A Prospective Randomised, Open, Multicentre, Phase III Study to Assess Different Durations of Anastrozole Therapy After 2 to 3 Years Tamoxifen as Adjuvant Therapy in Postmenopausal Women With Breast Cancer.
Phase: PHASE3
Conditions: Breast Cancer
Sponsor: Maastricht University Medical Center

 
 
Revised Clinical Study Protocol 
Drug Substance Anastrozole 
Study Code 
BOOG 2006-01, D5392-NL-003 
Edition Number 004 
Date 
31 October 2016 
A prospective randomised, open, multicentre, phase III study to assess 
different Durations of Anastrozole therapy after 2 to 3 years Tamoxifen as 
Adjuvant therapy in postmenopausal women with breast cancer.   
Sponsor:  Maastricht UMC+, P.O. Box 5800 AZ Maastricht, The Netherlands 
The study is accepted as a BOOG study under number 2006-01. BOOG, P.O. Box 9236, 1006 AE 
Amsterdam, The Netherlands 
This submission /document contains trade secrets and confidential commercial information, disclosure of which 
is prohibited without providing advance notice to AstraZeneca and opportunity to object. 
The following Amendment(s) and Administrative Changes are included in this revised protocol:  
Amendment No. 
Date of Amendment 
Local Amendment No. 
Date of local Amendment 
1 
23 January 2007 
2 
29 May 2009 
3 
15 April 2011 
4 
30 October 2014 
5 
31 October 2016 
Administrative 
change No. 
Date of Administrative 
Change 
Local Administrative 
change No. 
Date of local 
Administrative Change 
01 
03 July 2006 
 

Clinical Study Protocol 
Drug Substance Anastrozole   
Study Code BOOG 2006-01, D5392-NL-003  
Edition Number 004 
Date 31 October 2016 
2 
 
 
 
A prospective randomised, open, multicentre, phase III study to assess 
different Durations of Anastrozole therapy after 2 to 3 years Tamoxifen as 
Adjuvant therapy in postmenopausal women with breast cancer. 
 
 
Principal Investigator  
Dr. V.C.G. Tjan-Heijnen, Radboud University Nijmegen Medical Centre, Nijmegen 
From1 September 2006 
Prof. Dr. V.C.G. Tjan-Heijnen, University Hospital Maastricht, Maastricht 
 
Principal Investigator 
Prof. Dr. V.C.G. Tjan-Heijnen, Maastricht University Medical Centre, Maastricht 
 
Steering committee 
Dr. J.R. Kroep, Leiden University Medical Centre, Leiden 
Dr. M.J.C. van der Sangen, Catharina Hospital, Eindhoven 
Dr. C. Seynaeve, Erasmus MC Daniel den Hoed Cancer Centre, Rotterdam 
Dr. C.H. Smorenburg, Antoni van Leeuwenhoekziekenhuis, Amsterdam 
 
Statistician 
Dr. P. Peer, Radboudumc, Nijmegen 
 
Datamanagment 
IKNL clinical research department, location Nijmegen. 
 

Clinical Study Protocol 
Drug Substance Anastrozole   
Study Code BOOG 2006-01, D5392-NL-003  
Edition Number 004 
Date 31 October 2016 
3 
 
PROTOCOL SYNOPSIS  
Objectives 
Primary objective: 
To assess the disease free survival (DFS) with 6 years of adjuvant anastrozole compared with 
the current standard treatment of 3 years of adjuvant anastrozole in postmenopausal hormone 
sensitive breast cancer patients, subsequent to 2 to 3 years of adjuvant tamoxifen treatment. 
Secondary objectives: 
Secondary objectives of the study are:  
1. To compare the incidence of contralateral breast cancer after 6 years versus 3 years 
adjuvant anastrozole, subsequent to 2 to 3 years of tamoxifen.  
2. To compare overall survival (OS) in patients treated with 6 years versus 3 years of adjuvant 
anastrozole, subsequent to 2 to 3 years of tamoxifen. 
3. To compare toxicity of 6 years versus 3 years of adjuvant anastrozole in postmenopausal 
hormone sensitive breast cancer patients, subsequent to 2 to 3 years of tamoxifen. 
4. To determine regional differences in the initial treatment of breast cancer retrospectively by 
collecting baseline information on initial therapies. Aspects of the initial treatment that will be 
investigated are e.g. the kind of surgery performed (breast saving or mastectomy) and whether 
or not chemotherapy is given and which chemotherapy was used in postmenopausal patients 
in relation to the primary tumour and patient characteristics. 
5. To compare the cost effectiveness of 3 years versus 6 years of adjuvant anastrozole therapy, 
after subsequent 2 to 3 years of adjuvant tamoxifen treatment. 
6. To assess patterns of care in The Netherlands in prevention, detection and treatment of 
osteoporosis in postmenopausal women with breast cancer treated with adjuvant anastrozole. 
 To assess differences in management of bone health (DEXA scans, vitamin D / 
Calcium, bisphosphonates) in postmenopausal women with breast cancer treated with 
adjuvant anastrozole, between medical oncologists, surgeons, radiotherapists and nurse 
practitioners.  
 To assess loco regional differences in the Netherlands in management of bone health 
in postmenopausal women with breast cancer treated with adjuvant anastrozole.  
 To assess rate of compliance to Dutch guidelines on prevention, detection and 
treatment of osteopenia and osteoporosis in postmenopausal women with breast cancer 
throughout the period of treatment with adjuvant anastrozole and over time with new 
breast cancer guidelines. 

Clinical Study Protocol 
Drug Substance Anastrozole   
Study Code BOOG 2006-01, D5392-NL-003  
Edition Number 004 
Date 31 October 2016 
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 To relate the number of osteoporotic fractures during and following treatment with 
adjuvant anastrozole with the compliance to osteoporotic guidelines.  
 To analyse the impact of prolonged anastrozole treatment on BMD and to analyse the 
impact of short versus prolonged treatment (6 versus 3 years anastrozole) on pattern of 
care. 
 To analyse occurrence of distant (bone) metastases in relation to occurrence of 
osteopenia and osteoporosis, and in relation to use of supplements and therapy for 
reduced BMD. 
Study design 
A prospective, randomised, open, multicentre, phase III study, comparing 3 years versus 6 
years of adjuvant anastrozole. This could lead to patients receiving either a total of 5 to 6 
years adjuvant therapy or a total of 8 to 9 years adjuvant therapy, including the 2 to 3 years 
adjuvant tamoxifen.  
Statistical methods 
This study will be conducted in approximately 1900 subjects, recruited in The Netherlands. 
Because after randomisation all subjects receive the same therapy for 3 years, differences 
between both treatment groups will appear starting 3 years after randomisation. At that 
time, in both groups 91% of all subjects are expected to be disease-free (Coombes R.C. et al 
2004). It is assumed that 3 years later this rate has decreased to 80% in the control group, 
implying a 3-years adapted DFS (see section 6.2) rate of 90% for that period. This study is 
designed to detect an increase to 94% of this 3-years DFS in the anastrozole group, 
corresponding with a hazard ratio of 0.60. Originally, we designed the trial with a 
statistical power of 80 percent and a two-sided alpha level of 0.04 (correcting for one 
interim analysis), requiring 770 disease-free subjects in the treatment/control group of the 
trial, implying 850 assessable subjects to be randomised. Accounting for approximately 
10% drop-out, 950 subjects per group were decided to be included in this study. Kaplan-
Meier survival curves will be used for the graphical representation of the therapy’s effect on 
parameters of primary and secondary survival objectives (DFS and OS). Differences 
between the two treatment groups will be tested with the log-rank test (for DFS and OS) 
combined over the non-empty strata and logistic regression (for occurrence of contra lateral 
breast cancer) adjusted for the stratification factors. Hazard ratios and corresponding 95% 
confidence intervals (CIs) will be estimated with the Cox proportional-hazard model 
adjusted for stratification factors. We will not perform an interim analysis of DFS and OS 
for the ITT population, as we do not expect a relevant difference at this early time point 
because of the recent results from ATLAS and aTTOM trials. Therefore, the final analysis 
will be evaluated at a significance level of 0.05, increasing the power to 82 percent. 

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Drug Substance Anastrozole   
Study Code BOOG 2006-01, D5392-NL-003  
Edition Number 004 
Date 31 October 2016 
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For monitoring the quality of the study, an interim report will be made. A DSMB will evaluate 
this report according to instructions provided in the DSMB charter. 
 
Target subject population 
Postmenopausal female patients with hormone receptor positive breast cancer who have 
already received 2 to 3 years of adjuvant tamoxifen, and who never had signs of loco-regional 
recurrences or distant metastasis. Chemotherapy and/or radiotherapy before or after local 
surgical treatment is allowed. 
 
Study period 
Estimated date of first subject enrolled: March 2006 
Estimated date of last subject completed: 31 December 2013 

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Drug Substance Anastrozole   
Study Code BOOG 2006-01, D5392-NL-003  
Edition Number 004 
Date 31 October 2016 
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TABLE OF CONTENTS 
PAGE 
TITLE PAGE ............................................................................................................................ 1 
PROTOCOL SYNOPSIS ......................................................................................................... 3 
TABLE OF CONTENTS ......................................................................................................... 6 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ............................................. 9 
1. 
INTRODUCTION ................................................................................................. 10 
1.1 
Background ............................................................................................................ 10 
1.2 
Rationale for this study .......................................................................................... 11 
2. 
STUDY OBJECTIVES .......................................................................................... 12 
2.1 
Primary objective ................................................................................................... 12 
2.2 
Secondary objectives ............................................................................................. 12 
3. 
STUDY PLAN AND PROCEDURES .................................................................. 13 
3.1 
Overall study design and flow chart ...................................................................... 13 
3.2 
Rationale and risk/benefit assessment.................................................................... 16 
3.2.1 
Rationale for study design, doses and control groups ............................................ 16 
3.2.2 
Risk/benefit and ethical assessment ....................................................................... 16 
3.3 
Selection of study population ................................................................................. 16 
3.3.1 
Inclusion criteria .................................................................................................... 16 
3.3.2 
Exclusion criteria ................................................................................................... 17 
3.4 
Treatments .............................................................................................................. 18 
3.4.1 
Identity of investigational product and comparators.............................................. 18 
3.4.2 
Doses and treatment regimens ............................................................................... 18 
3.4.3 
Labelling ................................................................................................................ 18 
3.4.4 
Storage ................................................................................................................... 18 
3.5 
Randomisation procedure ...................................................................................... 18 
3.5.1 
Method for assigning patients to treatment groups ................................................ 18 
3.6 
Blinding and procedures for unblinding the study ................................................. 18 
3.7 
Pre-study, concomitant and post-study treatment(s) .............................................. 19 
3.8 
Treatment compliance ............................................................................................ 19 
3.9 
Discontinuation of subjects from treatment or assessment .................................... 19 
3.9.1 
Criteria for discontinuation .................................................................................... 19 
3.9.1.1 
Procedures for discontinuation .............................................................................. 19 
4. 
MEASUREMENTS OF STUDY VARIABLES AND DEFINITIONS OF 
OUTCOME VARIABLES .................................................................................... 20 
4.1 
Screening and demographic measurements ........................................................... 20 

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Drug Substance Anastrozole   
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4.2 
Primary variable ..................................................................................................... 22 
4.2.1 
Disease Free Survival ............................................................................................ 22 
4.2.2 
Overall survival ...................................................................................................... 23 
4.3 
Safety measurements and variables ....................................................................... 23 
4.3.1 
Adverse events ....................................................................................................... 23 
4.3.1.1 
Definitions .............................................................................................................. 23 
4.3.1.2 
Recording of adverse events .................................................................................. 24 
4.3.1.3 
Reporting of serious adverse events....................................................................... 26 
4.3.2 
Laboratory safety measurements and variables ..................................................... 26 
4.3.2.1 
Methods of assessment .......................................................................................... 26 
4.3.3 
Vital signs, ECG and physical examination .......................................................... 26 
5. 
DATAMANAGEMENT ........................................................................................ 29 
6. 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE 
SIZE ....................................................................................................................... 29 
6.1 
Statistical evaluation – general aspects .................................................................. 29 
6.2 
Description of outcome variables in relation to objectives and hypotheses .......... 29 
6.3 
Description of analysis sets .................................................................................... 30 
6.4 
Method of statistical analysis ................................................................................. 30 
6.5 
Determination of sample size ................................................................................. 30 
6.6 
Data and safety monitoring board .......................................................................... 31 
7. 
STUDYMANAGEMENT ..................................................................................... 32 
7.1 
Monitoring ............................................................................................................. 32 
7.2 
Audits and inspections ........................................................................................... 32 
7.3 
Training of staff ..................................................................................................... 33 
7.4 
Changes to the protocol ......................................................................................... 33 
7.5 
Study agreements ................................................................................................... 33 
7.6 
Study timetable and end of study ........................................................................... 33 
8. 
ETHICS .................................................................................................................. 34 
8.1 
Ethics review .......................................................................................................... 34 
8.2 
Ethical conduct of the study ................................................................................... 34 
8.3 
Informed consent ................................................................................................... 34 
8.4 
Subject data protection ........................................................................................... 35 
9. 
PROCEDURES IN CASE OF EMERGENCY, OVERDOSE OR 
PREGNANCY ....................................................................................................... 35 
9.1 
Procedures in case of medical emergency ............................................................. 35 

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9.2 
Procedures in case of overdose .............................................................................. 35 
9.3 
Procedures in case of pregnancy ............................................................................ 35 
10. 
PUBLICATION RULES ....................................................................................... 36 
11. 
REFERENCES ...................................................................................................... 36 
APPENDIX A: SIGNATURES ............................................................................................. 38 
APPENDIX A SIGNATURES ............................................................................................... 38 
APPENDIX B: SIDE STUDIES ............................................................................................ 42 
APPENDIX A SIGNATURES ............................................................................................... 42 
APPENDIX C: PATHOLOGY .............................................................................................. 43 
APPENDIX A SIGNATURES ............................................................................................... 43 
 
LIST OF TABLES 
PAGE 
Table 1 
Study plan ................................................................................................. 25 
 
LIST OF FIGURES 
PAGE 
Figure 1 
Study flow chart ....................................................................................... 13 
 
LIST OF APPENDICES 
 
Appendix A 
Signatures  
Appendix B 
Side studies 
Appendix C 
Pathology 
 
 

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Drug Substance Anastrozole   
Study Code BOOG 2006-01, D5392-NL-003  
Edition Number 004 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
The following abbreviations and special terms are used in this study protocol. 
Abbreviation or 
special term 
Explanation 
AE 
Adverse event (see definition in Section 4.3.1.1) 
ADFS 
Adapted Disease Free Survival 
AOS 
Adapted Overall Survival 
CRF 
Case Report Form 
CSA 
Clinical Study Agreement 
DFS 
Disease Free Survival 
ECG 
Electrocardiogram 
ER 
Estrogen Receptor 
GCP 
Good Clinical Practice 
HR 
Hazard Rate 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
N 
Node 
OAE 
Other Significant Adverse Event (ie, adverse events of particular clinical 
importance, other than SAEs and those AEs leading to discontinuation of 
the subject from study treatment; see definition in Section 4.3.1.1). 
OS 
Overall Survival 
PgR 
Progesteron Receptor 
RFS 
Relapse Free Survival 
SAE 
Serious adverse event (see definition in Section 4.3.1.1). 
SDV 
Source Data Verification 

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Drug Substance Anastrozole   
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1. 
INTRODUCTION 
1.1 
Background 
In the western world breast cancer is the most common malignancy in women. In the 
Netherlands annually approximately 12.000 women are diagnosed with breast cancer and each 
woman has a chance of more than 10% to develop breast cancer in her life.  
In early detected disease lesions, the chance of loco-regional cure is high. However, 
microscopic disease may already have spread before loco-regional therapy was applied. If this 
microscopic disease remains untreated, it could develop into a life-threatening clinical 
recurrence. Although the risk of recurrence is greatest during the first years after diagnosis, it 
is still substantial in the following decade (EBCTCG 2005). 
During the last decade the prognosis for women with breast cancer has improved due to 
implementation of systemic treatment. The dependence of 60% to 70% of breast cancers on 
estrogens for their continued growth has long been recognised. Several systemic therapies 
have been developed to deprive the breast cancer of this stimulus. Drug therapy can achieve 
this goal either by reducing circulating concentration of estrogens with an aromatase inhibitor 
and/or ovarian ablation, or by antagonising the effects of estrogens on the tumour with an anti-
estrogen. 
For many years the standard endocrine adjuvant treatment for breast cancer in postmenopausal 
women with a hormone receptor positive tumour was 5 years treatment with the anti-estrogen 
tamoxifen. Due to recently published study results concerning 7 adjuvant studies, all 
comparing the standard adjuvant treatment of 5 years tamoxifen with a regime consisting of 
an aromatase inhibitor, the standard adjuvant treatment has changed to include an aromatase 
inhibitor (mammacarcinoom richtlijn 2005, Winer E.P et al 2005,  Köberle D. and Thürlimann 
B. 2005). Two major studies compare 5 years of adjuvant tamoxifen with 5 years adjuvant 
aromatase inhibitor. In the ATAC study, with a follow-up of 68 months, anastrozole gives a 
relapse free survival hazard rate (RFS HR) of 0.74 compared with tamoxifen for receptor-
positive patients (Howell A. et al 2004). The BIG1-98 study, comparing tamoxifen and 
letrozole with a median follow-up of 26 months, confirms these results showing a RFS HR of 
0.72 (Thürlimann B. et al 2005). Three studies show that switching to an aromatase inhibitor 
after 2 to 3 years tamoxifen, for a total adjuvant treatment of 5 years, gives a better RFS HR, 
ranges from 0.70 (Coombes R.C. NEJM 2004), to 0.60 and 0.42 (Jakesz R. et al 2005, 
Boccardo F. et al 2005), then 5 years tamoxifen. There are two studies showing that switching 
patients to an aromatase inhibitor after 5 years of adjuvant tamoxifen gives a RFS HR 
advantage of 0.57 and 0.64 (Goss P. et al 2004, Jakesz R. et al 2005 6a).  
The Dutch EBRO guideline version 3.0 regarding breast cancer (mammacarcinoom richtlijn 
2005) advises switch to an aromatase inhibitor after 2 to 3 years of adjuvant tamoxifen in 
patients who already use tamoxifen, for a total duration of 5 years endocrine treatment. For 
newly diagnosed patients, sequential therapy with tamoxifen followed by an aromatase-

Clinical Study Protocol 
Drug Substance Anastrozole   
Study Code BOOG 2006-01, D5392-NL-003  
Edition Number 004 
Date 31 October 2016 
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inhibitor is advised for hormone receptor positive Her2neu receptor negative breast cancer, 
whereas upfront aromatase inhibitors is recommended for hormone receptor positive Her2neu 
positive breast cancer. Of note, the evidence for using these selection criteria for the first 
(sequential) versus the second (upfront) strategy should be considered as circumstantial.  
1.2 
Rationale for this study 
The standard endocrine adjuvant treatment is given for a duration of 5 years. However, data 
from the Oxford Overview (EBCTCG 2005) shows that there are as many recurrences during 
years 6 through 15 after primary surgery as between years 1 through 5 in women treated with 
tamoxifen versus controls. The risk of recurrence of breast cancer beyond 5 years is 
approximately 4% per year for women with node positive disease at the time of primary 
surgery and approximately 2% per year for women with node negative disease. Therefore it is 
important to undertake trials with additional randomisations beyond 5 years of endocrine 
treatment because past experience would suggest that these women will remain at a relatively 
high risk of recurrence (Pritchard KI 2005). 
Previously extended adjuvant treatment beyond 5 years of tamoxifen has been studied. In a 
trial conducted by the National Surgical Adjuvant Breast and Bowel Project (NSABP-B14), 
patients that already received 5 years of tamoxifen were randomised to receive an additional 5 
years of either placebo or tamoxifen. Unexpectedly, women who continued to receive 
tamoxifen therapy after 5 years had worse outcomes when compared to women in whom it 
was discontinued at 5 years (Fisher B et al 2001). Based on these data, it was worldwide 
recommended at that time to limit the use of adjuvant tamoxifen treatment to 5 years.  
Emergence of tamoxifen resistance is one of the proposed causes of this detrimental outcome. 
However, extended adjuvant treatment may still be beneficial in case resistance could be 
avoided, for instance by sequentially using a non-cross resistant alternative endocrine 
treatment. Aromatase inhibitors have demonstrated efficacy after tamoxifen resistance 
(Buzdar A.U. et al 1998, Robertson J.F.R. et al 2003) and are therefore candidates to be 
investigated in the setting of prolonged adjuvant endocrine therapy for hormone sensitive 
breast cancer. Two studies recently demonstrated that an extended treatment with an 
aromatase inhibitor for 2 or 3 more years, after 5 years of adjuvant treatment with tamoxifen, 
leads to an improved DFS (Goss P. et al 2004, Jakesz R. et al 2005 6a). 
According to the ASCO Technology Assessment Panel neither the optimal timing nor 
duration of aromatase inhibitor therapy is established (Winer E.P et al 2005). There are no 
studies investigating extended adjuvant therapy after 5 years, in patients that were switched to 
an aromatase inhibitor after prior tamoxifen treatment. It is currently unknown what the 
optimal length of aromatase inhibitor therapy is after 2 to 3 years of adjuvant tamoxifen 
therapy in postmenopausal hormone sensitive breast cancer patients.  

Clinical Study Protocol 
Drug Substance Anastrozole   
Study Code BOOG 2006-01, D5392-NL-003  
Edition Number 004 
Date 31 October 2016 
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2. 
STUDY OBJECTIVES 
2.1 
Primary objective 
The primary objective of this study is to assess the DFS with 6 years of adjuvant anastrozole 
compared with the current standard treatment of 3 years of adjuvant anastrozole in 
postmenopausal hormone sensitive breast cancer patients, subsequent to 2 to 3 years of 
adjuvant tamoxifen treatment. 
2.2 
Secondary objectives 
The secondary objectives of the study are: 
1. To compare the incidence of contralateral breast cancer after 6 years versus 3 years 
adjuvant anastrozole, subsequent to 2 to 3 years of tamoxifen, 
2. To compare the overall survival (OS) in patients treated with 6 years versus 3 years of 
adjuvant anastrozole, subsequent to 2 to 3 years of tamoxifen. 
3. To compare toxicity of 6 years versus 3 years of adjuvant anastrozole in postmenopausal 
hormone sensitive breast cancer patients, subsequent to 2 to 3 years of tamoxifen. 
4. To determine regional differences in the initial treatment of breast cancer retrospectively by 
collecting baseline information on initial therapies. Aspects of the initial treatment that will be 
investigated are e.g. the kind of surgery performed (breast saving or mastectomy) and whether 
or not chemotherapy is given and which chemotherapy was used in postmenopausal patients 
in relation to the primary tumour and patient characteristics. 
5. To compare the cost effectiveness of 3 years versus 6 years adjuvant anastrozole therapy, 
after subsequent 2 to 3 years of adjuvant tamoxifen treatment. 
6. To assess patterns of care in The Netherlands in prevention, detection and treatment of 
osteoporosis in postmenopausal women with breast cancer treated with adjuvant anastrozole. 
 To assess differences in management of bone health (DEXA scans, vitamin D / 
Calcium, bisphosphonates) in postmenopausal women with breast cancer treated with 
adjuvant anastrozole, between medical oncologists, surgeons, radiotherapists and nurse 
practitioners. 
 To assess loco regional differences in the Netherlands in management of bone health 
in postmenopausal women with breast cancer treated with adjuvant anastrozole. 
 To assess rate of compliance to Dutch guidelines on prevention, detection and 
treatment of osteopenia and osteoporosis in postmenopausal women with breast cancer 
throughout the period of treatment with adjuvant anastrozole and over time with new 
breast cancer guidelines. 

Clinical Study Protocol 
Drug Substance Anastrozole   
Study Code BOOG 2006-01, D5392-NL-003  
Edition Number 004 
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 To relate the number of osteoporotic fractures during and following treatment with 
adjuvant anastrozole with the compliance to osteoporotic guidelines. 
 To analyse the impact of prolonged anastrozole treatment on BMD and to analyse the 
impact of short versus prolonged treatment (6 versus 3 years anastrozole) on pattern of 
care. 
 To analyse occurrence of distant (bone) metastases in relation to occurrence of 
osteopenia and osteoporosis, and in relation to use of supplements and therapy for 
reduced BMD. 
 
3. 
STUDY PLAN AND PROCEDURES 
3.1 
Overall study design and flow chart 
This study is a prospective, randomised, open, parallel-group, multicentre, phase III study.  
Patients are randomised between two arms:  
A. Anastrozole 3 years, after 2 to 3 years adjuvant tamoxifen  
B. Anastrozole 6 years, after 2 to 3 years adjuvant tamoxifen  
 
 
 
 
 
 
 
 
 
Patients will be stratified for the following tumour characteristics:  
 ER+PgR- versus ER+PgR+ versus ER-PgR+ 
 N+ versus N-  
Randomization
Tamoxifen
2 to 3 years
3 years anastrozole
6 years anastrozole
5 to 6 years adjuvant
3 years extended adjuvant

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 Her2neu over expression versus no Her2neu over expression versus unknown Her2neu 
expression 
 Duration of adjuvant tamoxifen (2.0 to 2.5 years versus 2.5 to 3.0 years) treatment 
This study will be conducted in 1900 postmenopausal women in The Netherlands. 
Postmenopausal female patients with hormone receptor positive breast cancer who have 
already received 2 to 3 years adjuvant tamoxifen, and who never had signs of loco-regional 
recurrence or distant metastasis. Chemotherapy and/or radiotherapy before or after local 
surgical treatment is allowed. 
After randomisation and initiation of the patient in the study, the first two visits will be 
scheduled after 3 and 6 months. During the treatment period of 3 years anastrozole followed 
by three years nothing or 6 years anastrozole, patients are visiting the investigator every 6 
months. Treatment discontinuation can be due to disease recurrence or death or patient 
unwillingness to continue to participate in the study. After the treatment period patients are 
followed for survival and disease recurrence once a year. 
At each visit complaints will be recorded and a physical examination will be performed. A 
yearly X-mammography is performed. Furthermore, blood chemistry and haematology may 
be assessed according to local policy. 
Additional secondary endpoints will be investigated in separate side-studies. Details of the 
side studies are described in the sub-protocols. Centres and investigators can decide to 
participate only in the main protocol or in the main protocol and in one or more of the side 
studies. Subjects participating in these side studies will be asked to give additional informed 
consent for each side study. 

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Drug Substance Anastrozole   
Study Code BOOG 2006-01, D5392-NL-003  
Edition Number 004 
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Figure 1 
Study flow chart 
 
  
Postmenopausal women with hormone-receptor-positive early breast cancer who currently 
receive adjuvant tamoxifen for 2 to 3 years after adequate local treatment with surgery, with or 
without radiotherapy and/or chemotherapy, who do not have signs of recurrent disease. 
 
 
 
Screening  
 
  
Informed Consent 
 
 
 
 
 
 
 
 
 
Randomisation 1:1 and start of treatment 
 
  
 
 
 
 
Arm A 
3 years anastrozole and 
3 years no therapy   
(A total adjuvant 
treatment of 5-6 years)  
Regular follow-up of all 
subjects until death  
 
Arm B 
6 years anastrozole 
(A total adjuvant treatment of 
8-9 years) 
 
Treatment  
 
 
 
Follow-up 

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Drug Substance Anastrozole   
Study Code BOOG 2006-01, D5392-NL-003  
Edition Number 004 
Date 31 October 2016 
 
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3.2 
Rationale and risk/benefit assessment  
3.2.1 
Rationale for study design, doses and control groups 
The control arm in this study (arm A) is in accordance with the Dutch EBRO multidisciplinary 
guidelines “Treatment of breast cancer” revised version 3.0 2005 (mammacarcinoom richtlijn 
2005).  
The dose regime of anastrozole is 1 mg oral a day. This dose is registered for the adjuvant 
treatment of hormone receptor positive breast cancer (IB1 text). 
3.2.2 
Risk/benefit and ethical assessment 
According to the IB1 text anastrozole is not indicated for pre-menopausal breast cancer 
patients. In a recent publication by Smith et al. (2006) it is described that in a group of 45 
women with chemotherapy-induced amenorrhoea, 12 women had a return of their ovarian 
function after using an aromatase inhibitor (AI). As a consequence, it is recommended to 
monitor more closely the ovarian function of patients with no amenorrhoea or bilateral 
oophorectomy who have been prescribed an AI. Anastrozole has not been investigated in 
patients with severe renal or hepatic impairment. 
Drugs that lower the oestrogen blood levels, like anastrozole, can negatively influence the 
bone mineral density. The EBRO guidelines version 3.0 (mammacarcinoom richtlijn 2005) 
have included a section concerning osteoporosis prevention for therapy-induced osteoporosis. 
For postmenopausal women using aromatase inhibitors the following advice is given:  
Calcium intake (>1000 mg per day), sufficient physical exercise and adequate vitamin D 
status. To monitor osteoporosis for these high risk patients a baseline bone mineral density 
measurement can be performed. For treatment the investigator is also referred to these 
guidelines. 
3.3 
Selection of study population 
3.3.1 
Inclusion criteria 
For inclusion in the study subjects must fulfil all of the following criteria: 
1. 
Obtained written informed consent before entering the study 
2. 
Histologically proven operable invasive breast cancer at the time of breast cancer 
diagnosis 
3. 
Positive estrogen- and/or progesterone-receptor status (>10% positive cells) 
4. 
Postmenopausal at the time of randomization, according to one or more of the 
following:  
 
aged 55 or more and natural amenorrhoea;  
 
bilateral oophorectomy, irrespective of age; 

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 
Aged 45-54 years and FSH and 17 beta oestradiol values within the postmenopausal 
range confirmed by local laboratory values within the last three months (including: patients 
who have had a hysterectomy). 
 
5. 
No distant metastasis at the time of randomisation 
6. 
No recurrences after the primary diagnosis and treatment of breast cancer 
7. 
Patients currently using adjuvant tamoxifen for a duration of 2 to 3 years after 
surgery of the primary breast tumour  
8. 
Prior (neo)adjuvant radiotherapy and/or chemotherapy is allowed 
3.3.2 
Exclusion criteria 
Any of the following is regarded as a criterion for exclusion from the study: 
1. 
Patients who have received previous hormonal therapy as adjuvant breast cancer 
treatment besides tamoxifen 
2. 
Previous history of invasive breast cancer within the last 10 years, other then the 
breast cancer that is currently treated with adjuvant tamoxifen and diagnosed 2 to 3 
years ago  
3. 
Other invasive malignancy within the last 5 years, other than squamous or basal cell 
carcinoma of the skin or carcinoma in situ of the cervix, adequately cone biopsied. 
4. 
Treatment with a non-approved or experimental drug during the 3 months before 
informed consent. 
5. 
Performance status: Karnofski score 60% or less 
6. 
Patients who, for whatever reason (e.g. confusion, infirmity, alcoholism), are 
unlikely to comply with trial requirements 
7. 
Patients unwilling to stop taking any drug known to affect sex hormonal status 
(including HRT), or in whom it would be inappropriate to stop 
8. 
Patients known to have one of the following hereditary illnesses; galactose-
intolerance, Lapp lactase deficiency or glucose-galactose malabsorption 
 

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3.4 
Treatments 
3.4.1 
Identity of investigational product and comparators 
In this open label study commercially available Arimidex will be used. Each tablet of 
Arimidex contains 1 mg of anastrozole.  
3.4.2 
Doses and treatment regimens 
One tablet (1 mg) has to be taken orally once a day. Subjects should be instructed to take their 
daily dose at approximately the same time each day. The patients will take anastrozole for 3 
years or 6 years unless the patients receive a treatment end-point. No modification of the dose 
will be allowed. Temporary discontinuation (< 4 weeks) due to adverse events however is 
allowed. 
3.4.3 
Labelling 
Commercially available Arimidex will be used and these treatment packs are marked 
according to the national requirements. 
3.4.4 
Storage 
Arimidex must be kept in the original package and should not be stored above 30oC.  
3.5 
Randomisation procedure  
A total of 1900 patients will be entered in the study. After having properly checked all 
eligibility criteria, stratification parameters and having obtained patient’s written informed 
consent, patients will be randomised by fax at the IKO trial office in Nijmegen (fax 024- 
3619080). Randomisation will be performed 1:1 for 3 years vs 6 years Anastrozole. 
Randomised treatment will be confirmed by fax or email within one (1) working day. 
3.5.1 
Method for assigning patients to treatment groups 
Patients will be randomized based on stratification for the following tumour characteristics: 
 
ER+PgR- vs ER+PgR+ vs ER-PgR+ 
 
N+ vs N-  
 
Her2neu over expression vs no Her2neu over expression vs unknown Her2neu 
expression 
 
Duration of Tamoxifen (2.0 to 2,5 years vs 2,5 to 3.0 years). 
3.6 
Blinding and procedures for unblinding the study  
Not applicable 

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3.7 
Pre-study, concomitant and post-study treatment(s) 
Other medication, which is considered necessary for the subject’s safety and well-being, may 
be given at the discretion of the investigator(s).  The administration of all medication that is 
given for treatment of a SAE or defined AE or for treatment of breast cancer (including 
investigational products) must be recorded in the appropriate sections of the case report form 
(CRF). Post-study medication (during the follow-up period) for the indication breast cancer is 
registered during the whole follow-up period. 
3.8 
Treatment compliance 
Subject’s compliance to treatment schedule should be monitored by the investigator by asking 
the patient every visit if trial therapy has been interrupted. This must be recorded in the patient 
files and the CRF. 
3.9 
Discontinuation of subjects from treatment or assessment 
3.9.1 
Criteria for discontinuation  
Subjects may be discontinued from study treatment and assessments at any time.  Specific 
reasons for discontinuing a subject from this study are: 
 
Voluntary discontinuation by the subject who is at any time free to discontinue 
his/her participation in the study, without prejudice to further treatment 
 
Safety reasons as judged by the investigator and/or AstraZeneca 
 
Severe non-compliance to protocol as judged by the investigator and/or responsible 
physician 
 
Severe adverse events 
 
Incorrect enrolment (ie, the subject does not meet the required inclusion/exclusion 
criteria) of the subject 
 
Subject lost to follow-up 
3.9.1.1 
Procedures for discontinuation 
Subjects who discontinue should always be asked about the reason(s) for their discontinuation 
and the presence of any adverse events.  If possible, they should be seen and assessed by an 
investigator(s).  The reason for discontinuation should be recorded in the CRF. Adverse events 
should be followed up if possible. At the time of discontinuation of anastrozole therapy every 
attempt should be made to get information about the disease status of the patient to be able to 
determine the efficacy of the received treatment. 

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4. 
MEASUREMENTS OF STUDY VARIABLES AND 
DEFINITIONS OF OUTCOME VARIABLES 
4.1 
Screening and demographic measurements 
The following information is collected at entry (screenings visit), within 4 weeks before 
randomisation and start of trial therapy, and recorded in the CRFs: 
(a) 
Demography 
Date of birth will be recorded. 
(b) 
Medical history 
Any relevant past medical history (including details of all previous bone fractures, 
cardiovascular disease and any lipid related disorders, e.g. hyperlipidaemia), any concurrent 
illness, familial history of osteoporosis, DEXA scans down to 1 year before randomisation and 
up to 7 years after randomisation and whether the subject has had a hysterectomy, smoking 
history or had previous HRT are recorded at entry. The Karnofski score is registered at entry. 
(c) 
Concomitant medication 
Concomitant medication/treatments are recorded at entry (cardiovascular, bisphosphonates, 
calcium supplements, vitamin D supplements, corticosteroids, etc). Concomitant 
medication/treatments concerning bisphosphonates, calcium supplements, vitamin D 
supplements and corticosteroids will be recorded down to 1 year before randomisation 
independent to whether they were stopped or were ongoing at the time of randomisation. Any 
changes in medication, medication present at entry or during study treatment prescribed for 
treatment of SAE or predefined AE are recorded until the subject stops study treatment. After 
stop of study treatment only new medication for treatment of breast cancer is recorded. 
Nevertheless, concomitant medication/treatments concerning bisphosphonates, calcium 
supplements, vitamin D supplements and corticosteroids will be recorded up to 7 years after 
randomisation to the study.  
(d) 
Physical examination 
Height and weight is measured at entry. 
(e) 
Breast cancer history 
Primary tumour size, ER and PgR status, Her2neu status, nodal status, histological grade, 
lymph vascular invasion if available, primary surgery procedure and date of surgery, radiation 
(date of start) if applicable, chemotherapy (date of start and regimen) if applicable, date of 
diagnosis and start date of tamoxifen are recorded at entry. 
Retrospective histologic assessment, using paraffin blocks, of ER status, PgR status and other 
parameters may be carried out, in case of missing information. 

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Date of last X-mammography, must be performed within a year before screening, and 
outcome of the X-mammogram are recorded at entry.  
(e) 
Haematology and biochemistry 
The following routine laboratory assessments must be performed within three months before 
entry and repeated at visit 4, after 3 years and after 6 years:  
 
Haematology (Hb, WBC, platelets) 
 
Creatinine 
 
Calcium 
 
Alkaline phosphatase 
 
ALAT, ASAT 
 
LDL cholesterol 
 
HDL cholesterol 
 
Triglyceride 
Patients between 45 and 54 with intact ovaries must have FSH and 17 beta oestradiol 
determined, and values within postmenopausal ranges, within three months before entering 
and during the study. These measurements must be repeated for this group of patients at visit 4 
to 8. 
These assessments are performed and analysed locally. 

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4.2 
Primary variable 
The primary outcome variable of this study is the DFS. This variable was used as the basis for 
the sample size calculation as described in section 6. 
4.2.1 
Disease Free Survival  
Patients will be reviewed for recurrence of breast cancer at all visits during treatment and 
follow-up by history and physical examination. An X-mammography will be done once a year 
during treatment and follow-up, according to the Dutch EBRO guidelines.  
For recurrence the following criteria, which are based on British Breast Group 
recommendations, are used: 
SITE OF RECURRENCE 
METHOD OF CONFIRMATION 
LOCO-REGIONAL 
 
1.  Ipsilateral breast (including DCIS)1 
Histology or cytology 
2.  Chest wall 
Histology or cytology 
3.  Axillary lymph nodes 
Histology or cytology 
4.  Other regional nodes (supraclavicular 
and internal mammary) 
Histology or cytology 
DISTANT 
 
5.  Skeletal 
CT2 scan, or bone scan with confirmatory x-ray evaluation of 
hot spots.  Biopsy may be necessary in the case of a single 
lesion. 
6.  Pulmonary 
Chest x-ray, CT-scan, and preferably histology or cytology in 
case of a single lesion 
7.  Hepatic 
CT scan or ultrasound, and preferably histology or cytology in 
case of a single lesion 
8.  Other distant 
Imaging and/or biopsy.  (Rising tumour markers alone , eg 
CA15.3, are unacceptable) 
1 Ductal Carcinoma In Situ 
2 Computed Tomography 
 
The site and date of confirmed first loco-regional and first distant recurrence will be recorded 
in the CRF. After loco-regional and distant recurrence patient will be in follow-up for survival 
only. 
After second primaries patient who is treated with curative intent should be treated according 
to study. After second primaries patient who is treated with palliative intent will be in follow-
up for survival only. 

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New breast primaries (either contralateral or ipsilateral) will be regarded as disease recurrence 
events in the statistical analysis of DFS, as will intercurrent deaths without recurrence. 
4.2.2 
Overall survival  
All patients are followed for survival until death or end of the study. When a subject has died, 
the date of death and the reason are registered. 
4.3 
Safety measurements and variables 
The methods for collecting safety data are described below.  
4.3.1 
Adverse events 
4.3.1.1 
Definitions 
The definitions of adverse events (AEs), other significant adverse events (OAEs) and serious 
adverse events (SAEs) and are given below. It is of the utmost importance that all staff 
involved in the study is familiar with the content of this section.  The local investigator is 
responsible for ensuring this. 
Adverse event 
An adverse event is the development of an undesirable medical condition or the deterioration 
of a pre-existing medical condition following or during exposure to a pharmaceutical product, 
whether or not considered causally related to the product.  An undesirable medical condition 
can be symptoms (eg, nausea, chest pain), signs (eg, tachycardia, enlarged liver) or the 
abnormal results of an investigation (eg, laboratory findings, electrocardiogram).  In clinical 
studies, an AE can include an undesirable medical condition occurring at any time, including 
run-in or washout periods, even if no study treatment has been administered.  
In this study the following AE’s must be registered in the CRF:  
 
AEs leading to discontinuation of study medication 
 
AEs concerning osteoporosis 
 
AEs concerning fractures 
 
AEs concerning arthralgia 
 
AEs concerning cardiovascular events 
Other Significant Adverse Events (OAE) will be identified by the Drug Safety Physician 
and if applicable also by the Clinical Study Team Physician during the evaluation of safety 
data for the Clinical Study Report.  Significant adverse events of particular clinical 
importance, other than SAEs and those Aes leading to discontinuation of the subject from 
study treatment, will be classified as OAEs.  Examples of these are marked haematological 
and other laboratory abnormalities, and certain events that lead to intervention (other than 

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those already classified as serious), dose reduction or significant additional treatment.  For 
each OAE, a narrative may be written and included in the Clinical Study Report. 
Serious adverse event 
A serious adverse event is an AE occurring during any study phase (ie, run-in, treatment, and 
washout, follow-up), and at any dose of the investigational product, comparator or placebo, 
that fulfils one or more of the following criteria: 
 
results in death 
 
is immediately life-threatening 
 
requires in-patient hospitalisation or prolongation of existing hospitalisation 
 
results in persistent or significant disability or incapacity 
 
is a congenital abnormality or birth defect 
 
is an important medical event that may jeopardise the subject or may require 
medical intervention to prevent one of the outcomes listed above. 
4.3.1.2 
Recording of adverse events 
AEs and all SAEs, as described in section 4.3.1.1, occurring from informed consent, and up to 
30 days after end of study, should be recorded. Thus SAEs need to be reported during the total 
duration fo the study – 6 years – for both treatment arms. 
The following definitions are used to assign intensity: 
 
1- mild (awareness of sign or symptom, but easily tolerated) 
 
2- moderate (discomfort sufficient to cause interference with normal activities) 
 
3- severe (incapacitating, with inability to perform normal activities) 
 
4- life-threatening 
It is important to distinguish between serious and severe Aes.  Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Section 4.3.1.1.  An AE of severe 
intensity need not necessarily be considered serious.  For example, nausea that persists for 
several hours may be considered severe nausea, but not a SAE.  On the other hand, a stroke 
that results in only a limited degree of disability may be considered a mild stroke but would be 
a SAE.  
Should an overdose (accidental or deliberate) occur, it must be reported in accordance with the 
procedures described in Section 9.2, Procedures in case of overdose, regardless of whether the 

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overdose was associated with any symptom or not.  All symptoms associated with the 
overdose should be reported as Aes.  
The causality of (S)Aes  
The causality of (S)AE’s (ie, their relationship to study treatment) will be assessed by the 
investigator(s). The following factors should be considered when deciding if there is a 
“reasonable possibility” that an AE may have been caused by the drug. 
 
Time Course. Exposure to suspect drug.  Has the subject actually received the 
suspect drug? Did the AE occur in a reasonable temporal relationship to the 
administration of the suspect drug? 
 
Consistency with known drug profile. Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? Or could the AE be anticipated from its pharmacological 
properties? 
 
Dechallenge experience. Did the AE resolve or improve on stopping or reducing the 
dose of the suspect drug? 
 
Rechallenge experience. Did the AE reoccur if the suspected drug was reintroduced 
after having been stopped? AstraZeneca would not normally recommend or support 
a rechallenge. 
 
Laboratory tests. A specific laboratory investigation (if performed) has confirmed 
the relationship? 
 
No alternative cause. The AE cannot be reasonably explained by another aetiology 
such as the underlying disease, other drugs, other host or environmental factors. 
A “reasonable possibility” could be considered to exist for an AE where one or more of these 
factors exist. 
In contrast, there would not be a “reasonable possibility” of causality if none of the above 
criteria apply or where there is evidence of exposure and a reasonable time course but any 
dechallenge (if performed) is negative or ambiguous or there is another more likely cause of 
the AE. 
In difficult cases, other factors could be considered such as: 
 
Is this a recognised feature of overdose of the drug? 
 
Is there a known mechanism 
Ambiguous cases should be considered as being a “reasonable possibility” of a causal 
relationship unless further evidence becomes available to refute this. Causal relationship in 

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cases where the disease under study has deteriorated due to lack of effect should be classified 
as no reasonable possibility. 
Any conditions or hospitalisations that are unequivocally due to recurrence of breast cancer 
must not be recorded as an AE or SAE. 
4.3.1.3 
Reporting of serious adverse events 
Investigators and other site personnel must inform appropriate AstraZeneca representatives of 
any SAE that occurs in the course of the study within 1 day (ie, immediately but no later than 
the end of the next business day) of when he or she becomes aware of it. 
Follow-up information on SAEs must also be reported by the investigator within the same 
time frames. 
If a non-serious AE becomes serious, this and other relevant follow-up information must also 
be provided to AstraZeneca within 1 day as described above.  For a non-serious AE that 
become serious but which is not fatal or life-threatening a report should be received within 
5 days. 
The AstraZeneca representative will work with the investigator to compile all the necessary 
information and ensure that the appropriate AstraZeneca Drug Safety Department receives a 
report by day 1 for all fatal and life-threatening cases and by day 5 for all other SAEs. 
All SAEs have to be reported, whether or not considered causally related to the investigational 
product or to the study procedure(s).  AstraZeneca is responsible for informing the Ethics 
Committee and/or the Regulatory Authority of the SAE as per local requirements.   
4.3.2 
Laboratory safety measurements and variables 
4.3.2.1 
Methods of assessment 
No laboratory safety measures are scheduled. Additional laboratory safety measurements are 
made at the investigators discretion. 
4.3.3 
Vital signs, ECG and physical examination 
Not applicable 

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Table 1  Visit schedule 
Visit 
1 
2 
3  
4 
5 to 15 
16 etc.. 
Visit Description 
Screening 
Randomisation, Start 
Treatment 
Treatment 
Treatment 
First 6 years after 
randomization, both arms 
Follow-up, starting 6 
years after randomization 
Visit Window 
 
0-28 days After V 1 
at 3 months  
at 6 months 
Every 6 month 
Every year 
Informed consent 
X 
 
 
 
 
 
Medical history  
X 
 
 
 
 
 
In-/exclusion criteria 
X 
 
 
 
 
 
Tumour characteristics 
X 
 
 
 
 
 
Physical examination, weight  
X 
 
X 
X 
X 
 
Clinical chemistry and 
haematology, Hb, PLT, WBC, 
creatinine, calcium, ALAT, 
ASAT, AF, LDL, HDL and TG  
X 
 
 
X 
X (only after 3 years and 
after 6 years) 
 
FSH and 17 beta oestradiol** 
X 
 
 
X 
X (only at visits 5 to 8) 
 
Co-medication  
X*** 
 
X 
X 
X 
X*** (only for 
indication breast 
cancer) 
Interruption trial medication 
 
 
X 
X 
X 
 
Defined Adverse events 
 
 
X 
X 
X 
 
X-mammography 
X 
 
 
 
X (once a year, unless 
distant metastases) 
 
Recurrence/Survival status 
 
 
 
 
X 
X 
Fresh frozen blood sample 
(only when patient participates 
in side study) 
X 
 
 
 
 
 
Side study : neuropsychology* 
X 
 
 
 
X (only after 3 years and 
after 6 years) 
 

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* a side study, in due time  
** Patients between 45 and 54 with intact ovaries must have FSH and 17 beta oestradiol determined, and values within postmenopausal ranges. 
***Concomitant medication/treatments concerning bisphosphonates, calcium supplements, vitamin D supplements and corticosteroids will be recorded down 
to a year before randomisation and up to 7 years after randomisation independent to whether they were stopped or were ongoing at the time of randomisation.

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5. 
DATAMANAGEMENT 
The trial office of the IKO will be the Central Data Centre for this trial. The Central Data 
Centre will be responsible for randomisation of patients, check of receipt of CRF pages and 
generation of edits/queries. AstraZeneca will be responsible for the initiation of the study in 
the participating centres and will perform source data verification. 
CRF’s are used to record data. Data should be recorded legibly onto the CRF’s in black or 
blue ballpoint pen. Correction fluid or covering labels must not be used. At the participating 
centres the data will be recorded in the CRF's by the data managers working for the local IK's.  
Any missing, impossible or inconsistent recordings in the CRF’s are referred back to the 
investigator using a data query sheet (DQS), and is documented for each individual subject 
before clean file status is declared. 
The CRF’s must be completed and signed by the investigator or one of his/her authorized staff 
members as soon as the requested information is available. The time between the patient’s 
visit and completion/shipment of CRF pages should be kept to a reasonable minimum. It 
remains the responsibility of the investigator to verify that original CRF’s are completed and 
filled out correctly. 
After completion (within 1 month after the visit) of the CRF’s, the pages must be sent by mail 
to the Central Data Centre. Copies of the CRF pages are kept with the investigator and 
AstraZeneca (up to the sponsorship transfer). If information is not known, this must be clearly 
indicated.  
6. 
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE 
6.1 
Statistical evaluation – general aspects 
A comprehensive Statistical Analysis Plan (SAP) will be prepared before database lock.   
All main analyses will be according to the intention to treat principle. The data analysis will 
be performed by the department of Epidemiology and Biostatistics of the UMCN St Radboud 
Nijmegen.  
6.2 
Description of outcome variables in relation to objectives and 
hypotheses 
The primary efficacy variable is an adaptation of the disease-free survival (DFS), where DFS 
is defined as: the interval between randomisation and occurrence of one of the following 
events: 
 
Local recurrence  
 
Regional recurrence 

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 
Distant recurrence (soft tissue, bone, viscera) 
 
Occurrence of a secondary breast carcinoma (including contralateral breast cancer)  
 
Second, nonbreast cancer other than basal-cell or squamous-cell carcinoma of the skin or 
carcinoma in situ of the cervix 
 
Death without prior cancer event 
 
Because after randomisation all patients receive the same therapy for 3 years, differences 
between both treatment groups are only to be expected starting 3 years after randomisation. 
Consequently, the parameter to be used in the statistical analyses will be the adapted disease-
free survival (ADFS), defined as the DFS, but with starting point the date 3 years after 
randomisation instead of the randomisation date itself. 
Analogously, adapted overall survival (AOS), defined as the OS, is defined as interval 
between the date 3 years after randomisation and death from any cause.   
6.3 
Description of analysis sets 
The intention to treat (ITT) population comprises all randomised patients excluding ineligible 
patients. The primary objective and the secondary objectives contralateral breast cancer and 
OS will be analysed using the ITT population.  
6.4 
Method of statistical analysis 
Demography and baseline data will be listed for each patient and summarised by randomised 
treatment group. 
At randomisation, patients are stratified for nodal status, ER+/PgR- versus ER-/PgR+ versus 
ER+/PgR+, her2neu status and duration of tamoxifen treatment 2,0 to 2,5 years versus 2,5 to 
3,0 years. 
Kaplan-Meier survival curves will be used for the graphical representation of the therapy’s 
effect on parameters of primary and secondary survival objectives (ADFS and AOS). 
Differences between the two treatment groups will be tested with the log-rank test (for ADFS 
and AOS) combined over the non-empty strata and logistic regression (for occurrence of 
contralateral breast cancer) adjusted for the stratification factors.  
Hazard ratios and corresponding 95% confidence intervals (CIs) will be estimated with the 
Cox proportional-hazard model adjusted for stratification factors. 
6.5 
Determination of sample size 
Patients included in this study are by good prognosis selected considering the fact that they are 
still disease-free two to three years after the primary diagnosis of breast cancer. Because after 
randomisation all patients receive the same therapy for 3 years, differences between both 
treatment groups will appear starting 3 years after randomisation. At that time, in both groups 
91% of all subjects are expected to be disease-free (Coombes R.C. et al 2004). It is assumed 

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that 3 years later this rate has decreased to 80% in the control group, implying a 3-years 
ADFS (see section 6.2) rate of 90%. 
This study is designed to detect an increase to 94% of the 3-years ADFS in the anastrozole 
group, corresponding with a hazard ratio of 0.60. With a statistical power of 80 percent and a 
two-sided alpha level of 0.04 (correcting for one interim analysis), 770 disease-free subjects in 
each group will have to start the treatment/control part of the trial, implying 850 evaluable 
subjects to be randomised. Accounting for approximately 10% drop-out, 950 subjects per 
group will be included in this study. The hazard ratio of 0.60 is based on prior studies using an 
aromatase inhibitor after shorter or longer treatment with tamoxifen, and compared with no 
treatment or placebo. Three studies showed that switching to an aromatase inhibitor after 2 to 
3 years tamoxifen, for a total adjuvant treatment of 5 years, gave a better RFS HR (ranges 
from 0.70 (Coombes R.C. et al 2004), to 0.60 and 0.42 (Jakesz R. et al 2005, Boccardo F. et al 
2005) then 5 years tamoxifen. There were two studies showing that switching patients to an 
aromatase inhibitor after 5 years tamoxifen gave a RFS HR advantage with an hazard ratio of 
0.57 and 0.64 (Goss P. et al 2004, Jakesz R. et al 2005 6a).  
We will not perform an interim analysis of DFS and OS for the ITT population, as we do not 
expect relevant difference at this early time point because of the recent results from ATLAS 
and aTTOM trials. Therefore, the final analysis will be evaluated at a significance level of 
0.05, increasing the power to 82 percent. 
 
Interim analysis 
No interim analysis of ADFS and AOS for the ITT population will be performed. For 
monitoring the quality of the study an interim report will be made. 
Final analysis 
Final analyses will be performed after the last patient has reached a minimum follow-up of 6 
years after randomisation. 
Follow-up analysis 
In order to detect long term effect, a follow-up analyses will be performed after the last patient 
has reached a minimum follow-up of 12 years after randomisation. 
 
6.6 
Data and safety monitoring board 
An Independent Data Monitoring Committee (IDMC) will be established, which will be 
independent of the trial organisers, in case of and at the time of the planned and any 
unplanned interim-analysis for whatever reasons.  

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For monitoring the quality of the study an interim report will be  made. A DSMB will evaluate 
this report according to instructions provided in the DSMB charter. 
7. 
STUDYMANAGEMENT 
7.1 
Monitoring 
Before inclusion of the first subject into the study, a representative of AstraZeneca will visit 
the investigational study site to: 
 
determine the adequacy of the facilities 
 
discuss with the investigator(s) (and other personnel involved with the study) their 
responsibilities with regard to protocol adherence, and the responsibilities of 
AstraZeneca or its representatives. This will be documented in a Clinical Study 
Agreement between AstraZeneca and the investigator. 
 
discuss where the identification of the data will be recorded, e.g. medical records, 
CRF and other associated documents. This is documented in the clinical study 
agreement. 
During the study, a monitor from AstraZeneca or company representing AstraZeneca will 
have regular contacts with the study site, including visits to: 
 
provide information and support to the investigator(s) 
 
confirm that facilities remain acceptable 
 
confirm that the investigational team is adhering to the protocol, that data are being 
accurately recorded in the CRFs.  
 
perform source data verification (a comparison of the data in the CRFs with the 
subject’s medical records at the hospital or practice, and other records relevant to 
the study).  This will require direct access to all original records for each subject 
(eg, clinic charts). 
The monitor or another AstraZeneca representative will be available between visits if the 
investigator(s) or other staff at the centre need information and advice. 
7.2 
Audits and inspections 
Authorised representatives of AstraZeneca, a regulatory authority, an Independent Ethics 
Committee (IEC) or an Institutional Review Board (IRB) may visit the centre to perform 
audits or inspections, including source data verification for this study.  The purpose of an 
AstraZeneca audit or inspection is to systematically and independently examine all study-
related activities and documents to determine whether these activities were conducted, and 

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data were recorded, analysed, and accurately reported according to the protocol, Good Clinical 
Practice (GCP), guidelines of the International Conference on Harmonisation (ICH), and any 
applicable regulatory requirements. The investigator should contact AstraZeneca immediately 
if contacted by a regulatory agency about an inspection at his or her centre considering this 
study. 
7.3 
Training of staff 
The local responsible physician will maintain a record of all individuals involved in the study 
(medical, nursing and other staff).  He or she will ensure that appropriate training relevant to 
the study is given to all of these staff, and that any new information of relevance to the 
performance of this study is forwarded to the staff involved. 
7.4 
Changes to the protocol 
Study procedures will not be changed without the mutual agreement of the Principal 
Investigator, the Steering Committee and AstraZeneca. 
If it is necessary for the study protocol to be amended, the amendment or a new version of the 
study protocol (Amended Protocol) must be notified to or approved by each IRB or IEC, and 
if applicable, also the local regulatory authority, before implementation.  Local requirements 
must be followed. 
If a protocol amendment requires a change to a particular centre’s Informed Consent Form, 
then AstraZeneca and the centre’s IRB or IEC must be notified.  Approval of the revised 
Informed Consent Form by AstraZeneca (up to the sponsorship transfer) and by the IRB or 
IEC is required before the revised form is used.   
AstraZeneca will up to the sponsorship transfer distribute amendments and new versions of 
the protocol to each local responsible physician, who is in turn responsible for the distribution 
of these documents to his or her IRB or IEC, and to the staff at his or her centre. Thereafter, it 
is the responsibility of Maastricht UMC+. 
7.5 
Study agreements 
The responsible physician at each centre must comply with all the terms, conditions, and 
obligations of the Clinical Study Agreement for this study.  In the event of any inconsistency 
between this Clinical Study Protocol and the Clinical Study Agreement, the Clinical Study 
Protocol shall prevail. 
7.6 
Study timetable and end of study 
Before a subject's enrolment in the study and any study-related procedures are undertaken the 
following should be fulfilled: 
 
signed Clinical Study Protocol and other agreements between AstraZeneca and the 
Principal Investigator/Study Site. 

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 
approval of the study by the IRB/IEC 
The first subject is to be recruited by approximately March 2006. Recruitment is expected to 
be completed by December 2007. The last subject is expected to have completed the study by 
December 2013.  
8. 
ETHICS 
8.1 
Ethics review 
The final study protocol, including the final version of the Informed Consent Form, must be 
approved or given a favourable opinion in writing by an IRB or IEC as appropriate.  The 
investigator must submit written approval to AstraZeneca before he or she can enrol any 
subject into the study.   
The Principal Investigator is responsible for informing the IRB or IEC of any amendment to 
the protocol in accordance with local requirements. In addition, the IRB or IEC must approve 
all advertising used to recruit subjects for the study. The protocol must be re-approved by the 
IRB or IEC annually, as local regulations require.  
The Principal Investigator is also responsible for providing the IRB with reports of any serious 
and unexpected adverse drug reactions from any other study conducted with the 
investigational product.  AstraZeneca will provide this information to the Principal 
Investigator. 
Progress reports and notifications of serious and unexpected adverse drug reactions will be 
provided to the IRB or IEC according to local regulations and guidelines.  
8.2 
Ethical conduct of the study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/Good Clinical Practice, applicable 
regulatory requirements and the AstraZeneca policy on Bioethics.  
8.3 
Informed consent 
The principal investigator(s) at each centre will ensure that the subject is given full and 
adequate oral and written information about the nature, purpose, possible risk and benefit of 
the study.  Subjects must also be notified that they are free to discontinue from the study at 
any time.  The subject should be given the opportunity to ask questions and allowed time to 
consider the information provided. 
The subject’s signed and dated informed consent must be obtained before conducting any 
procedure specifically for the study. 
When the subject has agreed to participate in one of the sub-protocols an additional informed 
consent must be obtained. 

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The principal investigator(s) must store the original, signed Informed Consent Form in the 
investigator study file. A copy of the signed Informed Consent Form must be given to the 
subject. 
If modifications are made according to local requirements, the new version has to be approved 
by AstraZeneca. 
8.4 
Subject data protection 
The written Informed Consent Form will incorporate (or, in some cases, be accompanied by a 
separate document incorporating) wording that complies with relevant data protection and 
privacy legislation.  Pursuant to this wording, subjects will authorise the collection, use and 
disclosure of their study data by the Investigator and by those persons who need that 
information for the purposes of the study. 
9. 
PROCEDURES IN CASE OF EMERGENCY, OVERDOSE OR 
PREGNANCY 
9.1 
Procedures in case of medical emergency 
The principal investigator(s) is responsible for ensuring that procedures and expertise are 
available to handle medical emergencies during the study.  A medical emergency usually 
constitutes an SAE and should be reported as such, see Section 4.3.1.1. 
9.2 
Procedures in case of overdose 
 
Use of study medication in doses in excess of that specified in the protocol should 
not be recorded in the CRFs as an AE of ‘Overdose’ unless there are associated 
symptoms or signs. 
 
An overdose with associated SAEs should be recorded as the SAE 
diagnosis/symptoms on the relevant AE forms in the CRFs. 
 
An overdose with associated non-serious AEs should be recorded as the AE 
diagnosis/symptoms on the relevant AE forms in the CRFs.  In addition, the 
overdose should be reported on the separate AZ “Clinical Study Overdose Report 
Form.” 
 
An overdose without associated symptoms should not be recorded as an AE in the 
CRFs.  The overdose should be reported on the separate AZ “Clinical Study 
Overdose Report Form”. 
9.3 
Procedures in case of pregnancy 
Not applicable 

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10. 
PUBLICATION RULES 
The publication guidelines of the Dutch CCMO (Central Committee for Research in Humans, 
www.ccmo.nl, will be adhered to in full. These guidelines consist of a number of basic 
principles. First of all the results of scientific research involving human subjects must be 
disclosed unreservedly. All parties concerned must justify their actions in this regard. Both 
positive and negative research results will be disclosed, and submitted to peer-reviewed 
scientific journals. The principal investigator and steering committee will prepare the 
manuscripts together with the statistician, and other active writing committee members, in co-
operation with the Sponsor of the study, Maastricht UMC+. Co-authorship is reserved for 
those investigators (one per centre) that enter more than 5% of the patients, in addition to 
those who constructively contributed to the study at the discretion of the project leader and 
steering committee (i.e. datamanager, etc); all other participating centers/physicians will be 
acknowledged. And finally, disputes on the interpretation of the results may not lead to an 
unnecessary delay in publication.  
11. 
REFERENCES 
Boccardo F. et al. Switching to anastrozole versus continued tamoxifen treatment of early 
breast cancer: preliminary results of the Italian Tamoxifen Anastrozole trial. J Clin Oncol 
2005;23:5138-47 
Buzdar A.U. et al. Anastrozole versus Megestrol Acetate in the treatment of postmenopausal 
women with advanced breast carcinoma. Cancer 1998;83:1142-52 
Coombes R.C. et al. A randomized trial of exemestane after two to three years of tamoxifen 
therapy in postmenopausal women with primary breast cancer. N Eng J Med 2004;350:1081-
92 
Early Breast Cancer Trialists’ Collaborative Group(EBCTCG). Effects of chemotherapy and 
hormonal therapy for erly breast cancer on recurrence and 15-year survival: an overview of 
the randomised trial. Lancet 2005;365:1687-1717 
Fisher B. et al. Five versus more than five years of tamoxifen for lymph node-negative breast 
cancer: updated findings from the National Surgical Adjuvant Breast and bowel Project B-14 
randomized trial. J Natl Cancer Inst 2001;93:684-690 
Goss P. et al. Updated analysis of the NCIC CTG MA.17 randomized placebo controlled trial 
of letrozole after five years of tamoxifen in postmenopausal women with early breast cancer. 
Proc Am Soc Clin Oncol 2004;22:847 (abstr) 
Jakesz R. et al. Switching of postmenopausal women with endocrine-responsive early breast 
cancer to anastrozole after 2 years’ adjuvant tamoxifen: combined results of the ABCSG trial 
8 and ARNO 95 trial. Lancet 2005;366:455-62 

Clinical Study Protocol 
Drug Substance Anastrozole   
Study Code BOOG 2006-01, D5392-NL-003  
Edition Number 004 
Date 31 October 2016 
 
37 
 
Jakesz R. et al. Extended adjuvant treatment with anastrozole; results from the Austrian Breast 
and Colorectal Cancer Study Group Trail 6a (ABCSG-6a). Proc Am Soc Clin Oncol 
2005;23:10S (abstr) 
Köberle D. and Thürlimann B. Adjuvant endocrine therapy in postmenopausal breast cancer 
patients. The Breast 2005;14:446-451 
Mammacarcinoom. Kwaliteitsinstituut voor de gezondheidszorg CBO en NABON. Landelijke 
richtlijn versie 3.0 2005 
Pritchard K.I. Aromatase inhibitors in adjuvant therapy of breast cancer: before, instead of, or 
beyond tamoxifen. J Clin Oncol 2005;23:4850-52 
Robertson J.F.R. et al. Fulvestrant versus anastrozole for the treatment of advanced breast 
carcinoma in postmenopausal women. Cancer 2003;98:229-38 
Smith I.E. et al. Adjuvant Aromatase Inhibitors for Early Breast Cancer After Chemotherapy-
Induced Amenorrhoea: Caution and Suggested Guidelines. J.Clin Oncol 2006; 24:2444-2447 
 
The ATAC Trialists’ Group. Results of the ATAC (Arimidex, Tamoxifen, Alone or in 
Combination) trial after completion of 5 years’ adjuvant treatment for breast cancer. Lancet 
2005;365:60-62 
The Breast International Group (BIG) 1-98 Collaborative Group. A comparison of letrozole 
and tamoxifen in postmenopausal women with early breast cancer. N Eng J Med 
2005;353:2747-57 
Winer E.P. et al. American Society of Clinical Oncology technology assessment on the use of 
aromatase inhibitors as adjuvant therapy for postmenopausal women with hormone receptor-
positive breast cancer: status report 2004. J Clin Oncol 2005;23:619-629 

Clinical Study Protocol 
Drug Substance Anastrozole   
Study Code BOOG 2006-01, D5392-NL-003  
Edition Number 004 
Date 31 October 2016 
 
38 
 
  
APPENDIX A: SIGNATURES 
 

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39 (45) 
SIGNATURE(S) 
A prospective randomised, open, multicentre, phase III study to assess 
different Durations of Anastrozole therapy after 2 to 3 years Tamoxifen as 
Adjuvant therapy in postmenopausal women with breast cancer.   
I agree to the terms of this study protocol 
Maastricht UMC+  
representative 
Prof. dr. V.C.G. Tjan-Heijnen 
Principal Investigator 
Date 
(Day Month Year) 
Tel.: +31 43 3877025 
This document contains confidential information, which should not be copied, referred to, 
released or published without written approval from Maastricht UMC+.  Investigators are 
cautioned that the information in this protocol may be subject to change and revision. 
 

Revised Clinical Study Protocol 
Drug Substance Anastrozole   
Study Code BOOG 2006-01, D5392-NL-003  
Edition Number 004 
Date 31 October 2016 
40 (45) 
 
SIGNATURE PRINCIPAL INVESTIGATOR 
A prospective randomised, open, multicentre, phase III study to assess 
different Durations of Anastrozole therapy after 2 to 3 years Tamoxifen as 
Adjuvant therapy in postmenopausal women with breast cancer.   
I agree to the terms of this study protocol 
Dr V.G.C. Tjan-Heijnen 
Date 
(Day Month Year) 
This document contains confidential information, which should not be copied, referred to, 
released or published without written approval from AstraZeneca.  Investigators are cautioned 
that the information in this protocol may be subject to change and revision. 

Revised Clinical Study Protocol 
Drug Substance Anastrozole   
Study Code BOOG 2006-01, D5392-NL-003  
Edition Number 004 
Date 31 October 2016 
41 (45) 
 
SIGNATURE OF INVESTIGATOR 
A prospective randomised, open, multicentre, phase III study to assess 
different Durations of Anastrozole therapy after 2 to 3 years Tamoxifen as 
Adjuvant therapy in postmenopausal women with breast cancer.   
I agree to the terms of this study protocol.  I will conduct the study according to the procedures 
specified herein, and according to the principles of Good Clinical Practice (GCP) and local 
regulations. 
Centre No.: 
Signature: 
Date 
(Day Month Year) 
This document contains confidential information, which should not be copied, referred to, 
released or published without written approval from Maastricht UMC+.  Investigators are 
cautioned that the information in this protocol may be subject to change and revision. 
 

Revised Clinical Study Protocol 
Drug Substance Anastrozole   
Study Code BOOG 2006-01, D5392-NL-003  
Edition Number 004 
Date 31 October 2016 
42 (45) 
  
APPENDIX B: SIDE STUDIES 
 
1. BLOOD SAMPLING 
 
An extra blood samples of  10 ml will be taken only from subjects that are included in this 
sub-protocol considering the retrospective analysis of biological markers in the blood to 
determine which patients benefit most from extended adjuvant anastrozole.  
Patients included in this sub-protocol will be asked an additional informed consent concerning 
taking of the blood sample, storage of the blood sample and the future use.  
The whole blood sample will be collected and fresh frozen. In due time, the blood will be 
analysed by micro-array analysis and other techniques to determine whether predictive factors 
can be identified, predicting an improved ADFS by prolonged treatment with adjuvant 
anastrozole. 
 
 
2. NEUROPSYCHOLOGY 
An addendum will be written in due time on this topic. 
 

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Drug Substance Anastrozole   
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Edition Number 004 
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APPENDIX C: PATHOLOGY 
 
 

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Edition Number 004 
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44 (45) 
 
Guidelines for the determination of oestrogen receptors (ER) and progesterone receptors 
(PR) 
 
The formaline-fixed paraffin preparation will be used for immunohistochemistry 
 
Method for immunohistochemistry 
- Use the paraffin preparation 
- Antigen retrieval (standardize method in own laboratory) 
- The standard immunohistochemistry protocol can be used with antibodies against ER or PR  
 
Scoring method 
- The intensity of colouring is not included in this scoring method 
- The percentage positive tumour cells should be reported. The tumour is ER or PR positive 
when the percentage positive cells is > 10%  
- Tumours that have a negative ER or PR status should be investigated for colouring of the 
normal epithelium adjacent to the tumour. The result is ER or PR negative if some of the 
normal cells are positive. If some of the normal cells showed no positive colouring, the test 
should be repeated. Another tumour paraffin preparation can be used. In the report it should be 
noted if the internal control was positive or negative (if the result of the repeated test is also 
negative, it should be noted that this result is probably not reliable) 
 
Guidelines for the determination of HER2 
 
Method of immunohistochemistry 
- Use the paraffin preparation  
- Antigen retrieval (standardize method in own laboratory) 
- The standard immunohistochemistry protocol can be used with antibodies against HER2/neu 
- The determination of HER2/neu positive tumour cells should be performed within 2 months 
after the preparation of the formaline-fixed paraffin coupe. The intensity of the colouring is 
deteriorated if the determination is performed later. 
  
Scoring method 
- Only the colouring of the membranes of invasive proliferating tumour cells should be 
reported as positive (colouring of the cytoplasm should not be reported) 
- The following guideline should be used: 
 
0: less than 10% of the tumour cells is positive 

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1+: more than 10% of the tumour cells is positive, but not the total membrane is coloured and 
the intensity is very weak 
2+: more than 10% of the tumour cells show total colouring of the membranes but the 
intensity is not more than moderate  
 
3+: more than 10% of the tumour cells show total colouring of the membranes and the 
intensity is strong  
- The part of the tumour with the strongest colouring determines the score  
- If normal tissue shows colouring of the membranes, the intensity of the whole colouring is 
too strong and the result is not reliable  
A test of 3+ is considered positive, a test result of 0 or 1 is considered negative and a test 
result of 2+ is considered uncertain for HER2. 
 
FISH testing 
FISH testing is performed when the score is 2+. FISH testing should be performed in a 
refererence laboratory. In the near future PCR based amplification techniques should be 
validated.