer cases were known to carry BRCA
mutations [14]. Five of the 8 carriers of BRCA1 were treated with tamoxifen (RR 1.67,
95%CI 0.32 – 10.7), and 3 of the 11 BRCA2 carriers were treated with tamoxifen (RR
0.38, 95%CI 0.06 – 1.56). However, a higher proportion of BRCA2 patients were ER
positive compared to BRCA1 patients, which might explain their benefiting from
tamoxifen use. Owing to the small sample size, the study failed to reach statistical
significance for this subset of patients.
In a pooled analysis of 4 RCTs (including the RCT of Fisher et al. [19]), Cuzick et al.
found a decrease in ER positive cancers by 48% [20]. Overall, a 38% reduction (95% CI
28–46; p

18 Breast Cancer KCE reports 63
41. All patients should have a full clinical examination (1C evidence) [26, 27].
42. Where a localised abnormality is present, patients should have
mammography and ultrasonography followed by core biopsy and/or fine
needle aspirate cytology (1C evidence) [24-27].
43. A lesion considered malignant following clinical examination, imaging or
cytology alone should, where possible, have histopathological confirmation
of malignancy before any surgical procedure takes place (1C evidence) [26,
27].
44. Two-view mammography should be performed as part of triple assessment
(clinical assessment, imaging and tissue sampling) in a clinic specialised in
breast cancer (1C evidence) [26, 27].
45. Also young women presenting with breast symptoms and a strong suspicion
of breast cancer should be evaluated by means of the triple test approach to
exclude or establish a diagnosis of cancer (1C evidence) [28].
3.4.2 Magnetic resonance imaging (MRI)
Prospective cohort studies have shown that MRI is a sensitive procedure for the
diagnosis of breast cancer, with sensitivities ranging from 86 – 98% [29-31]. However,
this low quality evidence does not permit to advocate the routine use of MRI for the
diagnosis and staging of breast cancer. In some specific cases, such as suspicion of
multicentricity, patients with breast implants, or patients with positive lymph nodes
without an obvious tumour, MRI can be useful [15].
46. There is insufficient evidence to use MRI routinely for the diagnosis and
staging of breast cancer. MRI can be considered in specific clinical situations
where other imaging modalities are not reliable, or have been inconclusive,
and where there are indications that MRI is useful (invasive lobular
carcinoma, suspicion of multicentricity, genetic high-risk patients, T0N+
patients, patients with breast implants, diagnosis of recurrence, follow-up of
neoadjuvant treatment) (1C evidence) [15, 27].
3.4.3 99mTc-MIBI scintimammography (SMM)
Numerous observational studies have shown that SMM is a procedure with a moderate
sensitivity (ranging from 58 – 93%) and specificity (71 – 91%) for the diagnosis of breast
cancer [29, 30, 32-37]. However, this low quality evidence does not permit to advocate
the routine use of SMM for the diagnosis and staging of breast cancer. Overall, the same
specific indications for MRI can also be applied to SSM (invasive lobular carcinoma,
suspicion of multicentricity, genetic high-risk patients, T0N+ patients, patients with
breast implants, diagnosis of recurrence, follow-up of neoadjuvant treatment).
Two prospective cohort studies directly compared MRI and SSM for the diagnosis of
breast cancer [29, 30], showing that MRI is a slightly more sensitive procedure.
47. There is insufficient evidence to use 99mTc-MIBI scintimammography
routinely for the diagnosis and staging of breast cancer. 99mTc-MIBI
scintimammography can be considered in specific clinical situations where
other imaging modalities are not reliable, or have been inconclusive, and
where there are indications that 99mTc-MIBI scintimammography is useful
(1C evidence) [29, 30].

KCE reports 63 Breast Cancer 19
3.5 STAGING OF BREAST CANCER
3.5.1 Routine staging tests
There is no good evidence to support the pre-treatment routine screening for
metastatic disease in asymptomatic women with early operable breast cancer (i.e. cT1-2,
N0-1) [27, 38, 39]. Above this – although these are fairly inexpensive tests –, routine
bone scanning, liver ultrasonography and chest radiography are not indicated in
asymptomatic women with intraductal and pathological stage I disease.
Of course, if a patient presents with symptoms suggestive of metastatic disease,
appropriate investigation is required. Also, observational data have shown that specific
subsets of patients (e.g. triple negative patients, young patients) harbour a higher risk of
distant metastases [40, 41], and should therefore be staged more aggressively. However,
this is not routine practice.
These recommendations are confirmed by the results of a recent observational study
that reported an overall detection rate of 6.3% for skeletal metastases by bone
scintigraphy, 0.7% for liver metastases by liver ultrasonography, and 0.9% for lung
metatstases by chest radiography [42]. Of course, these results should be interpreted
with caution because of the retrospective study design.
48. There is no evidence for pretreatment routine bone scanning, liver
ultrasonography and chest radiography for asymptomatic patients with
negative clinical findings, unless there is at least clinical stage II disease
and/or neoadjuvant treatment is considered (2C evidence) [38, 39].
49. In asymptomatic women with ductal carcinoma in situ, routine bone
scanning, liver ultrasonography and chest radiography are not indicated as
part of baseline staging (2C evidence) [38, 39].
3.5.2 Tumour markers
There is no good evidence (only from very low quality observational studies) to support
the routine use of biochemical test, including tumour markers such as CA 15-3, TPA,
TPS, MCA and CEA, for the staging of breast cancer [43-46]. However, a positive
tumour marker can be used for the follow-up of the subsequent treatment.
50. There is no good evidence to include tumour markers in the staging workup
of breast cancer (2C evidence) [43-46].
3.5.3 Axillary ultrasonography
Two prospective cohort studies have shown that axillary ultrasonography is a specific
procedure for the detection of axillary lymph nodes [47, 48].
Altinyollar et al. performed ultrasonography of the axillary, infraclavicular and
supraclavicular region in 100 consecutive patients with breast cancer [47]. Specificity
and sensitivity for detecting metastatic lymph nodes were 92% and 79% respectively. In
the study of Podkrajsek et al., 165 patients with breast cancer with clinically negative
axilla underwent axillary ultrasonography (and US-guided fine-needle aspiration biopsy if
suspicious lymph nodes) [48]. A specificity and sensitivity of 89% and 58% were found.
51. Axillary ultrasonography with fine needle aspiration cytology of axillary
lymph nodes suspicious for malignancy can be recommended (2C evidence)
[47, 48].

20 Breast Cancer KCE reports 63
3.5.4 Sentinel lymph node biopsy
A large amount of evidence is available on the use of sentinel lymph node biopsy (SLNB)
in the staging of breast cancer [38, 49]. In 2004, the American Society of Clinical
Oncology (ASCO) identified 1 RCT, 4 meta-analyses and 60 controlled trials [49]. Since
this systematic review, one additional systematic review [50] and 1 additional RCT [51]
were published. Xing et al. identified 21 cohort studies examining the results of SLNB
after neoadjuvant chemotherapy [50]. The sensitivity of SLNB ranged from 67 to 100%,
with a pooled estimate of 88% (95%CI 85 to 90%).
Mansel et al. reported on a RCT that examined arm morbidity and quality of life after
SLNB or standard axillary treatment in 954 women with early-stage clinically nodenegative
breast cancer [51]. Both outcomes were statistically significant better in the
group allocated to SLNB.
Both the ASCO [49] and European guidelines [8] contain a section on the pathologic
evaluation of sentinel lymph nodes. A clear discussion can also be found in the CBO
guideline (in Dutch) [38].
52. Sentinel lymph node biopsy is not recommended for large T2 (i.e. > 3 cm)
or T3-4 invasive breast cancers; inflammatory breast cancer; pregnancy, in
the setting of prior non-oncologic breast surgery or axillary surgery; in the
presence of suspicious palpable axillary lymph nodes; multiple tumours; and
possible disturbed lymph drainage after recent axillary surgery or a large
biopsy cave after tumour excision (1A evidence) [38, 49].
53. Data are available to support the use of sentinel lymph node biopsy (SLNB)
for invasive tumors less than 3 cm. Also for high-grade ductal carcinoma in
situ, when mastectomy with or without immediate reconstruction is
planned, such data are available (1A evidence) [38, 49]. Age, gender or
obesity are no exclusion criteria for SLNB.
3.5.5 PET scan
FNCLCC made specific recommendations on the use of PET scan in the diagnosis and
staging of breast cancer [52]. In addition, the KCE recently published an HTA report on
the use of PET scan [53]. Since this HTA report, numerous observational studies have
been published [54-63].
A low-quality systematic review identified 18 observational studies that examined the
role of PET scan in the diagnosis of the primary tumour [59]. PET scan was found to
have a sensitivity of 64 – 100% and a specificity of 33 – 100%. An additional very lowquality
observational study found a sensitivity of 100% and a specificity of 75% [58]. Both
low-quality studies do not challenge the recommendation of the FNCLCC and the KCE
that PET scan is not recommended in the diagnosis of malignancy of breast tumours [52,
53].
The low-quality systematic review of Byrne et al. identified 24 observational studies that
examined the role of PET scan for axillary staging [59]. In these studies, the sensitivity of
PET scan ranged from 20 to 100% and the specificity from 66 to 100%. In 2 additional
prospective cohort studies, the sensitivity was 90% [56] and 40% [60] respectively, and
the specificity 99% [56] and 97% [60] respectively. Again, this additional evidence does
not challenge the recommendation of the KCE that PET scan is not recommended for
axillary staging of breast tumours [53].
One prospective [63] and one retrospective cohort study [61] were identified that
studied the role of PET scan in the evaluation of metastatic breast cancer. A sensitivity
of 17% [63] and 80% [61] was found, the specificity was found to be 100% [63] and 88%
[61]. However, both studies suffered from methodological flaws. In the study of Nakai
et al., the reference standard was not applied to all included patients [61], whereas the
study of Uematsu et al. only included 15 patients [63]. Therefore, the recommendation
of the FNCLCC and the KCE that PET scan can be useful for the evaluation of

KCE reports 63 Breast Cancer 21
metastatic disease of invasive breast cancer (i.e. in case clinical staging has shown
evidence of metastatic disease) remains unchanged [52, 53].
No recommendations were found on the use of PET/CT for the diagnosis, staging or
follow-up of breast cancer. In addition, only one cohort study was found that compared
PET scan to PET/CT for the restaging of breast cancer after neoadjuvant treatment [64].
In this study, PET/CT staged 90% of the patients correctly, overstaged 7% and
understaged 3% of the patients. In the absence of good evidence, PET/CT cannot yet be
recommended for the diagnosis and follow-up of breast cancer.
54. PET scan is not indicated in the diagnosis of malignancy of breast tumours
(1B evidence) [52, 53].
55. PET scan is not indicated for axillary staging (1C evidence) [53].
56. PET scan can be useful for the evaluation of metastatic disease of invasive
breast cancer (1C evidence) [52, 53].
57. PET/CT cannot be recommended for the diagnosis and follow-up of breast
cancer (2C evidence) [64].
3.6 TREATMENT OF NON-INVASIVE BREAST TUMORS
3.6.1 Early precursor and high-risk lesions
Since precursor lesions, such as atypical lobular hyperplasia (ALH), atypical ductal
hyperplasia (ADH) and (small cell) lobular carcinoma in situ (LCIS), have a small chance
of progression and a very slow progression rate, they are usually considered as
indicators of increased risk [38]. Therefore, when ALH/LCIS is found within or near the
margins of a wide excision specimen, re-excision is not necessary [65, 66]. On the other
hand, clear margins do not exclude the presence of residual ALH/LCIS elsewhere in the
breast.
The presence of ALH/LCIS in a core biopsy has a totally different meaning. Since only a
minority of ALH/LCIS is associated with microcalcifications, these lesions are not visible
on imaging, and hence are not the targeted lesion, but merely a coincidental finding.
Multidisciplinary discussion is essential as the abnormality identified radiologically may
not be represented in the core biopsy [65]. Furthermore, at present it is not yet known
whether ALH/LCIS diagnosed via a targeted core biopsy of a mammographic
abnormality carries the same (low) risk as ALH/LCIS encountered serendipitously in an
excision specimen. Therefore, these cases must be managed cautiously, and a surgical
diagnostic excision might be considered. Following a diagnosis of ALH/LCIS – even if
completely excised – careful follow-up is indicated [38]. As these lesions are only
recognized to constitute a separate entity for about a decade, no large follow-up studies
are available. Indeed, such lesions were until recently considered as DCIS and treated
accordingly. Many authorities advise to continue to do so. This means that when these
lesions are encountered in a core biopsy, complete excision is advocated. If margins are
not free, re-excision may be considered. Following surgical excision, radiotherapy and
hormonal therapy may be administered.

22 Breast Cancer KCE reports 63
58. Management of early precursor lesions is preferably discussed in a
multidisciplinary setting (expert opinion) [65, 66].
59. When atypical lobular hyperplasia, lobular carcinoma in situ, flat epithelial
atypia or atypical ductal hyperplasia is present near the margins of an
excision specimen, re-excision is not necessary (expert opinion) [65, 66].
60. When atypical lobular hyperplasia / lobular carcinoma in situ, flat epithelial
atypia or an atypical intraductal proliferation reminiscent of atypical ductal
hyperplasia, is found in a core biopsy, diagnostic excision can be
recommended (expert opinion) [65, 66].
61. When pleomorphic lobular carcinoma in situ or lobular carcinoma in situ
with comedonecrosis is found in a core biopsy, complete excision with
negative margins can be recommended, and anti-hormonal treatment as
well as radiotherapy are an option (expert opinion) [65, 66].
62. Annual follow-up mammography after a diagnosis of lobular carcinoma in
situ or atypical ductal hyperplasia is indicated (2C evidence) [38].
3.6.2 Ductal carcinoma in situ
3.6.2.1 Surgery
These recommendations are completely based on existing guidelines [27, 67, 68], no
additional evidence was identified.
The choice of breast conserving surgery versus total mastectomy (with the option for
reconstruction) is based on a subanalysis of an RCT and a meta-analysis of observational
studies [27], that showed similar mortality rates at 5 years for both procedures.
Multicentricity and residual disease (positive margins) are contraindications for local
wide excision [38]. Complete resection of the lesion should be achieved. Indeed, studies
have shown that positive or indeterminate resection margins increase the risk of local
recurrence [68].
Axillary surgery is not recommended [38, 67, 68], but can be considered for large or
stage III DCIS. As was stated above, SNLB can be considered for high-grade DCIS, when
mastectomy with or without immediate reconstruction is planned [49].
63. Women with high-grade and/or palpable and/or large ductal carcinoma in
situ of the breast who are candidates for breast conserving surgery should
be offered the choice of local wide excision or total mastectomy after the
patient is correctly informed. In case of multicentricity local wide excision
is not recommended (1B evidence) [27, 67, 68].
64. In women with ductal carcinoma in situ, mastectomy with or without
immediate reconstruction remains an acceptable choice for women
preferring to maximize local control or to avoid radiotherapy (1B evidence)
[67, 68].
65. When local wide excision is performed in women with ductal carcinoma in
situ, all evidence of disease should be resected (1C evidence) [67, 68].
66. Axillary clearance is not recommended for women with ductal carcinoma in
situ, but sentinel lymph node biopsy can be considered for large or grade III
ductal carcinoma in situ (1C evidence) [38].

KCE reports 63 Breast Cancer 23
3.6.2.2 Radiotherapy
Addition of radiotherapy to breast-conserving surgery in women with clinically or
mammographically detected DCIS measuring < 5cm resulted in a 4-year local relapsefree
rate of 91% versus 84% in patients not receiving radiotherapy [69]. However, no
difference in survival was found. These results are in line with those of the NSABP B-17
trial, a subanalysis of the NSABP B-06 trial, and the UK DCIS trial [27, 38, 68].
67. Radiotherapy is usually part of the breast-conserving treatment of ductal
carcinoma in situ (1A evidence) [38, 67, 68].
3.6.2.3 Hormonal therapy
The NSABP B-14 trial reported a lower disease recurrence rate at 7 years in women
with ER+ DCIS treated with adjuvant tamoxifen (11% vs. 17%, p=0.0004) [27, 68].
However, for women with negative margins, the absolute risk of ipsilateral breast
recurrence (invasive or DCIS) was not significantly different between the two groups
(tamoxifen group 7% vs. placebo group 9%, p=0.2). On the contrary, a significant
difference was found between the groups in the absolute risk of ipsilateral recurrence
for women with positive or unknown margins (tamoxifen group 11% vs. placebo group
18%, p=0.03) [68].
Of course, the benefits and harms of hormonal therapy should be discussed with
women with DCIS, and treatment decisions made should be based on individual
circumstances.
68. Adjuvant hormonal therapy can be considered for patients with estrogenreceptor
positive ductal carcinoma in situ (2A evidence) [27, 68].
3.6.3 Paget’s disease
In a prospective study, 61 patients with Paget’s disease without associated invasive
disease were treated with a cone excision and radiotherapy [70]. At a median follow-up
of 6.4 years, 4 patients developed a local recurrence. One patient with an invasive local
recurrence died of disseminated breast carcinoma. The 5-year local recurrence rate was
5.2% (95%CI 1.8 – 14.1%).
In rare and selected cases, such as Paget’s disease limited to the nipple or surrounding
skin, radiotherapy alone may be sufficient [71]. In these cases, surgery could be avoided.
However, these cases should first be discussed in the MDT.
Of course, patients with Paget’s disease and underlying DCIS or invasive breast cancer
should be treated according to the respective recommendations (see above).
69. Patients with Paget’s disease without underlying invasive breast cancer may
be treated with a cone excision of the nipple-areola-complex followed by
radiotherapy (2C evidence) [70].

24 Breast Cancer KCE reports 63
3.7 TREATMENT OF INVASIVE NON-METASTATIC BREAST
CANCER
For patients with T3-4 and/or N2-3 breast cancer, treatment consists of the following
components (see below) [38]:
- neoadjuvant chemotherapy
- surgery
- locoregional radiotherapy
- adjuvant hormonal treatment if HR-positive.
However, this treatment is multidisciplinary and should therefore be discussed on an
individual basis in the MDT.
70. All patients with T3-4 and/or N2-3 breast cancer should be discussed on an
individual basis in the multidisciplinary team meeting before any treatment
(expert opinion).
3.7.1 Surgery
Several RCTs compared breast-conserving surgery with total mastectomy and found no
difference in survival between the two procedures [27, 72, 73]. All patients eligible for
breast-conserving surgery should be fully informed about both options before the
choice of surgery is made.
As was stated above, SLNB is indicated in women with primary breast cancer less than
3 cm and clinically and ultrasonographically negative nodes [38, 49]. If the sentinel node
is positive (i.e. > 0.2 mm), axillary lymph node dissection level I and II is indicated [38].
However, if a SLNB is impossible, an axillary lymph node dissection level I and II is
indicated [38]. Also, for invasive tumors > 3 cm or for cN+ tumors, an axillary lymph
node dissection level I and II is mandatory.
71. Breast-conserving surgery offers the same survival benefits as modified
radical mastectomy in women with stage I or II breast cancer who are
candidates for breast-conserving surgery (1A evidence) [27, 73].
72. The choice of surgery must be tailored to the individual patient with stage I
or II breast cancer, who should be fully informed of the options (1A
evidence) [27, 73].
73. In women with primary breast cancer less than 3 cm and with clinically and
ultrasonographically negative nodes, a sentinel lymph node biopsy should be
performed (1A evidence) [38, 49].
74. If the sentinel node is positive (>0.2 mm), axillary lymph node dissection
level I and II is indicated (1A evidence) [38].
75. If a sentinel lymph node biopsy is impossible, an axillary lymph node
dissection level I and II is indicated (1A evidence) [38].
3.7.2 Radiotherapy
The recommendation to give adjuvant radiotherapy to patients treated breastconserving
surgery is based on the systematic review of the Early Breast Cancer
Trialists Collaborative Group (EBCTCG) and subsequent RCTs [27, 38]. However, the
effect on mortality of radiotherapy of the thoracic wall following mastectomy is less
clear [27]. In a systematic review of the EBCTCG of 34 RCTs involving approximately
20.000 women, no reduction of all-cause mortality or breast cancer mortality was found
with radiotherapy after mastectomy alone or mastectomy plus axillary clearance [27].
However, radiotherapy did reduce all cause mortality and breast cancer mortality after
mastectomy plus axillary sampling. A recent RCT showed a clear survival benefit of

KCE reports 63 Breast Cancer 25
radiotherapy in premenopausal women with node-positive breast cancer treated with
modified radical mastectomy and adjuvant chemotherapy [74].
The role of internal mammary chain irradiation is unclear at the moment [75], and is
currently being investigated in the EORTC 22922/10925 trial [76]. Patients eligible for
internal mammary chain irradiation are to be discussed in the MDT.
Veronesi et al. assessed the role of axillary radiotherapy in the treatment of nodenegative
early breast cancer [77]. No significant differences were found between the
axillary radiotherapy group vs. the no axillary treatment group in terms of local
recurrence and disease-free survival. In an RCT of Louis-Sylvestre et al. no difference in
long-term survival was found after axillary radiotherapy vs. axillary dissection in patients
with clinically node-negative invasive breast cancer [78]. Based on these data, axillary
radiotherapy cannot be considered routine practice and should be discussed in the
MDT on an individual basis.
In a recent Cochrane review, no significant differences were found between the various
methods of sequencing adjuvant therapy in terms of survival, distant metastases or local
recurrence [79]. However, radiotherapy before chemotherapy was associated with a
significantly increased risk of neutropenic sepsis (OR 2.96, 95%CI 1.26 to 6.98)
compared with chemotherapy before radiotherapy. Therefore, if both adjuvant
chemotherapy and radiotherapy are indicated, the chemotherapy should be given first.
76. In patients with invasive breast cancer, adjuvant irradiation is indicated
after breast conserving surgery (1A evidence) [27, 38].
77. Radiotherapy of the thoracic wall after mastectomy is indicated for the
following conditions (1B evidence) [26, 38]:
- pT3
- pN+ (whatever the number of invaded nodes)
- LVI
78. Internal mammary chain irradiation is to be discussed in the
multidisciplinary team meeting (expert opinion).
79. The target volume of percutaneous adjuvant radiotherapy encompasses the
entire breast and the adjoining thoracic wall. The dose amounts to
approximately 50 Gray fractionated in the conventional manner (1.8-2.0
Gray) with an additional local boost (1A evidence) [26, 38].
80. Axillary radiotherapy should be discussed on an individual basis in the MDT
(1A evidence) [38, 77, 78].
81. If adjuvant chemotherapy and radiotherapy are indicated, the
chemotherapy should be given first (1A evidence) [79].
3.7.3 Systemic therapy
According to the St. Gallen consensus, the choice of adjuvant treatment with
chemotherapy and/or hormonal therapy should be driven by the hormonal sensitivity
and risk profile of the tumour, and by the age of the patient [80].
Tumours with the following characteristics are considered to have a low risk for local
and/or distant recurrence:
• ER+ and/or PgR+ and all of the following:
o N0
o pT ≤ 2 cm
o G1
o ≥ 35 years
o no lymphovascular invasion (LVI)

26 Breast Cancer KCE reports 63
o no HER2 amplification
• pT < 1 cm
Tumours have an intermediate risk if they are ER+ and have one of the following
characteristics:
o pT > 2 cm
o G2-3
o N+ 1-3
High-risk tumours have the following characteristics:
• ER+ and/or PgR+ and:
o >3 N+
o Two of the following parameters:
pT > 2cm
G3
1-3 N+
• ER–, PgR– and pT > 1cm
• < 35 years
• HER2 amplification
• Lymphovascular invasion
Breast tumours are considered to be hormonal sensitive if they are ER+ >10% and
hormonal insensitive if they are ER+

KCE reports 63 Breast Cancer 27
based chemotherapy compared to patients not treated with chemotherapy (65% vs.
60%, p = 0.01) [82]. Also, the 10-year distant metastasis rates were significantly better
in the active treatment group (23% vs. 28%, p = 0.02). However, the 10-year local
recurrence rate did not differ significantly between the two treatment groups [82].
Hutchins et al. found a slightly better 10-year overall survival rate in node-negative
breast cancer patients treated with adjuvant FAC (cyclophosphamide, doxorubicin,
fluorouracil) compared to those treated with adjuvant CMF (cyclophosphamide,
methotrexate, fluorouracil) (85% vs. 82%, p = 0.03) [83]. However, disease-free survival
did not differ significantly, and FAC was associated with greater toxicity. In nodepositive
breast cancer patients, adjuvant FEC (cyclophosphamide, epirubicin,
fluorouracil) was associated with a better 10-year relapse-free survival (52% vs. 45%, p =
0.007) compared to adjuvant CMF (cyclophosphamide, methotrexate, fluorouracil) [84].
Toxicity associated with FEC was acceptable.
In a pooled analysis of 9 RCTs, Bria et al. found significant differences in favour of
taxanes in terms of disease-free survival in the overall (RR 0.86; 95%CI 0.81 – 0.90) and
lymph node-positive population (RR 0.84; 95%CI 0.79 – 0.89), and in terms of overall
survival in the overall (RR 0.87; 95%CI 0.81 – 0.83) and lymph node-positive population
(RR 0.84; 95%CI 0.77 – 0.92) [85].
For women with unifocal operable breast cancer who should actually undergo
mastectomy, owing to the size of their tumor (large T2 tumours), but who desire
breast-conserving surgery, neoadjuvant chemotherapy offers an alternative to adjuvant
systemic therapy [26]. However, in cases where this approach is successful, an increased
incidence of local recurrence is to be expected after breast-conserving surgery [86].
In a recent systematic review of Farquhar et al. – based on the results of 13 included
RCTs – no evidence was found to support the routine use of high-dose chemotherapy
with autologous stem-cell transplantation in women with early poor prognosis breast
cancer [87]. At six years there was no statistically significant difference between the
groups in event-free survival. With respect to overall survival, there was no statistically
significant difference between the groups at any stage of follow up. However, morbidity
was more common and more severe in the high dose group [87].
83. Preferred regimens are standard anthracycline-based regimens with or
without a taxane (1A evidence) [82-85].
84. In patients with unifocal operable tumours too large for breast conserving
surgery, downstaging with neoadjuvant therapy can be offered (1A
evidence) [26, 86].
85. High-dose chemotherapy with stem-cell transplantation cannot be
recommended (1A evidence) [87].
3.7.3.2 Hormonal therapy
Adjuvant treatment with tamoxifen substantially improves the 10-year survival of
women with ER-positive tumours and of women whose tumours are of unknown ER
status [88]. For ER-positive disease only, 5 years of adjuvant tamoxifen reduces the
mortality rate by 31%, largely irrespective of the use of chemotherapy and of age ( or =70 years), progesterone receptor status, or other tumour characteristics.
Five years of treatment is significantly more effective than 1-2 years of tamoxifen [88].
For women with HR-negative tumours, adjuvant tamoxifen remains a matter for
research.
In a recent systematic review of Sharma et al., three RCTs were identified that studied
the addition of LHRH agonists to adjuvant hormonal therapy in premenopausal women
with early breast cancer [89]. Overall, these studies demonstrated the efficacy of
adjuvant goserelin with or without tamoxifen. The authors concluded that combined
tamoxifen and LHRH agonists may be regarded as a treatment option for
premenopausal women with endocrine-responsive disease. The results of the two
studies of which the full publication was not yet available at the time of this systematic
review, were recently published [90, 91]. One additional RCT was identified through

28 Breast Cancer KCE reports 63
our literature search [92], in which the addition of tamoxifen and goserelin to adjuvant
chemotherapy was found to result in a significantly improved disease-free survival
(HR=0.74; 95%CI 0.56 – 0.99; p = 0.04). Very recently, the results of an additional RCT
were published (after our literature search), examining the benefits of adding ovarian
ablation or suppression to prolonged tamoxifen treatment in premenopausal women
with early breast cancer [93]. No added effect of ovarian ablation or suppression on
relapse-free survival or overall survival was found.
Upfront treatment with third-generation aromatase inhibitors is associated with
statistically significant improved survival in postmenopausal patients with advanced
breast cancer compared with standard hormonal treatments (relative hazard = 0.87,
95%CI 0.82 – 0.93; p

KCE reports 63 Breast Cancer 29
Besides a practical testing algorithm, this guideline also contains an interesting discussion
on HER2-testing variation and tissue handling requirement. An analogue discussion can
be found in the European guidelines [8].
89. Based on the criteria from the HERA trial (T > 1cm and/or previously
chemotherapy), a 1 year treatment with adjuvant trastuzumab is indicated
for women with HER2 FISH positive breast cancer, a left ventricular
ejection fraction of ≥ 55% and without cardiovascular exclusion criteria (1A
evidence) [99, 100].
90. During treatment with trastuzumab, cardiac function should be monitored
(1A evidence) [99].
3.8 TREATMENT OF METASTATIC BREAST CANCER
3.8.1 Systemic treatment
3.8.1.1 Hormonal therapy
In premenopausal patients with HR+ or HR unknown metastatic breast cancer,
suppression of ovarian function in combination with tamoxifen is the first-line hormonal
therapy [26, 38]. This recommendation is based on a meta-analysis of 4 RCTs, in which
a significant survival benefit (HR = 0.78, p = 0.02) and progression-free survival benefit
(HR = 0.70, p = 0.0003) was found in favour of the combined treatment [102].
In a recent systematic review including 6 RCTs, aromatase inhibitors were found to
have a clear advantage in overall response rate, clinical benefit, and time to progression
over tamoxifen as first-line hormonal treatment in postmenopausal patients with
metastatic breast cancer [103]. Overall survival did not differ significantly. These results
confirm the recommendations of CBO [38], the German Cancer Society [26] and
Cancer Care Ontario [104]. However, tamoxifen remains an acceptable alternative a
first-line treatment. Based on data from RCTs, anastrozole, letrozole or exemestane are
recommended as second-line hormonal treatment [104]. Again, it should be stressed
that the reimbursement of aromatase inhibitors in Belgium is subjected to strict criteria.
91. In premenopausal patients with hormone receptor positive or hormone
receptor unknown metastatic breast cancer, suppression of ovarian function
(e.g. with LHRH analogs, oophorectomy, irradiation of the ovaries) in
combination with tamoxifen is the first-line hormonal therapy (1A
evidence) [26, 38].
92. In postmenopausal patients with hormone receptor positive or hormone
receptor unknown metastatic breast cancer, first-line treatment consists of
aromatase inhibitors. Tamoxifen remains an acceptable alternative as firstline
treatment. As second-line treatment, anastrozole, letrozole or
exemestane are recommended (1A evidence) [26, 38, 104].

30 Breast Cancer KCE reports 63
3.8.1.2 Chemotherapy
Chemotherapy is indicated for women with hormone refractory or HR-negative
metastatic breast cancer, rapidly progressive disease, or invasion of vital organs (e.g.
diffuse lung or liver metastases, massive bone marrow metastases with pancytopenia)
[38]. Multiple systematic reviews exist evaluating different chemotherapy regimens for
women with metastatic breast cancer [105-108]. However, for each individual patient
the preferred chemotherapy regimen is to be discussed in the MDT.
93. Chemotherapy for patients with metastatic breast cancer is indicated for
the following conditions (expert opinion) [38]:
- hormone refractory or HR- tumours
- rapidly progressive disease
- invasion of vital organs
94. The preferred chemotherapy regimen is to be discussed in the
multidisciplinary team (expert opinion).
3.8.1.3 Trastuzumab
Based on observational data and subanalyses of RCTs that showed that patients with
FISH-positive breast tumours have clearly better response rates to trastuzumab than
patients with FISH-negative tumours, trastuzumab should be reserved for those patients
whose tumours have HER2 gene amplification [27]. Numerous RCTs have shown the
advantage of adding trastuzumab to chemotherapy with taxanes [27]. This was
confirmed by a recent RCT that showed that the combination of trastuzumab and
docetaxel is superior to docetaxel alone as first-line treatment of patients with HER2positive
metastatic breast cancer in terms of overall survival, response rate, response
duration, time to progression, and time to treatment failure [109].
95. Trastuzumab should be reserved for those patients whose tumours have
HER2 gene amplification (1C evidence) [27].
96. Combination therapy of trastuzumab with a taxane is recommended in
women with metastatic breast cancer with HER2 gene amplification (1A
evidence) [27, 38].
3.8.2 Treatment of bone metastases
Extensive evidence has shown the effectiveness of bisphosphonates in patients with
breast cancer and multiple lytic bone metastases in terms of pain reduction, reduction
of skeletal events, improvement of the quality of life, and time-to-progression [27, 38].
However, the optimal timing of initiation of bisphosphonate therapy and duration of
treatment remains uncertain. These findings were confirmed by a recent systematic
review of Pavlakis et al. including 21 RCTs [110]. Of course, in patients with painful
bone metastases, radiotherapy remains a treatment option [27, 38].
97. Bisphosphonates should be routinely used in combination with other
systemic therapy in patients with metastatic breast cancer with multiple
and lytic bone metastases (1A evidence) [27, 38].
98. In patients with painful bone metastases, radiotherapy is a treatment option
(1A evidence) [27, 38].

KCE reports 63 Breast Cancer 31
3.9 TREATMENT OF LOCOREGIONAL RELAPSE
In case of a local recurrence in the thoracic wall, the aim should be complete excision of
the tumour [26, 38]. Small recurrences in the scar can be removed by wide excision in
healthy tissue. Large chest-wall recurrences can be treated by chest wall resection. If no
radiotherapy has been performed as part of the primary therapy, radiotherapy should
be performed postoperatively [26, 38]. However, in the presence of unfavourable risk
factors, an additional course of (small-volume) radiotherapy may be given
postoperatively even in patients who have received prior adjuvant radiotherapy. This
should first be discussed in the MDT. In patients with a local recurrence after breastconserving
treatment, salvage mastectomy is recommended [38]. However, for some
cases breast-conserving surgery may be an option. Few trials exist on the use of
systemic treatment for a locoregional recurrence [38]. Therefore, this should be
discussed in the MDT for each individual patient.
99. A local recurrence in the thoracic wall should be treated preferentially with
surgery and adjuvant radiotherapy whenever possible (1C evidence) [26,
38].
100. A recurrence after breast-conserving treatment should be treated by a
salvage mastectomy (1C evidence) [38].
101. Systemic treatment for a locoregional recurrence should be discussed in
the multidisciplinary team (expert opinion).
3.10 SUPPORTIVE CARE FOR PATIENTS WITH BREAST
CANCER
A recent systematic review identified 3 RCTs examining the use of bisphosphonates in
the treatment of women with breast cancer but without clinically evident bone
metastases. No risk reduction for the development of skeletal metastases was found,
but a significant heterogeneity was found among the 3 studies [110]. In terms of survival,
the combined results indicate that adjuvant clodronate may improve survival. However,
there remains significant heterogeneity among these three studies [110]. The findings of
this systematic review confirm the conclusions of an earlier CPG of Cancer Care
Ontario [111].
Physiotherapeutic interventions can be useful after axillary clearance [38]. However, a
Cochrane review of Badger et al. identified 3 RCTs examining the use of physical
therapies for the reduction and control of lymphoedema of the limbs [112]. Only one of
these RCTs (a crossover study of manual lymph drainage followed by self-administered
massage versus no treatment) only included women with unilateral lymphoedema of the
upper limb following treatment for breast cancer. No extra benefit of manual lymph
drainage was found [112].
One meta-analysis was identified on the use of physical exercise on breast cancer
patients [113]. The authors identified 14 RCTs with important heterogeneity and small
sample sizes. It was found that physical exercise leads to statistically significant
improvements in quality of life and physical functioning [113].
There are no clear and uniform data as to whether the use of conventional hormonal
replacement therapy alleviates menopausal symptoms or alters outcomes in women
with breast cancer treated with endocrine agents [27, 38, 114]. In the Stockholm trial,
the risk of breast cancer recurrence was not associated with menopausal hormone
therapy (RH = 0.82, 95%CI 0.35 to 1.9) [114]. However, in the HABITS trial, a higher
risk for recurrence of breast cancer was identified among patients receiving menopausal
HRT [114]. Therefore, this treatment cannot be recommended after treatment for
breast cancer [38].
A systematic review of Edwards et al. identified 5 RCTs examining the use of
psychological interventions for women with metastatic breast cancer [115]. The authors
concluded that there was insufficient evidence to advocate that group psychological
therapies should be made available to all women diagnosed with metastatic breast

32 Breast Cancer KCE reports 63
cancer. Numerous additional RCTs on group interventions [116-120], individual
interventions [121-128], couple and family interventions [129-131], and computer- and
telephone-based interventions [132-134] were identified. However, many of these trials
were hampered by methodological limitations and small sample sizes, and reporting on
outcomes was heterogeneous. Nevertheless, psychological support should be available
to all patients diagnosed with breast cancer [27, 38].
Observational studies have shown that women undergoing reconstructive surgery after
mastectomy have a better cosmetic result and positive psychosocial effects [27, 38].
Therefore, the possibility of breast reconstruction should be discussed with all patients
prior to mastectomy.
102. Bisphosphonates are not part of the adjuvant treatment of breast cancer
(1A evidence) [110, 111].
103. Physiotherapy after axillary clearance can be recommended (2B
evidence) [38, 112].
104. Physical training after treatment for breast cancer can be recommended
(2A evidence) [113].
105. Menopausal hormonal replacement therapy is contraindicated in women
with breast cancer (1C evidence) [114].
106. Psychological support should be available to all patients diagnosed with
breast cancer (1A evidence) [27, 38].
107. The possibility of breast reconstruction should be discussed with all
patients prior to mastectomy (1C evidence) [27, 38].
3.11 SURVEILLANCE OF PATIENTS WITH BREAST CANCER
Local recurrences or second primaries in the treated breast are detected clinically or
mammographically [27, 38]. Mammography is the gold standard method of imaging for
cancer detection, but no evidence was identified to suggest the optimal frequency of this
procedure. Current practice offers this once yearly. Since there is evidence that
performing diagnostic tests such as X-rays, blood tests and scans to screen for distant
metastases does not improve survival, these tests should not be performed in
asymptomatic women [27, 38]. The frequency of follow-up consultations is not
extensively studied, and therefore mainly based on expert opinion. Follow-up
consultations could be provided every 3 months in the first year after diagnosis, every 6
months until 5 years after diagnosis, and every year after 5 years [38].
108. Yearly mammo/ultrasonography should be used to detect recurrence or
second primaries in patients who have undergone previous treatment for
breast cancer (1C evidence) [27].
109. Routine diagnostic tests to screen for distant metastases in
asymptomatic women should not be performed (1C evidence) [27].
110. Follow-up consultations could be provided every 3 months in the first
year after diagnosis, every 6 months until 5 years after diagnosis, and every
year after 5 years (expert opinion) [38].
3.12 MULTIDISCIPLINARY APPROACH OF PATIENTS WITH
BREAST CANCER
There is evidence from an observational study that a multidisciplinary breast clinic
provides an accurate and effective means of establishing a correct diagnosis in women
referred with breast symptoms [27]. A multidisciplinary clinic will usually involve breast
clinicians, radiologists and cytologists/pathologists. Above this, all women with a
potential or known diagnosis of breast cancer should have access to a breast care nurse
specialist for information and support at every stage of diagnosis and treatment [27].

KCE reports 63 Breast Cancer 33
111. Patients should be seen at a multidisciplinary clinic involving breast
clinicians, radiologists and pathologists (1C evidence) [27, 38].
112. All women with a potential or known diagnosis of breast cancer should
have access to a breast care nurse specialist for information and support at
every stage of diagnosis and treatment (1C evidence) [27].
3.13 BREAST CANCER AND PREGNANCY
In a recent population based descriptive study women aged

34 Breast Cancer KCE reports 63
4 IMPLEMENTATION AND UPDATING OF THE
BREAST CANCER GUIDELINE
4.1 IMPLEMENTATION
The implementation of the present guideline will be led by the College of Oncology. An
online implementation tool – similar to the tool accompanying the colorectal cancer
guideline [1] – will be developed. The tool will be based on the general algorithm of this
guideline.
4.2 QUALITY CONTROL
The implementation of the guideline has to be evaluated with appropriate quality
control criteria. These criteria should at least assess the following items of the
algorithm:
- population screening
- high-risk patients’ management
- diagnostic work-up
- staging
- treatment according to stage
- surveillance
- multidisciplinary approach
For each of these steps, quality indicators should be developed, which should be
preferentially based on the recommendations with a high level of evidence.
4.3 GUIDELINE UPDATE
In view of the changing evidence, and based on a pre-assessment of the literature, this
guideline should be updated in 3 – 5 years. Indeed, already during the finalisation of this
guideline, numerous new studies became available.
Examples of topics that will probably need updating are the impact of micrometastases
(less than 0.2 mm) on prognosis and adjuvant treatment, and the place of trastuzumab in
the adjuvant setting.

KCE reports 63 Breast Cancer 35
5 REFERENCES
1. Peeters, M., et al., Nationale Richtlijnen van het College voor oncologie: A. Algemeen kader
oncologish kwaliteitshandboek B. Wetenschappelijke basis voor klinische paden voor diagnose en
behandeling colorectale kanker en testiskanker, in KCE reports. 2006, Federaal Kenniscentrum
voor de Gezondheidszorg (KCE): Brussel.
2. Fervers, B., et al., Adaptation of clinical guidelines: literature review and proposition for a
framework and procedure. Int J Qual Health Care, 2006. 18(3): p. 167-76.
3. Paulus, D., F. Mambourg, and L. Bonneux, Borstkankerscreening, in KCE reports, KCE, Editor.
2005, Federaal Kenniscentrum voor de Gezondheidszorg (KCE): Brussel.
4. Gotzsche, P.C. and M. Nielsen, Screening for breast cancer with mammography. Cochrane
Database Syst Rev, 2006(4): p. CD001877.
5. Irwig, L., N. Houssami, and C. van Vliet, New technologies in screening for breast cancer: a
systematic review of their accuracy. Br J Cancer, 2004. 90(11): p. 2118-22.
6. Kosters, J.P. and P.C. Gotzsche, Regular self-examination or clinical examination for early
detection of breast cancer. Cochrane Database Syst Rev, 2003(2): p. CD003373.
7. Shen, Y., et al., Role of detection method in predicting breast cancer survival: analysis of
randomized screening trials. J Natl Cancer Inst, 2005. 97(16): p. 1195-203.
8. Perry, N., et al., European guidelines for quality assurance in breast cancer screening and diagnosis.
Fourth edition. 2006: Lyon.
9. Amir, E., et al., Evaluation of breast cancer risk assessment packages in the family history
evaluation and screening programme. J Med Genet, 2003. 40(11): p. 807-14.
10. Tyrer, J., S.W. Duffy, and J. Cuzick, A breast cancer prediction model incorporating familial and
personal risk factors. Stat Med, 2004. 23(7): p. 1111-30.
11. McIntosh, A., et al., Clinical guidelines and evidence review for the classification and care of
women at risk of familial breast cancer. 2004, National Collaborating Centre for Primary
Care/University of Sheffield: London.
12. U.S. Preventive Services Task Force, Clinical guidelines. Genetic risk assessment and BRCA
mutation testing for breast and ovarian cancer susceptibility: recommendation statement. Annals
of Internal Medicine, 2005. 143(5): p. 355-61.
13. National Collaborating Centre for Primary Care, Familial breast cancer: the classification and care
of women at risk of familial breast cancer in primary, secondary and tertiary care., NICE, Editor.
2006, NICE: London.
14. Calderon-Margalit, R. and O. Paltiel, Prevention of breast cancer in women who carry BRCA1 or
BRCA2 mutations: a critical review of the literature. Int J Cancer, 2004. 112(3): p. 357-64.
15. Demaerel, P., et al., Magnetische Resonantie Beeldvorming, in KCE reports. 2006, Federaal
Kenniscentrum voor de gezondheidszorg (KCE): Brussel.
16. Eisinger, F., et al., Cultural basis for differences between US and French clinical recommendations
for women at increased risk of breast and ovarian cancer. Lancet, 1999. 353(9156): p. 919-20.
17. Lostumbo, L., et al., Prophylactic mastectomy for the prevention of breast cancer. Cochrane
Database Syst Rev, 2004(4): p. CD002748.
18. Bermejo-Perez, M.J., S. Marquez-Calderon, and A. Llanos-Mendez, Effectiveness of preventive
interventions in BRCA1/2 gene mutation carriers: A systematic review. Int J Cancer, 2007. 121(2):
p. 225-231.
19. Fisher, B., et al., Tamoxifen for the prevention of breast cancer: current status of the National
Surgical Adjuvant Breast and Bowel Project P-1 study. J Natl Cancer Inst, 2005. 97(22): p. 1652-62.
20. Cuzick, J., et al., Overview of the main outcomes in breast-cancer prevention trials. Lancet, 2003.
361(9354): p. 296-300.

36 Breast Cancer KCE reports 63
21. Vogel, V.G., et al., Effects of tamoxifen vs raloxifene on the risk of developing invasive breast
cancer and other disease outcomes: the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2
trial. Jama, 2006. 295(23): p. 2727-41.
22. Guerrieri-Gonzaga, A., et al., Preliminary results on safety and activity of a randomized, doubleblind,
2 x 2 trial of low-dose tamoxifen and fenretinide for breast cancer prevention in
premenopausal women. J Clin Oncol, 2006. 24(1): p. 129-35.
23. Deitcher, S.R. and M.P. Gomes, The risk of venous thromboembolic disease associated with
adjuvant hormone therapy for breast carcinoma: a systematic review. Cancer, 2004. 101(3): p.
439-49.
24. Shoma, A., et al., Ultrasound for accurate measurement of invasive breast cancer tumor size.
Breast J, 2006. 12(3): p. 252-6.
25. Park, J.M., et al., Sonographic detection of multifocality in breast carcinoma. J Clin Ultrasound,
2003. 31(6): p. 293-8.
26. Kreienberg, R., et al., Interdisciplinary S3 Guidelines for the Diagnosis and Treatment of Breast
Cancer in Women., G.C. Society, Editor. 2003, German Cancer Society: Frankfurt.
27. Scottish Intercollegiate Guidelines Network (SIGN), Management of breast cancer in women. A
national clinical guideline., S.I.G. Network, Editor. 2003, Scottish Intercollegiate Guidelines
Network (SIGN): Edinburgh.
28. National Breast Cancer Centre, Clinical practice guidelines for the management and support of
younger women with breast cancer., N.B.C. Centre, Editor. 2004, National Breast Cancer Centre:
Camperdown,NSW.
29. Bagni, B., et al., Scintimammography with 99mTc-MIBI and magnetic resonance imaging in the
evaluation of breast cancer. Eur J Nucl Med Mol Imaging, 2003. 30(10): p. 1383-8.
30. Howarth, D., et al., Complementary role of adjunctive breast magnetic resonance imaging and
scintimammography in patients of all ages undergoing breast cancer surgery. Australas Radiol,
2005. 49(4): p. 289-97.
31. Van Goethem, M., et al., MR mammography in the pre-operative staging of breast cancer in
patients with dense breast tissue: comparison with mammography and ultrasound. Eur Radiol,
2004. 14(5): p. 809-16.
32. Bekis, R., et al., 99mTc sestamibi scintimammography. Screening mammographic non-palpable
suspicious breast lesions: preliminary results. Nuklearmedizin, 2004. 43(1): p. 16-20.
33. Chen, J., et al., Using Tc-99m MIBI scintimammography to differentiate nodular lesions in breast
and detect axillary lymph node metastases from breast cancer. Chinese Medical Journal, 2003.
116(4): p. 620-4.
34. Fondrinier, E., et al., Clinical experience with 99mTc-MIBI scintimammography in patients with
breast microcalcifications. Breast, 2004. 13(4): p. 316-20.
35. Krishnaiah, G., et al., Technetium-99m sestamibi scintimammography complements mammography
in the detection of breast cancer. Breast J, 2003. 9(4): p. 288-94.
36. Sampalis, F.S., et al., International prospective evaluation of scintimammography with
(99m)technetium sestamibi. Am J Surg, 2003. 185(6): p. 544-9.
37. Tiling, R., et al., Initial evaluation of breast cancer using Tc-99m sestamibi scintimammography.
European Journal of Radiology, 2005. 53(2): p. 206-12.
38. Richtlijn Behandeling van het mammacarcinoom 2005., V. Zuiden, Editor. 2005, Kwaliteitsinstituut
voor de Gezondheidszorg (CBO) en Vereniging van Integrale Kankercentra (VIKC): Alphen aan
den Rijn.
39. Myers, R.E., et al., Baseline staging tests in primary breast cancer: a practice guideline., C.C.
Ontario, Editor. 2003, Cancer Care Ontario: Toronto.
40. Zhou, P., S. Gautam, and A. Recht, Factors affecting outcome for young women with early stage
invasive breast cancer treated with breast-conserving therapy. Breast Cancer Res Treat, 2007.
101(1): p. 51-7.

KCE reports 63 Breast Cancer 37
41. Haffty, B.G., et al., Locoregional relapse and distant metastasis in conservatively managed triple
negative early-stage breast cancer. J Clin Oncol, 2006. 24(36): p. 5652-7.
42. Puglisi, F., et al., Baseline staging tests after a new diagnosis of breast cancer: further evidence of
their limited indications. Annals of Oncology, 2005. 16(2): p. 263-6.
43. Sliwowska, I., Z. Kopczynski, and S. Grodecka-Gazdecka, Diagnostic value of measuring serum CA
15-3, TPA, and TPS in women with breast cancer. Postepy Higieny i Medycyny do Swiadczalnej,
2006. 60: p. 295-9.
44. Seth, L.R.K., S. Kharb, and D.P. Kharb, Serum biochemical markers in carcinoma breast. Indian
Journal of Medical Sciences, 2003. 57(8): p. 350-4.
45. Kopczynski, Z. and A. Thielemann, The value of tissue polypeptide specific antigen TPS
determination in serum of women with breast cancer comparison to mucin-like associated antigen
MCA and CA 15-3 antigen. European Journal of Gynaecological Oncology, 1998. 19(5): p. 503-7.
46. Frenette, P.S., et al., The diagnostic value of CA 27-29, CA 15-3, mucin-like carcinoma antigen,
carcinoembryonic antigen and CA 19-9 in breast and gastrointestinal malignancies. Tumour
Biology, 1994. 15(5): p. 247-54.
47. Altinyollar, H., G. Dingil, and U. Berberoglu, Detection of infraclavicular lymph node metastases
using ultrasonography in breast cancer. Journal of Surgical Oncology, 2005. 92(4): p. 299-303.
48. Podkrajsek, M., et al., Role of ultrasound in the preoperative staging of patients with breast cancer.
European Radiology, 2005. 15(5): p. 1044-50.
49. Lyman, G.H., et al., American Society of Clinical Oncology guideline recommendations for sentinel
lymph node biopsy in early-stage breast cancer. Journal of Clinical Oncology, 2005. 23(30): p.
7703-20.
50. Xing, Y., et al., Meta-analysis of sentinel lymph node biopsy after preoperative chemotherapy in
patients with breast cancer. British Journal of Surgery, 2006. 93(5): p. 539-46.
51. Mansel, R.E., et al., Randomized multicenter trial of sentinel node biopsy versus standard axillary
treatment in operable breast cancer: the ALMANAC Trial.[see comment]. Journal of the National
Cancer Institute, 2006. 98(9): p. 599-609.
52. FNCLCC, 2003 update of recommendations for clinical practice: standards, options and
recommendations for the use of FDG-PET in the management of gynaecological and breast
cancers. Gynecologie, Obstetrique & Fertilite, 2004. 32(4): p. 352-71.
53. Cleemput, I., et al., HTA Positronen Emissie Tomografie in België, in KCE reports. 2005, Federaal
Kenniscentrum voor de Gezondheidszorg (KCE): Brussel. p. xi, 155 p.
54. Berg, W.A., et al., High-resolution fluorodeoxyglucose positron emission tomography with
compression ("positron emission mammography") is highly accurate in depicting primary breast
cancer. Breast Journal, 2006. 12(4): p. 309-23.
55. Chung, A., et al., Preoperative FDG-PET for axillary metastases in patients with breast cancer.
Archives of Surgery, 2006. 141(8): p. 783-8; discussion 788-9.
56. Gil-Rendo, A., et al., Fluorodeoxyglucose positron emission tomography with sentinel lymph node
biopsy for evaluation of axillary involvement in breast cancer. British Journal of Surgery, 2006.
93(6): p. 707-12.
57. Kumar, R., et al., Potential of dual-time-point imaging to improve breast cancer diagnosis with
(18)F-FDG PET. Journal of Nuclear Medicine, 2005. 46(11): p. 1819-24.
58. Landheer, M.L.E.A., et al., Value of fluorodeoxyglucose positron emission tomography in women
with breast cancer. British Journal of Surgery, 2005. 92(11): p. 1363-7.
59. Byrne, A.M., et al., Positron emission tomography in the staging and management of breast cancer.
British Journal of Surgery, 2004. 91(11): p. 1398-409.
60. Lovrics, P.J., et al., A prospective evaluation of positron emission tomography scanning, sentinel
lymph node biopsy, and standard axillary dissection for axillary staging in patients with early stage
breast cancer.[see comment]. Annals of Surgical Oncology, 2004. 11(9): p. 846-53.

38 Breast Cancer KCE reports 63
61. Nakai, T., et al., Pitfalls of FDG-PET for the diagnosis of osteoblastic bone metastases in patients
with breast cancer. Eur J Nucl Med Mol Imaging, 2005. 32(11): p. 1253-8.
62. Tafra, L., et al., Pilot clinical trial of 18F-fluorodeoxyglucose positron-emission mammography in
the surgical management of breast cancer. American Journal of Surgery, 2005. 190(4): p. 628-32.
63. Uematsu, T., et al., Comparison of FDG PET and SPECT for detection of bone metastases in
breast cancer.[see comment]. AJR, 2005. American Journal of Roentgenology. 184(4): p.
1266-73.
64. Fueger, B.J., et al., Performance of 2-deoxy-2-[F-18]fluoro-D-glucose positron emission
tomography and integrated PET/CT in restaged breast cancer patients. Mol Imaging Biol, 2005.
7(5): p. 369-76.
65. Reis-Filho, J.S. and S.E. Pinder, Non Operative Breast Pathology: lobular neoplasia. J Clin Pathol,
2006.
66. Pinder, S.E. and J.S. Reis-Filho, Non Operative Breast Pathology: columnar cell lesions. J Clin
Pathol, 2006.
67. FNCLCC, Recommandations pour la pratique clinique : Standards, Options et Recommandations
2004 pour la prise en charge des carcinomes canalaires in situ du sein., FNCLCC, Editor. 2004,
FNCLCC: Paris.
68. Wright, J.R., et al., Management of Ductal Carcinoma In Situ of the Breast., C.C. Ontario, Editor.
2003, Cancer Care Ontario: Toronto.
69. Bijker, N., et al., Breast-conserving treatment with or without radiotherapy in ductal carcinoma-insitu:
ten-year results of European Organisation for Research and Treatment of Cancer randomized
phase III trial 10853--a study by the EORTC Breast Cancer Cooperative Group and EORTC
Radiotherapy Group. J Clin Oncol, 2006. 24(21): p. 3381-7.
70. Bijker, N., et al., Breast-conserving therapy for Paget disease of the nipple: a prospective European
Organization for Research and Treatment of Cancer study of 61 patients. Cancer, 2001. 91(3): p.
472-7.
71. Bulens, P., et al., Breast conserving treatment of Paget's disease. Radiother Oncol, 1990. 17(4): p.
305-9.
72. Jatoi, I. and M.A. Proschan, Randomized trials of breast-conserving therapy versus mastectomy for
primary breast cancer: a pooled analysis of updated results. American Journal of Clinical Oncology,
2005. 28(3): p. 289-94.
73. McCready, D., et al., Surgical management of early stage invasive breast cancer: a practice
guideline. Canadian Journal of Surgery, 2005. 48(3): p. 185-94.
74. Ragaz, J., et al., Locoregional radiation therapy in patients with high-risk breast cancer receiving
adjuvant chemotherapy: 20-year results of the British Columbia randomized trial.[see comment].
Journal of the National Cancer Institute, 2005. 97(2): p. 116-26.
75. Kaija, H. and P. Maunu, Tangential breast irradiation with or without internal mammary chain
irradiation: results of a randomized trial. Radiother Oncol, 1995. 36(3): p. 172-6.
76. Musat, E., et al., Quality assurance in breast cancer: EORTC experiences in the phase III trial on
irradiation of the internal mammary nodes. Eur J Cancer, 2007. 43(4): p. 718-24.
77. Veronesi, U., et al., Avoiding axillary dissection in breast cancer surgery: a randomized trial to
assess the role of axillary radiotherapy. Annals of Oncology, 2005. 16(3): p. 383-8.
78. Louis-Sylvestre, C., et al., Axillary treatment in conservative management of operable breast
cancer: dissection or radiotherapy? Results of a randomized study with 15 years of follow-up.
Journal of Clinical Oncology, 2004. 22(1): p. 97-101.
79. Hickey, B.E., D. Francis, and M.H. Lehman, Sequencing of chemotherapy and radiation therapy for
early breast cancer. Cochrane Database of Systematic Reviews, 2006. 4: p. 4.
80. Goldhirsch, A., et al., Meeting highlights: international expert consensus on the primary therapy of
early breast cancer 2005. Ann Oncol, 2005. 16(10): p. 1569-83.

KCE reports 63 Breast Cancer 39
81. The Breast Cancer Disease Site Group, Adjuvant Systemic Therapy for Node-negative Breast
Cancer., C.C. Ontario, Editor. 2003, Cancer Care Ontario: Toronto.
82. Arriagada, R., et al., Results of two randomized trials evaluating adjuvant anthracycline-based
chemotherapy in 1146 patients with early breast cancer. Acta Oncologica, 2005. 44(5): p. 458-66.
83. Hutchins, L.F., et al., Randomized, controlled trial of cyclophosphamide, methotrexate, and
fluorouracil versus cyclophosphamide, doxorubicin, and fluorouracil with and without tamoxifen
for high-risk, node-negative breast cancer: treatment results of Intergroup Protocol INT-0102.
Journal of Clinical Oncology, 2005. 23(33): p. 8313-21.
84. Levine, M.N., et al., Randomized trial comparing cyclophosphamide, epirubicin, and fluorouracil
with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with nodepositive
breast cancer: update of National Cancer Institute of Canada Clinical Trials Group Trial
MA5. Journal of Clinical Oncology, 2005. 23(22): p. 5166-70.
85. Bria, E., et al., Benefit of taxanes as adjuvant chemotherapy for early breast cancer: pooled analysis
of 15,500 patients. Cancer, 2006. 106(11): p. 2337-44.
86. Mauri, D., N. Pavlidis, and J.P.A. Ioannidis, Neoadjuvant versus adjuvant systemic treatment in
breast cancer: a meta-analysis.[see comment]. Journal of the National Cancer Institute, 2005.
97(3): p. 188-94.
87. Farquhar, C., et al., High dose chemotherapy and autologous bone marrow or stem cell
transplantation versus conventional chemotherapy for women with early poor prognosis breast
cancer. Cochrane Database Syst Rev, 2005(3): p. CD003139.
88. Early Breast Cancer Trialists' Collaborative, G., Effects of chemotherapy and hormonal therapy for
early breast cancer on recurrence and 15-year survival: an overview of the randomised trials.[see
comment]. Lancet, 2005. 365(9472): p. 1687-717.
89. Sharma, R., J. Beith, and A. Hamilton, Systematic review of LHRH agonists for the adjuvant
treatment of early breast cancer. Breast, 2005. 14(3): p. 181-91.
90. Baum, M., et al., Adjuvant goserelin in pre-menopausal patients with early breast cancer: Results
from the ZIPP study. European Journal of Cancer, 2006. 42(7): p. 895-904.
91. Davidson, N.E., et al., Chemoendocrine therapy for premenopausal women with axillary lymph
node-positive, steroid hormone receptor-positive breast cancer: results from INT 0101
(E5188).[see comment]. Journal of Clinical Oncology, 2005. 23(25): p. 5973-82.
92. De Placido, S., et al., A randomised factorial trial of sequential doxorubicin and CMF vs CMF and
chemotherapy alone vs chemotherapy followed by goserelin plus tamoxifen as adjuvant treatment
of node-positive breast cancer. British Journal of Cancer, 2005. 92(3): p. 467-74.
93. Ovarian ablation or suppression in premenopausal early breast cancer: results from the
international adjuvant breast cancer ovarian ablation or suppression randomized trial. J Natl
Cancer Inst, 2007. 99(7): p. 516-25.
94. Mauri, D., et al., Survival with aromatase inhibitors and inactivators versus standard hormonal
therapy in advanced breast cancer: meta-analysis.[see comment]. Journal of the National Cancer
Institute, 2006. 98(18): p. 1285-91.
95. Bria, E., et al., Early switch with aromatase inhibitors as adjuvant hormonal therapy for
postmenopausal breast cancer: pooled-analysis of 8794 patients. Cancer Treatment Reviews, 2006.
32(5): p. 325-32.
96. Eisen, A., et al., The Role of Aromatase Inhibitors in Adjuvant Therapy for Postmenopausal
Women with Hormone Receptor-positive Breast Cancer. Evidence-based Series #1-18., C.C.
Ontario, Editor. 2005, Cancer Care Ontario: Toronto.
97. Goss, P.E., Preventing relapse beyond 5 years: the MA.17 extended adjuvant trial. Seminars in
Oncology, 2006. 33(2 Suppl 7): p. S8-12.
98. Kim, R., et al., Rationale for sequential tamoxifen and anticancer drugs in adjuvant setting for
patients with node- and receptor-positive breast cancer. Int J Oncol, 2005. 26(4): p. 1025-31.
99. Huybrechts, M., et al., Trastuzumab bij vroegtijdige stadia van borstkanker, in KCE reports. 2006,
Federaal Kenniscentrum voor de gezondheidszorg (KCE): Brussel.

40 Breast Cancer KCE reports 63
100. Smith, I., et al., 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2positive
breast cancer: a randomised controlled trial. Lancet, 2007. 369(9555): p. 29-36.
101. Wolff, A.C., et al., American Society of Clinical Oncology/College of American Pathologists
guideline recommendations for human epidermal growth factor receptor 2 testing in breast
cancer. J Clin Oncol, 2007. 25(1): p. 118-45.
102. Klijn, J.G., et al., Combined tamoxifen and luteinizing hormone-releasing hormone (LHRH)
agonist versus LHRH agonist alone in premenopausal advanced breast cancer: a meta-analysis of
four randomized trials. J Clin Oncol, 2001. 19(2): p. 343-53.
103. Ferretti, G., et al., Second- and third-generation aromatase inhibitors as first-line endocrine
therapy in postmenopausal metastatic breast cancer patients: a pooled analysis of the randomised
trials. Br J Cancer, 2006. 94(12): p. 1789-96.
104. Eisen, A., et al., Role of aromatase inhibitors in the treatment of postmenopausal women
with metastatic breast cancer., C.C. Ontario, Editor. 2003, Cancer Care Ontario: Toronto.
105. Farquhar, C., et al., High dose chemotherapy and autologous bone marrow or stem cell
transplantation versus conventional chemotherapy for women with metastatic breast cancer.
Cochrane Database Syst Rev, 2005(3): p. CD003142.
106. Carrick, S., et al., Platinum containing regimens for metastatic breast cancer. Cochrane
Database Syst Rev, 2004(3): p. CD003374.
107. Carrick, S., et al., Single agent versus combination chemotherapy for metastatic breast
cancer. Cochrane Database of Systematic Reviews, 2005(2): p. CD003372.
108. Ghersi, D., et al., Taxane containing regimens for metastatic breast cancer. Cochrane
Database Syst Rev, 2003(3): p. CD003366.
109. Marty, M., et al., Randomized phase II trial of the efficacy and safety of trastuzumab combined
with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic
breast cancer administered as first-line treatment: the M77001 study group.[see comment]. Journal
of Clinical Oncology, 2005. 23(19): p. 4265-74.
110. Pavlakis, N., R. Schmidt, and M. Stockler, Bisphosphonates for breast cancer. Cochrane
Database Syst Rev, 2005(3): p. CD003474.
111. Warr, D., M. Johnston, and Breast Cancer Disease Site Group, Use of Bisphosphonates in
Women with Breast Cancer. Practice Guideline Report #1-11., C.C. Ontario, Editor. 2004,
Cancer Care Ontario: Toronto.
112. Badger, C., et al., Physical therapies for reducing and controlling lymphoedema of the limbs.
Cochrane Database Syst Rev, 2004(4): p. CD003141.
113. McNeely, M.L., et al., Effects of exercise on breast cancer patients and survivors: a systematic
review and meta-analysis. Cmaj, 2006. 175(1): p. 34-41.
114. von Schoultz, E. and L.E. Rutqvist, Menopausal hormone therapy after breast cancer: the
Stockholm randomized trial. J Natl Cancer Inst, 2005. 97(7): p. 533-5.
115. Edwards, A.G., S. Hailey, and M. Maxwell, Psychological interventions for women with
metastatic breast cancer. Cochrane Database Syst Rev, 2004(2): p. CD004253.
116. Lane, L.G. and L.L. Viney, The effects of personal construct group therapy on breast cancer
survivors. Journal of Consulting & Clinical Psychology, 2005. 73(2): p. 284-92.
117. Savard, J., et al., Randomized study on the efficacy of cognitive-behavioral therapy for
insomnia secondary to breast cancer, part II: Immunologic effects. Journal of Clinical Oncology,
2005. 23(25): p. 6097-106.
118. Taylor, K.L., et al., Psychological adjustment among African American breast cancer patients:
one-year follow-up results of a randomized psychoeducational group intervention. Health
Psychology, 2003. 22(3): p. 316-23.
119. Antoni, M.H., et al., Reduction of cancer-specific thought intrusions and anxiety symptoms
with a stress management intervention among women undergoing treatment for breast cancer.
American Journal of Psychiatry, 2006. 163(10): p. 1791-7.

KCE reports 63 Breast Cancer 41
120. Vos, P.J., et al., Effects of delayed psychosocial interventions versus early psychosocial
interventions for women with early stage breast cancer. Patient Education & Counseling, 2006.
60(2): p. 212-9.
121. Andersen, B.L., et al., Psychological, behavioral, and immune changes after a psychological
intervention: a clinical trial. Journal of Clinical Oncology, 2004. 22(17): p. 3570-80.
122. Hack, T.F., et al., Impact of providing audiotapes of primary adjuvant treatment consultations
to women with breast cancer: a multisite, randomized, controlled trial. Journal of Clinical
Oncology, 2003. 21(22): p. 4138-44.
123. Lee, V., et al., Meaning-making intervention during breast or colorectal cancer treatment
improves self-esteem, optimism, and self-efficacy. Social Science & Medicine, 2006. 62(12): p. 3133-
45.
124. McGregor, B.A., et al., Cognitive-behavioral stress management increases benefit finding and
immune function among women with early-stage breast cancer. Journal of Psychosomatic
Research, 2004. 56(1): p. 1-8.
125. Scheier, M.F., et al., Interventions to enhance physical and psychological functioning among
younger women who are ending nonhormonal adjuvant treatment for early-stage breast cancer.
Journal of Clinical Oncology, 2005. 23(19): p. 4298-311.
126. Shapiro, S.L., et al., The efficacy of mindfulness-based stress reduction in the treatment of
sleep disturbance in women with breast cancer: an exploratory study. Journal of Psychosomatic
Research, 2003. 54(1): p. 85-91.
127. Stanton, A.L., et al., Outcomes from the Moving Beyond Cancer psychoeducational,
randomized, controlled trial with breast cancer patients. Journal of Clinical Oncology, 2005.
23(25): p. 6009-18.
128. Tatrow, K. and G.H. Montgomery, Cognitive behavioral therapy techniques for distress and
pain in breast cancer patients: a meta-analysis. Journal of Behavioral Medicine, 2006. 29(1): p. 17-
27.
129. Manne, S.L., et al., Couple-focused group intervention for women with early stage breast
cancer. Journal of Consulting & Clinical Psychology, 2005. 73(4): p. 634-46.
130. Northouse, L., et al., Effects of a family intervention on the quality of life of women with
recurrent breast cancer and their family caregivers. Psycho-Oncology, 2005. 14(6): p. 478-91.
131. Scott, J.L., W.K. Halford, and B.G. Ward, United we stand? The effects of a couple-coping
intervention on adjustment to early stage breast or gynecological cancer. Journal of Consulting &
Clinical Psychology, 2004. 72(6): p. 1122-35.
132. Owen, J.E., et al., Randomized pilot of a self-guided internet coping group for women with
early-stage breast cancer. Annals of Behavioral Medicine, 2005. 30(1): p. 54-64.
133. Sandgren, A.K. and K.D. McCaul, Short-term effects of telephone therapy for breast cancer
patients. Health Psychology, 2003. 22(3): p. 310-5.
134. Winzelberg, A.J., et al., Evaluation of an internet support group for women with primary
breast cancer. Cancer, 2003. 97(5): p. 1164-73.
135. Ives, A., et al., Pregnancy after breast cancer: population based study. Bmj, 2007. 334(7586):
p. 194.
136. MacLean, A.B., P. Sauven, and for the Royal College of Obstetricians and Gynaecologists,
Pregnancy and breast cancer., R.C.o.O.a. Gynaecologists, Editor. 2004, Royal College of
Obstetricians and Gynaecologists: London.
137. Trudeau, M., et al., Adjuvant Taxane Therapy for Women with Early-stage, Invasive Breast
Cancer. Practice Guideline Report #1-7, C.C. Ontario, Editor. 2006, Cancer Care Ontario:
Toronto.
138. Tomiak, E., et al., Capecitabine in Stage IV Breast Cancer. Practice Guideline Report #1-16,
C.C. Ontario, Editor. 2003, Cancer Care Ontario: Toronto.

42 Breast Cancer KCE reports 63
139. Findlay, B.P., et al., Epirubicin, as a Single Agent or in Combination, for Metastatic Breast
Cancer. Practice Guideline Report # 1-6, C.C. Ontario, Editor. 2003, Cancer Care Ontario:
Toronto.
140. Trudeau, M., et al., The Role of Taxanes in Neoadjuvant Chemotherapy for Women with
Non-metastatic Breast Cancer. Practice Guideline Report #1-20., C.C. Ontario, Editor. 2004,
Cancer Care Ontario: Toronto.
141. Verma, S., et al., The Role of the Taxanes in the Management of Metastatic Breast Cancer.
Practice Guideline Report # 1-3, C.C. Ontario, Editor. 2003, Cancer Care Ontario: Toronto.
142. Truong, P.T., et al., Clinical practice guidelines for the care and treatment of breast cancer:
16. Locoregional post-mastectomy radiotherapy.[see comment]. CMAJ Canadian Medical
Association Journal, 2004. 170(8): p. 1263-73.
143. Carlson, R.W. and B. McCormick, NCCN breast cancer Clinical Practice Guidelines. Journal
of the National Comprehensive Cancer Network, 2005. 3(1).
144. Hillner, B.E., et al., American Society of Clinical Oncology 2003 update on the role of
bisphosphonates and bone health issues in women with breast cancer.[erratum appears in J Clin
Oncol. 2004 Apr 1;22(7):1351]. Journal of Clinical Oncology, 2003. 21(21): p. 4042-57.
145. Shenkier, T., et al., Clinical practice guidelines for the care and treatment of breast cancer:
15. Treatment for women with stage III or locally advanced breast cancer. CMAJ: Canadian
Medical Association Journal, 2004. 170(6): p. 983-94.
146. Whelan, T., et al., Clinical practice guidelines for the care and treatment of breast cancer:
breast radiotherapy after breast-conserving surgery (summary of the 2003 update). CMAJ
Canadian Medical Association Journal, 2003. 168(4): p. 437-9.
147. Smith, R.A., V. Cokkinides, and H.J. Eyre, American Cancer Society guidelines for the early
detection of cancer, 2006. Ca-A Cancer Journal for Clinicians, 2006. 56(1): p. 11-25.
148. Lea, R., et al., Use of hormonal replacement therapy after treatment of breast cancer. Journal
of Obstetrics & Gynaecology Canada: JOGC, 2004. 26(1): p. 49-60; quiz 62-4.
149. Institute for Clinical Systems Improvement (ICSI), Breast Cancer Treatment., ICSI, Editor.
2005, ICSI.
150. Institute for Clinical Systems Improvement (ICSI), Diagnosis of Breast Disease., ICSI, Editor.
2005, ICSI.
151. Anderson, B.O., et al., Breast cancer in limited-resource countries: an overview of the Breast
Health Global Initiative 2005 guidelines. Breast Journal, 2006. 12(1): p. Jan-Feb.
152. Sauven, P. and P. Association of Breast Surgery Family History Guidelines, Guidelines for the
management of women at increased familial risk of breast cancer. European Journal of Cancer,
2004. 40(5): p. 653-65.
153. Alberta Medical Association, Guidelines for the early detection of breast cancer., A.M.
Association, Editor. 2005, Alberta Medical Association: Edmonton.
154. Loibl, S., et al., Breast carcinoma during pregnancy. International recommendations from an
expert meeting. Cancer, 2006. 106(2): p. 237-46.
155. Pestalozzi, B.C., et al., ESMO Minimum Clinical Recommendations for diagnosis, adjuvant
treatment and follow-up of primary breast cancer. Annals of Oncology, 2005. 16(1).
156. Kaufmann, M., et al., Recommendations from an international expert panel on the use of
neoadjuvant (primary) systemic treatment of operable breast cancer: an update. Journal of Clinical
Oncology, 2006. 24(12): p. 1940-9.
157. Guidelines for the management of symptomatic breast disease. European Journal of Surgical
Oncology, 2005. 31(SUPPL.): p. S1-S21.
158. American College of Radiology, ACR Appropriateness Criteria: Appropriate imaging workup
of palpable breast masses., A.C.o. Radiology, Editor. 2003, American College of Radiology:
Reston.

KCE reports 63 Breast Cancer 43
159. Ellis, I.O., et al., Best Practice No 176: Updated recommendations for HER2 testing in the
UK.[see comment]. Journal of Clinical Pathology, 2004. 57(3): p. 233-7.
160. Ellis, I.O., et al., Best Practice No 179. Guidelines for breast needle core biopsy handling and
reporting in breast screening assessment. Journal of Clinical Pathology, 2004. 57(9): p. 897-902.
161. Pinero, A., et al., Palpable breast lesions: utility of Doppler sonography for diagnosis of
malignancy. Breast, 2003. 12(4): p. 258-63.
162. Schelfout, K., et al., Contrast-enhanced MR imaging of breast lesions and effect on treatment.
Eur J Surg Oncol, 2004. 30(5): p. 501-7.
163. Hind, D., et al., Surgery versus primary endocrine therapy for operable primary breast cancer
in elderly women (70 years plus). Cochrane Database Syst Rev, 2006(1): p. CD004272.
164. Poggi, M.M., et al., Eighteen-year results in the treatment of early breast carcinoma with
mastectomy versus breast conservation therapy: the National Cancer Institute Randomized
Trial.[see comment]. Cancer, 2003. 98(4): p. 697-702.
165. Fentiman, I.S., et al., Treatment of operable breast cancer in the elderly: a randomised clinical
trial EORTC 10850 comparing modified radical mastectomy with tumorectomy plus
tamoxifen.[see comment]. European Journal of Cancer, 2003. 39(3): p. 300-8.
166. Arriagada, R., et al., Late local recurrences in a randomised trial comparing conservative
treatment with total mastectomy in early breast cancer patients.[see comment]. Annals of
Oncology, 2003. 14(11): p. 1617-22.
167. Rudenstam, C.-M., et al., Randomized trial comparing axillary clearance versus no axillary
clearance in older patients with breast cancer: first results of International Breast Cancer Study
Group Trial 10-93.[see comment]. Journal of Clinical Oncology, 2006. 24(3): p. 337-44.
168. Kodama, H., et al., Ten-year follow-up results of a randomised controlled study comparing
level-I vs level-III axillary lymph node dissection for primary breast cancer. Br J Cancer, 2006.
95(7): p. 811-6.
169. Purushotham, A.D., et al., Morbidity after sentinel lymph node biopsy in primary breast
cancer: results from a randomized controlled trial. Journal of Clinical Oncology, 2005. 23(19): p.
4312-21.
170. Martelli, G., et al., A randomized trial comparing axillary dissection to no axillary dissection in
older patients with T1N0 breast cancer: results after 5 years of follow-up. Annals of Surgery, 2005.
242(1): p. 1-6; discussion 7-9.
171. Tominaga, T., S. Takashima, and M. Danno, Randomized clinical trial comparing level II and
level III axillary node dissection in addition to mastectomy for breast cancer. British Journal of
Surgery, 2004. 91(1): p. 38-43.
172. Ford, H.T., et al., Long-term follow-up of a randomised trial designed to determine the need
for irradiation following conservative surgery for the treatment of invasive breast cancer. Annals of
Oncology, 2006. 17(3): p. 401-8.
173. Clarke, M., et al., Effects of radiotherapy and of differences in the extent of surgery for early
breast cancer on local recurrence and 15-year survival: an overview of the randomised trials.
Lancet, 2005. 366(9503): p. 2087-106.
174. Winzer, K.J., et al., Radiation therapy after breast-conserving surgery; first results of a
randomised clinical trial in patients with low risk of recurrence. European Journal of Cancer, 2004.
40(7): p. 998-1005.
175. Vinh-Hung, V. and C. Verschraegen, Breast-conserving surgery with or without radiotherapy:
pooled-analysis for risks of ipsilateral breast tumor recurrence and mortality.[see comment].
Journal of the National Cancer Institute, 2004. 96(2): p. 115-21.
176. Van de Steene, J., et al., Adjuvant radiotherapy for breast cancer: effects of longer follow-up.
Radiotherapy & Oncology, 2004. 72(1): p. 35-43.
177. Fyles, A.W., et al., Tamoxifen with or without breast irradiation in women 50 years of age or
older with early breast cancer.[see comment]. New England Journal of Medicine, 2004. 351(10): p.
963-70.

44 Breast Cancer KCE reports 63
178. Rutqvist, L.E., C. Rose, and E. Cavallin-Stahl, A systematic overview of radiation therapy
effects in breast cancer. Acta Oncologica, 2003. 42(5-6): p. 532-45.
179. Malmstrom, P., et al., Breast conservation surgery, with and without radiotherapy, in women
with lymph node-negative breast cancer: a randomised clinical trial in a population with access to
public mammography screening. European Journal of Cancer, 2003. 39(12): p. 1690-7.
180. Rouesse, J., et al., A phase III randomized trial comparing adjuvant concomitant
chemoradiotherapy versus standard adjuvant chemotherapy followed by radiotherapy in operable
node-positive breast cancer: final results. International Journal of Radiation Oncology, Biology,
Physics, 2006. 64(4): p. 1072-80.
181. Cuncins-Hearn, A., et al., A systematic review of intraoperative radiotherapy in early breast
cancer. Breast Cancer Res Treat, 2004. 85(3): p. 271-80.
182. Poole, C.J., et al., Epirubicin and cyclophosphamide, methotrexate, and fluorouracil as
adjuvant therapy for early breast cancer.[see comment]. New England Journal of Medicine, 2006.
355(18): p. 1851-62.
183. Land, S.R., et al., Health-related quality of life in axillary node-negative, estrogen receptornegative
breast cancer patients undergoing AC versus CMF chemotherapy: findings from the
National Surgical Adjuvant Breast and Bowel Project B-23. Breast Cancer Research & Treatment,
2004. 86(2): p. 153-64.
184. Fargeot, P., et al., Disease-free survival advantage of weekly epirubicin plus tamoxifen versus
tamoxifen alone as adjuvant treatment of operable, node-positive, elderly breast cancer patients: 6year
follow-up results of the French adjuvant study group 08 trial.[see comment][erratum appears
in J Clin Oncol. 2005 Jan 1;23(1):248]. Journal of Clinical Oncology, 2004. 22(23): p. 4622-30.
185. Bonadonna, G., et al., Clinical relevance of different sequencing of doxorubicin and
cyclophosphamide, methotrexate, and Fluorouracil in operable breast cancer. Journal of Clinical
Oncology, 2004. 22(9): p. 1614-20.
186. Fumoleau, P., et al., Randomized trial comparing six versus three cycles of epirubicin-based
adjuvant chemotherapy in premenopausal, node-positive breast cancer patients: 10-year follow-up
results of the French Adjuvant Study Group 01 trial. Journal of Clinical Oncology, 2003. 21(2): p.
298-305.
187. Martin, M., et al., Doxorubicin in combination with fluorouracil and cyclophosphamide (i.v.
FAC regimen, day 1, 21) versus methotrexate in combination with fluorouracil and
cyclophosphamide (i.v. CMF regimen, day 1, 21) as adjuvant chemotherapy for operable breast
cancer: a study by the GEICAM group. Annals of Oncology, 2003. 14(6): p. 833-42.
188. Sartor, C.I., et al., Effect of addition of adjuvant paclitaxel on radiotherapy delivery and
locoregional control of node-positive breast cancer: cancer and leukemia group B 9344.[see
comment]. Journal of Clinical Oncology, 2005. 23(1): p. 30-40.
189. Green, M.C., et al., Weekly paclitaxel improves pathologic complete remission in operable
breast cancer when compared with paclitaxel once every 3 weeks.[see comment]. Journal of
Clinical Oncology, 2005. 23(25): p. 5983-92.
190. Brain, E.G.C., et al., Life-threatening sepsis associated with adjuvant doxorubicin plus
docetaxel for intermediate-risk breast cancer.[see comment]. JAMA, 2005. 293(19): p. 2367-71.
191. Bear, H.D., et al., Sequential preoperative or postoperative docetaxel added to preoperative
doxorubicin plus cyclophosphamide for operable breast cancer:National Surgical Adjuvant Breast
and Bowel Project Protocol B-27. Journal of Clinical Oncology, 2006. 24(13): p. 2019-27.
192. Gianni, L., et al., Feasibility and tolerability of sequential doxorubicin/paclitaxel followed by
cyclophosphamide, methotrexate, and fluorouracil and its effects on tumor response as
preoperative therapy. Clinical Cancer Research, 2005. 11(24 Pt 1): p. 8715-21.
193. Cleator, S.J., et al., Good clinical response of breast cancers to neoadjuvant chemoendocrine
therapy is associated with improved overall survival. Annals of Oncology, 2005. 16(2): p. 267-72.
194. Danforth, D.N., Jr., et al., Preoperative FLAC/granulocyte-colony-stimulating factor
chemotherapy for stage II breast cancer: a prospective randomized trial.[see comment]. Annals of
Surgical Oncology, 2003. 10(6): p. 635-44.

KCE reports 63 Breast Cancer 45
195. Peters, W.P., et al., Prospective, randomized comparison of high-dose chemotherapy with
stem-cell support versus intermediate-dose chemotherapy after surgery and adjuvant
chemotherapy in women with high-risk primary breast cancer: a report of CALGB 9082, SWOG
9114, and NCIC MA-13. Journal of Clinical Oncology, 2005. 23(10): p. 2191-200.
196. Brandberg, Y., et al., Quality of life in women with breast cancer during the first year after
random assignment to adjuvant treatment with marrow-supported high-dose chemotherapy with
cyclophosphamide, thiotepa, and carboplatin or tailored therapy with Fluorouracil, epirubicin, and
cyclophosphamide: Scandinavian Breast Group Study 9401.[see comment]. Journal of Clinical
Oncology, 2003. 21(19): p. 3659-64.
197. Bushnell, C.D. and L.B. Goldstein, Risk of ischemic stroke with tamoxifen treatment for
breast cancer: a meta-analysis. Neurology, 2004. 63(7): p. 1230-3.
198. Braithwaite, R.S., et al., Meta-analysis of vascular and neoplastic events associated with
tamoxifen. Journal of General Internal Medicine, 2003. 18(11): p. 937-47.
199. Colleoni, M., et al., Tamoxifen after adjuvant chemotherapy for premenopausal women with
lymph node-positive breast cancer: International Breast Cancer Study Group Trial 13-93.[see
comment]. Journal of Clinical Oncology, 2006. 24(9): p. 1332-41.
200. Noguchi, S., et al., Postoperative adjuvant therapy with tamoxifen, tegafur plus uracil, or both
in women with node-negative breast cancer: a pooled analysis of six randomized controlled trials.
Journal of Clinical Oncology, 2005. 23(10): p. 2172-84.
201. Ryden, L., et al., Two years of adjuvant tamoxifen in premenopausal patients with breast
cancer: a randomised, controlled trial with long-term follow-up. European Journal of Cancer, 2005.
41(2): p. 256-64.
202. Kaufmann, M., et al., Tamoxifen versus control after adjuvant, risk-adapted chemotherapy in
postmenopausal, receptor-negative patients with breast cancer: a randomized trial (GABG-IV D-
93)--the German Adjuvant Breast Cancer Group. Journal of Clinical Oncology, 2005. 23(31): p.
7842-8.
203. Bottini, A., et al., Cytotoxic and antiproliferative activity of the single agent epirubicin versus
epirubicin plus tamoxifen as primary chemotherapy in human breast cancer: a single-institution
phase III trial. Endocrine-Related Cancer, 2005. 12(2): p. 383-92.
204. Fisher, B., et al., Treatment of lymph-node-negative, oestrogen-receptor-positive breast
cancer: long-term findings from National Surgical Adjuvant Breast and Bowel Project randomised
clinical trials.[see comment]. Lancet, 2004. 364(9437): p. 858-68.
205. Fentiman, I.S., et al., Treatment of operable breast cancer in the elderly: a randomised clinical
trial EORTC 10851 comparing tamoxifen alone with modified radical mastectomy.[see comment].
European Journal of Cancer, 2003. 39(3): p. 309-16.
206. Nordenskjold, B., et al., Coronary heart disease mortality after 5 years of adjuvant tamoxifen
therapy: results from a randomized trial. Journal of the National Cancer Institute, 2005. 97(21): p.
1609-10.
207. Belfiglio, M., et al., Twelve-year mortality results of a randomized trial of 2 versus 5 years of
adjuvant tamoxifen for postmenopausal early-stage breast carcinoma patients (SITAM 01). Cancer,
2005. 104(11): p. 2334-9.
208. Tada, K., et al., Comparison of two-year and five-year tamoxifen use in Japanese postmenopausal
women. European Journal of Surgical Oncology, 2004. 30(10): p. 1077-83.
209. Pagani, O., et al., Toremifene and tamoxifen are equally effective for early-stage breast
cancer: first results of International Breast Cancer Study Group Trials 12-93 and 14-93. Annals of
Oncology, 2004. 15(12): p. 1749-59.
210. Johnston, S.R.D., et al., A cancer research (UK) randomized phase II study of idoxifene in
patients with locally advanced/metastatic breast cancer resistant to tamoxifen. Cancer
Chemotherapy & Pharmacology, 2004. 53(4): p. 341-8.
211. Berry, J., Are all aromatase inhibitors the same? A review of controlled clinical trials in breast
cancer. Clinical Therapeutics, 2005. 27(11): p. 1671-84.

46 Breast Cancer KCE reports 63
212. Gerber, B., et al., Anastrozole versus tamoxifen treatment in postmenopausal women with
endocrine-responsive breast cancer and tamoxifen-induced endometrial pathology. Clinical Cancer
Research, 2006. 12(4): p. 1245-50.
213. The Arimidex, T.A.o.i.C.T.G., et al., Comprehensive side-effect profile of anastrozole and
tamoxifen as adjuvant treatment for early-stage breast cancer: long-term safety analysis of the
ATAC trial. Lancet Oncology, 2006. 7(8): p. 633-43.
214. Irish, W., et al., Quality-adjusted survival in a crossover trial of letrozole versus tamoxifen in
postmenopausal women with advanced breast cancer. Annals of Oncology, 2005. 16(9): p. 1458-
62.
215. Wilcken, N., J. Hornbuckle, and D. Ghersi, Chemotherapy alone versus endocrine therapy
alone for metastatic breast cancer. Cochrane Database of Systematic Reviews, 2003(2): p.
CD002747.
216. Carlini, P., et al., New aromatase inhibitors as second-line endocrine therapy in
postmenopausal patients with metastatic breast carcinoma: a pooled analysis of the randomized
trials. Cancer, 2005. 104(7): p. 1335-42.
217. Rose, C., et al., An open randomised trial of second-line endocrine therapy in advanced
breast cancer. comparison of the aromatase inhibitors letrozole and anastrozole.[see comment].
European Journal of Cancer, 2003. 39(16): p. 2318-27.
218. Robertson, J.F.R., et al., Fulvestrant versus anastrozole for the treatment of advanced breast
carcinoma in postmenopausal women: a prospective combined analysis of two multicenter trials.
Cancer, 2003. 98(2): p. 229-38.
219. Howell, A., et al., Comparison of fulvestrant versus tamoxifen for the treatment of advanced
breast cancer in postmenopausal women previously untreated with endocrine therapy: a
multinational, double-blind, randomized trial. Journal of Clinical Oncology, 2004. 22(9): p. 1605-13.
220. Arpino, G., et al., Idoxifene versus tamoxifen: a randomized comparison in postmenopausal
patients with metastatic breast cancer. Annals of Oncology, 2003. 14(2): p. 233-41.
221. Jones, D., D. Ghersi, and N. Wilcken, Addition of drug/s to a chemotherapy regimen for
metastatic breast cancer. Cochrane Database of Systematic Reviews, 2006. 3.
222. Gennari, A., et al., Lack of benefit of maintenance paclitaxel in first-line chemotherapy in
metastatic breast cancer. Journal of Clinical Oncology, 2006. 24(24): p. 3912-8.
223. Langley, R.E., et al., Phase III trial of epirubicin plus paclitaxel compared with epirubicin plus
cyclophosphamide as first-line chemotherapy for metastatic breast cancer: United Kingdom
National Cancer Research Institute trial AB01. Journal of Clinical Oncology, 2005. 23(33): p. 8322-
30.
224. Bria, E., et al., Taxanes with anthracyclines as first-line chemotherapy for metastatic breast
carcinoma. Cancer, 2005. 103(4): p. 672-9.
225. Lyman, G.H., et al., A Southwest Oncology Group Randomized Phase II Study of doxorubicin
and paclitaxel as frontline chemotherapy for women with metastatic breast cancer. Breast Cancer
Research & Treatment, 2004. 85(2): p. 143-50.
226. Chan, S., et al., Phase III trial of liposomal doxorubicin and cyclophosphamide compared with
epirubicin and cyclophosphamide as first-line therapy for metastatic breast cancer. Annals of
Oncology, 2004. 15(10): p. 1527-34.
227. Bottomley, A., et al., Randomized, controlled trial investigating short-term health-related
quality of life with doxorubicin and paclitaxel versus doxorubicin and cyclophosphamide as firstline
chemotherapy in patients with metastatic breast cancer: European Organization for Research
and Treatment of Cancer Breast Cancer Group, Investigational Drug Branch for Breast Cancer
and the New Drug Development Group Study. Journal of Clinical Oncology, 2004. 22(13): p.
2576-86.
228. Bonneterre, J., et al., Phase II multicentre randomised study of docetaxel plus epirubicin vs 5fluorouracil
plus epirubicin and cyclophosphamide in metastatic breast cancer. British Journal of
Cancer, 2004. 91(8): p. 1466-71.

KCE reports 63 Breast Cancer 47
229. Biganzoli, L., et al., Doxorubicin-paclitaxel: a safe regimen in terms of cardiac toxicity in
metastatic breast carcinoma patients. Results from a European Organization for Research and
Treatment of Cancer multicenter trial. Cancer, 2003. 97(1): p. 40-5.
230. Robert, N., et al., Randomized phase III study of trastuzumab, paclitaxel, and carboplatin
compared with trastuzumab and paclitaxel in women with HER-2-overexpressing metastatic breast
cancer. Journal of Clinical Oncology, 2006. 24(18): p. 2786-92.
231. Lord, S., et al., Antitumour antibiotic containing regimens for metastatic breast cancer.
Cochrane Database Syst Rev, 2004(4): p. CD003367.
232. Vredenburgh, J.J., et al., A randomized phase III comparative trial of immediate consolidation
with high-dose chemotherapy and autologous peripheral blood progenitor cell support compared
to observation with delayed consolidation in women with metastatic breast cancer and only bone
metastases following intensive induction chemotherapy.[see comment]. Bone Marrow
Transplantation, 2006. 37(11): p. 1009-15.
233. Kroger, N., et al., Randomized trial of single compared with tandem high-dose chemotherapy
followed by autologous stem-cell transplantation in patients with chemotherapy-sensitive
metastatic breast cancer. Journal of Clinical Oncology, 2006. 24(24): p. 3919-26.
234. Zielinski, C., et al., Gemcitabine, epirubicin, and paclitaxel versus fluorouracil, epirubicin, and
cyclophosphamide as first-line chemotherapy in metastatic breast cancer: a Central European
Cooperative Oncology Group International, multicenter, prospective, randomized phase III trial.
Journal of Clinical Oncology, 2005. 23(7): p. 1401-8.
235. Miller, K.D., et al., Randomized phase III trial of capecitabine compared with bevacizumab
plus capecitabine in patients with previously treated metastatic breast cancer. Journal of Clinical
Oncology, 2005. 23(4): p. 792-9.
236. Levy, C. and P. Fumoleau, Gemcitabine plus docetaxel: a new treatment option for
anthracycline pretreated metastatic breast cancer patients? Cancer Treatment Reviews, 2005.
31(4).
237. Sparano, J.A., et al., Randomized phase III trial of marimastat versus placebo in patients with
metastatic breast cancer who have responding or stable disease after first-line chemotherapy:
Eastern Cooperative Oncology Group trial E2196.[erratum appears in J Clin Oncol. 2005 Jan
1;23(1):248]. Journal of Clinical Oncology, 2004. 22(23): p. 4683-90.
238. Keller, A.M., et al., Randomized phase III trial of pegylated liposomal doxorubicin versus
vinorelbine or mitomycin C plus vinblastine in women with taxane-refractory advanced breast
cancer.[see comment]. Journal of Clinical Oncology, 2004. 22(19): p. 3893-901.
239. Ejlertsen, B., et al., Phase III study of intravenous vinorelbine in combination with epirubicin
versus epirubicin alone in patients with advanced breast cancer: a Scandinavian Breast Group Trial
(SBG9403). Journal of Clinical Oncology, 2004. 22(12): p. 2313-20.
240. Boogerd, W., et al., The relevance of intraventricular chemotherapy for leptomeningeal
metastasis in breast cancer: a randomised study. European Journal of Cancer, 2004. 40(18): p.
2726-33.
241. Verma, S. and A.L. Ilersich, Population-based pharmacoeconomic model for adopting
capecitabine/docetaxel combination treatment for anthracycline-pretreated metastatic breast
cancer. Oncologist, 2003. 8(3): p. 232-40.
242. Parnes, H.L., et al., Phase III study of cyclophosphamide, doxorubicin, and fluorouracil (CAF)
plus leucovorin versus CAF for metastatic breast cancer: Cancer and Leukemia Group B 9140.
Journal of Clinical Oncology, 2003. 21(9): p. 1819-24.
243. Nooij, M.A., et al., Continuing chemotherapy or not after the induction treatment in
advanced breast cancer patients. clinical outcomes and oncologists' preferences. European Journal
of Cancer, 2003. 39(5): p. 614-21.
244. Elomaa, I., H. Joensuu, and C. Blomqvist, Vinorelbine, methotrexate and fluorouracil (VMF) as
first-line therapy in metastatic breast cancer: a randomized phase II trial.[see comment]. Annals of
Oncology, 2003. 14(5): p. 699-703.

48 Breast Cancer KCE reports 63
245. Cresta, S., et al., A randomized phase II study of combination, alternating and sequential
regimens of doxorubicin and docetaxel as first-line chemotherapy for women with metastatic
breast cancer. Annals of Oncology, 2004. 15(3): p. 433-9.
246. Conte, P.F., et al., Concomitant versus sequential administration of epirubicin and paclitaxel
as first-line therapy in metastatic breast carcinoma: results for the Gruppo Oncologico Nord
Ovest randomized trial. Cancer, 2004. 101(4): p. 704-12.
247. Baldini, E., et al., Multicenter randomized phase III trial of epirubicin plus paclitaxel vs
epirubicin followed by paclitaxel in metastatic breast cancer patients: focus on cardiac safety.
British Journal of Cancer, 2004. 91(1): p. 45-9.
248. Alba, E., et al., Multicenter randomized trial comparing sequential with concomitant
administration of doxorubicin and docetaxel as first-line treatment of metastatic breast cancer: a
Spanish Breast Cancer Research Group (GEICAM-9903) phase III study. Journal of Clinical
Oncology, 2004. 22(13): p. 2587-93.
249. Paridaens, R., et al., A randomized phase II study of alternating and sequential regimens of
docetaxel and doxorubicin as first-line chemotherapy for metastatic breast cancer. Annals of
Oncology, 2003. 14(3): p. 433-40.
250. Wardley, A., et al., Zoledronic acid significantly improves pain scores and quality of life in
breast cancer patients with bone metastases: a randomised, crossover study of community vs
hospital bisphosphonate administration. British Journal of Cancer, 2005. 92(10): p. 1869-76.
251. Diel, I.J., et al., Improved quality of life after long-term treatment with the bisphosphonate
ibandronate in patients with metastatic bone disease due to breast cancer. European Journal of
Cancer, 2004. 40(11): p. 1704-12.
252. Tripathy, D., et al., Oral ibandronate for the treatment of metastatic bone disease in breast
cancer: efficacy and safety results from a randomized, double-blind, placebo-controlled trial.[see
comment]. Annals of Oncology, 2004. 15(5): p. 743-50.
253. Hartsell, W.F., et al., Randomized trial of short- versus long-course radiotherapy for
palliation of painful bone metastases. Journal of the National Cancer Institute, 2005. 97(11): p.
798-804.
254. Rauschecker, H., et al., Systemic therapy for treating locoregional recurrence in women with
breast cancer. Cochrane Database Syst Rev, 2001(4): p. CD002195.
255. Powles, T., et al., Reduction in bone relapse and improved survival with oral clodronate for
adjuvant treatment of operable breast cancer [ISRCTN83688026]. Breast Cancer Res, 2006. 8(2):
p. R13.
256. Fuleihan Gel, H., et al., Pamidronate in the prevention of chemotherapy-induced bone loss in
premenopausal women with breast cancer: a randomized controlled trial. J Clin Endocrinol Metab,
2005. 90(6): p. 3209-14.
257. Ahmed, R.L., et al., Randomized controlled trial of weight training and lymphedema in breast
cancer survivors. Journal of Clinical Oncology, 2006. 24(18): p. 2765-72.
258. Wilburn, O., P. Wilburn, and S.G. Rockson, A pilot, prospective evaluation of a novel
alternative for maintenance therapy of breast cancer-associated lymphedema [ISRCTN76522412].
BMC Cancer, 2006. 6(84).
259. Didem, K., et al., The comparison of two different physiotherapy methods in treatment of
lymphedema after breast surgery. Breast Cancer Research & Treatment, 2005. 93(1): p. 49-54.
260. Demark-Wahnefried, W., et al., Lifestyle intervention development study to improve physical
function in older adults with cancer: outcomes from Project LEAD. Journal of Clinical Oncology,
2006. 24(21): p. 3465-73.
261. Kim, C.-J., et al., Cardiopulmonary responses and adherence to exercise in women newly
diagnosed with breast cancer undergoing adjuvant therapy. Cancer Nursing, 2006. 29(2): p. 156-
65.
262. Ohira, T., et al., Effects of weight training on quality of life in recent breast cancer survivors:
the Weight Training for Breast Cancer Survivors (WTBS) study. Cancer, 2006. 106(9): p. 2076-83.

KCE reports 63 Breast Cancer 49
263. Pinto, B.M., et al., Home-based physical activity intervention for breast cancer patients.
Journal of Clinical Oncology, 2005. 23(15): p. 3577-87.
264. Rojas, M.P., et al., Follow-up strategies for women treated for early breast cancer. Cochrane
Database Syst Rev, 2005(1): p. CD001768.
265. Grunfeld, E., et al., Randomized trial of long-term follow-up for early-stage breast cancer: a
comparison of family physician versus specialist care.[see comment]. Journal of Clinical Oncology,
2006. 24(6): p. 848-55.
266. Kokko, R., M. Hakama, and K. Holli, Follow-up cost of breast cancer patients with localized
disease after primary treatment: a randomized trial. Breast Cancer Research & Treatment, 2005.
93(3): p. 255-60.
267. de Bock, G.H., et al., Effectiveness of routine visits and routine tests in detecting isolated
locoregional recurrences after treatment for early-stage invasive breast cancer: a meta-analysis and
systematic review. Journal of Clinical Oncology, 2004. 22(19): p. 4010-8.
268. Koinberg, I.L., et al., Nurse-led follow-up on demand or by a physician after breast cancer
surgery: a randomised study. European Journal of Oncology Nursing, 2004. 8(2): p. 109-17;
discussion 118-20.
269. Collins, R.F., H.L. Bekker, and D.J. Dodwell, Follow-up care of patients treated for breast
cancer: a structured review. Cancer Treatment Reviews, 2004. 30(1): p. 19-35.

50 Breast Cancer KCE reports 63
6 APPENDICES
APPENDIX 1
GRADE SYSTEM
Grade of Recommendation/ Benefit vs. Risk and Burdens Methodological Quality of
Implications
Description
Supporting Evidence
1A/ Strong recommendation, high Benefits clearly outweigh risk and RCTs without important limitations or Strong recommendation, can apply to
quality evidence
burdens, or vice versa
overwhelming evidence from observational most patients in most circumstances
studies
without reservation
1B/ Strong recommendation, moderate Benefits clearly outweigh risk and RCTs with important limitations
Strong recommendation, can apply to
quality evidence
burdens, or vice versa
(inconsistent results, methodological flaws, most patients in most circumstances
indirect, or imprecise) or exceptionally
strong evidence from observational studies
without reservation
1C/ Strong recommendation, low Benefits clearly outweigh risk and Observational studies or case series Strong recommendation, but may change
quality evidence
burdens, or vice versa
when higher quality evidence becomes
available
2A/ Weak recommendation, high Benefits closely balanced with risks and RCTs without important limitations or Weak recommendation, best action may
quality evidence
burden
overwhelming evidence from observational differ depending on circumstances or
studies
patients’ or societal values
2B/ Weak recommendation, moderate Benefits closely balanced with risks and RCTs with important limitations
Weak recommendation, best action may
quality evidence
burden
(inconsistent results, methodological flaws, differ depending on circumstances or
indirect, or imprecise) or exceptionally
strong evidence from observational studies
patients’ or societal values
2C/ Weak recommendation, low quality Benefits closely balanced with risks and Observational studies or case series Very weak recommendation, other
evidence
burden
alternatives may be equally reasonable

KCE reports 63 Breast Cancer 51
APPENDIX 2
IDENTIFIED GUIDELINES AND THEIR QUALITY APPRAISAL
Source Title Standardised Score #
I II III IV V VI
Final Appraisal
Cancer Care Ontario
[137]
Adjuvant Taxane therapy for women with early-stage, invasive breast
cancer
100% 25% 95% 75% 11% 100% Recommended with modifications
SIGN [27] Management of breast cancer in women 67% 50% 90% 83% 67% 50% Recommended with modifications
NICE [11] The classification and care of women at risk of familial breast cancer in
primary, secondary and tertiary care
89% 75% 86% 100% 100% 0% Recommended
ASCO [49] American Society of Clinical Oncology Guideline Recommendations
for Sentinel Lymph Node Biopsy in Early-Stage Breast Cancer
89% 58% 86% 92% 22% 100% Recommended with modifications
Cancer Care Ontario The role of Aromatase Inhibitors in adjuvant therapy for
[96]
postmenopausal women with hormone receptor-positive breast
cancer
67% 33% 86% 75% 0% 100% Recommended with modifications
Cancer Care Ontario
[138]
Capecitabine in stage IV breast cancer
89% 50% 86% 67% 0% 100% Recommended with modifications
Cancer Care Ontario
[139]
Epirubicin, as a single agent or in combination, for metastatic breast
cancer
100% 50% 86% 67% 0% 100% Recommended with modifications
Cancer Care Ontario
[140]
The role of Taxanes in neoadjuvant chemotherapy for women with
non-metastatic breast cancer
89% 25% 86% 67% 11% 100% Recommended with modifications
Cancer Care Ontario
[141]
The role of the Taxanes in the management of metastatic breast
cancer
89% 50% 86% 75% 11% 100% Recommended with modifications
Cancer Care Ontario
[73]
Surgical management of early-stage invasive breast cancer
100% 67% 86% 75% 33% 50% Recommended with modifications
FNCLCC [52] Utilisation de la tomographie par émission de positons au [18F]-FDG
en cancérologie
67% 25% 81% 83% 0% 50% Recommended with modifications
German Cancer Society
[26]
Interdisciplinary S3 guidelines for the diagnosis and treatment of
breast cancer in women
78% 50% 81% 75% 67% 100% Recommended with modifications
Cancer Care Ontario
[104]
The role of Aromatase Inhibitors in the treatment of postmenopausal
women with metastatic breast cancer
89% 50% 81% 67% 11% 100% Recommended with modifications
Cancer Care Ontario
[68]
Management of ductal carcinoma in situ of the breast
89% 50% 81% 75% 0% 50% Recommended with modifications
National Breast Cancer
Centre [28]
Clinical practice guidelines for the management and support of
younger women with breast cancer
78% 83% 76% 92% 33% 0% Recommended with modifications
CBO [38] Behandeling van het mammacarcinoom 89% 75% 76% 75% 33% 33% Recommended with modifications
Cancer Care Ontario Adjuvant systemic therapy for node-negative breast cancer 100% 58% 76% 58% 0% 50% Recommended with modifications

52 Breast Cancer KCE reports 63
Source Title Standardised Score #
I II III IV V VI
Final Appraisal
[81]
Cancer Care Ontario
[111]
Use of Bisphosphonates in women with breast cancer
78% 50% 76% 67% 0% 100% Recommended with modifications
USPSTF [12] Genetic risk assessment and BRCA mutation testing for breast and
ovarian cancer susceptibility: recommendation statement
78% 17% 71% 92% 22% 100% Recommended with modifications
FNCLCC [67] Standards, Options et Recommandations 2004 pour la prise en charge
des carcinomes canalaires in situ du sein
67% 42% 71% 83% 0% 100% Recommended with modifications
Truong et al. [142] Clinical practice guidelines for the care and treatment of breast
cancer: 16. Locoregional post-mastectomy radiotherapy
78% 58% 67% 92% 11% 50% Recommended with modifications
NCCN [143] Breast cancer 44% 58% 62% 83% 0% 50% Not recommended
ASCO [144] American Society of Clinical Oncology 2003 update on the role of
bisphosphonates and bone health issues in women with breast cancer
78% 58% 52% 100% 44% 50% Not recommended
Shenkier et al. [145] Clinical practice guidelines for the care and treatment of breast
cancer: 15. Treatment for women with stage III or locally advanced
breast cancer
56% 58% 52% 92% 11% 50% Not recommended
Whelan et al. [146] Clinical practice guidelines for the care and treatment of breast
cancer: 6. Breast radiotherapy after breast-conserving surgery (2003
update)
89% 17% 52% 83% 11% 50% Not recommended
RCOG [136] Pregnancy and breast cancer 67% 17% 52% 75% 0% 0% Not recommended
ACS [147] American Cancer Society guidelines for the early detection of cancer,
2006
67% 25% 52% 67% 0% 50% Not recommended
SOGC [148] Use of hormonal replacement therapy after treatment of breast
cancer
78% 0% 52% 50% 0% 0% Not recommended
ICSI [149] Breast cancer treatment 78% 50% 43% 100% 67% 83% Not recommended
ICSI [150] Diagnosis of breast disease 78% 50% 43% 100% 56% 83% Not recommended
Breast Health Global
Initiative [151]
Breast cancer in limited-resource countries: an overview of the breast
health global initiative 2005 guidelines
78% 42% 43% 42% 33% 0% Not recommended
Association of Breast
Surgery [152]
Guidelines for the management of women at increased familial risk of
breast cancer
67% 25% 38% 75% 22% 0% Not recommended
Alberta Medical
Association [153]
The early detection of breast cancer
89% 75% 33% 100% 0% 0% Not recommended
Loibl et al. [154] Breast carcinoma during pregnancy 67% 33% 33% 58% 11% 0% Not recommended
ESMO [155] ESMO Minimum Clinical Recommendations for diagnosis, adjuvant
treatment and follow-up of primary breast cancer
22% 0% 24% 58% 11% 0% Not recommended
Kaufmann et al. [156] Recommendations from an international expert panel on
the use of neoadjuvant (primary) systemic treatment of operable
breast cancer: an update
67% 25% 24% 17% 11% 50% Not recommended
Association of Breast
Surgery [157]
Guidelines for the management of symptomatic breast disease
22% 0% 19% 67% 33% 0% Not recommended
American College of Appropriate imaging work-up of palpable breast masses 67% 33% 14% 83% 22% 0% Not recommended

KCE reports 63 Breast Cancer 53
Source Title Standardised Score #
I II III IV V VI
Final Appraisal
Radiology [158]
Ellis et al. [159] Best Practice No 176: Updated recommendations for HER2 testing in
the UK
56% 17% 10% 17% 22% 0% Not recommended
Ellis et al. [160] Best Practice No 179: Guidelines for breast needle core biopsy
handling and reporting in breast screening assessment
56% 8% 10% 17% 22% 0% Not recommended
# These scores represent the standardised scores of the two appraisers (JV, JG). Domain I = Scope and purpose; domain II = Stakeholder involvement; domain III = Rigour
of development; domain IV = Clarity and presentation; domain V = Applicability; domain VI = Editorial indepence.

54 Breast Cancer KCE reports 63
APPENDIX 3
EVIDENCE TABLES BY CLINICAL QUESTION
Study ID Ref Search
date
Population screening for breast cancer.
Population Intervention Outcomes Results Comments Study type Level of
evidence
Kosters JP [6] 2002 Screening for breast
cancer by regular self-
Irwig L 2004 [5] 2002 Asymptomatic
women
examination
New technologies for
breast cancer screening
Mortality
Morbidity
Breast cancer mortality: RR 1.05 (95% CI 0.90-
1.24)
Accuracy of tests US as an adjunct to mammography in women
with radiologically dense breasts, detects
additional cancers and causes additional false
positives.
MRI: better sensitivity (but lower specificity)
than mammography in selected high-risk
women, but studies of this technology included
small number of cancers. Computer-aided
detection may enhance the sensitivity of
mammography and warrants further evaluation
in large prospective trials. One study of FFDM
suggests that it may identify some cancers not
identified on conventional mammography and
may result in a lower recall rate.
No beneficial effect SR High
Medline search
No RCTs
SR Low

KCE reports 63 Breast Cancer 55
Study ID Ref Search
date
Shen Y 2005 [7] NA General population
(40-64 years)
Gotzsche PC
2006
[4] 2005 Women without
previously diagnosed
breast cancer
Population Intervention Outcomes Results Comments Study type Level of
evidence
Mammographic
screening
Screening with
mammography
Mortality from
breast cancer
Mortality from any
cancer
All-cause mortality
Use of surgical
interventions
Use of adjuvant
therapy
Harms of
mammography
Breast cancers detected by screening
mammography had a shift in stage distribution
to earlier stages (for HIP, P

56 Breast Cancer KCE reports 63
Breast cancer susceptibility gene testing.
No additional SR or RCTs were found (MeSH term(s) used: Breast Neoplasms/Genetics, BRCA1 Protein, BRCA2 Protein).

KCE reports 63 Breast Cancer 57
Study ID Ref Search
date
Treatment of patients with a high risk (familial or genetic) of developing breast cancer.
Prophylactic mastectomy
Lostumbo L et al [17] 2002 Women at risk from breast cancer:
positive family history of breast
cancer, previous cancer in one breast,
previous multiple breast biopsies, and
previous diagnosis of lobular
carcinoma in situ, atypical hyperplasia,
Calderon-Margalit R
et al
Prophylactic oophorectomy
Calderon-Margalit R
et al
Population Intervention Outcomes Results Comments Study
type
or proliferative breast disease.
Prophylactic mastectomy Overall mortality
BC mortality
BC incidence
Morbidity
Quality of life
Reduced BC mortality and incidence.
Unanticipated re-operations form 30-
49%.
No RCTs!
22 observational
studies
[14] 2004 High-risk women Prophylactic mastectomy Reduced BC incidence by 89.5-100%. No RCTs!
Medline only
English only
Lower quality
[14] 2004 High-risk women Prophylactic salpingooophorectomy
Tamoxifen
Fisher B 2005 [19] NA Women aged ≥60 years, or aged 35-
59 years and a 5-year breast cancer
risk of 1.66%, or a history of LCIS or
atypical hyperplasia
Tamoxifen 20 mg/d (n =
6681) vs. placebo (n =
6707) for 5 years
Invasive breast cancer
incidence
HR for breast cancer of 0.32 – 0.47. No RCTs!
Medline only
English only
Lower quality
RR invasive breast cancer:
0.57 (95%CI 0.46-0.70) in favour of
TAM
RR non-invasive breast cancer:
0.68 (95%CI 0.51-0.92)
SR Low
SR Low
SR Low
Level of
evidence
Unblinded RCT Moderate

58 Breast Cancer KCE reports 63
Study ID Ref Search
date
Population Intervention Outcomes Results Comments Study
type
Cuzick J 2003 [20] NA Chemoprevention with
tamoxifen or raloxifene
Vogel VG 2006 [21] NA Postmenopauzal women with a 5-year
breast cancer risk of 1.66% based on
the Gail model
Guerrieri-Gonzaga
A 2006
[22] NA Premenopauzal women (n = 235)
with either an in situ cancer or a
small invasive cancer of favorable
prognosis in the previous 3 years, or
a Gail 5-year risk for breast cancer of
1.3% (n = 54)
Tamoxifen (n = 9872) vs.
Raloxifene (n = 9875)
Tamoxifen vs. Fenretinide
in 2X2 factorial design
MeSH term(s) used: Breast Neoplasms/Prevention & Control.
Breast cancer incidence
Vascular events
Mortality
Invasive breast cancer
incidence
38% (95%CI 28–46; p

KCE reports 63 Breast Cancer 59
Diagnosis of breast cancer with triple test approach.
Study ID Ref Search
date
Park JM 2003 [25] NA 19 patients with breast
carcinoma and another
nodule of 1 cm or less
Population Intervention Outcomes Results Comments Study type Level of
evidence
(30 nodules)
Pinero A 2003 [161] NA 43 patients with 45
palpable breast lesions
Shoma A 2006 [24] NA 124 consecutive
patients with palpable
breast cancer
MeSH term(s) used: Breast Neoplasms/Diagnosis.
Sonography
Gold standard:
histopathology
Ultrasonography
Gold standard:
histopathology
Clinical evaluation vs.
mammography vs.
sonography
Gold standard:
histopathology
Tumour size
measurement
Sensitivity 100%
Specificity 67%
PPV 75%
NPV 100%
No information on
diagnostic features
US significantly more
accurate
Prospective
cohort study
Prospective
cohort study
Prospective
cohort study
Low
Low
Low

60 Breast Cancer KCE reports 63
Diagnosis of breast cancer with MRI.
Study ID Ref Search
date
Bagni B 2003 [29] NA 45 patients with suspicious
breast mass
Van Goethem M
2004
Population Intervention Outcomes Results Comments Study type Level of
evidence
[31] NA 67 patients with dense
breast tissue and a
malignant breast tumour
detected on clinical
examination,
mammography, and/or US
Howarth D 2005 [30] NA 72 patients with suspicious
breast mass
Schelfout K 2004 [162] NA 204 women with suspect
breast lesion with triple
assessment (332 lesions)
99m Tc-MIBI scintimammography
(SMM) and contrast-enhanced
magnetic resonance imaging
(MRI); histological findings as the
gold standard
Sensitivity 92%
Specificity 43%
PPV 90%
NPV 50%
Preoperative MR mammography Sensitivity 98%
Specificity 0%
PPV 97%
NPV 0%
99m Tc-MIBI scintimammography
(SMM) and contrast-enhanced
magnetic resonance imaging
(MRI); histological findings as the
gold standard
MeSH term(s) used: Breast Neoplasms, Magnetic Resonance Imaging.
Sensitivity 86%
Specificity 100%
MRI Sensitivity 96% Not enough
information to
calculate specificity
Prospective
cohort study
Prospective
cohort study
Prospective
cohort study
Prospective
cohort study
Low
Low
Low
Very low

KCE reports 63 Breast Cancer 61
Diagnosis of breast cancer with scintigraphy.
Study ID Ref Search
date
Bagni B 2003 [29] NA 45 patients with
suspicious breast
mass
Sampalis FS 2003 [36] NA 1734 women with
suspected breast
cancer; diagnostic
features based on
Population Intervention Outcomes Results Comments Study type Level of
evidence
1243 patients
Bekis R 2004 [32] NA 35 women with
suspicious nonpalpable
breast
lesions detected by
screening
mammography
Fondrinier E 2004 [34] NA 41 women with 45
clusters of
microcalcifications
Krishnaiah G
2003
[35] NA 95 women with
palpable breast
lesions and/or
abnormal
mammography (104
lesions)
Tiling R 2005 [37] NA 462 women with
suspicious lesion
Howarth D 2005 [30] NA 72 patients with
suspicious breast
mass
Chen J 2003 [33] NA 60 women with
unilateral palpable
breast mass
99m Tc-MIBI scintimammography (SMM) and
contrast-enhanced magnetic resonance imaging
(MRI); histological findings as the gold standard
(FNAB and surgery if positive)
99m Tc-MIBI scintimammography (SMM);
histological findings as the gold standard
99m Tc-MIBI scintimammography (SMM);
histological findings as the gold standard
99m Tc-MIBI scintimammography (SMM);
histological findings as the gold standard
99m Tc-MIBI scintimammography (SMM);
histological findings as the gold standard
99m Tc-MIBI scintimammography (SMM);
histological findings as the gold standard in 252
patients
99m Tc-MIBI scintimammography (SMM) and
contrast-enhanced magnetic resonance imaging
(MRI); histological findings as the gold standard
99m Tc-MIBI scintimammography (SMM);
histological findings as the gold standard
MeSH term(s) used: Breast Neoplasms/Diagnosis, Breast Neoplasms/Radionuclide Imaging.
Sensitivity 84%
Specificity 71%
Accuracy 82%
PPV 94%
NPV 45%
Sensitivity 93%
Specificity 87%
PPV 58%
NPV 98%
Sensitivity 85%
Specificity 82%
PPV 73%
NPV 90%
Sensitivity 58%
Specificity 81%
PPV 78%
NPV 63%
Sensitivity 83%
Specificity 83%
PPV 59%
NPV 94%
Sensitivity 84%
Specificity 85%
PPV 88%
NPV 80%
Sensitivity 85%
Specificity 89%
Sensitivity 93%
Specificity 91%
PPV 90%
NPV 94%
Gold standard not
applied to all patients
(selection bias)
Not clear if prospective
Prospective
cohort study
Prospective
cohort study
Prospective
cohort study
Prospective
cohort study
Prospective
cohort study
Prospective (?)
cohort study
Prospective
cohort study
Prospective
cohort study
Low
Low
Low
Low
Low
Very low
Low
Low

62 Breast Cancer KCE reports 63
Staging of breast cancer with imaging procedures (lung X-ray, US liver, bone scintigraphy, CAT thorax, …).
Study ID Ref Search Population Intervention Outcome
date
s
Ultrasonography for lymph node metastases
Altinyollar H
2005
Podkrajsek M
2005
[47] NA 100 women with locally
advanced breast cancer
[48] NA 165 patients with
cytologically or
histologically proven
breast cancer and clinically
non-palpable axillary LNs
Liver ultrasonography
Puglisi F 2005 [42] NA 516 patients with newly
diagnosed invasive breast
cancer
Thorax X-ray
Puglisi F 2005 [42] NA 516 patients with newly
diagnosed invasive breast
cancer
Bone scintigraphy
Nakai T 2005 [61] NA 89 breast cancer patients
evaluated for bone
metastases
Ultrasonography of axillary and
infraclavicular region
Gold standard: histology
Ultrasonography of axillary region (n
= 165) and US-FNAB if suspicious
ALND if cytologically proven
malignant cells (n = 33); SLNB
otherwise (n = 132)
Bone scintigraphy (n = 412) (gold
standard: X-ray and/or CT scan
and/or MRI), liver US (n = 412) (gold
standard: CT scan and/or MRI),
thorax X-ray (n = 428) (gold
standard: CT scan)
Bone scintigraphy (n = 412) (gold
standard: X-ray and/or CT scan
and/or MRI), liver US (n = 412) (gold
standard: CT scan and/or MRI),
thorax X-ray (n = 428) (gold
standard: CT scan)
18-FDG-PET vs. bone scintigraphy
Bone metastases confirmed by biopsy
and MRI (n = 55)
Results Comments Study type Level of
evidence
Sensitivity 48%
Specificity 98%
PPV 95%
NPV 74%
US:
Sensitivity 58%
Specificity 89%
PPV 78%
NPV 77%
US + US-FNAB:
Sensitivity 52%
Specificity 96%
PPV 89%
NPV 76%
Sensitivity 100%
Specificity 94%
PPV 10%
NPV 100%
Sensitivity 100%
Specificity 97%
PPV 24%
NPV 100%
18-FDG-PET:
Sensitivity 80%
Specificity 88%
Accuracy 83%
Bone scintigraphy:
Sensitivity 78%
Specificity 82%
Accuracy 80%
Correct reference
standard?
Correct reference
standard?
Reference standard
not applied to all 89
patients
Prospective
cohort study
Prospective
cohort study
Retrospective
study
Retrospective
study
Retrospective
cohort study
Low
Low
Very low
Very low
Very low

KCE reports 63 Breast Cancer 63
Study ID Ref Search
date
Puglisi F 2005 [42] NA 516 patients with newly
diagnosed invasive breast
cancer
Population Intervention Outcome
s
MeSH term(s) used: Breast Neoplasms, Neoplasm Staging.
Bone scintigraphy (n = 412) (gold
standard: X-ray and/or CT scan
and/or MRI), liver US (n = 412) (gold
standard: CT scan and/or MRI),
thorax X-ray (n = 428) (gold
standard: CT scan)
Results Comments Study type Level of
evidence
Sensitivity 100%
Specificity 94%
PPV 51%
NPV 100%
Correct reference
standard?
Retrospective
study
Very low

64 Breast Cancer KCE reports 63
Study ID Ref Search
date
Sliwowska I
2006
Staging of breast cancer with biochemical tests (including tumour markers).
Population Intervention Outcomes Results Comments Study type Level of
evidence
[43] NA 90 women with a
diagnosis of breast
cancer, 30 women with
benign breast disease
Seth LRK 2003 [44] NA 25 patients with breast
cancer and 25 controls
Kopczynski Z
1998
Frenette PS
1994
[45] NA 139 women with
diagnosis of breast
cancer
[46] NA 213 patients with
breast cancer or
gastrointestinal cancer
Measurement of CA 15-3
(cut-off 28 U/ml), TPA (75
U/l) and TPS (80 U/l)
Serum gamma glutamyl
transpeptidase (GGTP),
lactate dehydrogenase
(LDH) and superoxide
dismutase (SOD)
Measurement of TPS, MCA
and CA 15-3
CA 27-29, CA 15-3, MCA,
and CEA
CA 15-3: sensitivity 44%, specificity 90%,
PPV 93%, NPV 35%
TPA: sensitivity 82%, specificity 83%, PPV
94%, NPV 61%
TPS: sensitivity 69%, specificity 73%, PPV
89%, NPV 44%
Mean serum GGTP, LDH and SOD
activities in patients with carcinoma
breast were observed to be
tremendously increased as compared to
controls; however no data to calculate
sensitivity, specificity, PPV and NPV
Higher levels of TPS, CA 15-3 and MCA
in women with cancer, compared with
values in healthy women and women
with mastopathy
MeSH term(s) used: Breast Neoplasms; Tumor Markers, Biological; Immunoenzyme Techniques.
Receiver operating curves (ROC)
revealed a sensitivity for the 90%
specificity cutoff for breast cancers
compared to breast benign diseases of
70% for CA 27-29, 67.5% for CA 15-3,
52.5% for MCA and 40% for CEA.
Case-control
study
Case-control
study
Case-control
study
Cross-sectional
study
Very low
Very low
Very low
Very low

KCE reports 63 Breast Cancer 65
Study ID Ref Search
date
Staging of breast cancer with sentinel biopsy.
Xing Y et al [50] 2004 Women with
operable breast
cancer, having
undergone
preoperative
Population Intervention Outcomes Results Comments Study
type
chemotherapy
Mansel R 2006 [51] NA Women with
early-stage
clinically nodenegative
breast
cancer
SLNB
Standard: axillary node
dissection
SLNB (n = 478) vs. standard
axillary treatment (n = 476)
If positive node on SLNB:
axillary lymph node dissection
or axillary RT
MeSH term(s) used: Breast Neoplasms, Sentinel Lymph Node Biopsy.
Arm morbidity
Quality of life
Sensitivity: 67 – 100% (pooled estimate
88%, 95%CI 85-90)
Lymphedema at 12 mo: RR 0.37 (95%CI
0.23-0.60) in favour of SLNB
Sensory loss at 12 mo: RR 0.37 (95%CI
0.27-0.50) in favour of SLNB
Quality of life: statistically significantly
better for SLNB group
21 cohort studies included
(total of 1273 patients)
Level of
evidence
SR Moderate
RCT High

66 Breast Cancer KCE reports 63
Staging of breast cancer with PET scan.
Study ID Ref Search
date
18 FDG PET for primary tumour staging
Kumar R 2005 [57] NA 54 women with 57
breast lesions
Landheer M 2005 [58] NA 42 women of which
17 were evaluated
shortly after surgery
Byrne A 2004 [59] Not
stated
Population Intervention Outcomes Results Comments Study type Level of
evidence
Women with breast
cancer
18 FDG PET for axillary staging
Chung A 2006 [55] NA 51 women with 54
invasive cancers
Gil-Rendo A 2006 [56] NA 275 women with
breast cancer
Byrne A 2004 [59] Not
stated
Women with breast
cancer
Lovrics P 2004 [60] NA 98 women with
stage I or II breast
cancer
18 FDG PET for metastatic disease
Dual-time-point imaging with
18-FDG-PET
Standard: surgical pathology
18-FDG-PET
If positive: confirmation by
pathological examination or
additional radiological
evaluation (MRI and/or CT)
% change in average SUV 3.75:
Sensitivity 82%
Specificity 83%
Sensitivity 100%
Specificity 75%
PPV 20%
NPV 100%
18-FDG-PET Sensitivity: 64 – 100%
Specificity: 33 – 100%
18-FDG-PET preoperatively SUV threshold of 2.3:
Sensitivity 60%
Specificity 100%
18-FDG-PET + ALND (n =
150)
18-FDG-PET + SLNB if PET
negative (n = 125)
PPV 100%
PET + ALND group:
Sensitivity 90%
Specificity 99%
PPV 98%
NPV 92%
18-FDG-PET Sensitivity: 20 – 100%
Specificity: 66 – 100%
18-FDG-PET + ALND Sensitivity 40%
Specificity 97%
PPV 75%
NPV 89%
Prospective
cohort study
Gold standard correct? Prospective
cohort study
Medline search only + crossreferencing
No quality appraisal
18 observational studies
included on diagnosis of
primary tumour
Retrospective analysis with
selection bias!
Medline search only + crossreferencing
No quality appraisal
24 observational studies
included on axillary staging
Low
SR Low
Retrospective
cohort study
Prospective
cohort study
Very low
Very low
Low
SR Low
Good quality study Prospective
cohort study
Low

KCE reports 63 Breast Cancer 67
Study ID Ref Search
date
Nakai T 2005 [61] NA 89 breast cancer
patients evaluated
for bone metastases
Uematsu T 2005 [63] NA 15 patients with
breast cancer
18 FDG PEM
Berg W 2006 [54] NA 77 patients with
biopsy-proven
breast cancer or
suspicious breast
Population Intervention Outcomes Results Comments Study type Level of
evidence
lesions
Tafra L 2005 [62] NA 44 women with
confirmed breast
cancer
18-FDG-PET vs. bone
scintigraphy
Bone metastases confirmed by
biopsy and MRI (n = 55)
18-FDG-PET vs. bone scanning
with SPECT
Standard: MDCT, MRI and
clinical course
18-FDG-PEM
Standard: pathologic
examination
18-FDG-PEM
Standard: pathologic
examination
MeSH term(s) used: Breast Neoplasms, Positron-Emission Tomography.
18-FDG-PET:
Sensitivity 80%
Specificity 88%
Accuracy 83%
Bone scintigraphy:
Sensitivity 78%
Specificity 82%
Accuracy 80%
18-FDG-PET:
Sensitivity 17%
Specificity 100%
SPECT:
Sensitivity 85%
Specificity 99%
Sensitivity 93%
Specificity 83%
PPV 87%
NPV 91%
Reference standard not
applied to all 89 patients
Retrospective (?)
cohort study
Prospective
cohort study
Prospective
cohort study
Sensitivity 89% Prospective
cohort study
Very low
Low
Low
Low

68 Breast Cancer KCE reports 63
Surgery for the treatment of ductal carcinoma in situ.
No additional RCTs or SR found (MeSH: Carcinoma, Intraductal, Noninfiltrating/su; free text word: breast$.ti,ab)

KCE reports 63 Breast Cancer 69
Radiotherapy for the treatment of ductal carcinoma in situ.
Study ID Ref Search
date
Bijker N 2006 [69] NA Women with clinically or
mammographically
detected DCIS measuring
≤ 5 cm
Population Intervention Outcomes Results Comments Study
type
Local excision: n = 503
Local excision + RT (50 Gy in 5
weeks): n = 507
MeSH: Carcinoma, Intraductal, Noninfiltrating/rt; free text word: breast$.ti,ab.
Local recurrence 4-year local relapse-free fraction: 84%
vs. 91% (log rank p = 0.005, HR 0.62)
Follow-up report of
Julien JP et al 2000
RCT High
Level of
evidence

70 Breast Cancer KCE reports 63
Hormonal therapy for the treatment of ductal carcinoma in situ.
No additional RCTs or SRs found (search terms: MeSH: Carcinoma, Intraductal, Noninfiltrating/dt, th; free text word: breast$.ti,ab)

KCE reports 63 Breast Cancer 71
Treatment of Paget’s disease.
Study ID Ref Search
date
Bijker N 2001 [70] NA Women with
histologically
proven Paget
disease of the
nipple
Population Intervention Ouctomes Results Comments Study type Level of
evidence
complete excision of the
nipple-areolar complex
including the underlying breast
tissue with tumor free margins,
followed by external irradiation
to the whole breast (50 gray in
25 fractions)
NB: no RCTs or SR found (MeSH: Paget’s Disease, Mammary/)
Local
recurrence
At a median follow-up of 6.4 years, 4 of
the 61 patients developed a recurrence in
the treated breast (1 patient with DCIS
and 3 patients with invasive disease). One
patient with an invasive local recurrence
died of disseminated breast carcinoma.
The 5-year local recurrence rate was 5.2%
(95% confidence interval, 1.8 –14.1%)
Prospective
cohort study
Very low

72 Breast Cancer KCE reports 63
Surgery for invasive breast cancer.
Study ID Ref Search
date
Hind D et al [163] 2003 Women aged 70
years or over with
early breast cancer
and who are fit for
surgery
Jatoi I 2005 [72] NA Women with
primary breast
cancer
Population Intervention Outcomes Results Comments Study
type
Primary endocrine
therapy (PET) vs. surgery
Mastectomy and axillary
dissection (MT) versus
breast-conserving
surgery, axillary
dissection, and breast
radiotherapy (BCT)
Poggi M 2003 [164] NA Stage I and II Mastectomy (MT) versus
breast conservation
therapy (BCT)
Fentiman I 2003 [165] NA Women aged 70
years or over with
operable breast
cancer (T1 T2 T3a,
N0 N1a N1b, M0)
Modified radical
mastectomy (MRM)
(n=120) or wide local
excision (WLE) and
tamoxifen (T) 20 mg daily
(n=116)
Overall survival
Progression-free
survival
Adverse events
Locoregional
recurrence
Mortality
Overall survival
Disease-free survival
Primary outcome:
survival
Overall survival:
surgery alone vs. PET: HR 0.98
(95% CI 0.74 – 1.30, p 0.9)
surgery + ET vs. PET: HR 0.86
(95% CI 0.73 – 1.00, p 0.06)
Progression-free survival:
surgery alone vs. PET: HR 0.55
(95% CI 0.39 – 0.77, p 0.0006)
surgery + ET vs. PET: HR 0.65
(95% CI 0.53 – 0.81, p 0.0001)
Four of the 6 trials show that MT
significantly reduces the risk of
locoregional recurrence when
compared with BCT, and the
pooled odds ratio also shows a
significant benefit for MT (OR 1.56;
95%CI 1.29-1.89; P < 0.001).
However, only 1 trial shows a
statistically significant benefit for
MT in reducing mortality, and the
pooled odds ratio shows no
significant difference between MT
and BCT (OR, 1.07; 95%CI, 0.94-
1.22; P = 0.33).
Overall survival: 58% for MT vs.
54% for BCT (p = 0.67)
Disease-free survival: 67% for MT
vs. 63% for BCT (p = 0.64)
No difference in progression-free
survival
Significantly more loco-regional
relapses in the WLE+T group
More distant metastases in the
MRM group, but with a similar
overall survival in both groups
7 RCTs SR High
Pooled analysis of 6 RCTs MA High
Mean follow-up of 18.4 years RCT High
RCT High
Level of
evidence

KCE reports 63 Breast Cancer 73
Study ID Ref Search
date
Arriagada R
2003
[166] NA Women with breast
cancer measuring

74 Breast Cancer KCE reports 63
Axillary treatment for invasive breast cancer.
Study ID Ref Search
date
Rudenstam C
2006
[167] NA Women > or =
60 years old
with clinically
node-negative
operable breast
cancer (stage
T1a, T1b, T2a,
T2b, T3, N0, or
M0)
Population Intervention Outcomes Results Comments Study
type
Primary surgery plus
axillary clearance (Sx +
Ax) followed by
tamoxifen (Tam)
(n=234) versus Sx
without Ax followed by
Tam for 5 consecutive
years (n=239)
Kodama H 2006 [168] NA T1-3 N0-1b M0 Level I (n = 256) vs.
level III (n = 258)
axillary dissection
Mansel R 2006 [51] NA Women with
clinically nodenegative
breast
cancer
Purushotham A
2005
[169] NA Women with
early breast
cancer (T ≤3
cm on US) and
cN0
SLNB (n = 478) vs.
standard axillary
treatment (n = 476)
If positive node on
SLNB: axillary lymph
node dissection or
axillary RT
ALND (n = 155) vs.
SLNB + ALND if SN+
(n = 143)
Quality of life
Disease-free survival
Overall survival
Post-surgical
complications
Arm morbidity
Quality of life
Physical morbidity
Psychological morbidity
In both the patients’ subjective
assessment of their QL and the
physicians’ perception of the patients’
QL, the largest adverse QL effects of Ax
were observed from baseline to the first
postoperative assessment, but the
differences tended to disappear in 6 to
12 months.
At a median follow-up of 6.6 years,
results for Sx + Ax and
Sx yielded similar DFS (6-year DFS, 67% v
66%; HR Sx + Ax/Sx, 1.06; 95%CI 0.79-
1.42; p=0.69) and OS (6-year OS, 75% v
73%; HR Sx + Ax/Sx, 1.05; 95%CI 0.76-
1.46; p=0.77).
No significant differences in the
frequencies of arm oedema and shoulder
disturbance.
No significant differences in the 10-year
overall and disease-free survival rates.
Significantly longer operation time (77.0
vs 60.5 min, P=0.0001) and significantly
larger blood loss (62.1 vs 48.1 ml,
P=0.0001) after level III dissection.
Lymphedema at 12 mo: RR 0.37 (95%CI
0.23-0.60) in favour of SLNB
Sensory loss at 12 mo: RR 0.37 (95%CI
0.27-0.50) in favour of SLNB
Quality of life: statistically significantly
better for SLNB group
Arm swelling at 12 mo:
OR 0.36 (95%CI 0.15-0.86, p=0.02) in
favour of SLNB
Psychological morbidity:
Significantly better in SLNB group
RCT High
RCT High
RCT High
RCT High
Level of
evidence

KCE reports 63 Breast Cancer 75
Study ID Ref Search
date
Martelli G 2005 [170] NA Women, 65 to
80 years of age,
with early
breast cancer
(T ≤2 cm) and
Population Intervention Outcomes Results Comments Study
type
cN0
Tominaga T 2004 [171] NA Stage II breast
cancer (T2 N0
or T2 N1a)
(n=1209)
Louis-Sylvestre C
2004
[78] NA Patients with a
breast
carcinoma less
than 3 cm in
diameter and
N0M0 (n=658)
Conservative breast
surgery with(n = 109)
or without axillary
dissection (n = 110)
Level II (n = 604) vs.
level III axillary node
dissection (n = 605)
Lumpectomy plus
axillary radiotherapy (n
= 332) versus
lumpectomy plus
axillary dissection (n =
326)
MeSH term(s) used: Breast Neoplasms, Lymphatic Metastasis.
Axillary events
Overall mortality
Breast cancer mortality
Breast events
Survival
Disease-free survival
Survival
Axillary events
No significant differences in overall or
breast cancer mortality, or crude
cumulative incidence of breast events
10-year cumulative survival rate: 86.6%
after level II vs. 85.7% after level III
axillary dissection (HR 1.02; P = 0.931,
log rank test)
10-year disease-free survival rate: 73.3%
vs. 77.8% respectively (HR 0.94, P =
0.666)
Overall survival and disease-free survival
rates in the two groups were similar after
both procedures
Increased survival rate in the axillary
dissection group at 5 years (p=0.009), but
not at 10 and 15 years (73.8% v 75.5% at
15 years).
Recurrences in the axillary node were
less frequent in the axillary dissection
group at 15 years (1% v 3%; p=0.04).
There was no difference in recurrence
rates in the breast or supraclavicular and
distant metastases between the two
groups.
RCT High
RCT High
RCT High
Level of
evidence

76 Breast Cancer KCE reports 63
Study ID Ref Search
date
Radiotherapy for invasive breast cancer.
Indication for radiotherapy
Ford HT 2006 [172] NA Women under 70
years of age and T1-
2 N0–1 M0 invasive
breast cancer
Ragaz J 2005 [74] NA Premenopausal
patients with N+
breast cancer
treated by modified
radical mastectomy
and adjuvant
chemotherapy
Population Intervention Outcomes Results Comments Study
type
Post-operative radiotherapy (n
= 208) or not (n = 192)
No further therapy (n = 154)
or radiation therapy (37.5 Gy
in 16 fractions) (n = 164)
Local recurrence
Distal recurrence
Mortality
Event-free survival
Disease-free survival
Systemic disease-free
survival
Breast-cancer
specific survival
Overall survival
Locoregional
recurrence
20-year Kaplan–Meier rates for local breast
recurrence: 28.6% (95%CI 19.6% - 37.6%) for
radiotherapy vs. 49.8% (95%CI 40.8% - 58.9%).
No significant difference between the two
groups with regard to disease-free or overall
survival.
HR for death among women who received
radiation, as compared with those that did not,
was 0.91 (95%CI 0.64–1.28; P = 0.59).
Therefore, post-operative radiotherapy
produced a clear-cut reduction in locoregional
recurrence 0.45 (0.31–0.64; P = 0.0001), but
did not influence the incidence of distant
metastases or time of death.
At the 20 year follow up CT + RT, compared
with CT alone, were associated with a
statistically significant improvement in all end
points analyzed, including survival free of
isolated locoregional recurrences (74% vs. 90%;
RR 0.36, 95%CI 0.18 to 0.71; p=0.002),
systemic relapse–free survival (31% vs. 48%; RR
0.66, 95%CI 0.49 to 0.88; p=0.004), breast
cancer-free survival (48% vs. 30%; RR 0.63,
95%CI 0.47 to 0.83; p=0.001), event-free
survival (35% vs. 25%; RR 0.70, 95%CI 0.54 to
0.92; p=0.009), breast cancer-specific survival
(53% vs. 38%; RR 0.67, 95%CI 0.49 to 0.90;
p=0.008), and, in contrast to the 15-year
follow-up results, overall survival (47% vs. 37%;
RR 0.73, 95%CI 0.55 to 0.98; p=0.03).
RCT High
RCT High
Level of
evidence

KCE reports 63 Breast Cancer 77
Study ID Ref Search
date
Clarke M 2005 [173] Every 5
years
Population Intervention Outcomes Results Comments Study
type
Women with early
breast cancer
Winzer KJ 2004 [174] NA Women with
primary breast
cancer (stage
pT1pN0M0) (n =
361)
Vinh-Hung V 2004 [175] Not
mentioned
Women with early
breast cancer (stage
I and II)
Post-mastectomy radiotherapy The reduction in local recurrence (mainly in the
conserved breast) produced by allocation to
radiotherapy is substantial and highly significant
(p=0.00001) in every separate trial.
5-year risk of local recurrence: absolute
reduction of 19%.
15-year breast cancer mortality risks 30.5% vs.
35.9% (reduction 5.4%, SE 1.7, p=0.0002;
overall mortality reduction 5.3%, SE 1.8,
p=0.005).
Radiotherapy and Tamoxifen in
a 2X2 factorial design
Radiotherapy Mortality
Locoregional
recurrence
No difference could be established between the
four treatment groups for distant disease-free
survival rates. Mainly due to the presence of
local recurrences, the event rate was about
three times higher in the group with BCS only
than in the other three
groups.
RR of ipsilateral breast tumor recurrence after
breast-conserving surgery, comparing patients
treated with no RT or RT: 3.00 (95%CI 2.65 to
3.40). Mortality data were available for 13 trials
with a pooled total of 8206 patients: RR 1.09
(95%CI 1.00 to 1.18), corresponding to an
estimated 8.6% (95%CI 0.3% to 17.5%) relative
excess mortality if radiotherapy was omitted.
Pooled analysis of
individual patient
data of 42,000
women in 78
randomised
treatment
comparisons
(radiotherapy vs no
radiotherapy,
23,500; more vs
less surgery, 9300;
more surgery vs
radiotherapy, 9300)
Pooled analysis of
15 RCTs
RCTs High
RCT High
Level of
evidence
SR Moderate

78 Breast Cancer KCE reports 63
Study ID Ref Search
date
Van de Steene J
2004
[176] NA Women with early
breast cancer
Fyles AW 2004 [177] NA Women with breast
cancer (T1-2 N0)
Population Intervention Outcomes Results Comments Study
type
aged >50 years
Rutqvist LE 2003 [178] 2001 Women with breast
cancer
Radiotherapy Comparison of early with more mature data
reveals that the odds ratios for overall survival
remain stable as data become more mature.
The analyses of trials’ age and trials’ size, as
predictors of overall survival benefit, indicate
that these factors become statistically more
significant with increasing maturity of the trials.
In the large recent trials an overall survival
benefit due to radiotherapy (odds reduction) of
10, 10, 12 and 13%, respectively P < 0.3; 0.2,
0.005 and 0.00005 is found in the successive
publications. The difference in survival benefit of
radiotherapy between the group of large recent
trials and group of old or small trials becomes
more significant at the successive updates: 10
via 9% and 12 to 13% (odds reductions), with
RT + Tamoxifen (n = 386) vs.
Tamoxifen alone (n = 383)
Disease-free survival
Locoregional
recurrence
respectively P = 0.2; 0.2, 0.004 and 0.00005.
Local relapse: HR 8.3 (95%CI 3.3 to 21.2;
P

KCE reports 63 Breast Cancer 79
Study ID Ref Search
date
Malmstrom P
2003
[179] NA Women with stage I-
II
Population Intervention Outcomes Results Comments Study
type
Postoperative RT (n = 593) vs.
no RT (n = 594)
Ipsilateral breast
recurrence
that the omission of postoperative RT to the
breast following breast conservation surgery
has no impact on overall survival. In one metaanalysis
including three RCTs a survival
advantage is demonstrated by Bayesian
statistics;
that the addition of a radiation boost after
conventional RT to the tumour bed after breast
conservation surgery significantly decreases the
risk of ipsilateral breast recurrences but has no
impact on overall survival after short follow-up;
for the use of postoperative RT to the breast
following breast conservation surgery for DCIS
(ductal breast cancer in situ). RT leads to a
clinically and statistically significant reduction of
both non-invasive and invasive ipsilateral breast
recurrences.
There are conflicting data :
regarding the impact of postmastectomy RT
upon overall survival;
whether breast conservation surgery plus RT is
comparable to modified radical mastectomy
alone in terms of local recurrence rate.
There is some evidence:
that overall survival is increased by optimal
postmastectomy RT.
There is moderate evidence:
that the decrease in non-breast cancer specific
survival is attributed to cardiovascular disease
in irradiated patients.
There is insufficient evidence to define the
optimal integration of systemic adjuvant therapy
and postoperative radiotherapy.
There are limited data on radiotherapy-related
morbidity in breast cancer. No conclusions can
be drawn.
RR of ipsilateral breast recurrence: 3.33 (95%CI
2.13–5.19, P

80 Breast Cancer KCE reports 63
Study ID Ref Search
date
Population Intervention Outcomes Results Comments Study
type
lymph node-negative
breast cancer
Axillary radiotherapy
Veronesi U 2005 [77] NA Women with breast
cancer (≤1.2 cm) and
cN0
Louis-Sylvestre C
2004
[78] NA Patients with a
breast carcinoma
less than 3 cm in
diameter and N0M0
(n=658)
Sequencing of chemotherapy and
radiotherapy
Hickey B et al [79] 2005 Women with early
breast cancer
Axillary RT (n = 221) vs. no RT
(n = 214)
Lumpectomy plus axillary
radiotherapy (n = 332) versus
lumpectomy plus axillary
dissection (n = 326)
Sequencing of chemotherapy
and radiotherapy
Overall survival
Recurrence-free
survival
Breast cancer death
Contralateral breast
cancer
Survival
Axillary events
Overall survival was similar, RR=1.16 (95%
CI 0.81–1.65, P=0.41)
Recurrence-free survival (RFS) at 5 years was
significantly lower in the non-irradiated women,
77%versus 88%(P

KCE reports 63 Breast Cancer 81
Study ID Ref Search
date
Rouessé J 2006 [180] NA N+ M0 invasive
breast cancer, with
prior surgery and
positive axillary
dissection
Intra-operative radiotherapy
Cuncins-Hearn A
2004
Population Intervention Outcomes Results Comments Study
type
Chemotherapy (500 mg/m2 5fluorouracil,
12 mg/m2
mitoxantrone, and 500 mg/m2
cyclophosphamide) with
concomitant radiotherapy (50
Gy +/- 10–20Gy boost) vs.
chemotherapy (500 mg/m2 5fluorouracil,
60 mg/m2
epirubicin, and 500 mg/m2
cyclophosphamide) with
subsequent radiotherapy
No significant difference in overall or diseasefree
survival
Five-year locoregional relapse-free survival
favored patients with conservative surgery (two
thirds of the population), with less local and/or
regional recurrence in Arm A than in
Arm B (3% vs. 9%; p=0.01).
[181] 2002 Early breast cancer Intra-operative RT Current evidence base is poor, making
definitive assessment on IORT very difficult.
MeSH term(s) used: Breast Neoplasms/Radiotherapy.
Updated results of
the RCT included
in the Cochrane
review
7 studies on IORT
(with 1 RCT)
RCT High
SR Low
Level of
evidence

82 Breast Cancer KCE reports 63
Chemotherapy for invasive breast cancer.
Study ID Ref Search
date
Anthracycline-based regimens
Arriagada 2005 [82] 311 high risk N0
premenopausal
women
835 high risk
postmenopausal
women
Hutchins 2005 [83] Women with T1 to
T3a node negative
invasive
adenocarcinoma
Poole 2006 [182] Early breast cancer
(T1-3)
(n= 2391)
Population Intervention Outcomes Results Comments Study
type
No adjuvant
chemotherapy (n = 573)
vs. 6 courses of
anthracycline-based
chemotherapy (FAC or
FEC) (n = 573)
CMF (cyclophosphamide,
methotrexate and
fluorouracil) vs. CAF
(cyclophosphamide,
doxorubicin and
fluroruracil) with or
without tamoxifen (TAM)
NEAT:
4 cycles of epirubicin
followed by 4 cycles of
CMF
versus 6 cycles of CMF
alone
BR9601
4 cycles of epirubicin
followed by 4 cycles of
CMF
versus 8 cycles of CMF
alone
10-year survival
10-year distant
metastasis
10 year local
recurrence rates
Disease free
survival (DFS)
Overall survival
(OS)
Disease free
survival (DFS)
Overall survival
(OS)
Survival: 60% in control group and 65% in CT
group): p = 0.01
Metas: 28% (control) and 23% (CT group): p
= 0.02
Local rec: 12% (control) and 10% (CT
group): p= 0.024
Chemotherapy was significantly less effective
in post menopausal women with estrogen
receptor tumors.
After up to 10 years of follow-up, deferring
radiotherapy after chemotherapy did not
compromise local control
Ten years estimates indicated that CAF was
not significantly better than CMF for DFS.
Slight effect of CAF on OS (IC 0.99 to 1.43)
Greater toxicity of CAF
Epirubicin + CMF is superior to CMF alone
as adjuvant treatment
Randomization after
primary surgery
In post menop women: + at
least 2 years tamoxifen
Combined results of 2
RCTs
Combined two studies
RCTs
RCT High
RCT High
Level of
evidence
High

KCE reports 63 Breast Cancer 83
Study ID Ref Search
date
De Placido S
2005
Levine MN
2005
[92] 466 premenopausal
N+ women
[84] 710 pre- or
perimenopausal
women with N+
breast cancer
Land SR 2004 [183] 160 women with
node-negative and
HR-negative breast
Population Intervention Outcomes Results Comments Study
type
cancer
Fargeot P 2004 [184] 338 BC operable N+
elderly patients (> 65
years)
Bonadonna G
2004
[185] Operable breast
cancer ≥3 nodes
(a) CMF (CMF)
(b) Doxorubicin followed
by CMF(A => CMF)
(c) CMF followed by
groserelin + tamoxifen
(CMF => GT)
(d) Doxorubicin followed
by CMF followed by
goserelin + tamoxifen (A
=> CMF => GT)
Either cyclophosphamide/
epirubicin/ fluorouracil
(CEF)
Or Cyclophosphamide/
methotrexate/
fluorouracil (CMF)
AC (doxorubicin and
cyclophos) vs CMF
(Cyclophos,
methotrexate and 5 FU)
Tamoxifen alone (TAM)
versus epirubicin +
tamoxifen (EPI-TAM)
First study: CMF
(cyclophos, mehtotrexate
and 5FU) versus DOX
(doxorubicin) followed by
CMF (DOX->CMF)
Second study: DOX
followed by CMF (DOX-
>CMF)° versus
alternating DOX and
CMF (DOX/CMF)
Disease free
survival
Overall survival
Relapse free
survival (RFS)
Overall survival
(OS)
At a median follow-up of 72 months,
A=>CMF as compared to CMF significantly
improved disease-free survival (DFS) with a
multivariate hazard ratio (HR =0.740 (95%
confidence interval (CI): 0.556–0.986;
P=0.040) and produced a nonsignificant
improvement of overall survival (OS)
(HR=0.764; 95% CI: 0.489–1.193).
The addition of GT after chemotherapy
significantly improved DFS (HR=0.74; 95% CI:
0.555–0.987; P=0.040), with a nonsignificant
improvement of OS
(HR=0.84; 95% CI: 0.54–1.32).
The 10-year RFS is 52% for patients who
received CEF compared with 45% for CMF
patients (hazard ratio [HR] for CMF v CEF =
1.31; stratified log-rank, P = .007).
The 10-year OS for patients who received
CEF and CMF are 62% and 58%, respectively
(HR for CMF v CEF =1.18; stratified log-rank,
P = .085).
RCT High
Level of
evidence
Allocation concealment? RCT Moderate
QOL Not significant differences RCT High
DFS (disease free
survival)
OS
Long terms
results of
previous studies
Relapse free
survival
Total survival
The 6-year DFS rates were 69.3% with TAM
and 72.6% with EPI-TAM (P =.14). The
multivariate analysis shows a relative risk of
relapse of 1.93 (95% CI, 1.70 to 2.17) with
TAM compared with EPI-TAM (P = .005).
The 6-year OS, related to disease
progression, was 79.1% and 79.8%,
respectively (P =.41).
After a median observation of 210 months,
no statistically significant difference was
documented in the first study (relapse-free
survival hazard rate [HR], 1.06; total survival
HR, 1.03). In contrast, the delivery of DOX
first, followed by CMF significantly reduced
the risk of disease relapse (HR, 0.68; 95% CI,
0.54 to 0.87; P = .0017) and death (HR, 0.74;
95% CI, 0.57 to 0.95; P = .018) compared
with the alternating regimen.
2 RCTs activated in the
early 1980s
RCT
High
RCTs High

84 Breast Cancer KCE reports 63
Study ID Ref Search
date
Fumoleau P
2003
[186] 621 BC N+ in
premenaopausal
women
Martin M 2003 [187] 985 T1-3, N0-2, M0
BC
Taxanes
Bria 2006 [85] Early breast cancer:
15.500 patients
All trials including N+
patients
Population Intervention Outcomes Results Comments Study
type
Six versus three cycles of
epirubicin adj chemo
6 FEC 50 (FU +
epirubicin +
Cyclophosph)
versus 3 FEC 50
or 3 FEC 75
FAC (5FU, doxorub,
cyclophos)
Versus CMF (5FU,
methot, cyclophos)
Assess the advantages of
adjuvant taxane
chemotherapy (placitaxel
or docetaxel) over
standard chemotherapy
DFS disease free
survival
OS overall
survival
DFS
OS
Disease free
survival (DFS)
Overall survival
(OS)
After a 131-month median follow-up, the 10year
disease-free survival (DFS) was 53.4%,
42.5%, and 43.6% (P = .05) in the three arms,
respectively. Pairwise comparisons
demonstrate that 6 FEC 50 was superior
both to 3 FEC 50 (P = .02) and to 3 FEC 75
(P = .05). The 10-year overall survival (OS)
for the 6 FEC 50 arm was 64.3%, for the 3
FEC 50 arm it was 56.6%, and for the 3 FEC
75 arm, it was 59.7% (P = .25), respectively.
Pairwise comparisons demonstrate that 6
FEC 50 was more effective than 3 FEC 50 (P
=.10). Cox regression analysis demonstrates
that OS was significantly better in the 6 FEC
50 than in the 3 FEC 50 arm (P = .046).
In the prospectively formed subset of nodenegative
patients, disease-free survival and
overall survival were statistically superior in
the FAC treatment arm (P = 0.041 and 0.034,
respectively), but this advantage was not seen
in the subset of nodepositive patients.
Adjusting data for size of treatment effect
and potential interactions (number of positive
nodes, tumor size, treatment center), the
overall relative risk (RR) of disease
recurrence and death were significantly
lower with FAC treatment (RR 1.2, P = 0.03,
and RR 1.3, P = 0.05, respectively). This
result was mainly due to the difference
observed in the node-negative patient
population. Toxicity was mild: FAC induced
more alopecia, emesis, mucositis and
cardiotoxicity; this last was of clinical
concern, but was infrequent and manageable.
CMF induced more conjunctivitis and weight
gain. There were no toxic deaths.
Significant differences in favour of taxanes in
DFS in the overall (RR: 0.86) and lymph node
positive population (RR: 0.84) and in OS in
the overall (RR 0.87à and lymph node
positive population (RR: O.84).
Lack of significant
heterogeneity in the
sensitivity analysis of
subpopulations
RCT High
RCT High
Pooled
analysis of
9 phase III
trials
Level of
evidence
Sartor CI 2005 [188] N=3170 Adjuvant AC Loco regional For patients treated with breast-conserving BCS data concern a RCT Moderate
High

KCE reports 63 Breast Cancer 85
Study ID Ref Search
date
Green MC
2005
[189] 258 women operable
breast cancer with
primary systemic
chemotherapy
stage I-IIIA breast
cancer
Brain GC 2005 [190] 627 women with N0
to N3
Neoadjuvant chemotherapy
Mauri D 2005 [86] 2003 Breast cancer
patients
Population Intervention Outcomes Results Comments Study
type
N+, M0 breast cancer (doxorubicin/
cyclophosphamide)
Or AC followed by
paclitaxel (AC + T)
Weekly paclitaxel (12
weekly doses) versus
every 3 week paclitaxel
(4 cyclus over 12 weeks)
All groups followed by
FAC (fluorouracil/
doxorubicin/
cyclophosphamide),
radiotherapy and
tamoxifen (if ER- and/or
PR+))
Doxorubicin + docetaxel
Versus doxorubicin +
cyclophosphamide
Neoadjuvant vs. adjuvant
therapy
recurrence (LRR)
Pathologic
complete
response (pCR)
Disease free
survival
Safety
Overall survival
surgery and RT, the 5-year cumulative
incidence of isolated LRR was 9.7% in the AC
arm and 3.7% in the AC_T arm (P=0.04) and
of LRR as any component of failure was
12.9% versus 6.1%, respectively (P = 0.04).
Although LRR rates in patients who did not
receive postmastectomy RT were lower in
the AC_T arm, the difference was not
statistically significant.
Clinical response to treatment was similar
between groups (P =0.25). Patients receiving
weekly paclitaxel had a higher pCR rate
(28.2%) than patients treated with onceevery-3-weeks
paclitaxel (15.7%; P =0 .02),
with improved breastconservation rates (P
=0.05).
2 deaths related to drug toxicity and 1 case
of perforative peritonitis occurred among
patients with febrile neutropenia, all in the
doxorubicin-docetaxel group. The incidence
of febrile neutropenia was significantly higher
with the doxorubicin-docetaxel regimen
(40.8%) than with the doxorubicincyclophosphamide
regimen (7.1%) (P=.001).
No statistically or clinically significant
difference between neoadjuvant therapy and
adjuvant therapy arms associated with death
(RR = 1.00, 95%CI = 0.90 to 1.12), disease
progression (RR = 0.99, 95%CI = 0.91 to
1.07), or distant disease recurrence (RR =
0.94, 95% CI = 0.83 to 1.06). However,
neoadjuvant therapy was statistically
significantly associated with an increased risk
of loco-regional disease recurrences (RR =
1.22, 95%CI = 1.04 to 1.43) compared with
adjuvant therapy.
subanalysis
Trial terminated
prematurely related to drug
toxicity
Time too short to analyse
the primary endpoint
9 RCTs included
Not only concerns
neoadjuvant chemotherapy
RCT High
Level of
evidence
RCT Moderate
SR High

86 Breast Cancer KCE reports 63
Study ID Ref Search
date
Bear HD 2006 [191] NA Women with
operable breast
cancer (n = 2411)
Gianni L 2005 [192] NA 1355 women
T2-T3, N0-N1, M0
Population Intervention Outcomes Results Comments Study
type
Preoperative AC
(doxorubicin and
cyclophosphamide)
followed by surgery,
or AC followed by T
(docetaxel) and surgery,
or AC followed by
surgery and then T
Adjuvant doxorubicin
followed by i.v.
cyclophosphamide,
methotrexate, and
fluorouracil (CMF;
doxorubicin-->CMF, arm
A) vs. the same regimen
plus paclitaxel
(doxorubicin/ paclitaxel--
>CMF) as adjuvant (arm
B) or primary systemic
therapy (PST, arm C)
Addition of T to AC did not significantly
impact DFS or OS. There were trends
toward improved DFS with addition of T.
The addition of T reduced the incidence of
local recurrences as first events (P = .0034).
Preoperative T, but not postoperative T,
significantly improved DFS in patients who
had a clinical partial response after AC (HR =
0.71; 95%CI, 0.55 to 0.91; P = .007).
Pathologic complete response, which was
doubled by addition of preoperative T, was a
significant predictor of OS regardless of
treatment (HR = 0.33; 95% CI, 0.23 to 0.47;
P < .0001). Pathologic nodal status after
chemotherapy was a significant predictor of
OS (P < .0001).
Grade 3 or 4 National Cancer Institute
toxicities were low (

KCE reports 63 Breast Cancer 87
Study ID Ref Search
date
Cleator SJ
2005
Danforth DN
2003
[193] NA 309 women Operable
breast cancer
[194] NA 53 BC T2N0, T1N1,
T2N1
High-dose chemotherapy with stem-cell Tx
Population Intervention Outcomes Results Comments Study
type
Primary surgery followed
by 8 cycles of adjuvant
mitoxantrone,
methotrexate with
tamoxifen (2MT) or 2MT
with mitomycin-C (3MT)
versus the same regimen
for 4 cycles before
followed by 4 cycles after
surgery
Either preop, either
postop
Same chemo: FU,
Leucovorin, doxorubicin
and cyclphosphamide
(FLAC)/granulocyte
colony stimulating factor
Clinical response
rate
Pathologic
complete
response
OS
DFS
After 10 years follow-up there is no
statistically significant difference in diseasefree
survival (DFS) (71% versus 71%) or
overall survival (OS) (63% versus 70%) when
comparing adjuvant versus neoadjuvant
treatment, respectively. Of 144 evaluable
patients in the neoadjuvant arm, 74 achieved
a good clinical response and 70 patients
achieved a poor clinical response. Good
responders had a superior DFS (80% versus
64%, P=0.01) and OS (77% versus 63%,
P=0.03) compared to poor responders.
RCT High
No significant difference RCT High
Level of
evidence

88 Breast Cancer KCE reports 63
Study ID Ref Search
date
Farquhar 2007 [87] 2006 Women of any age
with early poor
prognosis breast
cancer either at first
diagnosis or as a
recurrence. Not
limited to first line
therapy.
Includes women with
any size of breast
tumour.
Peters WP
2005
[195] N= 785 (22 to 66
years)
stage IIA, IIB, IIIA
breast cancer with
≥10 nodes
Population Intervention Outcomes Results Comments Study
type
High dose chemotherapy
with autologous bone
marrow or stem
cell transplantation versus
conventional
chemotherapy
After surgery and
standart adjuvant therapy
Either high doses
cyclophosphamide,
cisplastine and carmustine
with stem-cell support
(HD-CPB)
Either intermediate doses
with G-CSF but without
stem cells (ID-CPB)
Treatmentrelated
mortality
Survival
Event-free
survival
Morbidity
Quality of life
Event free
survival
Death from
treatment
Overall survival
Analysis included 2535 women randomised
to receive high dose chemotherapy with
autograft and 2529 randomised to receive
conventional chemotherapy.
65 treatment-related deaths on the high dose
arm and four on the conventional dose arm
(RR
8.58 (95% CI 4.13, 17.80).
There was a statistically significant benefit in
event-free survival for women in the high
dose group at three years (RR 1.19 (95% CI
1.06, 1.19)) and at four years (RR 1.24 (95%
CI 1.03, 1.50)) and at five years there was a
benefit for the high dose group that
approached statistical significance (RR 1.06
(95% CI
1.00, 1.13).
With respect to overall survival, there was
no statistically significant difference between
the groups at any stage of follow up.
Morbidity was more common and more
severe in the high dose group. However
there was no statistically significant difference
between the groups in the incidence of
second cancers at five to seven years’ median
follow up. Women in the high dose group
reported significantly worse quality of life
scores immediately after treatment, but few
statistically significant differences were found
between the groups by one year.
Median follow-up was 7.3 years. Event-free
survival was not significantly different
between the two treatment groups (P =
0.24). The probability of being free of an
event at 5 years with HD-CPB was 61% (95%
CI, 56% to 65%), and was 58% (95% CI, 53%
to 63%) for ID-CPB.
Thirty-three patients died of causes
attributed to HD-CPB, compared with no
therapy-related deaths among women
treated with ID-CPB. Overall survival for the
two arms was identical at 71% at 5 years (P
=0.75).
13 RCTs included SR High
RCT High
Level of
evidence

KCE reports 63 Breast Cancer 89
Study ID Ref Search
date
Brandberg Y
2003
[196] 525 BC with
estimated risk relapse
> 70% within 5 years
with standard therapy
Population Intervention Outcomes Results Comments Study
type
Either FU, epirubicin,
cyclophos (FEC)
Versus FEC followed by
High dose cyclophos,
thiotepa and carboplastin
(CTBc) + peripheral
blood stem cells
HRQoL
evaluation
No statistically significant overall differences
were found between the tailored FEC group
and the CTCb group for any of the HRQoL
variables.
RCT High
MeSH term(s) used: Breast Neoplasms; Chemotherapy, Adjuvant; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Drug
Therapy; Drug Therapy, Combination.
Level of
evidence

90 Breast Cancer KCE reports 63
Study ID Ref Search
date
Hormonal therapy for invasive breast cancer.
Deitcher SR 2004 [23] 2003 Women with
breast cancer
Tamoxifen vs. placebo/surgery
Hind D et al [163] 2003 Women aged 70
years or over with
early breast cancer
and who are fit for
surgery
Cochrane Breast
Cancer Group
[88] 2000 (every 5
years)
Population Intervention Ouctomes Results Comments Study
type
Women with early
breast cancer
Bushnell CD 2004 [197] ? Women with breast
cancer
Adjuvant hormonal therapy The risk of VTE was increased twofold to
threefold during tamoxifen or raloxifene
use for breast carcinoma
chemoprevention. In the setting of earlystage
breast carcinoma, the risk of
VTE is increased both with tamoxifen use
and anastrozole use. Such risk appeared to
be lower, albeit not negligible, with
anastrozole.
Primary endocrine therapy
(PET) vs. surgery
Tamoxifen vs. no such adjuvant
treatment
Overall survival
Progression-free
survival
Adverse events
Overall survival:
surgery alone vs. PET: HR 0.98 (95% CI
0.74 – 1.30, p 0.9)
surgery + ET vs. PET: HR 0.86 (95% CI
0.73 – 1.00, p 0.06)
Progression-free survival:
surgery alone vs. PET: HR 0.55 (95% CI
0.39 – 0.77, p 0.0006)
surgery + ET vs. PET: HR 0.65 (95% CI
0.53 – 0.81, p 0.0001)
For women with tumours that have been
reliably shown to be ER-negative, adjuvant
tamoxifen remains a matter for research.
However, some years of adjuvant
tamoxifen treatment substantially improves
the 10-year survival of women with ERpositive
tumours and of women whose
tumours are of unknown ER status, with
the proportional reductions in breast
cancer recurrence and in mortality
appearing to be largely unaffected by other
patient characteristics or treatments.
Tamoxifen OR 1.82 (95% CI, 1.41 to 2.36) for
ischemic stroke and 1.40 (1.14 to 1.72) for
any stroke. During a mean follow-up
period of 4.9 years, the frequency of
ischemic stroke was 0.71% with tamoxifen
vs 0.39% for controls (absolute increased
risk, 0.32%; number needed to harm 313).
Medline only
49 studies included (17
RCTs)
Medline only
One reviewer
9 RCTs included
Level of
evidence
SR Moderate
SR High
SR High
SR Moderate

KCE reports 63 Breast Cancer 91
Study ID Ref Search
date
Braithwaite RS
2003
[198] 2002 Women with breast
cancer
Colleoni M 2006 [199] NA Premenopausal
patients with N+
breast cancer, who
were not suitable for
endocrine therapy
alone (T1-3, N1, M0)
Noguchi S 2005 [200] NA Women with early
stage breast cancer
Population Intervention Ouctomes Results Comments Study
type
(T1-3, N0, M0)
Ryden L 2005 [201] NA Premenopausal
patients with stage II
breast cancer
Kaufmann M 2005 [202] NA Postmenopausal
women up to 70
years of age with
invasive breast
Tamoxifen Tamoxifen was associated with significantly
increased risks of endometrial cancer (RR
2.70; 95% CI, 1.94 to 3.75), gastrointestinal
cancers (RR 1.31; 95% CI, 1.01 to 1.69),
strokes (RR 1.49; 95% CI, 1.16 to 1.90),
and pulmonary emboli (RR 1.88; 95% CI,
1.77 to 3.01). Tamoxifen had no effect on
secondary malignancies other than
endometrial and gastrointestinal cancers
(RR 0.96; 95% CI, 0.81 to 1.13). In
contrast, tamoxifen significantly decreased
myocardial infarction deaths
(RR 0.62; 95% CI, 0.41 to 0.93) and was
associated with a statistically insignificant
decrease in myocardial infarction incidence
(RR 0.90; 95% CI, 0.66 to 1.23).
Postmenopausal women had greater risk
Tamoxifen (20mgdaily) for up
to 5 years (n = 624) or no
hormonal therapy after
administration of
chemotherapy (n = 622)
Postoperative adjuvant therapy
with tamoxifen,
tegafur plus uracil, or both
2 years of Tamoxifen vs. no
treatment
Tamoxifen (30 mg daily for 5
years; n = 421) or no
additional treatment (n = 408)
Recurrence-free
survival
Overall survival
increases for neoplastic outcomes.
Tamoxifen improved DFS in the ERpositive
cohort (HR for tamoxifen vs. no
tamoxifen 0.59; 95%CI, 0.46 to 0.75;
p=0.0001) but not in the ER-negative
cohort (HR 1.02; 95%CI, 0.77 to 1.35;
p=0.89). Tamoxifen had a detrimental
effect on patients with ER-absent tumors
compared with no tamoxifen in an
unplanned exploratory analysis (HR 2.10;
95%CI, 1.03 to 4.29; p=0.04). Patients with
ER-positive tumors who achieved
chemotherapy-induced amenorrhea had a
significantly improved outcome (HR for
amenorrhea v no amenorrhea 0.61; 95%CI,
0.44 to 0.86; p=0.004), whether or not
they received tamoxifen.
The 5-year survival rate (95.2%) in the
TAM group was not significantly different
from that (93.9%) in the non-TAM group.
RFS in patients with ER+ and/or PR+
tumours: RR 0.65; 95%CI: 0.48-0.89,
P=0.006, in favour of TAM
Event-free survival rates after 5 years were
70.3% (95%CI, 65.5% to 75.0%) and 72.8%
(95%CI, 68.2% to 77.5%) for the tamoxifen
and control groups, respectively. The
Medline and Cancerlit,
English only
32 RCTs included
Pooled analysis of 6
Japanese RCTs
Level of
evidence
SR Moderate
RCT High
RCT High
RCT High
RCT High

92 Breast Cancer KCE reports 63
Study ID Ref Search
date
Population Intervention Ouctomes Results Comments Study
type
cancer, negative
hormone receptor
status, stage pT1-3,
N0-3, M0
Hutchins LF 2005 [83] NA Women with early
stage breast cancer,
T1-3b, N0
Bottini A 2005 [203] NA Breast cancer
patients with
operable or locally
advanced disease
(T2–4, N0–1, M0)
Fisher B 2004 [204] NA Women with ER+
and N0 breast
cancer
Fentiman I 2003 [205] NA Women aged 70
years or over with
operable breast
cancer (T1 T2 T3a,
N0 N1a N1b, M0)
CMF, CAF, CMF + Tamoxifen
(CMFT), or CAF +Tamoxifen
(CAFT)
Epirubicin alone (EPI) (n = 105)
vs. epirubicin plus tamoxifen
(EPI-TAM) (n = 106)
B-14 patients were randomly
assigned to placebo (n=1453)
or tamoxifen (n=1439); B-20
patients to tamoxifen (n=788)
or cyclophosphamide,
methotrexate, fluorouracil, and
tamoxifen (CMFT, n=789)
Modified radical mastectomy
(MRM) (n=120) or wide local
excision (WLE) and tamoxifen
(T) 20 mg daily (n=116)
Primary
outcome: survival
estimated HR of tamoxifen versus control
was 1.13 (95%CI, 0.87 to 1.48; p=0.34).
Overall, TAM had no benefit (DFS, p=0.16;
OS, p=0.37), but the TAM effect differed
by HR groups. For HR-positive patients,
TAM was beneficial (DFS, HR 1.32 for no
TAM v TAM; 95%CI, 1.09 to 1.61;
p=0.003; OS, HR 1.26; 95%CI, 0.99 to
1.61; p=0.03), but not for HR-negative
patients (DFS, HR 0.81 for no TAM v
TAM; 95%CI, 0.64 to 1.03; OS, HR 0.79;
95%CI, 0.60 to 1.05).
Tumor shrinkage of >50% was obtained in
76% of patients randomized in the EPI arm
and 81.9% of patients randomized in the
EPI-TAM arm (NS). The corresponding
rates of clinical and pathological complete
response were 20.2 and 21.9% (NS), and
4.8 and 6.7% (NS), respectively.
Compared with placebo, tamoxifen
benefited women in B-14 through 15
years, irrespective of age, menopausal
status, or tumour ER concentration (HR
for recurrence-free survival 0·58,
95%CI 0·50–0·67, p

KCE reports 63 Breast Cancer 93
Study ID Ref Search
date
Tamoxifen 2y vs. 5y
Nordenskjöld B
2005
Population Intervention Ouctomes Results Comments Study
type
years or over with
operable breast
cancer (T1 T2 T3a,
N0 N1a N1b, M0)
[206] NA Postmenopausal
women (less then 75
years) with early
stage breast cancer
Belfiglio M 2005 [207] NA Women with breast
carcinoma T1-3, N0-
3, M0, aged 50-70
years
Tada K 2004 [208] NA Postmenopausal
patients with ER+
breast cancer
Tamoxifen vs. other SERM
Pagani O 2004 [209] NA Post- and
perimenopausal
women with N+,
ER+ breast cancer
who were
considered suitable
for endocrine
therapy alone
Johnston S 2004 [210] NA Postmenopausal
patients with
progressive locally
advanced/ metastatic
breast cancer who
had previously
(MRM) (n=82) vs. tamoxifen
(TAM) (n=82)
Tamoxifen 20 mg/d for 2 years
(n = 2129) vs. 5 years (n =
2046)
2 years vs. 5 years of
Tamoxifen therapy
Tamoxifen 20 mg/d for 2 years
(n = 130) vs. 5 years (n = 126)
Toremifene (n = 525) vs.
tamoxifen (n = 510)
Tamoxifen 40 mg (n = 26) vs.
Idoxifene (n = 30)
outcome: survival Significantly decreased time to progression
in the TAM only group (logrank P

94 Breast Cancer KCE reports 63
Study ID Ref Search
date
Population Intervention Ouctomes Results Comments Study
type
demonstrated
resistance to the
standard 20 mg/day
dose of tamoxifen
Switch Tamoxifen → Aromatase inhibitors
Bria E 2006 [95] 2005 Women with early
breast cancer
Berry J 2005 [211] 2005 Women with breast
cancer
Early switch to aromatase
inhibitors (after 2-3 years of
tamoxifen)
Aromatase inhibitors Tolerability
Efficacy
flushes 13% vs 15%, mild nausea 20% vs
15%).
The risk of any event is reduced with AIs
of 23%, with an absolute benefit of 3.8%
(RR 0.67, 95%CI 0.59 - 0.76). Again, RFS
(RR 0.68, 95%CI 0.59 - 0.79) or both LRFS
and DFRS, were significantly improved
with AIs. OS was significantly prolonged
with AIs, with an absolute benefit of 1.2%
(RR 0.76, 95%CI 0.62 - 0.93), without
significant heterogeneity. Bone fractures
were significantly higher in patients
receiving AIs (RR 1.50, 95%CI 1.12 - 2.02),
and endometrial cancer in patients who
continued to receive tamoxifen (RR 0.32,
95%CI 0.13 - 0.77), without significant
heterogeneity.
Disease-free survival was significantly
improved with anastrozole and letrozole
compared with tamoxifen as initial adjuvant
treatment (P = 0.01 and P = 0.003,
respectively). A switch to either
anastrozole or exemestane after 2 to 3
years of adjuvant tamoxifen therapy was
more effective in reducing the risk of
recurrence than continued tamoxifen
therapy (P = 0.006, P < 0.002, and P <
0.001, respectively). Letrozole was found
to improve disease-free survival in the
extended adjuvant setting (P < 0.001) and
was the only AI consistently more effective
than tamoxifen in the neoadjuvant setting.
Both anastrozole and letrozole were more
efficacious than tamoxifen in the first-line
setting, and some patients receiving
letrozole had better overall response rates
compared with those receiving anastrozole
in the second-line setting (19.1% vs. 12.3%,
respectively; P = 0.013).
Search in Medline,
ASCO, ESMO, FECS and
SABCS
Meta-analysis of 5 RCTs
Medline + abstracts of
proceedings
English only
SR High
Level of
evidence
SR Moderate

KCE reports 63 Breast Cancer 95
Study ID Ref Search
date
Gerber B 2006 [212] NA Postmenopausal
women with
endocrineresponsive,
invasive
breast cancer, who
were receiving
adjuvant tamoxifen
treatment and had
suspected
endometrial changes
(stage I – IIIB)
Upfront Aromatase Inhibitors
Berry J 2005 [211] 2005 Women with breast
cancer
ATAC Trial 2006 [213] NA Postmenopausal
women with
localised breast
cancer
Population Intervention Ouctomes Results Comments Study
type
Continued tamoxifen
treatment (n = 88) or switch
to anastrozole1 mg/d (n = 83)
Aromatase inhibitors Tolerability
Efficacy
Anastrozole (n=3125) or
tamoxifen (n=3116)
Throughout the treatment period,
therewas no significant difference in
recurrent vaginalbleeding between groups
(anastrozole 4.8%; tamoxifen 10.2%; P =
0.18). Six months after randomization, the
mean endometrial thickness for patients
who switched to anastrozole was
significantly reduced compared with those
who continued tamoxifen treatment (P <
0.0001). Significantly fewer anastrozole
patients required a repeat hysteroscopy
and D&C compared with those on
tamoxifen
(4.8% and 33.0% respectively; P < 0.0001).
Disease-free survival was significantly
improved with anastrozole and letrozole
compared with tamoxifen as initial adjuvant
treatment (P = 0.01 and P = 0.003,
respectively). A switch to either
anastrozole or exemestane after 2 to 3
years of adjuvant tamoxifen therapy was
more effective in reducing the risk of
recurrence than continued tamoxifen
therapy (P = 0.006, P < 0.002, and P <
0.001, respectively). Letrozole was found
to improve disease-free survival in the
extended adjuvant setting (P < 0.001) and
was the only AI consistently more effective
than tamoxifen in the neoadjuvant setting.
Both anastrozole and letrozole were more
efficacious than tamoxifen in the first-line
setting, and some patients receiving
letrozole had better overall response rates
compared with those receiving anastrozole
in the second-line setting (19.1% vs. 12.3%,
respectively; P = 0.013).
At median follow-up of 68 months (range
1-93), treatment-related adverse events
occurred significantly less often with
anastrozole than with tamoxifen (1884
[61%] vs 2117 [68%]; p

96 Breast Cancer KCE reports 63
Study ID Ref Search
date
Mauri D et al [94] 2006 Patients with
advanced breast
cancer
Irish W 2005 [214] NA Postmenopausal
women with
advanced breast
cancer
Extended use of Aromatase Inhibitors
Goss P 2006 [97] NA Postmenopausal
women with
hormone-receptorpositive
or receptorunknown
early stage
breast cancer
Population Intervention Ouctomes Results Comments Study
type
Aromatase inhibitors vs.
standard hormonal treatment
Letrozole (n = 453) vs.
tamoxifen (n = 454)
Letrozole compared with
placebo after adjuvant
tamoxifen during 5 years
adverse events leading to withdrawal (344
[11%] vs 442 [14%]; p=0.0002).
Statistically significant survival benefits with
third-generation aromatase inhibitors and
inactivators (vorozole, letrozole,
examestane, and anastrazole) (RH = 0.87,
95%CI 0.82 to 0.93; P

KCE reports 63 Breast Cancer 97
Study ID Ref Search
date
LHRH agonists
Sharma R et al [89] ? Premenopausal
women with early
breast cancer
De Placido S
2005
[92] NA Premenopausal
women with breast
cancer (T0-3, N1-2,
M0
Population Intervention Ouctomes Results Comments Study
type
Adjuvant treatment with LHRH
agonists
(a) CMF6 cycles (CMF)
(b) doxorubicin 4 cycles
followed by CMF 6 cycles (A-
CMF)
(c) CMF 6 cycles followed by
goserelin plus tamoxifenfor 2
years (CMF-GT)
(d) doxorubicin 4 cycles
followed by CMF 6 cycles
followed by goserelin plus
tamoxifen for2 years (A-CMF-
GT)
= .002). Overall survival was the same in
both arms (HR for death from any cause =
0.82, 95% CI = 0.57 to 1.19; P = .3).
In three trials, adjuvant suppression of
ovarian function using LHRH agonists, with
or without TAM, had similar benefits at 5-
6 years follow-up in terms of disease-free
survival (DFS) and overall survival (OS) to
adjuvant CMF chemotherapy. These
findings suggest that ovarian suppression
using LHRH agonists (+/-TAM) is a
reasonable alternative to CMF
chemotherapy in women with oestrogen
receptor (ER) positive tumours. The role
of chemotherapy in addition to LHRH
agonists is not clearly defined and mature
results of four trials are awaited. Data is
also inadequate at the time of publication
to inform decisions about the efficacy of
LHRH agonists in comparison with TAM
for the treatment of ER-positive early
breast cancer.
The addition of GT after chemotherapy
significantly improved DFS (HR 0.74;
95%CI: 0.56–0.99; P=0.040), with a
nonsignificant improvement of OS
(HR 0.84; 95%CI: 0.54–1.32).
MeSH term(s) used: Breast Neoplasms; Antineoplastic Agents, Hormonal; Tamoxifen; Aromatase Inhibitors.
11 RCTs SR High
RCT High
Level of
evidence

98 Breast Cancer KCE reports 63
Study ID Ref Search
date
Hormonal therapy for metastatic breast cancer.
Deitcher SR 2004 [23] 2003 Women with breast
cancer
Chemotherapy vs. endocrine therapy
Wilcken N et al [215] 2002 Women with
metastatic breast
cancer
Aromatase inhibitors (general)
Carlini P 2005 [216] 2004 Women with
metastatic breast
cancer
Population Intervention Ouctomes Results Comments Study
type
Adjuvant hormonal therapy The risk of VTE was increased twofold to
threefold during tamoxifen or raloxifene
use for breast carcinoma
chemoprevention. In the setting of earlystage
breast carcinoma, the risk of
VTE is increased both with tamoxifen use
and anastrozole use. Such risk appeared to
be lower, albeit not negligible, with
anastrozole.
Chemotherapy alone vs.
endocrine therapy alone
Aromatase inhibitors (AI) vs.
Megestrol acetate (MEG)
Overall response rate
(ORR)
Time to disease
progression (TTP)
Toxicity
Survival: HR 0.94, 95%CI 0.79 – 1.12,
p=0.5
Response rate: RR 1.25 (1.01 – 1.54,
p=0.04) in favour of chemotherapy;
however heterogeneous trials
No significant differences in ORR (RR 1.07,
95%CI, 0.88 –1.29) and TTP (RR 1.00,
95%CI, 0.89 –1.12; p=0.99) were noted in
the entire group of 9 trials comparing AI
with MEG (3908 patients) and in the 6
trials comparing nonsteroidal AI and MEG
(2415 patients). AI yielded significantly
more hot flashes than MEG (p=0.004), but
caused significantly less toxicity than MEG
in weight gain (p=0.001), dyspnea
(p=0.008), and peripheral edema (p=0.03).
Medline only
49 studies
included (17
RCTs)
Medline search
9 RCTs included
Level of
evidence
SR Moderate
SR High
SR Moderate

KCE reports 63 Breast Cancer 99
Study ID Ref Search
date
Berry J 2005 [211] 2005 Women with breast
cancer
Aromatase inhibitors vs. Tamoxifen
Ferretti G 2006 [103] 2004 Postmenopausal
women with
metastatic breast
cancer
Aromatase inhibitors (head-to-head)
Rose C 2003 [217] NA Locally advanced or
metastatic breast
cancer
Fulvestrant vs. Aromatase inhibitors
Robertson J 2003 [218] NA Postmenopausal
women with locally
advanced or
metastatic breast
carcinoma that
progressed after
adjuvant endocrine
Population Intervention Ouctomes Results Comments Study
type
Aromatase inhibitors Tolerability
Efficacy
Aromatase inhibitors (AI) vs.
Tamoxifen (TAM)
Anastrozole 1 mg (n = 357) vs.
Letrozole 2.5 mg (n = 356)
Fulvestrant (n = 428) vs.
Anastrozole (n = 423)
(+ subanalysis of patients with
and without visceral M+)
Overall response rate
Time to progression
Time to progression
Disease-free survival was significantly
improved with anastrozole and letrozole
compared with tamoxifen as initial adjuvant
treatment (P = 0.01 and P = 0.003,
respectively). A switch to either
anastrozole or exemestane after 2 to 3
years of adjuvant tamoxifen therapy was
more effective in reducing the risk of
recurrence than continued tamoxifen
therapy (P = 0.006, P < 0.002, and P <
0.001, respectively). Letrozole was found
to improve disease-free survival in the
extended adjuvant setting (P < 0.001) and
was the only AI consistently more effective
than tamoxifen in the neoadjuvant setting.
Both anastrozole and letrozole were more
efficacious than tamoxifen in the first-line
setting, and some patients receiving
letrozole had better overall response rates
compared with those receiving anastrozole
in the second-line setting (19.1% vs. 12.3%,
respectively; P = 0.013).
ORR: RR = 1.13, 95%CI 1.00–1.28,
p=0.042 in favour of AI
TTP: RR 0.88, 95%CI 0.80–0.96, p=0.007 in
favour of AI
No difference for TTP, with median TTP
being 5.7 months for both treatments.
Letrozole was significantly better than
anastrozole in ORR (19.1% vs. 12.3%;
adjusted OR=1.70, P=0.013). The overall
clinical benefit rate was also greater for
letrozole (27.0% vs. 23.0%; OR=1.24, NS).
Time to progression Median TTP: 5.5 months vs. 4.1 months
(HR, 0.95; 95% CI, 0.82–1.10; p=0.48).
Objective response (OR) rates were
similar in patients treated with fulvestrant
and anastrozole, respectively (21.9% versus
19.3%-patients with no visceral metastases;
15.7% versus 13.2%-all of the patients with
Medline +
abstracts of
proceedings
English only
Search in Medline,
Embase and
ASCO
8 RCTs included
Combined analysis
of 2 RCTs
Level of
evidence
SR Moderate
SR High
RCT High
RCTs High

100 Breast Cancer KCE reports 63
Study ID Ref Search
date
Population Intervention Ouctomes Results Comments Study
type
therapy (primarily
with tamoxifen) or
after first-line
endocrine therapy
for advanced disease
Fulvestrant vs. Tamoxifen
Howell A 2004 [219] NA Postmenopausal
women with
metastatic or locally
advanced breast
cancer who had
received no endocrine
or cytotoxic
chemotherapy for
advanced disease, or
had received no
adjuvant endocrine
therapy within 12
months before trial
entry, and whose
tumors were ER+
and/or PgR+, or with
ER or PgR status
unknown
Tamoxifen
Braithwaite RS
2003
[198] 2002 Women with breast
cancer
Fulvestrant (n = 313) vs.
Tamoxifen (n = 274)
visceral metastases; 18.8% versus 14.0%patients
with visceral metastases only). The
proportion of patients with clinical benefit
(CB) was also similar between treatments
and between subgroups with and without
visceral disease.
Time to progression No significant difference between
fulvestrant and tamoxifen for TTP (median
TTP 6.8 months and 8.3 months,
respectively; HR 1.18; 95%CI 0.98 - 1.44; P
=.088). In a prospectively planned subset
analysis of patients with known ER+ and/or
PgR+ tumors (approximately 78%), median
TTP was 8.2 months for fulvestrant and 8.3
months for tamoxifen (HR 1.10; 95%CI
0.89 to 1.36; P =.39). The objective
response rate for the overall population
was 31.6% with fulvestrant and 33.9% with
tamoxifen, and 33.2% and 31.1%,
respectively, in the known hormone
receptor-positive subgroup.
Tamoxifen Tamoxifen was associated with significantly
increased risks of endometrial cancer (RR
2.70; 95% CI, 1.94 to 3.75), gastrointestinal
cancers (RR 1.31; 95% CI, 1.01 to 1.69),
strokes (RR 1.49; 95% CI, 1.16 to 1.90),
and pulmonary emboli (RR 1.88; 95% CI,
1.77 to 3.01). Tamoxifen had no effect on
secondary malignancies other than
endometrial and gastrointestinal cancers
(RR 0.96; 95% CI, 0.81 to 1.13). In
contrast, tamoxifen significantly decreased
myocardial infarction deaths
(RR 0.62; 95% CI, 0.41 to 0.93) and was
associated with a statistically insignificant
decrease in myocardial infarction incidence
(RR 0.90; 95% CI, 0.66 to 1.23).
Postmenopausal women had greater risk
Medline and
Cancerlit, English
only
32 RCTs included
RCT High
Level of
evidence
SR Moderate

KCE reports 63 Breast Cancer 101
Study ID Ref Search
date
Bushnell CD 2004 [197] ? Women with breast
cancer
Johnston S 2004 [210] NA Postmenopausal
patients with
progressive locally
advanced/metastatic
breast cancer who
had previously
demonstrated
resistance to the
standard 20 mg/day
Population Intervention Ouctomes Results Comments Study
type
dose of tamoxifen
Arpino G 2003 [220] NA Postmenopausal
patients with
hormone receptorpositive
or -unknown
metastatic breast
cancer
increases for neoplastic outcomes.
Tamoxifen OR 1.82 (95% CI, 1.41 to 2.36) for
ischemic stroke and 1.40 (1.14 to 1.72) for
any stroke. During a mean follow-up
period of 4.9 years, the frequency of
ischemic stroke was 0.71% with tamoxifen
vs 0.39% for controls (absolute increased
Tamoxifen 40 mg (n = 26) vs.
Idoxifene (n = 30)
Tamoxifen (n = 162) vs.
Idoxifene (n = 159)
Response rate
Time to progression
MeSH term(s) used: Breast Neoplasms; Antineoplastic Agents, Hormonal; Tamoxifen; Aromatase Inhibitors.
risk, 0.32%; number needed to harm 313).
Overall clinical benefit rate of Idoxifene:
16%, 95%CI 4.5-36.1%. Median duration of
clinical benefit: 9.8 months. Idoxifene was
well tolerated and the reported possible
drug-related toxicities were similar in
frequency to those with tamoxifen (hot
flushes 13% vs 15%, mild nausea 20% vs
15%).
None of the endpoints was significantly
different for the two drugs, nor was
survival. Adverse events (lethal, serious but
not lethal and important but not life
threatening) were similar in the two arms.
Medline only
One reviewer
9 RCTs included
Phase II trial
Randomization
process?
No statistical
comparison due
to low sample size
Interim analysis
Trial stopped at
that time because
of economic
considerations
Level of
evidence
SR Moderate
RCT Low
RCT Moderate

102 Breast Cancer KCE reports 63
Chemotherapy for metastatic breast cancer.
Study ID Ref Search
date
General
Carrick S et al [107] 2003 Women with
metastatic breast
cancer
Wilcken N et al [215] 2002 Women with
metastatic breast
cancer
Jones D et al [221] 2004 Women with
metastatic breast
cancer
Taxane-based regimens
Ghersi D et al [108] 2004 Women with
metastatic breast
cancer
Population Intervention Ouctomes Results Comments Study
type
Single chemotherapy agents vs.
regimens containing a
combination of agents
Chemotherapy alone vs.
endocrine therapy alone
Addition of one or more
chemotherapy agents to an
established regimen
Overall survival: HR 0.88 (95%CI 0.83 –
0.94, p

KCE reports 63 Breast Cancer 103
Study ID Ref Search
date
Gennari A 2006 [222] NA Metastatic breast
cancer patients
not experiencing
progression after
first-line
anthracycline/
paclitaxel
combination
Population Intervention Ouctomes Results Comments Study
type
chemotherapy
Verma S 2005 [141] NA Patients with
anthracyclinepretreated
metastatic breast
carcinoma
Langley RE 2005 [223] Women with
metastatic breast
cancer previously
untreated with
chemotherapy
Bria E 2005 [224] 2003 Patients with
metastatic breast
cancer
Lyman GH 2004 [225] NA Metastatic invasive
adenocarcinoma
of the breast
or unresectable
Maintenance paclitaxel (n =
109) vs. Control (n = 106)
21-day cycles of oral
capecitabine 1250 mg/m² twice
daily, on Days 1-14, plus
docetaxel 75 mg/m² Day 1 (n =
255), or docetaxel 100 mg/m²
on Day 1 (n = 256)
Epirubicin plus paclitaxel (n =
353) compared with epirubicin
plus cyclophosphamide as firstline
chemotherapy (n = 352)
Combination of anthracyclines
plus taxanes vs. standard
anthracyclines-based regimens
Doxorubicin (60mg/m²)
followed immediately by
paclitaxel (200mg/m² over 3 h)
(AT) (n = 63), or with
Progressionfree
survival
(heterogeneity!)
No significant difference in median
progression-free survival was observed
(8.0 months for maintenance paclitaxel and
9.0 months for control). There was no
significant difference in median survival
time (28.0 v 29.0 months).
Capecitabine/docetaxel increased the
median overall survival by 3 months
compared with docetaxel alone (14.5 vs.
11.5 months). The mean quality-adjusted
survival was increased by 1.8 months in the
capecitabine/docetaxel group.
Median progression-free survival time was
7.0 months for the EP group and 7.1
months for the EC group (HR = 1.07;
95%CI, 0.92 to 1.24; P = .41), and median
overall survival time was 13 months for the
EP group and 14 months for the EC group
(HR = 1.02; 95%CI, 0.87 to 1.19; P = .8).
EP patients, compared with EC patients,
had more grade 3 and 4 mucositis (6% v
2%, respectively; P = .0006) and grade 3
and 4 neurotoxicity (5% v 1%, respectively;
P < .0001).
When data were pooled and plotted,
significant differences in favor of taxanes
were seen for ORR (RR(A-B) 1.21,
P

104 Breast Cancer KCE reports 63
Study ID Ref Search
date
Population Intervention Ouctomes Results Comments Study
type
locally advanced
disease
Chan S 2004 [226] NA Women with
anthracyclinenaïve
metastatic
breast cancer
Bottomley A
2004
Bonneterre J
2004
[227] NA Women with
anthracyclinenaïve
metastatic
breast cancer
[228] NA Women with
metastatic breast
cancer
Biganzoli L 2003 [229] NA Women with
metastatic breast
cancer
doxorubicin (60 mg/m²)
followed immediately by
cyclophosphamide (600 mg/m²)
(AC) (n = 64)
Doxorubicin +
cyclophosphamide (n = 80) vs.
epirubicin + cyclophosphamide
(n = 80) as first-line therapy
Doxorubicin + Paclitaxel (n =
114) vs. Doxorubicin +
cyclophosphamide (n = 105) as
first-line therapy
Docetaxel + epirubicin (n = 70)
vs. 5FU + epirubicin +
cyclophosphamide (n = 72)
Doxorubicin + paclitaxel (n =
138) vs. doxorubicin +
cyclophosphamide (n = 137) as
lower than anticipated on the standard AC
arm. On average the reduction of LVEF
was similar in the two groups, with no
patients developing congestive heart failure
during the six cycles of therapy, although
one patient in the AT group died of
delayed congestive heart failure.
Overall response rates were 46% and 39%
for MC and EC treatment, respectively (P
= 0.42). MC was superior to EC with
respect to median time to treatment
failure (5.7 versus
4.4 months; P = 0.01) and median time to
disease progression (7.7 versus 5.6
months; P = 0.02). Median survival times
were 18.3 and 16.0 months for MC and
EC, respectively (P = 0.504).
Unsurprisingly, given an equimolar
comparison, neutropenia and
stomatitis/mucositis were significantly
more common in patients who received
MC. However, there was less injection site
toxicity with MC. Both treatments showed
a low incidence of cardiotoxicity.
No statistically significant differences in
HRQOL between the two treatment
groups.
Overall response rate for ET of 59%
(95%CI 47–70%) and for FEC 32% (95%CI
21–43%) after a median seven and six
cycles, respectively. The median response
duration for ET was 8.6 months (95%CI
7.2–9.6 months) and for FEC 7.8 months
(95%CI 6.5–10.4 months). The median
time to progression for ET was 7.8 months
(95%CI 5.8–9.6 months) and for FEC 5.9
months (95%CI 4.6–7.8 months). After a
median follow-up of 23.8 months, median
survival for ET and FEC were 34 and 28
months, respectively.
Congestive heart failure (CHF) occurred in
three patients in the AT arm and in one
patient in the AC arm (p=0.62). Decreases
Randomization
procedure?
Level of
evidence
RCT Moderate
RCT High
RCT High
RCT High

KCE reports 63 Breast Cancer 105
Study ID Ref Search
date
Platinum-containing regimens
Carrick S et al [106] 2003 Women with
metastatic breast
cancer
Robert N 2006 [230] NA Women with
HER-2overexpressing
metastatic breast
cancer
Other
Farquhar C et al [105] 2004 Women with
metastatic breast
cancer
Lord S et al [231] 2003 Women with
metastatic breast
cancer
Population Intervention Ouctomes Results Comments Study
type
first-line in left ventricular ejection fraction to
below the limit of normal were
documented in 33% AT and 19% AC
patients and were not predictive of CHF
development.
Platinum-containing
chemotherapy
Trastuzumab, paclitaxel, and
carboplatin (n = 98) vs.
trastuzumab and paclitaxel (n =
98)
High dose chemotherapy +
autograft vs. conventional
chemotherapy
Antitumour antibiotic
containing regimens
Overall survival: HR 1.00 (95%CI 0.88 –
1.15, p=0.96)
Time to progression: HR 1.06 (95%CI 0.95
– 1.19, p=0.31)
Overall response: OR 1.47 (95%CI 1.23 –
1.76, p=0.0001) in favour of platinumcontaining
regimens (heterogeneity!)
Toxicity: higher toxicity level for
leukopenia, hair loss, nausea and vomiting
and anaemia with platinum-containing
regimens (statistically significant)
Objective response rate (ORR) was 52%
(95%CI, 42% to 62%) for TPC versus 36%
(95%CI, 26% to 46%) for TP (P = .04).
Median progression-free survival (PFS) was
10.7 months for TPC and 7.1 months for
TP (HR 0.66; 95%CI 0.59 to 0.73; P = .03).
Treatment-related death: RR 8.58 (95%CI
4.13 – 17.80) in favour of conventional
chemotherapy
Event-free survival at 4y: RR 1.30 (95%CI
1.16 – 1.45) in favour of high-dose group;
not at 5 and 6 years
Morbidity: more severe in high dose group
No statistically significant difference in
survival between regimens that contained
antitumour antibiotics and those that did
not (HR 0.97, 95% CI 0.91 to 1.03, P =
0.35). Antitumour antibiotic regimens
were favourably associated with time-toprogression
(HR 0.84, 95% CI 0.77 to
0.91) and tumour response rates (OR
1.34, 95% CI 1.21 to 1.48) although
statistically significant heterogeneity was
observed for these outcomes. No
statistically significant difference was
13 trials
No RCTs containing
oxaliplatin
Randomization
procedure?
SR High
Level of
evidence
RCT Moderate
13 RCTs High
33 RCTs included SR High

106 Breast Cancer KCE reports 63
Study ID Ref Search
date
Vredenburgh JJ
2006
[232] NA women with
metastatic breast
cancer and only
bone M+ (n = 69)
Kroger N 2006 [233] NA Chemotherapysensitive
metastatic breast
cancer patients (n
= 187)
Zielinski C 2005 [234] NA Stage IV breast
cancer
Miller KD 2005 [235] NA Patients with
previously treated
metastatic breast
cancer
Levy C 2005 [236] NA Anthracycline
pretreated
metastatic breast
cancer
Population Intervention Ouctomes Results Comments Study
type
Immediate consolidation with
high-dose chemotherapy and
hematopoietic support (n = 35)
vs. observation with high-dose
consolidation at the time of
disease progression (n = 34)
One (n = 94) or two cycles (n
= 93) of HDT, consisting of
thiotepa (125 mg/m2/d for 4
days), cyclophosphamide (1,500
mg/m2/d for 4 days), and
carboplatin (200 mg/m2/d for 4
days), followed by autologous
stem-cell transplantation
Gemcitabine (1,000 mg/m²,
days 1 and 4), epirubicin (90
mg/m², day 1), and paclitaxel
(175 mg/m², day 1) (n = 124)
vs. FU (500 mg/m², day 1),
epirubicin (90 mg/m², day 1),
and cyclophosphamide (500
mg/m², day 1) (n = 135) as firstline
Capecitabine (2,500 mg/m²/d)
twice daily on day 1 through 14
every 3 weeks, alone (n = 230)
or in combination with
bevacizumab (15 mg/kg) on day
1 (n = 232)
Docetaxel (75 mg/m², day 1)
plus gemcitabine (1000 mg/m²,
days 1, 8) (n = 153) vs.
docteaxel plus capecitabine
(1250 mg/m², bid days 1-14)
every 3 weeks (n = 152) until
Progressionfree
survival
observed in any outcome between
mitoxantrone-containing and non-
antitumour antibiotic-containing regimens.
Median event-free survival (EFS) for the
immediate transplant arm: 12 months and
for the observation arm 4.3 months
(P

KCE reports 63 Breast Cancer 107
Study ID Ref Search
date
Sparano JA 2004 [237] NA Breast cancer that
was responding or
stable after
treatment with
first-line
chemotherapy for
metastatic disease
Keller AM 2004 [238] NA Women with
taxane-refractory
advanced breast
cancer (M+)
Ejlertsen B 2004 [239] NA Women with
metastatic breast
cancer
Boogerd W 2004 [240] NA Women with
breast cancer and
leptomeningeal
M+
Population Intervention Ouctomes Results Comments Study
type
disease progression response duration (36 vs. 42 weeks).
Oral marimastat (10 mg bid; n
= 114) or a placebo (n = 65)
within 3 to 6 weeks of
completing six to eight cycles
of first-line doxorubicin- and/or
taxane-containing
chemotherapy
Pegylated liposomal
doxorubicin (PLD) (n = 150)
vs. comparator-vinorelbine or
mitomycin C plus vinblastine
every 6 to 8 weeks (n = 151)
Vinorelbine plus epirubicin (n =
193) or epirubicin alone (n =
194)
Intraventricular chemotherapy
(n = 17) vs. no IT (n = 18)
When comparing placebo with marimastat,
there was no significant difference in PFS
(median, 3.1 months v 4.7 months,
respectively; HR 1.26; 95% CI, 0.91 to
1.74; p=0.16) or overall survival (median,
26.6 months v 24.7 months, respectively;
HR 1.03; 95% CI, 0.73 to 1.46; p=0.86).
Patients treated with marimastat were
more likely to
develop grade 2 or 3 musculoskeletal
toxicity (MST), a known complication of
the drug indicative of achieving a biologic
effect, compared with patients
administered placebo (63%
v 22%, respectively; p=0.0001).
Progression-free survival (PFS) and overall
survival (OS) were similar for PLD and
comparator (PFS: HR 1.26; 95% CI, 0.98 to
1.62; P =.11; median, 2.9 months [PLD]
and
2.5 months [comparator]; OS: HR, 1.05;
95% CI, 0.82 to 1.33; P =.71; median, 11.0
months [PLD] and 9.0 months
[comparator]).
Overall response rates to vinorelbine and
epirubicin, and epirubicin alone, were 50%
and 42%, respectively (p=0.15). The
complete response rate was significantly
superior in the combination arm (17% v
10%; p=0.048) as was median duration of
progression-free survival (10.1 months v
8.2 months;
p=0.019). Median survival was similar in
the two arms (19.1 months v 18.0 months;
p=0.50).
Neurological improvement or stabilisation
in 59% of the IT and in 67% of the non-IT
group, with median time to progression of
23 weeks (IT) and 24 weeks (non-IT).
Median survival of IT patients was 18.3
weeks and 30.3 weeks for non-IT patients
(difference 12.9 weeks; 95%CI 5.5 to +34.3
weeks; P = 0.32). Neurological
Randomization
procedure?
RCT High
Level of
evidence
RCT Moderate
RCT High
Small sample size RCT Moderate

108 Breast Cancer KCE reports 63
Study ID Ref Search
date
Verma S 2003 [241] Anthracyclinepretreated
women with
metastatic breast
Population Intervention Ouctomes Results Comments Study
type
cancer
Parnes HL 2003 [242] NA Women with
metastatic breast
cancer
Nooij MA 2003 [243] NA Women with nonprogressive
metastatic breast
cancer after
induction
chemotherapy
with CMF
Single-agent docetaxel (n =
255) vs. docetaxel +
capecitabine (n = 251)
Cyclophosphamide +
doxorubicin + fluorouracil with
(n = 120) or without
leucovorin (n = 121) as firstline
Continue CMF (n = 97) or not
(n = 107)
complications of treatment occurred in
47% (IT) vs 6% (non-IT) (P = 0.0072).
Projected survival gain of 136 life-years
with combination therapy. Small
incremental cost of Can$ 3.691 per lifeyear
gained.
The overall response rate was 29% for
CAF versus 28% for CAF plus LV. The
median time to treatment failure (9
months) and median survival (1.7 years)
did not differ by treatment arm. The two
study arms were similar with regard to
serious adverse events.
Continuation of CMF had a significantly
longer time to treatment failure (TTF) 5.2
versus 3.5 months (P=0.011). There was
no overall survival (OS) difference 14.0
versus 14.4 months (P=0.77). Mean qualityadjusted
survival time was equal to 8.4
months for no further treatment and
decreased to 7.9 months for continuation
of CMF (95%CI of difference equals 0.5-2.5
months).
Randomization
procedure?
Randomization
procedure?
RCT High
Level of
evidence
RCT Moderate
RCT Moderate

KCE reports 63 Breast Cancer 109
Study ID Ref Search
date
Elomaa I 2003 [244] NA Women with
metastatic breast
cancer
Sequencing of chemotherapy
Cresta S 2004 [245] NA Women with
metastatic breast
cancer
Population Intervention Ouctomes Results Comments Study
type
Dose-finding study of
Vinorelbine (VMF): 20 + 20
mg/m² vs. 30 + 10 mg/m² vs. 40
+ 0 mg/m² (first line)
Doxorubicin and DOC either
in combination (60 mg/m² of
each drug) (n = 42), or by
alternated (n = 42) or
sequential schedule (100
mg/m2 DOC and 75 mg/m²
doxorubicin) (n = 39) every 3
weeks
World Health Organization (WHO) grade
3 hematological toxicity occurred in 23%,
36% and 50% of patients and grade 4 in
39%, 32% and 50% of patients in groups 1,
2 and 3, respectively; grade 3 infections
were observed in 15%, 9% and 10% of
patients in groups 1, 2 and 3, and grade 4
infections in 5% and 10% of patients in
groups 2 and 3, respectively.
Nonhematological toxicity included a mild
to moderate neurotoxicity manifesting as
constipation, abdominal colics and myalgia
in the majority of patients. One patient in
group 3 had serious convulsions after
vinorelbine administration; she also
developed neutropenic sepsis; all
symptoms were reversible. No patient
died from side-effects. The objective
response rates were 50%, 55% and 44%
for groups 1, 2 and 3, respectively. Median
time to progression was 7, 10 and 8
months and median survival time was 26,
23 and 16 months in groups 1, 2 and 3,
respectively.
The overall response was 63%, 52% and
61% in the combination, alternating and
sequential schedules, respectively.
Corresponding rates of complete response
were 15%, 14% and 11%. Grade 4
neutropenia was common in all arms (81%)
and, together with febrile neutropenia, was
significantly more frequent with the
combination.
RCT in 2 phases (second
phase: expansion of 2
least toxic groups)
Randomization
procedure?
Level of
evidence
RCT Moderate
RCT Moderate

110 Breast Cancer KCE reports 63
Study ID Ref Search
date
Conte PF 2004 [246] NA Women with
metastatic breast
cancer
Baldini E 2004 [247] NA Women with
metastatic breast
cancer
Alba E 2004 [248] NA Women with
metastatic breast
cancer
Population Intervention Ouctomes Results Comments Study
type
Combination of epirubicin at a
dose of 90 mg/m² plus
paclitaxel at a dose²of 200
mg/m² for 8 cycles
(concomitant arm, n =108) or
epirubicin at a dose of 120
mg/m² for 4 cycles followed by
paclitaxel at a dose of 250
mg/m² over 3 hours for 4
cycles every 21 days (sequential
arm, n = 94)
Epirubicin + Paclitaxel (n = 72)
vs. epirubicin followed by
palcitaxel (n = 64)
Sequential vs. concommitant
Doxorubicin and Docetaxel as
first line
The median progression-free and overall
survival periods were 11.0 months (95%CI
9.7–12.3) and 20.0 months (95%CI 17.2–
22.6), respectively, in the concomitant arm
and 10.8 months (95%CI 7.9 –13.6) and 26
months (95%CI 18.1–33.8), respectively, in
the sequential arm (NS). Patients who
received the sequential regimen
experienced a higher incidence of Grade
3/4 (according to the World Health
Organization grading system) neutropenia
(62.2% of courses vs. 50.62%; p=0.003) and
Grade ≥ 2 neuropathy (45.5% vs. 30.4% of
patients; p=0.03), whereas 6 patients who
received the concomitant regimen
developed Grade II cardiotoxicity
according to New York Heart Association
criteria. QOL analyses failed to provide
clear differences.
After eight courses, the median left
ventricular ejection fraction in arm A
declined to 50% while no further reduction
was detected in arm B by adding four
courses of high-dose Paclitaxel. Seven
episodes of congestive heart failure were
observed during treatment in arm A.
Febrile neutropenia was less common in
the A3T arm (29.3% of patients, 6.9% of
cycles) compared with the AT arm (47.8%
of patients, 14.8% of cycles; p=0.02 and
p=0.0004, respectively). Asthenia, diarrhea,
and fever occurred more frequently in the
AT arm. The overall responses rates were
61% in the A3T arm (95% CI, 50% to 72%)
and 51% in the AT arm (95% CI, 39% to
63%). The median duration of response
was 8.7 months (A3T) and 7.6 months
(AT); the median time to progression was
10.5 months (A3T) and 9.2 months (AT);
the median overall survival was 22.3
months (A3T) and 21.8 months (AT); and
no significant differences were found.
Randomization
procedure?
RCT High
Level of
evidence
RCT Moderate
RCT High

KCE reports 63 Breast Cancer 111
Study ID Ref Search
date
Paridaens R 2003 [249] NA Women with
metastatic breast
cancer
Population Intervention Ouctomes Results Comments Study
type
Sequential (n = 55) vs.
alternating Doxorubicin and
Docetaxel (n = 51) as first line
The alternating and sequential groups
achieved similar objective tumor response
rates (60% and 67%, respectively) and
similar median duration of response (47
and 44 weeks, respectively). With a
median follow-up of 31 months, median
survival times were estimated at 20 and 26
months in the alternating and sequential
groups, respectively. No unexpected
toxicities were reported. Compared with
alternating therapy, patients receiving
sequential therapy were more likely to
complete the planned eight chemotherapy
cycles (69% versus 63%), and had a lower
incidence of febrile neutropenia (2% versus
14%).
RCT High
MeSH term(s) used: Breast Neoplasms; Chemotherapy, Adjuvant; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Drug
Therapy; Drug Therapy, Combination.
Level of
evidence

112 Breast Cancer KCE reports 63
Trastuzumab for metastatic breast cancer.
Study ID Ref Search
date
Marty M 2005 [109] NA HER2-positive MBC
Population Intervention Ouctomes Results Comments Study
type
6 cycles of docetaxel 100
mg/m2 every 3 weeks,
with (n = 92) or without (n =
94) trastuzumab 4 mg/kg
loading dose followed by 2
mg/kg weekly until disease
progression
MeSH term(s) used: Breast Neoplasms; Antibodies, Monoclonal. Free text word: trastuzumab.
Overall response rate: 61% vs. 34%;
p=0.0002)
Overall survival: 31.2 vs. 22.7 months;
p=0.03)
Time to disease progression: 11.7 vs. 6.1
months; p=0.0001)
Time to treatment failure: 9.8 vs. 5.3
months; p=0.0001)
Duration of response: 11.7 vs. 5.7 months;
p=0.009)
All in favour of trastuzumab
RCT High
Level of
evidence

KCE reports 63 Breast Cancer 113
Treatment of bone metastases.
Study ID Ref Search
date
Bisphosphonates
Pavlakis N et al [110] 2004 Women with
metastatic
breast cancer
Wardley A 2005 [250] NA Histologically
confirmed
diagnosis of
breast cancer
and ≥1 bone
M+
Population Intervention Ouctomes Results Comments Study
type
Bisphosphonates In 9 studies (2189 women with advanced
breast cancer and existing
bonemetastases), BP reduced the risk of
developing a skeletal event by 17% (RR
0.83; 95%CI 0.78 to 0.89; P <
0.00001). The BP most effective in
reducing the risk of developing a skeletal
event by 41% was 4 mg IV zolendronate
(RR 0.59, 95%CI 0.42-0.82). Women with
advanced breast cancer and clinically
evident bone M+ treated with BP showed
significant delays in the median time to a
skeletal event. Compared with placebo or
no BP, with BP significant improvements in
bone pain were reported in seven studies.
Improvements in global quality of life were
reported in only the three studies of iv and
oral ibandronate.
Treatment with BP does not appear to
affect survival in women with advanced
Zoledronic acid in community
setting (n = 56) vs. hospital
setting (n = 45)
breast cancer.
Significantly greater improvements in pain
scores after treatment in the community
setting compared with the hospital
crossover setting for worst pain (P=0.021),
average pain (P=0.003), and interference
with general activity (P=0.001).
21 RCTs included (18
RCTs involved women
with bone M+)
SR High
RCT High
Level of
evidence

114 Breast Cancer KCE reports 63
Study ID Ref Search
date
Diel IJ 2004 [251] NA Patients with
histologically
confirmed
breast cancer
and bone M+
Tripathy D 2004 [252] NA Histologically
confirmed
breast cancer
and
radiologically
confirmed bone
M+
Radiotherapy
Hartsell WF 2005 [253] NA Histologically
proven primary
malignancy of
breast or
prostate and
radiographic
evidence of
painful bone M+
Population Intervention Ouctomes Results Comments Study
type
2 mg ibandronate by iv bolus
injection (n = 154), or placebo
(n = 158) or 6 mg ibandronate
by iv infusion
over 1–2 h (n = 154)
Ibandronate 20 mg (n = 144)
vs. 50 mg (n = 148) vs. placebo
(n = 143)
Radiotherapy 8 Gy (n = 455)
vs. 30 Gy (n = 443)
MeSH term(s) used: Breast Neoplasms; Bone Neoplasms.
Adverse events
QoL
Bone pain
Skeletal
morbidity
period rate
(SMPR)
Compared with baseline measurements,
the bone pain score was increased at the
last assessment in both the placebo and 2
mg ibandronate groups, but was
significantly reduced in the patients
receiving 6 mg ibandronate (-0.28± 1.11, P
< 0.001). A significant improvement in
QoL was demonstrated for patients
treated with ibandronate (P < 0:05) for all
global health status. Overall, at the last
assessment, the 6 mg ibandronate group
showed significantly better functioning
compared with placebo (P = 0.004), and
had significantly better scores on the
domains of physical, emotional, and social
functioning, and in global health status (P <
0.05).
SMPR was significantly reduced with oral
ibandronate (placebo 1.2, 20 mg group
0.97 (p=0.024), 50 mg group 0.98
(p=0.037)). Ibandronate 50 mg significantly
reduced the need for radiotherapy
(p=0.005 vs. placebo). The relative risk of
skeletal events was reduced by 38% (20 mg
dose) and 39% (50 mg dose) vs. placebo
(p=0.009 and p=0.005).
Complete and partial response rates were
15% and 50%, respectively, in the 8-Gy
arm compared with 18% and 48% in the
30-Gy arm (p=0.6). At 3 months, 33% of
all patients no longer required narcotic
medications. The incidence of subsequent
pathologic fracture was
5% for the 8-Gy arm and 4% for the 30-Gy
arm. The retreatment rate was statistically
signifi cantly higher in the 8-Gy arm (18%)
than in the 30-Gy arm (9%) (p

KCE reports 63 Breast Cancer 115
Treatment of locoregional relapse of breast cancer.
Study ID Ref Search
date
Rauschecker H et
al
[254] 2005 Women with
potentially curatively
resected locoregional
recurrence following
breast cancer
Population Intervention Ouctomes Results Comments Study
type
MeSH term(s) used: Breast Neoplasms; Recurrence.
Adjuvant systemic treatment The trial of 32 women who received either
RT alone or in combination with systemic
administration of actinomycin-D found that
chemotherapy improved the local control
rate but had no apparent effect on overall
survival. The interferon trial, which also
included a total of only 32 patients,
showed that the addition of alphainterferon
to local treatment of
locoregional recurrent breast cancer had
no apparent effect on the further course of
the disease. The Swiss SAKK trial of
tamoxifen (178 women randomised) found
an improvement in disease-free survival
but not in overall survival. No results were
available for the 50 women randomised
into the concurrent trial of chemotherapy.
3 RCTs (4 randomised
comparisons)
SR High
Level of
evidence

116 Breast Cancer KCE reports 63
Bisphosphonates for non-metastatic breast cancer.
Study ID Ref Search
date
Powles T 2006 [255] NA Primary operable stage I-
III breast cancer
Pavlakis N
2005
Fuleihan GE
2005
Population Intervention Ouctomes Results Comments Study
type
[110] 2004 Advanced breast cancer
without clinically evident
bone M+
[256] NA Newly diagnosed
premenopausal women
with histologically proven,
nonmetastatic breast
cancer
MeSH term(s) used: Breast Neoplasms; Diphosphonates.
Oral clodronate 1600 mg/d for
2 years (n = 530) vs. placebo
(n = 539)
Time to first
bone M+
Risk of bone M+ over the 5 year study period:
HR = 0.69, p=0.043, in favour of clodronate.
The difference was also statistically significant
over the 2 year medication period (HR = 0.55, p=
0.031).
Bisphosphonates vs. placebo In the three studies of bisphosphonates in 320
women with advanced breast cancer without
clinically evident bone M+, there was no
significant reduction in the incidence of skeletal
Pamidronate 60 mg IV every 3
months (n = 21) vs. placebo (n
= 19)
BMD of spine
and hip
events (RR 0.99; 95% CI 0.67-1.47; P = 0.97).
The mean difference in percent change in BMD at
12 months between the two treatment groups
was 5.1% at the lumbar spine (P = 0.002) in the
overall study group and 5% at the lumbar spine
and 5.2% at the total hip in the amenorrheic
subgroup (P < 0.03).
RCT High
SR High
Level of
evidence
RCT Moderate

KCE reports 63 Breast Cancer 117
Physiotherapy after axillary surgery.
Study ID Ref Search
date
Badger C et al [112] 2003 Patients with
lymphoedema of
Population Intervention Ouctomes Results Comments Study
type
the limbs
Ahmed RL 2006 [257] NA Breast cancer
patients with
axillary dissection
as part of their
treatment
Wilburn O 2006 [258] NA Patients with
lymphedema of
the upper
extremity after
surgical and/or
radiotherapeutic
interventions for
breast carcinoma
(n = 10)
Didem K 2005 [259] NA Unilatreral
lymphedema after
breast
cancer treatment
Physical treatment programmes Insufficient evidence
3 trials with limitations and all 3 different
Twice-a-week weight training
(n = 42) vs. control (n = 43)
Self-administered treatment
with the Flexitouch or
massage, 1 hour daily for
14days, respectively, followed
by crossover to the alternate
treatment phase.
Complex decongestive
physiotherapy (CDP)
applications including lymph
drainage, multi layer
compression bandage,
elevation, remedial exercises
and skin care (n = 27) vs.
standard physiotherapy
(SP) applications including
bandage, elevation, head–neck
and shoulder exercises and skin
care (n = 26)
treatments
None of the intervention-group
participants experienced a change in arm
circumferences ≥ 2.0 cm after a 6-month
exercise intervention. Self-reported
incidence of a clinical diagnosis of
lymphedema or symptom changes over 6
months did not vary by intervention status
(p=0.40 and p=0.22, respectively).
Post-treatment arm volume reduced
significantly after the Flexitouch, but not
after self-administered massage.
The overall improving in the CDP group
was shown to be greater than the SP
group but when the evaluation results of
both groups were compared before and
after treatment, a significant statistical
difference in edema according to
circumferential and volumetric
measurements results was found in favor
of the CDP group (p < 0.05).
3 RCTs included
1 study with breast
cancer patients only
SR High
Blinded evaluation RCT High
Randomization poorly
described
Very low power
MeSH term(s) used: Breast Neoplasms; Exercise; Physical education and training; Physical therapy modalities; Musculoskeletal manipulations; Exercise movement
techniques; Physical therapy (specialty); Exercise Movement Techniques.
RCT Low
RCT High
Level of
evidence

118 Breast Cancer KCE reports 63
Study ID Ref Search
date
McNeely ML
2006
Demark-
Wahnefried W
2006
Physical exercise after treatment of breast cancer.
[113] 2005 Women with early to
later stage (Stage 0–III)
breast cancer or who
had undergone breast
cancer surgery with or
without adjuvant
cancer
therapy
[260] NA Locoregionally staged
breast and prostate
cancer patients, who
were aged ≥ 65 years
old and within 18
months of diagnosis
Population Intervention Ouctomes Results Comments Study
type
Exercise (defined as a form of
leisure-time physical activity
that was performed on a
repeated basis over an
extended period of time, with
the intention of improving
fitness, performance or
health)
Intervention (n = 89):
telephone counseling and
tailored print materials aimed
at increased exercise and an
improved overall diet
(increased diet diversity with
increased F&Vs and whole
grains; decreased total fat,
saturated fat, and
cholesterol; and adequate iron
and calcium)
Control (n = 93): general
health counseling and materials.
Both interventions included 12
bimonthly 20- to 30-minute
sessions over a 6-month
period.
Exercise led to statistically significant
improvements in quality of life as assessed
by the Functional
Assessment of Cancer Therapy–General
(WMD 4.58, 95%CI 0.35 to
8.80) and Functional Assessment of Cancer
Therapy–Breast (WMD 6.62, 95%CI 1.21
to 12.03). Exercise also led to significant
improvements in physical functioning and
peak oxygen consumption and in reducing
symptoms of fatigue.
No significant differences between
treatment groups
14 RCTs included (4 of
high quality)
Randomization poorly
described
SR High
RCT Low
Level of
evidence

KCE reports 63 Breast Cancer 119
Study ID Ref Search
date
Kim C 2006 [261] NA Women with breast
cancer undergoing
adjuvant treatment
Population Intervention Ouctomes Results Comments Study
type
8-week moderate intensity
(60Y70% VO2 peak) supervised
aerobic exercise program 3
times a week (n = 22) vs. usual
cancer care (n = 19)
Ohira T 2006 [262] NA Breast cancer survivors Exercise (n = 43) vs. control (n
= 43)
Pinto BM 2005 [263] Women who had
completed treatment
for stage 0 to II breast
cancer
12-week, home-based
moderate-intensity PA program
(n = 43) vs. control (n = 43)
Only the intervention group showed
significant decreases in resting heart rate,
resting systolic blood pressure (SBP),
p

120 Breast Cancer KCE reports 63
Hormonal replacement therapy after treatment for breast cancer.
Study ID Ref Search
date
Von Schoultz E
2005
[114] NA Women with
breast cancer
Population Intervention Ouctomes Results Comments Study
type
Postmenopauzal hormone
replacement therapy
MeSH term(s) used: Breast Neoplasms; Hormone Replacement Therapy.
HABITS trial: risk for recurrence of breast
cancer among patients receiving
menopausal HRT was statistically
signifi cantly higher (relative hazard
[RH] = 3.3, 95%CI = 1.5 to 7.4) than
among those receiving no treatment.
Stockholm trial: risk of breast cancer
recurrence was not associated
with menopausal HRT (RH = 0.82, 95%CI
= 0.35 to 1.9).
Description of 2 RCTs RCT Low
Level of
evidence

KCE reports 63 Breast Cancer 121
Psychological support for women with breast cancer.
Study ID Ref Search
date
Edwards AGK et
al
[115] 2003 Women with
metastatic breast
cancer
Group interventions
Lane LG 2005 [116] NA Breast cancer
survivors (nonmetastatic)
Savard J 2005 [117] NA Women who had
completed
radiotherapy and
chemotherapy
for a stage I to III
breast cancer
Taylor KL 2003 [118] NA African American
women with Stage
0 to IIIA breast
cancer who had
undergone
Population Intervention Ouctomes Results Comments Study
type
surgery
Antoni MH 2006 [119] NA Breast cancer at
stage III or below
having undergone
surgery
Vos PJ 2006 [120] NA Women with
primary breast
cancer having
Psychological interventions
(educational, individual
cognitive behavioural or
psychotherapeutic, or group
support)
Brief personal construct group
therapy (n = 20) vs. wait-list
control condition (n = 22)
Cognitive behavioural therapy
during 8-weekly group sessions
(n = 27) vs. a waiting-list
control condition (n = 30)
Support group intervention (n
= 40) or the assessment-only
control condition (n = 33)
Structured, group-based
cognitive behavior stress
management (n = 92) vs.
control (n = 107)
Intervention program (group
psychotherapy or social
support group) (n = 34) vs.
Insufficient evidence 5 primary studies (RCTs) SR High
Analyses showed that the beneficial
effects of therapy achieved
posttreatment were maintained at
3-month follow-up.
Significantly better subjective sleep
indices (daily sleep diary, Insomnia
Severity Index), a lower frequency
of medicated nights, lower levels of
depression and anxiety, and greater
global quality of life at posttreatment
compared
In treatment group. Results were
more equivocal on
polysomnographic indices.
Therapeutic effects were well
maintained up to 12 months after
the intervention and generally were
clinically significant.
At 12 months, the intervention
resulted in improved mood as well
as improved general and cancerspecific
psychological functioning
among women with greater baseline
distress or lower income.
The intervention reduced reports
of thought intrusion, interviewer
ratings of anxiety, and emotional
distress across 1 year significantly
more than was seen with the
control condition. The beneficial
effects were maintained well past
the completion of adjuvant therapy.
Women who participated in the
group intervention programs did
not differ from women in the
Level of
evidence
Short follow-up RCT Moderate
Randomization procedure? RCT Low
Randomization procedure
not mentioned
Drop-outs equally
distributed?
No intention-to-treat
RCT High
RCT Low
RCT Low

122 Breast Cancer KCE reports 63
Study ID Ref Search
date
Individual interventions
Andersen BL
2004
Population Intervention Ouctomes Results Comments Study
type
undergone
surgery (n = 87)
[121] NA Stage II or III
breast cancer,
surgically treated,
and awaiting
adjuvant therapy
Hack TF 2003 [122] NA Women newly
diagnosed with
breast cancer (n =
628)
control (on a waiting list) (n =
35)
Intervention (small patient
groups, with one session per
week for 4 months; including
strategies to reduce stress,
improve mood, alter health
behaviors, and maintain
adherence to cancer treatment
and
Careor) (n = 114) vs.
assessment only (n = 113)
Audiotape of primary adjuvant
treatment consultation
Four groups: standard care
control, not audiotaped;
audiotaped, no audiotape given;
audiotaped, patient given
audiotape; and audiotaped,
patient offered choice of
receiving audiotape or not.
control group regarding
psychosocial adjustment at the end
of the first study. Women who
participated in the social support
groups reported to receive more
social support from others not very
close to them. They also used more
palliative coping than women from
the psychotherapy group.
Women who started with their
intervention early were less
distressed at 6 months follow-up
than women who were in the
delayed condition. Medical and
demographic variables were
predictive for some psychosocial
adjustment indicators, but were not
associated with time of enrolment.
Regardless of time of enrolment,
women improved in distress, body
image and recreational activities,
but showed a decrease in social
interaction.
Patients receiving the intervention
showed significant lowering of
anxiety, improvements in perceived
social support, improved dietary
habits, and reduction in smoking (all
P < .05).
Patients receiving the consultation
audiotape had significantly better
recall of having discussed side
effects of treatment than patients
who did not receive the audiotape.
Audiotape benefit was not
significantly related to patient
satisfaction with communication,
mood state, or quality of life at 12
weeks postconsultation, and was
RCT High
RCT High
Level of
evidence

KCE reports 63 Breast Cancer 123
Study ID Ref Search
date
Lee V 2006 [123] NA Patients with
breast or
colorectal cancer
receiving
anticancer
treatment
McGregor BA
2004
[124] NA Women who had
recently been
treated for Stage I
or Stage II breast
Population Intervention Ouctomes Results Comments Study
type
cancer
Scheier MF 2005 [125] NA Women with
stage 0-II breast
cancer, who
recently
completed their
nonhormonal
adjuvant therapy
Shapiro SL 2003 [126] NA Women with
stage II breast
cancer, currently
in remission,
within 2 years
posttreatment
Stanton AL 2005 [127] NA Women with
newly diagnosed
stage I-II breast
cancer
Routine care (control group) (n
= 39) or up to four sessions
that explored the meaning of
the emotional responses and
cognitive
appraisals of each individual’s
cancer experience within the
context of past life events and
future goals (experimental
group) (n = 39)
10-week cognitive-behavioural
stress management
intervention (n = 18) vs. a
comparison experience (n =
11)
Standard medical care (n = 84)
vs. educational intervention
(information provision, n = 83)
vs. nutritional intervention
(promotion of healthy diet, n =
85)
Mindfulness-based stress
reduction (MBSR) intervention
(n = 31) vs. free choice
intervention (n = 32)
Provision of information with
standard National Cancer
Institute print material (CTL)
(n = 187); standard print
material and peer-modeling
videotape (VID) (n = 187); or
standard print material,
videotape, two sessions with a
trained cancer educator, and
not significantly affected by choice
of receiving the audiotape.
After controlling for baseline
scores, the experimental group
participants demonstrated
significantly higher levels of selfesteem,
optimism, and self-efficacy
compared to the control group.
Benefit finding Women in the CBSM intervention
reported greater perceptions of
benefit from having breast cancer
compared to the women in the
comparison group.
Participants assigned to the two
active treatment arms had
significantly less depressive
symptomatology and better physical
functioning by 13-month follow-up
(differences between the two active
arms were nonsignificant).
Both MBSR and the free choice
(FC) control condition produced
significant improvement on daily
diary sleep quality measures though
neither showed significant
improvement on sleep-efficiency.
Participants in the MBSR who
reported greater mindfulness
practice improved significantly more
on the sleep quality measure most
strongly associated with distress.
VID produced significant
improvement in energy/fatigue at
6 months relative to CTL,
particularly among women who felt
less prepared for re-entry at
baseline. No significant main effect
of the interventions emerged on
cancer-specific distress, but EDU
prompted greater reduction in this
RCT High
Randomization procedure? RCT Low
Randomization procedure? RCT Low
Randomization procedure?
Bias in intervention (cfr.
free choice)
RCT Low
RCT High
Level of
evidence

124 Breast Cancer KCE reports 63
Study ID Ref Search
date
Tatrow K 2006 [128] 2004 Breast cancer
patients
Couple & family interventions
Manne SL 2005 [129] NA Women with
early stage breast
cancer who had
undergone
breast cancer
surgery within the
last 6 months
Population Intervention Ouctomes Results Comments Study
type
informational workbook (EDU)
(n = 184)
Cognitive-behavioural therapy Pain
Distress
6 sessions of a couple-focused
group intervention (n = 120)
vs. usual care (n = 118)
outcome relative to CTL at 6
months for patients who felt more
prepared for re-entry. Betweengroup
differences in the primary
outcomes were not significant at 12
months, and no significant effects
emerged on the secondary end
points.
Results revealed effect sizes of
d=0.31 for distress (p0.05). The
correlation between effect sizes for
distress and pain was not significant
(p=0.07).
Participants assigned to the couples’
group reported lower depressive
symptoms. Women rating their
partners as more unsupportive
benefited more from the
intervention than did women with
less unsupportive partners, and
women with more physical
impairment benefited more from
the intervention group than did
women with less impairment.
20 RCTs included SR High
Randomization procedure? RCT Low
Level of
evidence

KCE reports 63 Breast Cancer 125
Study ID Ref Search
date
Northouse L
2005
[130] NA Recurrent or
progressive breast
cancer
Scott JL 2004 [131] NA Early-stage breast
(n = 57) or
gynaecological
cancer
Computer & telephone based interventions
Owen JE 2005 [132] NA Women with
early-stage breast
cancer
Sandgren AK
2003
[133] NA Women with
stage I-III breast
cancer
Population Intervention Ouctomes Results Comments Study
type
Usual care vs. usual care plus
the family intervention
Couples-based coping training,
individual coping training for
the woman, or a medical
education control
Small online coping group (n =
32) vs. waiting-list control
condition (n = 30)
Standard care (n = 55) vs.
health education by phone (n =
78) vs. emotional expression by
phone (n = 89)
Patients in the family intervention
reported significantly less
hopelessness and less negative
appraisal of illness than controls;
their family caregivers reported
significantly less negative appraisal
of caregiving. Intervention effects
were evident at three-months, but
were not sustained at six-months.
No difference was found in the
quality of life of dyads in
experimental or control conditions.
Couples’ observed support
communication and self-reported
psychological distress, coping effort,
and sexual adjustment were
assessed at diagnosis, after cancer
surgery, and at 6- and 12-month
follow-ups. CanCOPE produced
significant improvements in couples’
supportive communication, reduced
psychological distress and coping
effort, and improved sexual
adjustment. Training in couples
rather than individual coping was
more effective in facilitating
adaptation to cancer.
No main effects for treatment were
observed at the 12-week follow up.
However, there was a significant
interaction between baseline selfreported
health status and
treatment, such that women with
poorer self-perceived health status
showed greater improvement in
perceived health over time when
assigned to the treatment
condition.
Women in the cancer education
condition reported greater
perceived control than women in
the standard care condition. No
treatment effects were obtained for
Only analysis of stage III
and IV patients
Randomization procedure?
RCT Low
Randomization procedure? RCT Low
RCT High
Randomization procedure? RCT Low
Level of
evidence

126 Breast Cancer KCE reports 63
Study ID Ref Search
date
Winzelberg AJ
2003
[134] NA Women with
primary breast
cancer
MeSH term(s) used: Breast Neoplasms/Psychology.
Population Intervention Ouctomes Results Comments Study
type
12-week, web-based, social
support group (n = 36) vs.
waiting-list condition group (n
= 36)
mood or quality of life.
The results indicate that a webbased
support group can be useful
in reducing depression and cancerrelated
trauma, as well as perceived
stress, among women with primary
breast carcinoma. The effect sizes
ranged from 0.38 to 0.54.
Participants perceived a variety of
benefits and high satisfaction from
their participation in the
intervention.
Randomization procedure? RCT Low
Level of
evidence

KCE reports 63 Breast Cancer 127
Reconstructive surgery.
No additional RCTs or SR found (MeSH: Reconstructive Surgical Procedures; Surgery, Plastic).

128 Breast Cancer KCE reports 63
Surveillance of breast cancer patients.
Study ID Ref Search
date
Rojas MP et al [264] 2004 Women treated for
stage I, II and III
breast cancer
Grunfeld E 2006 [265] NA Women with earlystage
breast cancer
who had completed
adjuvant
chemotherapy,
radiotherapy, or
both at least 3
months previously;
who were disease
free; and who were
between 9 and 15
months after
Population Intervention Ouctomes Results Comments Study
type
diagnosis
Kokko R 2005 [266] NA Breast cancer
patients with
localized disease
after primary
treatment
Follow-up after primary
treatment
Follow-up either in a
cancer center according
to usual practice (CC
group) (n = 485) or from
their own family
physician (FP group) (n =
483)
Visit every 3 rd (frequent
arms A, B) vs. 6 th
(infrequent arms C, D)
month and diagnostic
tests routinely (routine
arms A, C) vs. only when
clinically indicated (no
routine arms B, D).
A: n = 125
B: n = 114
C: n = 118
D: n = 115
Recurrencerelated
serious
clinical event
QoL
Follow-up based on clinical visits and mammography
vs. a more intensive scheme including radiological and
laboratory tests (2 RCTs): no significant differences in
overall survival (HR 0.96, 95%CI 0.80 to 1.15) or
disease-free survival (HR 0.84, 95%CI 0.71 to 1.00).
Follow-up performed by a hospital-based specialist vs.
follow-up performed by general practitioners (1 RCT):
no significant differences in time to detection of
recurrence and quality of life. Patient satisfaction was
greater among patients treated by general
practitioners.
Regularly scheduled follow-up visits vs. less frequent
visits restricted to the time of mammography (1 RCT):
no significant differences in interim use of telephone
and frequency of GP’s consultations.
In the FP group, there were 54 recurrences (11.2%)
and 29 deaths (6.0%). In the CC group, there were 64
recurrences (13.2%) and 30 deaths (6.2%). In the FP
group, 17 patients (3.5%) compared with 18 patients
(3.7%) in the CC group experienced an SCE (0.19%
difference; 95%CI 2.26% to 2.65%). No statistically
significant differences were detected between groups
on any of the HRQL questionnaires.
Neither the frequency of visits nor the intensity of
diagnostic examinations had any effect on disease-free
or overall survival of patients. The total costs of
follow-up, however, were different in the four
followup schedules and varied between arms per
patient from 1050 to 2269 € and per detected
recurrence from 4166 to 9149 €. Outpatient visits
every third month compared to every sixth month and
routine examinations in the followup of asymptomatic
primary breast cancer patients do not improve patient
disease-free or overall survival, but increase the costs
of follow-up 2.2 times.
4 RCTs included
(3055 women)
SR High
RCT High
RCT High
Level of
evidence

KCE reports 63 Breast Cancer 129
Study ID Ref Search
date
De Bock GH
2004
Koinberg IL
2004
[267] 2002 Primary operable
breast cancer (M0)
[268] NA Stage I and II breast
cancer
Collins RF 2004 [269] 2001 Patients treated for
breast cancer
Population Intervention Ouctomes Results Comments Study
type
Follow up Locoregional
recurrence
Routine medical followup,
the physician group
(PG, n = 131) vs. on
demand by a specialist
nurse, the nurse group
(NG, n = 133)
MeSH term(s) used: Breast Neoplasms; Follow-up Studies; Continuity of Patient Care.
Pooling data showed an overall estimate of 40% of
isolated locoregional recurrences diagnosed during
routine visits or routine tests in asymptomatic patients
(95%CI 35 to 45). Of these, 47% (95%CI 39 to 54)
were diagnosed after mastectomy, and 36% (95%CI 28
to 43) were diagnosed after breast-conserving therapy
(RR 1.327; 95%CI 1.014 to 1.738). Apart from
differences in therapy, we have not been able to
discern subgroups of patients for whom results were
different.
The levels of anxiety and depression were generally
low and levels of patient satisfaction high. There were
no differences between the groups concerning time to
recurrence or death.
Follow up Patient survival and quality of life were not affected by
intensity of follow-up or location of care. Patients held
positive attitudes towards follow-up but psychological
distress was consistently high regardless of location of
services. Few studies assessed patient involvement in
treatment choices. Studies’ research quality was poor
with inadequate measures of effectiveness or research
designs. There is insufficient primary empirical
evidence to draw broad conclusions regarding best
practice for breast cancer follow-up care in terms of
(a) patient involvement in care, (b) reductions in
morbidity, and (c) cost effectiveness of service
provision.
Extensive search
12 trials included: 1
RCT, 1 prospective
cohort study, 10
retrospective
cohort studies
2 Swedish hospitals
involved
English only
38 trials included of
which 5 were RCTs
Level of
evidence
SR Moderate
RCT High
SR High

130 Breast Cancer KCE reports 63
APPENDIX 4
SCORES AND COMMENTS OF EXTERNAL REVIEWERS
1. Based on the comments of the external reviewers, the following original recommendations
(see below) were removed:
Recommendation n° 50
Recommendation n° 59 – 66: were replaced by the final recommendations n° 58 – 61
For all other recommendations, the comments of the external reviewers
- were taken into account to reformulate the recommendation
- or were used in the discussion.
2. After this process, some recommendations were rephrased to some extent because of clarity
reasons (recommendation 21, 22, 30, 31, 46, 49, 51, 62, 67, 69, 73, 75, 79, 97).
3. Based on the comments of the validators the original recommendation 94 was removed and
some other original recommendations were slightly rephrased (recommendation 46, 47, 52,
74, 108, 109, 110, 116).

KCE reports 63 Breast Cancer 131
N° Recommendation 1 2 3 4 5 6 7 8 9 10 11 Mean Median SD % 4 or 5
1 Based on the literature, the present breast cancer
screening programme by mammography for women
aged 50 – 69 years remains justified (2A evidence).
2 There is no hard evidence to recommend other
screening methods (e.g. ultrasonography, MRI, selfexamination)
than two-view mammography (1C
evidence).
3 Routine referral for genetic counseling or routine
breast cancer susceptibility gene (BRCA) testing for
women whose family history is not associated with an
increased risk for deleterious mutations in breast
cancer susceptibility gene 1 (BRCA1) or breast cancer
susceptibility gene 2 (BRCA2) is not recommended
(1B evidence).
4 Women whose family or personal history is associated
with an increased risk for:
a. deleterious mutations in BRCA 1 or BRCA 2 gene
(early-age-onset breast cancer, two primary breast
cancers and/or breast and ovarian cancers in the
same individual or close relatives on the same side of
the family, known mutation in a family member,
Ashkenazi Jewish decent with breast cancer in women
< 50 years or ovarian cancer, male breast cancer,
more than one ovarian cancer on the same side of the
family);
b. Li-Fraumeni and Cowden Syndrome (thyroid cancer,
sarcoma, adrenocortical cancer, endometrium cancer,
pancreatic cancer, brain tumors, dermatologic
manifestations, leukemia/lymphoma)
should be referred for genetic counselling (1B
evidence).
5 All high-risk women should have access to information
on genetic tests aimed at mutation finding (1C
evidence).
6 Pre-test counselling (preferably two sessions) is
mandatory (1A evidence).
7 Discussion of genetic testing (predictive and mutation
finding) should be undertaken by someone with
appropriate training (1A evidence).
8 High-risk women and their affected relatives should be
informed about the likely informativeness of the test
(the meaning of a positive and a negative test) and the
likely timescale of being given the results (1A
evidence).
2 3 5 5 5 4 5 5 5 4 4 4,27 5 1,01 82%
3 5 4 4 5 5 4 5 5 4 5 4,45 5 0,69 91%
5 5 5 2 5 5 4 NA 2 4 5 4,20 5 1,23 80%
5 5 5 5 5 5 5 NA 5 5 5 5,00 5 0,00 100%
5 5 5 5 5 5 5 NA 5 5 5 5,00 5 0,00 100%
5 5 5 5 5 5 5 NA 4 5 4,89 5 0,33 100%
5 5 5 5 5 5 5 NA 5 5 5 5,00 5 0,00 100%
5 5 5 5 5 5 5 NA 5 5 5 5,00 5 0,00 100%
1. OK for level of evidence but not
recommendation as formulated see
réf Gotzsche
2. quid before 50 and after 70?
1. clinical exam adds 5% to
sensitivity, US do better than
mammo in BI-RADS 3 and 4 for
invasive cancer
3. the group with BRCA mutations is
an exception
4. where it says "whose family
history" should say "whose family
and/or personal history"
9. We reccomend Genetic testing for
all tumour under the age of 35

132 Breast Cancer KCE reports 63
9 Women from families with a 20% or greater chance of
carrying a mutation such as BRCA1, BRCA2 or TP53
should have access to testing (1C evidence).
10 The development of a genetic test for a family should
usually start with the testing of an affected individual
(mutation searching/screening) to try to identify a
mutation in the appropriate gene (such as BRCA1,
BRCA2 or TP53) (1C evidence).
11 A search/screen for a mutation in a gene (such as
BRCA1, BRCA2 or TP53) should aim for as close to
100% sensitivity as possible for detecting coding
alterations and the whole gene(s) should be searched
(1C evidence).
12 For women from families with BRCA1, BRCA2 or
TP53 mutations, or with equivalent high breast cancer
risk, individualised screening strategies should be
developed (1C evidence).
13 There is a lack of evidence for a high risk population
that either clinical breast examination or selfexamination
is useful as the sole surveillance modality
(1A evidence).
14 All women with a genetic or familial high risk should be
offered mammographic and ultrasound surveillance
from age 30 years (1C evidence).
15 For women aged 40–49 years at moderate risk or
greater, mammographic and ultrasound surveillance
should be annual (1C evidence).
16 On the basis of current evidence, MRI should be
added to routine surveillance practice of patients with
high genetic risk (1C evidence).
5 5 5 5 5 5 5 NA 5 5 3 4,80 5 0,63 90%
5 5 4 5 5 5 5 NA 5 4 4,78 5 0,44 100%
5 5 5 5 5 5 5 NA 5 5 4 4,90 5 0,32 100%
5 5 5 5 5 5 5 NA 5 5 4 4,90 5 0,32 100%
5 5 4 5 5 5 5 5 5 5 5 4,91 5 0,30 100%
4 5 4 2 5 4 2 1 2 3 5 3,36 4 1,43 55%
5 4 5 5 5 4 5 5 5 4 4 4,64 5 0,50 100%
3 5 5 5 5 5 5 5 5 4 5 4,73 5 0,65 91%
3. You must take in consideration
the age of the youngest familiy
memeber with breast cancerand
MRI has a central place in young
patients
4. MRI should also be offered and is
prefered for young ages
7. MRI?
8. No: MRI should be the first-line
imaging tool. The age at which
screening starts is patientdependent.
Mammographic
screening will not start before age
35, because of the radiation risk.
See references at point 16.
9. and MRI
10. MRI
8. Important references: Radiology.
2007 Mar;242(3):698-715 - JAMA.
2004 Sep 15;292(11):1317-25 - J
Clin Oncol. 2005 Nov
20;23(33):8469-76.

KCE reports 63 Breast Cancer 133
17 Bilateral risk-reducing mastectomy is appropriate only
for a small proportion of women who are from high-risk
families and should be managed by a multidisciplinary
team (1C evidence).
5 5 5 5 5 5 5 NA 5 4 5 4,90 5 0,32 100%
18 Bilateral mastectomy should be raised as a riskreducing
strategy option with all women at high risk
(1C evidence).
4 3 3 5 5 4 5 NA 5 4 3 4,10 4 0,88 70%
19 Women considering bilateral risk-reducing
mastectomy should have genetic counselling in a
specialist cancer genetics clinic, before a decision is
made (1C evidence).
5 4 3 5 5 4 2 NA 4 3 3 3,80 4 1,03 60%
20 Discussion of individual breast cancer risk and its
potential reduction by surgery should take place and
take into account individual risk factors, including the
woman's current age (especially at extremes of age
ranges) (1C evidence).
5 4 5 5 5 4 5 NA 5 4 4 4,60 5 0,52 100%
21 Family history should be verified where no mutation
has been identified before bilateral risk-reducing
mastectomy (1C evidence).
5 5 5 5 5 4 5 NA 5 5 5 4,90 5 0,32 100%
22 Where no family history verification is possible,
agreement by a multidisciplinary team should be
sought before proceeding with bilateral risk-reducing
mastectomy (1C evidence).
5 4 5 2 5 4 5 NA 5 4 5 4,40 5 0,97 90%
23 Pre-operative counselling about psychosocial and
sexual consequences of bilateral risk-reducing
mastectomy should be undertaken (1C evidence).
5 5 5 5 5 4 5 NA 5 5 5 4,90 5 0,32 100%
24 The possibility of breast cancer being diagnosed
histologically following a risk-reducing mastectomy
4,90 5 0,32 100%
should be discussed pre-operatively (1C evidence). 5 5 5 5 5 5 4 NA 5 5 5
25 All women considering bilateral risk-reducing
mastectomy should be able to discuss their breast
reconstruction options (immediate and delayed) with a
member of a surgical team with specialist oncoplastic
or breast reconstructive skills (1C evidence).
5,00 5 0,00 100%
5 5 5 5 5 5 5 NA 5 5 5
26 A surgical team with specialist oncoplastic/breast
reconstructive skills should carry out risk reducing
4,90 5 0,32 100%
mastectomy and/or reconstruction (1C evidence). 5 5 5 5 5 4 5 NA 5 5 5
27 Women considering bilateral risk-reducing
mastectomy should be offered access to support
groups and/or women who have undergone the
4,70 5 0,67 90%
procedure (1C evidence). 5 3 5 5 5 5 5 NA 5 5 4
28 Risk-reducing bilateral salpingo-oophorectomy is
appropriate only for a small proportion of women who
are from high risk families and should be managed by
a multidisciplinary team (1C evidence).
4,67 5 0,71 89%
5 3 5 4 5 5 NA NA 5 5 5
3. This depends on definition "high
risk"
7. High risk patient???
4. please considerer changing the
word "should" for "MUST"

134 Breast Cancer KCE reports 63
29 Information about bilateral salpingo-oophorectomy as
a potential risk-reducing strategy should be made
available to women who are classified as high risk (1C
evidence). 3 5 5 5 5 4 5 NA 5 5 5
30 Family history should be verified where no mutation
has been identified before bilateral risk-reducing
salpingo-oophorectomy (1C evidence). 5 5 5 5 5 4 5 NA 5 5 4
31 Where no family history verification is possible,
agreement by a multidisciplinary team should be
sought before proceeding with bilateral risk-reducing
salpingo-oophorectomy (1C evidence). 5 4 5 2 5 4 5 NA 5 4 5
32 Any discussion of bilateral salpingo-oophorectomy as
a risk-reducing strategy should take fully into account
factors such as anxiety levels on the part of the woman
concerned (1C evidence). 5 4 5 5 5 4 5 NA 5 4 4
33 Healthcare professionals should be aware that women
being offered risk-reducing bilateral salpingooophorectomy
may not have been aware of their risks
of ovarian cancer as well as breast cancer and should
be able to discuss this (1C evidence).
5 5 5 5 5 5 5 NA 5 4 5
34 The effects of early menopause should be discussed
with any woman considering risk-reducing bilateral
salpingo-oophorectomy (1C evidence).
5 5 5 5 5 5 5 NA 5 5 5
35 Options for management of early menopause should
be discussed with any woman considering riskreducing
bilateral salpingo-oophorectomy, including
the advantages, disadvantages and risk impact of HRT
(1C evidence).
5 5 5 5 5 4 NA 5 5 5
36 Women considering risk-reducing bilateral salpingooophorectomy
should have access to support groups
and/or women who have undergone the procedure (1C
evidence). 5 3 3 5 5 4 5 NA 5 5 4
37 Women considering risk-reducing bilateral salpingooophorectomy
should be informed of possible
psychosocial and sexual consequences of the
procedure and have the opportunity to discuss these
issues (1C evidence). 5 4 5 5 5 5 5 NA 5 5 5
38 Women not at high risk who raise the possibility of riskreducing
bilateral salpingo-oophorectomy should be
offered appropriate information, and if seriously
considering this option should be offered referral to the
team that deals with women at high risk (1C evidence).
3 4 3 5 5 5 5 NA 5 3 5
39 Women undergoing bilateral risk-reducing salpingooophorectomy
should have their fallopian tubes
removed as well (1C evidence). 5 5 5 4 5 5 4 NA 5 5 5
4,70 5 0,67 90%
4,80 5 0,42 100%
4,40 5 0,97 90%
4,60 5 0,52 100%
4,90 5 0,32 100%
5,00 5 0,00 100%
4,89 5 0,33 100%
4,40 5 0,84 80%
4,90 5 0,32 100%
4,30 5 0,95 70%
4,80 5 0,42 100%
3. they must also be informed about
remaining small risk of developing
peritoneal cancer
3. patient must be informed about
the remaining small risk of
developing peritoneal cancer
4. please considerer changing the
word "should" for "MUST"
3. Also possible impact on sexuality
3. A woman that keeps haar uterus
must receive a HST with
combination of E and Prog. This is
associated with increased
cardiovascular and cerebral
morbidity
3. only if it happens at young age.
Usually it is reommended after 35
years

KCE reports 63 Breast Cancer 135
40 Based on results from a moderate quality RCT,
Tamoxifen can be recommended as a
chemoprevention therapy for women a BRCA2 genetic
high risk for developing breast cancer (1B evidence).
4 5 4 5 5 5 5 NA 5 2 5
41 All patients should have a full clinical examination (1C
evidence). 5 5 5 5 5 5 5 NA 5 5 5
42 Where a localised abnormality is present, patients
should have mammography and ultrasonography
followed by fine needle aspirate cytology and/or core
biopsy (1C evidence).
5 5 5 5 5 3 5 4 5 5 5
43 A lesion considered malignant following clinical
examination, imaging or cytology alone should, where
possible, have histopathological confirmation of
malignancy before any surgical procedure takes place
(1C evidence). 5 5 5 5 5 5 5 4 5 5 5
44 Three-view mammography should be performed as
part of triple assessment (clinical assessment, imaging
and tissue sampling) in a designated breast clinic (1C
evidence).
3 5 5 4 5 5 3 2 5 5 5
45 Young women (< 40 years) presenting with breast
symptoms and a strong suspicion of breast cancer
should be evaluated by means of the triple test
approach to exclude or establish a diagnosis of cancer
(1C evidence). 3 5 5 5 5 5 5 4 5 5 4
46 There is insufficient evidence to use MRI routinely for
the diagnosis and staging of breast cancer. MRI
should be considered in specific clinical situations
where other imaging modalities are not reliable, or
have been inconclusive, and where there are
indications that MRI is useful (invasive lobular
carcinoma, suspicion of multicentricity, T0N+ patients,
breast implants, diagnosis of recurrence, follow-up of
neodjuvant treatment) (1C evidence). 3 5 4 5 5 5 5 4 5 4 5
4,50 5 0,97 90%
5,00 5 0,00 100%
4,73 5 0,65 91%
4,91 5 0,30 100%
4,27 5 1,10 73%
4,64 5 0,67 91%
4,55 5 0,69 91%
3. fine needle aspiration is to be
replaced in most cases by core
biopsy or mammotome procedure
6. Breast cytology may be difficult for
some pathologist, Histology should
be the standard. Mammotoom
Vacuum biopsy should be
considered when the ultrasound is
not conclusive.
8. mammography and/or US,
possibly followed
1. What is a designated breast
clinic? Réf are meagre
8. Why three-view??? Taking
additional views (rolled views,
magnifications, extra incidence
views…) can be left at the
radiologist's discretion. A
supplementary laterolateral view is
not needed in all circumstances.
1. what about women > 40 years?
1. all breast cancer is potentially
multicentric, and imaging modalities
not reliable…
3. MRI is usefull in young women
that undergoes breast conservative
surgery to exclude bilaterality and in
case of lobular leisons (muticentricity
and bilaterality as well)

136 Breast Cancer KCE reports 63
47 There is insufficient evidence to use 99mTc-MIBI
scintimammography routinely for the diagnosis and
staging of breast cancer. 99mTc-MIBI
scintimammography should be considered in specific
clinical situations where other imaging modalities are
not reliable, or have been inconclusive, and where
there are indications that 99mTc-MIBI
scintimammography is useful (1C evidence).
48 There is no evidence for pretreatment routine bone
scanning, liver ultrasonography and chest radiography,
unless there is stage III disease or neoadjuvant
treatment is considered (2C evidence).
49 In women with intraductal and pathological stage I
tumours, routine bone scanning, liver ultrasonography
and chest radiography are not indicated as part of
baseline staging (2C evidence).
3 5 5 5 5 5 5 NA 5 5 4
5 3 5 1 5 3 1 4 2 5 3
4 3 4 1 5 3 1 5 1 4 3
4,70 5 0,67 90%
3,36 3 1,57 45%
3,09 3 1,51 45%
1. not enough restrictive
recommendation see 47
4. it is now proven that biology is far
more important in determining risk of
metastasis than staging (size and
lymph nodes) - even the staging
system is being challenged- HER-2
positive or triple negative patients,
for example, can have distant
metastasis even if T1N0. It is wrong
not to stage properly patients with
simples, inexpensive exams such as
bone scan, chest X-ray, liver US,
and full blood tests. The differences
in both prognosis and treatment
between early and metastatic breast
cancer are too big to be missed
(both for the patient and for society,
in terms of costs).
9. Routine pre op Evaluation
4. it is now proven that biology is far
more important in determining risk of
metastasis than staging (size and
lymph nodes) - even the staging
system is being challenged- HER-2
positive or triple negative patients,
for example, can have distant
metastasis even if T1N0. It is wrong
not to stage properly patients with
simples, inexpensive exams such as
bone scan, chest X-ray, liver US,
and full blood tests. The differences
in both prognosis and treatment
between early and metastatic breast
cancer are too big to be missed
(both for the patient and for society,
in terms of costs).
9. For stage I: complete work up
should be performed

KCE reports 63 Breast Cancer 137
50 In women who have pathological stage II tumours, a
postoperative bone scan is recommended as part of
baseline staging. Routine liver ultrasonography and
chest radiography are not indicated in this group, but
could be considered for patients with four or more
positive lymph nodes (2C evidence).
51 There is no good evidence to include tumour markers
in the staging work-up of breast cancer (2C evidence).
4 3 4 1 5 3 1 NA 1 3 3
3 4 4 4 5 3 3 NA 2 3 5
52 Axillary ultrasonography with aspiration of lymph nodes
suspicious for malignancy is recommended (2C
evidence). 5 4 5 2 5 4 5 5 5 3 5
53 SNB is not recommended for large T2 or T3-4 invasive
breast cancers; inflammatory breast cancer;
pregnancy, in the setting of prior nononcologic breast
surgery or axillary surgery; in the presence of
suspicious palpable axillary lymph nodes; multiple
tumours; and possible disturbed lymph drainage after
recent axillary surgery or a large biopsy cave after
tumour excision. 5 5 4 5 5 5 5 NA 5 5 5
54 Data are available to support the use of SNB for
tumors less than 3 cm; high-grade DCIS, when
mastectomy or immediate reconstruction is planned;
for older or obese patients; in male breast cancer; and
prior excisional or diagnostic large biopsy (1A
evidence). 5 4 5 5 5 5 5 NA 5 5 5
55 PET scan is not indicated in the diagnosis of
malignancy of breast tumours (1B evidence). 5 5 5 5 5 5 5 NA 5 3 5
56 PET scan is not indicated for axillary staging (1C
evidence). 5 5 5 5 5 5 5 NA 5 3 5
57 PET scan can be useful for the evaluation of
metastatic disease of invasive breast cancer (1C
evidence). 5 5 4 5 5 4 5 NA 5 4 4
2,80 3 1,40 30%
3,60 3,5 0,97 50%
4,36 5 1,03 82%
4,90 5 0,32 100%
4,90 5 0,32 100%
4,80 5 0,63 90%
4,80 5 0,63 90%
4,60 5 0,52 100%
4. it is now proven that biology is far
more important in determining risk of
metastasis than staging (size and
lymph nodes) - even the staging
system is being challenged- HER-2
positive or triple negative patients,
for example, can have distant
metastasis even if T1N0. It is wrong
not to stage properly patients with
simples, inexpensive exams such as
bone scan, chest X-ray, liver US,
and full blood tests. The differences
in both prognosis and treatment
between early and metastatic breast
cancer are too big to be missed
(both for the patient and for society,
in terms of costs).
9. For stage II: complete Work up
3. exclusion of patients with basically
elevated tumor markers level
9. Initial evaluation to follow
4. should be added "unless,
neoadjuvant systemic treatment is
planned"
3. with esception of treatment
protocols. SNB can be valuable as
pre-chemotherapy evaluation of the
axillary state
3. Only for high grade DCIS proven
on true cut biopsy (risico of
underestimation).In high grade DCIS
proven after wireloopbiospy with
excision of the majority of
calcifications SNB is of no value

138 Breast Cancer KCE reports 63
58 PET/CT cannot yet be recommended for the diagnosis
and follow-up of breast cancer (2C evidence).
5 5 5 4 5 4 3 3 5 4 5
59 When ALH/LCIS is found within or near the margins of
a wide excision specimen, re-excision is not
necessary. On the other hand, clear margins do not
exclude the presence of residual ALH/LCIS elsewhere
in the breast (expert opinion). 5 5 5 3 5 3 5 NA 2 4 5
60 In case of a ALH/LCIS in a (VA)CNB, a
multidisciplinary discussion is essential (expert
opinion).
3 5 2 4 5 5 4 NA 5 4 5
61 For a ALH/LCIS diagnosed with a targeted (VA)CNB of
a mammographic abnormality, a surgical diagnostic
excision might be considered (expert opinion).
4 5 5 4 5 5 4 NA 5 3 4
62 Following a diagnosis of ALH/LCIS (even if
"completely" excised), careful follow-up is indicated
(annual mammography, …) (expert opinion).
5 5 5 4 5 5 5 4 5 4 5
63 Hormonal treatment may be an option for a ALH/LCIS
(expert opinion).
4 5 2 4 5 5 NA NA 5 4 4
64 LCIS with comedonecrosis is the only type of LCIS that
is visible on mammography and hence can be targeted
by (VA)CNB (expert opinion). 4 3 NA 5 4 4 4 2 3 3
65 These lesions carry a higher risk of progression and a
higher rate of progression than ALH/LCIS. They should
not be considered as a risk factor, but as a precursor
lesion (and hence malignant) (expert opinion).
4 4 5 3 5 5 5 NA 4 3 4
4,36 5 0,81 82%
4,20 5 1,14 70%
4,20 4,5 1,03 80%
4,40 4,5 0,70 90%
4,73 5 0,47 100%
4,22 4 0,97 89%
3,56 4 0,88 56%
4,20 4 0,79 80%
6. small cell LCIS versus large cell
LCIS ?
9. " is reccoménded"
1. May be usefull.The reliability of
the pathological diagnosis is
important
3. ALH/LCIS in corebiopsy can be
associated with underestimation risk
for invasive cancer by 15%. Excision
must be recommended in every
case with a visible radiologic leison.
1. usually recommended
3. Patient information about the
associated increased in relative risk
of developing breast cancer
bilaterally
3. Combinations of Est/Prog can be
better avoioded. Increase relative
risk upto 30%. See WHI

KCE reports 63 Breast Cancer 139
66 When a LIN3 is encountered in a (VA)CNB, complete
excision is advocated. If margins are not free, reexcision
may be considered. Following surgical
excision, radiotherapy and hormonal therapy may be
administered (expert opinion). 4 4 5 4 5 5 NA NA 3
67 Annual mammography of lobular carcinoma in situ is
indicated (2C evidence). 5 5 5 4 5 4 5 3 5 3 5
68 Women with high-grade and/or palpable and/or large
ductal carcinoma in situ (DCIS) of the breast who are
candidates for breast conserving surgery should be
offered the choice of local wide excision or total
mastectomy after the patient is correctly informed. In
case of multicentricity local wide excision is not
recommended (1B evidence). 5 5 5 2 5 5 5 NA 5 5 5
69 Mastectomy with the option for reconstruction remains
an acceptable choice for women preferring to
maximize local control (1B evidence). 5 5 5 5 5 5 4 NA 5 5 5
70 When local wide excision is performed, all evidence of
disease should be resected (1C evidence).
5 5 5 5 5 5 5 NA 5 4 5
71 Axillary surgery is not recommended, but can be
considered for large tumours (> 5 cm) (1C evidence).
3 5 3 4 5 4 1 NA 2 4 5
72 Radiotherapy is usually part of the treatment of DCIS
(1A evidence). 5 5 5 5 5 5 5 NA 4 4 5
73 Adjuvant hormonal therapy should be considered for
patients with ER+ DCIS (expert opinion). 3 5 4 5 5 5 5 NA 5 3 5
74 Patients with Paget’s disease without underlying
invasive breast cancer should be treated with a connus
excision of the nipple-areola-complex and
radiotherapy. In rare cases, radiotherapy alone is
sufficient (expert opinion). 5 5 5 NA 5 5 5 NA 2 4 4
75 All patients with T3-4 and/or N2-3 breast cancer
should be discussed on an individual basis in the MDT
before any treatment (expert opinion). 5 5 4 5 5 5 5 NA 5 5 5
4,29 4 0,76 86%
4,45 5 0,82 82%
4,70 5 0,95 90%
4,90 5 0,32 100%
4,90 5 0,32 100%
3,60 4 1,35 60%
4,80 5 0,42 100%
4,50 5 0,85 80%
4,44 5 1,01 89%
4,90 5 0,32 100%
9. LIN3 is ?
4. please consider replacing "or total
mastectomy" by " or total
mastectomy with reconstruction"
1. SN biopsy is an option depending
on age, size, grade
7. ALND ? TUMOR > 3CM???
9. Never heard about this , large
tumour should undergo Primary
Chemo then surgery including
Axillary clearance except in case of
palliative treatment
1. is to be discussed with the patient
9. I guess mastectomy can be
another option avoiding Rxt

140 Breast Cancer KCE reports 63
76 All women with stage I or II breast cancer who are
candidates for breast conserving surgery should be
offered the choice of breast conserving surgery
(excision of tumour with clear margins) or modified
radical mastectomy (1A evidence). 5 5 5 5 4 5 5 NA 5 5 4
77 The choice of surgery must be tailored to the individual
patient with stage I or II breast cancer, who should be
fully informed of the options (1A evidence).
5 5 5 5 5 5 5 NA 5 5 5
78 In women with primary breast cancer less than 3 cm
and with clinically and ultrasonographically negative
nodes, a sentinel lymph node biopsy should be done
(1A evidence). 5 3 5 5 5 5 5 NA 5 5 5
79 If the sentinel node is positive (>0.2 mm), axillary
lymph node dissection level I and II is indicated (1A
evidence).
4 5 4 5 5 5 5 NA 5 5 5
80 If a sentinel lymph node biopsy is impossible, at least
an axillary lymph node dissection level I and II is
indicated (1A evidence). 5 5 5 5 5 5 3 NA 5 5 5
81 In patients with invasive breast cancer, adjuvant
irradiation is indicated after breast conserving surgery
(1A evidence). 5 5 5 5 5 5 5 NA 5 5 5
82 Radiotherapy of the thoracic wall after mastectomy is
indicated for the following conditions (1B evidence):
a. pT3
b. pN+ (whatever the number of invaded nodes)
c. LVI
3 5 5 5 5 5 5 NA 4 5 5
83 Internal mammary chain irradiation is to be discussed
in the MDT (expert opinion).
5 5 3 5 5 5 5 NA 5 5 1
84 The target volume of percutaneous adjuvant
radiotherapy encompasses the entire breast and the
adjoining thoracic wall. The dose amounts to
approximately 50 Gy fractionated in the conventional
manner (1.8-2.0 Gy) with an additional local dose
saturation (boost) (1A evidence). 5 4 5 5 5 5 5 NA 4 5 5
4,80 5 0,42 100%
5,00 5 0,00 100%
4,80 5 0,63 90%
4,80 5 0,42 100%
4,80 5 0,63 90%
5,00 5 0,00 100%
4,70 5 0,67 90%
4,40 5 1,35 80%
4,80 5 0,42 100%
5. Veronesi U. N Engl J Med 2002;
347:1227-32; FisherB. N Engl J Med
2002; 347:1233-41
1. usually indicated
3. in some cases radiotherapy of
axilla can be an alternaticve. The
number of the positive SN in function
of totally removed SN must alsobe
considered
7. WHAT ABOUT PICKING?
1. no proven benefit for less than 3 +
nodes as the only indication
3. We need to point out clear
indications to avoid overtreatment in
this setting that can be associated
with increased morbidity
11. There has never been a well
conducted randomized trial proving
this argument. Patients after
irradiation of the internal mammary
chain do worse than others

KCE reports 63 Breast Cancer 141
85 Axillary radiotherapy should be discussed on an
individual basis in the MDT (1A evidence).
5 5 3 4 5 5 5 NA 5 5 4
86 If anthracycline-based or taxane-based chemotherapy
and radiotherapy are indicated, the chemotherapy
should be given first (1A evidence). 3 5 5 5 5 5 5 NA 5 5 5
87 The choice of chemotherapy and/or hormonal therapy
as adjuvant treatment for invasive breast cancer
should be driven by the hormonal sensitivity and risk
profile of the tumour and the age of the patient (1A
evidence). 5 5 5 5 5 5 5 NA 5 5 5
88 Preferred regimens are standard anthracycline-based
regimens (FAC, FEC) with or without a taxane. Based
on the available evidence, no preferred anthracycline
or taxane exists (1A evidence).
89 In patients with T2 tumours too large for breast
conserving surgery, downstaging with neoadjuvant
therapy can be offered (1A evidence).
4 5 5 2 5 5 NA NA NA 3 5
4 5 5 2 5 5 5 NA 5 4 5
90 High-dose chemotherapy with stem-cell transplantation
cannot be recommended (1A evidence).
5 5 5 5 5 5 NA NA 5 5 5
91 Premenopausal patients with any HR+ breast cancer
should receive adjuvant endocrine treatment with
Tamoxifen for 5 years (1A evidence). 5 5 5 1 5 4 5 NA 5 3 5
92 Postmenopausal patients with HR+ breast cancer
should receive adjuvant endocrine treatment with
either upfront Tamoxifen during 5 years, Tamoxifen
during 2 - 3 years followed by an aromatase inhibitor
during 3 - 2 years, or upfront aromatase inhibitor (1A
evidence). 5 5 5 5 5 5 5 NA 5 5 5
93 Postmenopausal women with HR+ tumours who have
completed five years of adjuvant tamoxifen therapy
(20mg daily) should be considered for extended AI
treatment if N+ or high-risk N- (pT2 or grade III) (1A
evidence). 5 5 5 5 5 5 5 NA 5 4 5
94 Adjuvant hormonal therapy should be given after
chemotherapy (expert opinion). 5 5 4 5 5 5 5 NA 5 4 5
4,60 5 0,70 90%
4,80 5 0,63 90%
5,00 5 0,00 100%
4,25 5 1,16 75%
4,50 5 0,97 90%
5,00 5 0,00 100%
4,30 5 1,34 80%
5,00 5 0,00 100%
4,90 5 0,32 100%
4,80 5 0,42 100%
3. We need to point out clear
indications to avoid overtreatment in
this setting that can be associated
with increased morbidity
4. "and should not be condidered
standard"
1. this has been challenged during
the last St Gallen meeting
4. ATTENTION: 3-weekly paclitaxel
has been shown to be inferior to
both weekly paclitaxel and 3-weekly
docetaxel and should be avoided in
the adjuvant setting.
10. disagree for taxane
1. patients should be informed of the
higher recurrence risk if breast
conserving surgery is proposed
following neoadjuvant therapy
4. please change the word "should"
for "MUST"
7. MUST
4. "with or without

142 Breast Cancer KCE reports 63
95 Based on the criteria from the HERA trial (T > 1cm
and/or previously chemotherapy), a 1 year treatment
with adjuvant trastuzumab is indicated for women with
HER2 FISH positive breast cancer, a LVEF of ≥ 55%
and without cardiovascular exclusion criteria (1A
evidence).
5 5 5 1 5 4 5 NA 4 3 5
96 During treatment with trastuzumab, cardiac function
should be monitored (1A evidence). 5 5 5 5 5 4 5 NA 5 4 5
97 In premenopausal patients with HR+ or HR unknown
metastatic breast cancer, suppression of ovarian
function (e.g. with GnRH analogs, oophorectomy,
irradiation of the ovaries) in combination with
tamoxifen is the first-line hormonal therapy (1A
evidence). 5 5 5 4 5 5 5 NA 5 5 4
98 In postmenopausal patients with HR+ or HR unknown
metastatic breast cancer, first-line treatment consists
of aromatase inhibitors. Tamoxifen remains an
acceptable alternative as first-line treatment. As
second-line treatment, anastrozole, letrozole or
exemestane are recommended (1A evidence).
5 5 5 1 5 5 5 NA NA 3 4
99 Chemotherapy for patients with metastatic breast
cancer is indicated for the following conditions (1A
evidence):
a. hormone refractory or HR- tumours
b. rapidly progressive disease
c. invasion of life-threatening organs 5 5 5 5 5 4 5 NA 5 5 5
100 The preferred chemotherapy regimen is to be
discussed in the MDT (expert opinion).
101 Trastuzumab should be reserved for those patients
whose tumours have HER2 overexpression (1A
evidence).
5 5 5 2 5 5 5 NA 5 4 5
5 5 5 2 5 5 NA NA 5 5 5
102 Combination therapy of trastuzumab with a taxane is
recommended in women with metastatic breast cancer
(1A evidence). 5 5 5 2 5 5 NA NA NA 4 4
4,20 5 1,32 80%
4,80 5 0,42 100%
4,80 5 0,42 100%
4,22 5 1,39 78%
4,90 5 0,32 100%
4,60 5 0,97 90%
4,67 5 1,00 89%
4,38 5 1,06 88%
4. in HERA (and in the US studies)
HER-2 positivity by IHC 3+ was also
considered positive and other
studies have shown it to be highly
correlated with response to
Herceptin; additionally, very recent
results from the NCCTG study show
that IHC 3+ may even respond better
to Herceptin than FISH+ IHC 2+; our
reimbursement law should include
both FISH+ or IHC 3+
10. 1 year? Or concomitant with
taxanes?
4. should be added "when
chemotherapy is not indicated"
4. There is enough data to support
the use of Fulvestrant after an AI
and as a very valuable option for
metastatic breast cancer
10. AI not mandatory
4. It must be discussed and decided
in a group meeting of medical
oncologists not in a multidisciplinary
team meeting
4. the correct wording would be
"whose tumours have HER2
overexpression or amplification (1A
evidence)."
9. and Fish control
10. gene amplification rather than
overexpression
4. is recommended in women with
HER-2 positive metastatic breast
cancer (1A evidence).

KCE reports 63 Breast Cancer 143
103 Bisphosphonates should be routinely used in
combination with other systemic therapy in patients
with metastatic breast cancer with bone metastases
(1A evidence). 5 5 5 4 5 5 5 NA 5 1 5
104 In patients with painful bone metastases, radiotherapy
is a viable treatment option (1A evidence).
5 5 5 5 5 5 5 NA 5 3 5
105 A local recurrence in the thoracic wall should be
treated preferentially with surgery and adjuvant
radiotherapy (1C evidence).
106 A recurrence after breast-conserving surgery should
be treated by a salvage mastectomy (1C evidence).
107 Systemic treatment for a locoregional recurrence
should be discussed in the MDT (expert opinion).
4 5 4 2 5 4 5 NA 2 5 5
4 5 5 5 5 5 5 NA 4 5 5
5 5 5 2 5 5 5 NA 5 5 5
108 Treatment with bisphosphonates is not recommended
in women with breast cancer without clinically evident
bone metastases (1A evidence). 5 2 5 5 5 5 5 NA 5 5 5
109 Physiotherapy after axillary surgery is recommended
(2A evidence).
4 4 3 5 5 5 1 NA 5 4 3
110 Physical training after treatment for breast cancer is
recommended (2A evidence). 4 4 5 4 5 4 5 NA 5 4 4
111 Menopausal HRT is contraindicated in women with
breast cancer (1C evidence). 4 5 5 5 5 5 5 NA 5 5 3
112 Psychological support should be available to all
patients diagnosed with breast cancer (1A evidence).
5 5 5 5 5 5 5 NA 5 5 5
113 The possibility of breast reconstruction should be
discussed with all patients prior to mastectomy (1C
evidence). 4 5 5 5 5 5 5 NA 5 5 5
114 Yearly mammo/ultrasonography should be used to
detect recurrence or second primaries in patients who
have undergone previous treatment for breast cancer
(1C evidence). 4 5 5 5 5 5 1 5 5 5 5
4,50 5 1,27 90%
4,80 5 0,63 90%
4,10 4,5 1,20 80%
4,80 5 0,42 100%
4,70 5 0,95 90%
4,70 5 0,95 90%
3,90 4 1,29 70%
4,40 4 0,52 100%
4,70 5 0,67 90%
5,00 5 0,00 100%
4,90 5 0,32 100%
4,55 5 1,21 91%
10. only if multiple and lytic
10. if localized; with systemic trt
3. if the chest wall was not irradiated
before
4. and adjuvant radiotherapy (1C
evidence) if not given before - like it
is it seems re-irradiation should
always be considered and that is not
the case
9. Not clear to me , complete
evaluation is necessary to confirme
the recur is isolated
1. breast conserving surgery may be
an option
4. since the answer to this question
is unknown it should also say "and
patients should be offered to
participate in clinical trials"
2. except in osteoporotic patients
3. Not with the case of SNB. Reeducation
on the first postoperative
day is usually sufficient
7. NO PROOF AVAILABLE
1. every 6 moths for the treated
breast during the first 2-3 years
7. TWICE YEARLY ?

144 Breast Cancer KCE reports 63
115 Routine diagnostic tests to screen for distant
metastases in asymptomatic women should not be
performed (1C evidence).
5 5 4 1 5 4 5 2 5 5
116 Follow-up consultations should be provided every 3
months in the first 2 years after diagnosis, every 6
months until 5 years after diagnosis, and every year
after 5 years (1C evidence). 4 5 5 5 5 4 5 NA 4 5 5
117 Patients should be seen at a multidisciplinary clinic
involving breast clinicians, radiologists and
pathologists (1C evidence). 3 5 3 5 5 5 5 NA 5 4 5
118 All women with a potential or known diagnosis of
breast cancer should have access to a breast care
nurse specialist for information and support at every
stage of diagnosis and treatment (1C evidence).
5 4 4 5 5 5 5 NA 5 4 5
119 Breast cancer is not a contraindication for a later
pregnancy or breastfeeding, but should be individually
discussed (2C evidence). 5 2 5 5 5 4 5 NA 5 5 5
4,10 5 1,45 80%
4,70 5 0,48 100%
4,50 5 0,85 80%
4,70 5 0,48 100%
4,60 5 0,97 90%
3. in case of normal findings on
clinical examination and normal CA
15.3 level
4. Should be re-worded to "Routine
diagnostic tests to screen for distant
metastases in asymptomatic women
should not be performed (1C
evidence) except blood tests.
9. after ? years of follow up
1. breast cancer patients should be
…
2. lactation discussed in many
papers

5
10
15
20
25
30
35
KCE reports 63 Breast Cancer 145
APPENDIX 5
TNM CLASSIFICATION
cTNM
(Source: J Clin Oncol 2002; 20 (17): 3628-36)
T – Primary tumor
Tx Primary tumor cannot be assessed
T0 No evidence of primary tumor
Tis Carcinoma in situ
- Tis (DCIS) Ductal carcinoma in situ
- Tis (LCIS) Lobular carcinoma in situ
- Tis (Paget’s) Paget’s disease of the nipple with no tumor (when associated
with a tumor, it is classified according to the size of the tumor)
T1 Tumor 2 cm or less in greatest dimension
- T1mic Microinvasion 0.1 cm or less in greatest dimension
When there are multiple foci of microinvasion, the size of only the largest focus is
used to classify the microinvasion (do not use the sum of all individual foci). The size
of multipele foci should be noted however as with multiple larger invasive
carcinomas.
- T1a tumor more than 0.1 cm but not more than 0.5 cm in greatest
dimension
- T1b tumor more than 0.5 cm but not more than 1 cm in greatest dimension
- T1c tumor more than 1 cm but not more than 2 cm in greatest dimension
T2 Tumor more than 2 cm but not more than 5 cm in greatest dimension
T3 Tumor more than 5 cm in greatest dimension
T4 Tumor of any size with direct extension to (a) chest wall or (b) skin, only as described
below (chest wall includes ribs, intercostals muscles, and serratus anterior muscle, but
not pectoralis muscle)
- T4a extension to chest wall, not including pectoralis muscle
- T4b edema (including peau d’orange) or ulceration of the skin of the breast,
or satellite skin nodules confined to the same breast
N – regional lymph nodes
- T4c both T4a and T4b
- T4d inflammatory carcinoma
This is characterized by diffuse, brawny induration of the skin with an
erysipeloid edge, usually with no underlying mass. Dimpling of the skin,
nipple retraction, or other skin changes, except those in T4b and T4d,
may occur in T1, T2, or T3 without affecting the classification.
Nx Regional lymph nodes cannot be assessed (e.g. previously removed)
N0 No regional lymph node metastasis

5
10
15
20
25
30
35
40
45
146 Breast Cancer KCE reports 63
N1 Metastasis in movable ipsilateral axillary lymph node(s)
N2 Metastasis in fixed ipsilateral axillary lymph node(s) or in clinically apparent* ipsilateral
internal mammary lymph nodes(s) in the absence of clinically evident axillary lymph node
metastases
- N2a metastasis in axillary lymph node(s) fixed to one another or to other
structures
- N2b metastasis only in clinically apparent* ipsilateral internal mammary
lymph nodes(s) in the absence of clinically evident axillary lymph node
metastases
N3 Metastasis in ipsilateral infraclavicular lymph node(s) with or without axillary lymph node
involvement; or in clinically apparent* ipsilateral internal mammary axillary lymph node
metastasis; or metastasis in ipsilateral supraclavicular lymph node(s) with or without
axillary or internal mammary lymph node involvement
- N3a metastasis in infraclavicular lymph node(s)
- N3b metastasis in internal mammary and axillary lymph nodes
- N3c metastasis in supraclavicular lymph node(s)
*clinically apparent = detected by clinical examination or by imaging studies excluding
lymphoscintigraphy
M- Distant metastasis
Mx Distant metastasis cannot be assessed
M0 No distant metastasis
M1 Distant metastasis
pTNM
pT: corresponds to cT categories, but there may not be gross tumor at the margins of
resection. Only the invasive component counts (not in situ).
pM: corresponds to cM categories.
pN: at least level I should have been resected to allow evaluation (generally 6 or more lymph
nodes). If classification is based only on sentinel node biopsy without subsequent axillary
lymph node dissection, it should be designated with (sn).
- pNx: regional lymph nodes cannot be assessed (e.g. previously removed, or
not removed for pathologic study)
- pN0: no regional lymph node metastasis.
Cases with isolated tumor cells in regional lymph nodes are classified as pN0.
Isolated tumor cells are single tumor cells or small clusters of cells, not more than
0.2 mm in greatest dimension, that are usually detected by immunohistochemistry or
molecular methods but which may be verified on HeE stains. Isolated tumor cells do
not typically show evidence of metastatic activity, e.g., proliferation of stromal
reaction.
- pN1mi: micrometastasis (larger than 0.2 mm, but none larger than 2 mm in
greatest dimension)
- pN1: metastasis in 1-3 ipsilateral axillary lymph node(s), and/or in ipsilateral
internal mammary nodes with microscopic metastasis detected by sentinel lymph
node dissection but not clinically apparent*
o pN1a metastasis in 1-3 axillary lymph node(s), including at least one
larger than 2 mm in greatest diameter.

5
10
15
20
25
KCE reports 63 Breast Cancer 147
o pN1b internal mammary nodes with microscopic metastasis detected
by sentinel lymph node dissection but not clinically apparent*
o pN1c metastasis in 1-3 axillary lymph node(s) and internal mammary
nodes with microscopic metastasis detected by sentinel lymph node
dissection but not clinically apparent*
*not clinically apparent = not detected by clinical examination or by imaging studies excluding
lymphoscintigraphy
- pN2 metastasis in 4-9 ipsilateral axillary lymph node(s), or in clinically
apparent ipsilateral internal mammary nodes in the absence of axillary lymph node
metastasis (clinically apparent = detected by clinical examination or by imaging
studies (excluding lymphoscintigraphy) or grossly visible pathologically).
o pN2a metastasis in 4-9 axillary lymph node(s), including at least one
larger than 2 mm.
o pN2b metastasis in clinically apparent internal mammary nodes, in the
absence of axillary lymph node metastasis
- pN3 metastasis in 10 or more ipsilateral axillary lymph node(s); or in
ipsilateral infraclavicular lymph nodes; or in clinically apparent ipsilateral internal
mammary nodes in the presence of one or more positive axillary lymph nodes; or in
more than 3 axillary lymph nodes with clinically negative, microscopic metastasis in
internal mammary lymph nodes; or in ipsilateral supraclavicular lymph nodes.
o pN3a metastasis in 10 or more axillary lymph nodes (at least one
larger than 2 mm) or metastasis in infraclavicular lymph nodes
o pN3b metastasis in clinically apparent ipsilateral internal mammary
nodes in the presence of one or more positive axillary lymph nodes; or
metastasis in more than 3 axillary lymph nodes and in internal mammary
lymph nodes with microscopic metastasis detected by sentinel lymph node
dissection but not clinically apparent.
o pN3c metastasis in supraclavicular lymph node(s)

148 Breast Cancer KCE reports 63
Stage grouping
Stage 0 Tis N0 M0
Stage I T1 N0 M0
Stage II A T0 N1 M0
T1 N1 M0
T2 N0 M0
Stage IIB T2 N1 M
T3 N0 M0
Stage IIIA T0 N2 M0
T1 N2 M0
T2 N2 M0
T3 N1, N2 M0
Stage IIIB T4 N0, N1, N2 M0
Stage IIIC Any T N3 M0
Stage IV Any T Any N M1

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Wettelijk depot : D/2007/10.273/35

KCE reports
1. Effectiviteit en kosten-effectiviteit van behandelingen voor rookstop. D/2004/10.273/1.
2. Studie naar de mogelijke kosten van een eventuele wijziging van de rechtsregels inzake
medische aansprakelijkheid (fase 1). D/2004/10.273/2.
3. Antibioticagebruik in ziekenhuizen bij acute pyelonefritis. D/2004/10.273/5.
4. Leukoreductie. Een mogelijke maatregel in het kader van een nationaal beleid voor
bloedtransfusieveiligheid. D/2004/10.273/7.
5. Het preoperatief onderzoek. D/2004/10.273/9.
6. Validatie van het rapport van de Onderzoekscommissie over de onderfinanciering van de
ziekenhuizen. D/2004/10.273/11.
7. Nationale richtlijn prenatale zorg. Een basis voor een klinisch pad voor de opvolging van
zwangerschappen. D/2004/10.273/13.
8. Financieringssystemen van ziekenhuisgeneesmiddelen: een beschrijvende studie van een
aantal Europese landen en Canada. D/2004/10.273/15.
9. Feedback: onderzoek naar de impact en barrières bij implementatie – Onderzoeksrapport:
deel 1. D/2005/10.273/01.
10. De kost van tandprothesen. D/2005/10.273/03.
11. Borstkankerscreening. D/2005/10.273/05.
12. Studie naar een alternatieve financiering van bloed en labiele bloedderivaten in de
ziekenhuizen. D/2005/10.273/07.
13. Endovasculaire behandeling van Carotisstenose. D/2005/10.273/09.
14. Variaties in de ziekenhuispraktijk bij acuut myocardinfarct in België. D/2005/10.273/11.
15. Evolutie van de uitgaven voor gezondheidszorg. D/2005/10.273/13.
16. Studie naar de mogelijke kosten van een eventuele wijziging van de rechtsregels inzake
medische aansprakelijkheid. Fase II : ontwikkeling van een actuarieel model en eerste
schattingen. D/2005/10.273/15.
17. Evaluatie van de referentiebedragen. D/2005/10.273/17.
18. Prospectief bepalen van de honoraria van ziekenhuisartsen op basis van klinische paden en
guidelines: makkelijker gezegd dan gedaan.. D/2005/10.273/19.
19. Evaluatie van forfaitaire persoonlijk bijdrage op het gebruik van spoedgevallendienst.
D/2005/10.273/21.
20. HTA Moleculaire Diagnostiek in België. D/2005/10.273/23, D/2005/10.273/25.
21. HTA Stomamateriaal in België. D/2005/10.273/27.
22. HTA Positronen Emissie Tomografie in België. D/2005/10.273/29.
23. HTA De electieve endovasculaire behandeling van het abdominale aorta aneurysma (AAA).
D/2005/10.273/32.
24. Het gebruik van natriuretische peptides in de diagnostische aanpak van patiënten met
vermoeden van hartfalen. D/2005/10.273/34.
25. Capsule endoscopie. D/2006/10.273/01.
26. Medico–legale aspecten van klinische praktijkrichtlijnen. D2006/10.273/05.
27. De kwaliteit en de organisatie van type 2 diabeteszorg. D2006/10.273/07.
28. Voorlopige richtlijnen voor farmaco-economisch onderzoek in België. D2006/10.273/10.
29. Nationale Richtlijnen College voor Oncologie: A. algemeen kader oncologisch
kwaliteitshandboek B. wetenschappelijke basis voor klinische paden voor diagnose en
behandeling colorectale kanker en testiskanker. D2006/10.273/12.
30. Inventaris van databanken gezondheidszorg. D2006/10.273/14.
31. Health Technology Assessment prostate-specific-antigen (PSA) voor
prostaatkankerscreening. D2006/10.273/17.
32. Feedback : onderzoek naar de impact en barrières bij implementatie – Onderzoeksrapport :
deel II. D/2006/10.273/19.
33. Effecten en kosten van de vaccinatie van Belgische kinderen met geconjugeerd
pneumokokkenvaccin. D/2006/10.273/21.
34. Trastuzumab bij vroegtijdige stadia van borstkanker. D/2006/10.273/23.
35. Studie naar de mogelijke kosten van een eventuele wijziging van de rechtsregels inzake
medische aansprakelijkheid (fase III)- precisering van de kostenraming. D/2006/10.273/26.
36. Farmacologische en chirurgische behandeling van obesitas. Residentiële zorg voor ernstig
obese kinderen in België. D/2006/10.273/28.
37. HTA Magnetische Resonantie Beeldvorming. D/2006/10.273/32.

38. Baarmoederhalskankerscreening en testen op Human Papillomavirus (HPV).
D/2006/10.273/35
39. Rapid assessment van nieuwe wervelzuil technologieën : totale discusprothese en
vertebro/ballon kyfoplastie. D/2006/10.273/38.
40. Functioneel bilan van de patiënt als mogelijke basis voor nomenclatuur van kinesitherapie in
België? D/2006/10.273/40.
41. Klinische kwaliteitsindicatoren. D/2006/10.273/43.
42. Studie naar praktijkverschillen bij electieve chirurgische ingrepen in België. D/2006/10.273/45.
43. Herziening bestaande praktijkrichtlijnen. D/2006/10.273/48.
44. Een procedure voor de beoordeling van nieuwe medische hulpmiddelen. D/2006/10.273/50.
45. HTA Colorectale Kankerscreening: wetenschappelijke stand van zaken en budgetimpact
voor België. D/2006/10.273/53.
46. Health Technology Assessment. Polysomnografie en thuismonitoring van zuigelingen voor de
preventie van wiegendood. D/2006/10.273/59.
47. Geneesmiddelengebruik in de belgische rusthuizen en rust- en verzorgingstehuizen.
D/2006/10.273/61
48. Chronische lage rugpijn. D/2006/10.273/63.
49. Antivirale middelen bij seizoensgriep en grieppandemie. Literatuurstudie en ontwikkeling van
praktijkrichtlijnen. D/2006/10.273/65.
50. Eigen betalingen in de Belgische gezondheidszorg. De impact van supplementen.
D/2006/10.273/68.
51. Chronische zorgbehoeften bij personen met een niet- aangeboren hersenletsel (NAH)
tussen 18 en 65 jaar. D/2007/10.273/01.
52. Rapid Assessment: Cardiovasculaire Primaire Preventie in de Belgische Huisartspraktijk.
D/2007/10.273/03.
53. Financiering van verpleegkundige zorg in ziekenhuizen. D/2007/10 273/06
54. Kosten-effectiviteitsanalyse van rotavirus vaccinatie van zuigelingen in België
55. Evidence-based inhoud van geschreven informatie vanuit de farmaceutische industrie aan
huisartsen. D2007/10.273/12.
56. Orthopedisch Materiaal in België: Health Technology Assessment. D2007/10.273/14.
57. Organisatie en Financiering van Musculoskeletale en Neurologische Revalidatie in België.
D2007/10.273/18.
58. De Implanteerbare Defibrillator: een Health Technology Assessment. D2007/10.273/21.
59. Laboratoriumtesten in de huisartsgeneeskunde. D2007/10.273/24.
60. Longfunctie testen bij volwassenen. D2007/10.273/27.
61. Vacuümgeassisteerde Wondbehandeling: een Rapid Assessment. D2007/10.273/30
62. Intensiteitsgemoduleerde Radiotherapie (IMRT). D2007/10.273/32.
63. Wetenschappelijke ondersteuning van het College voor Oncologie: een nationale
praktijkrichtlijn voor de aanpak van borstkanker. D2007/10.273/35.