Conditions: Breast Cancer
Keywords: Hormone receptor positive breast cancer
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 3484
Healthy volunteers: no

Brief summary:
The study assesses the effect of further 2 years vs further 5 years of adjuvant treatment with anastrozole after initial 5 years of adjuvant endocrine therapy.

Detailed description:
ABCSG 16 S.A.L.S.A is assessing the effect of further 2 years vs further 5 years of adjuvant treatment with anastrozole after initial 5 years of adjuvant endocrine therapy. S.A.L.S.A. is a randomized open multicentered phase III study comparing the efficacy of secondary adjuvant endokrine treatment of Arimidex® (Anastrozol) for 2 or 5 years after primary adjuvant endokrine therapy in patients with hormonreceptor positive mammakarzinom. Patients are examined at screening, after 6 months, then every year until 5 years. The subsequent yearly follow up with mammographie and clinical examination ends 10 years after the screening. S.A.L.S.A. started in February 2004 and has recruited 3484 patients until June 2010 at 78 sites all over Austria.

Primary Endpoint:

1\. Proof of the effect of 2 years versus 5 years of Anastrozol after 5 years of adjuvant endocrine therapy on the disease free survival

Secondary endpoint:

1. Proof of the effect of 2 years versus 5 years of Anastrozol after 5 years of adjuvant endocrine therapy on the overall survival
2. Comparison of fracture rate in both therapy groups
3. Comparison of incidence of

   1. a secondary carcinoma except the contralateral mammacarcinoma
   2. contralateral mammacarcinoma in both therapie groups

Arms:
arm 1: 1 mg per day for 2 years arm 2: 1 mg per day for 5 years

Interventions: intervention 1: Anastrozole
Intervention descriptions: intervention 1: 1mg tablet daily

Protocol document:
Prot_000.pdf: 
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Clinical Study Protocol Amendment Number 1 
Study Code 1033AU/0003, 
ABCSG Protocol 16, S.A.L.S.A. 
SOP-00008-G T02 Clinical Study Protocol Amendment Template 
Version 6, Date: 1 May 2004 
2(12) 
Old text: 
Inclusion criteria: 
1. 
Postmenopausal patients with histologically verified invasive or minimally invasive 
breast cancer that has been radically treated locally with or without previous 
chemotherapy and/or radiotherapy 
2. 
Aged 80 years  
3. 
No distant metastasis at randomisation  
4. 
No recurrence at randomisation  
5. 
TNM-classification at the time of diagnosis: T1-3, N0-1, M0 
6. 
Oestrogen and/or progesterone receptor-positive before the start of primary  
endocrine therapy  
7. 
Endocrine therapy for 5 years (maximum deviation ± 12 months) 
8. 
Therapy break (from the preliminary therapy) maximum 12 months  
9. 
At the time of randomisation, the results of the following tests must be available: 
a) Medical history and clinical examination (within one month prior to randomisation) 
b) Gynaecological examination (within one month prior to randomisation)  
c) Chest x-ray or CT scan (within one year prior to randomisation) 
d) Bilateral mammogram (within one year prior to randomisation) – exception are 
women with mastectomy (unilateral) 
f) Ultrasound of the abdomen or abdominal CT (within one year prior to randomisation) 
e) Laboratory parameters (within 3 months prior to randomisation) 
- Adequate liver function (GOT or GPT >d 2.5 x ULN; total bilirubin < 2 x ULN, 
AP < 2 x ULN) 
- Serum creatinine d 1.5 x ULN 
10. Informed consent prior to randomisation 
Amended text: 
Inclusion criteria: 
1. 
Postmenopausal patients with histologically verified invasive or minimally invasive 
breast cancer that has been radically treated locally with or without previous 
chemotherapy and/or radiotherapy 
2. 
Aged 80 years  
3. 
No distant metastasis at randomisation 1 
4. 
No recurrence at randomisation 1 
5. 
TNM-classification at the time of diagnosis: T1-3, N0-1, M0 
6. 
Oestrogen and/or progesterone receptor-positive before the start of primary  
endocrine therapy  
7. 
Endocrine therapy for 5 years (maximum deviation ± 12 months) 
8. 
Therapy break (from the preliminary therapy) maximum 12 months  
9. 
Informed consent prior to randomisation 
                                                 
1 See section 5.4 


Clinical Study Protocol Amendment Number 1 
Study Code 1033AU/0003, 
ABCSG Protocol 16, S.A.L.S.A. 
SOP-00008-G T02 Clinical Study Protocol Amendment Template 
Version 6, Date: 1 May 2004 
3(12) 
Old text: 
Exclusion criteria:  
1. 
Premenopausal patients or patients with non-determinable menopausal status at 
randomisation 
2. 
Manifest secondary malignancy or status post secondary malignancy between the time 
of initial diagnosis and randomisation  
3. 
General contraindications and/or hypersensitivity to anastrozole  
4. 
Carcinoma in situ of any size with or without Paget's disease of the nipple or T4 
tumours at the time of initial diagnosis  
5. 
Receptor determination unknown or negative at the time of diagnosis or at the start of 
the primary endocrine therapy 
6. 
Age > 80 years  
7. 
Performance index > 3 as per WHO 
8. 
Regular use of hormone products and hormone replacement therapy (HRT) for more 
than 6 months since the primary breast cancer surgery 
9. 
Serious concomitant disease preventing implementation of adjuvant therapy in line with 
the protocol and/or controlled follow-up 
10. Lack of patient cooperation 
11. Legal incapacity and/or other circumstances preventing the patient from understanding 
the nature, significance and implications of the clinical trial 
12. Existing psychiatric disease as per ICD at study enrolment (especially alcohol dependency) 
Amended text: 
Exclusion criteria:  
1. 
Premenopausal patients or patients with non-determinable menopausal status at 
randomisation 
2. 
Manifest secondary malignancy or status post secondary malignancy  
3. 
General contraindications and/or hypersensitivity to anastrozole  
4. 
Carcinoma in situ of any size with or without Paget's disease of the nipple or T4 
tumours at the time of initial diagnosis  
5. 
Receptor determination unknown or negative at the time of diagnosis or at the start of 
the primary endocrine therapy 
6. 
Age > 80 years  
7. 
Known hepatic and/or renal impairment 
8. 
Performance index >2 as per WHO 
9. 
Regular use of hormone products and hormone replacement therapy (HRT) for more 
than 6 months since the primary breast cancer surgery 
10. Serious concomitant disease preventing implementation of adjuvant therapy in line with 
the protocol and/or controlled follow-up 
11. Lack of patient cooperation 
12. Legal incapacity and/or other circumstances preventing the patient from understanding 
the nature, significance and implications of the clinical trial 
13. Existing psychiatric disease as per ICD at study enrolment (especially alcohol dependency) 


Clinical Study Protocol Amendment Number 1 
Study Code 1033AU/0003, 
ABCSG Protocol 16, S.A.L.S.A. 
SOP-00008-G T02 Clinical Study Protocol Amendment Template 
Version 6, Date: 1 May 2004 
4(12) 
Affected protocol point: 
Amendment of the text under point 1 "Patient population – exclusion criteria" or addition  
as a separate item under point 5 "Study population": 5.4. Diagnosis 
New text:  
Distant metastasis and local recurrence at the time of randomisation are ruled out in any  
case using the following examinations at the least, or using methods regarded as equivalent 
or better according the current state of scientific knowledge: 
a) Medical history within one month prior to randomisation 
b) Gynaecological examination including ultrasound within six months  
prior to randomisation (exceptions are women with a hysterectomy) 
c) Chest x-ray or CT scan within one year prior to randomisation 
d) Bilateral mammogram within one year prior to randomisation – exception  
are women with mastectomy (unilateral) 
e) Ultrasound of the abdomen or abdominal CT within one year prior to randomisation 
Affected protocol point: 
5.4. Premature termination of the clinical study (page 23) 
Old text: 
5.4.  
Premature termination of the clinical study 
5.4.1.  Premature termination in an individual case 
Reasons leading to study discontinuation are: 
- 
Withdrawal of patient consent 
- 
Occurrence of intolerable adverse events 
- 
Occurrence of relapse, secondary cancer or death of the patient 
- 
Lack of compliance or cooperation of the patient 
- 
Serious protocol violation 
- 
Other personal reasons for the patient (e.g. change of location); there is usually  
the possibility of ongoing care at another ABCSG study site 
- 
Patient no longer attends (lost to follow-up): the maximum time frame for this is  
- 
In the therapy phase: +6 months calculated from the scheduled visit  
date (see 6.5.) 
- 
In the follow-up phase: +12 months from the scheduled visit date  
The investigator must make every effort to establish contact with the patient.  
5.4.2.  Discontinuation of the entire study 
5.4.3.  Closure of an individual site 


Clinical Study Protocol Amendment Number 1 
Study Code 1033AU/0003, 
ABCSG Protocol 16, S.A.L.S.A. 
SOP-00008-G T02 Clinical Study Protocol Amendment Template 
Version 6, Date: 1 May 2004 
5(12) 
Amended text: 
5.5.  
Premature termination of the clinical study 
5.5.1.  Premature termination in an individual case 
Reasons leading to study discontinuation are: 
- 
Withdrawal of patient consent 
- 
Occurrence of intolerable adverse events 
- 
Occurrence of relapse, secondary cancer or death of the patient 
- 
Lack of compliance or cooperation of the patient 
- 
Serious protocol violation 
- 
Other personal reasons for the patient (e.g. change of location); there is usually  
the possibility of ongoing care at another ABCSG study site 
- 
Patient no longer attends (lost to follow-up): the maximum time frame for this is  
- 
In the therapy phase: +6 months calculated from the scheduled visit date  
(see 6.5.) 
- 
In the follow-up phase: +12 months from the scheduled visit date  
The investigator must make every effort to establish contact with the patient. 
- 
Development of hepatic, renal insufficiency 
5.5.2.  Discontinuation of the entire study 
5.5.3.  Closure of an individual site 


Clinical Study Protocol Amendment Number 1 
Study Code 1033AU/0003, 
ABCSG Protocol 16, S.A.L.S.A. 
SOP-00008-G T02 Clinical Study Protocol Amendment Template 
Version 6, Date: 1 May 2004 
6(12) 
Affected protocol point: 
7. Implementation 
7.1. Examination parameters before study start (page 27) 
Old text: 
7.1.  
Examination parameters before study start 
1. 
Medical history, e.g. histological findings, HR status findings, WHO status (within one 
month prior to randomisation) 
2. 
Clinical examinations (within one month prior to randomisation): 
x 
Clinical examination  
x 
Gynaecological examination  
3. 
Radiological investigations (within one year prior to randomisation): 
x 
Sonography of the abdomen or abdominal CT  
x 
Chest x-ray or CT  
x 
Bilateral mammogram (unilateral mammogram in the case of mastectomy) 
x 
Bone density measurement (optional) 
4. 
Laboratory parameters (within 3 months prior to randomisation): 
x 
LFP (GOT, GPT, total bilirubin, AP) 
x 
RFP (serum creatinine)  
x 
Optional tumour markers: CEA, CA 15-3 
Amended text: 
7.1.  
Examination parameters before study start 
1. 
Medical history, e.g. histological findings, HR status findings (within one month prior to 
randomisation) 
2. 
Physical examinations, medical history, WHO status (within one month prior to 
randomisation) 
3. 
Gynaecological examination (including ultrasound) (within 6 months prior to 
randomisation) 
4. 
Radiological investigations (within one year prior to randomisation): 
x 
Sonography of the abdomen or abdominal CT  
x 
Chest x-ray or CT  
x 
Bilateral mammogram (unilateral mammogram in the case of mastectomy) 
x 
Bone density measurement (optional) 
5. 
Query known hepatic, renal insufficiency 
6. 
Optional tumour markers: CEA, CA 15-3 


Clinical Study Protocol Amendment Number 1 
Study Code 1033AU/0003, 
ABCSG Protocol 16, S.A.L.S.A. 
SOP-00008-G T02 Clinical Study Protocol Amendment Template 
Version 6, Date: 1 May 2004 
7(12) 
Affected protocol point: 
7. Implementation  
7.2. Examination parameters during the study (page 27) 
Old text: 
7.2.2.  After 12 and 24 months (Arm A and B) 
1. 
Clinical examination  
2. 
Survey of fracture rate 
3. 
Adverse events leading to discontinuation of therapy 
4. 
Serious adverse events 
5. 
Laboratory parameters: 
x 
LFP (GOT, GPT, total bilirubin, AP) 
x 
RFP (serum creatinine) 
x 
Optional TU marker: CEA, CA 15-3  
6. 
Gynaecological examination 
7. 
Radiological examinations  
x 
Sonography of the abdomen or abdominal CT  
x 
Chest x-ray or CT 
x 
Bilateral mammogram (unilateral mammogram in the case of 
x 
mastectomy) 
6. 
Bone density measurement (optional) 
Amended text: 
7.2.2.  After 12, 24, 36, 48 and 60 months 
1. 
Physical examination 
2. 
Survey of fracture rate 
3. 
Adverse events leading to discontinuation of therapy 
4. 
Serious adverse events 
5. 
Development of hepatic, renal insufficiency 
6. 
Optional TU marker: CEA, CA 15-3  
7. 
Gynaecological examination 
8. 
Radiological examinations  
x 
Sonography of the abdomen or abdominal CT  
x 
Chest x-ray or CT 
x 
Bilateral mammogram (unilateral mammogram in the case of 
x 
mastectomy) 
9. 
Bone density measurement (optional) 


Clinical Study Protocol Amendment Number 1 
Study Code 1033AU/0003, 
ABCSG Protocol 16, S.A.L.S.A. 
SOP-00008-G T02 Clinical Study Protocol Amendment Template 
Version 6, Date: 1 May 2004 
8(12) 
Affected protocol point: 
7. Implementation  
7.3. Follow-up (page 28) 
Old text: 
7.3.  
Follow-up 
After the therapy is complete, follow-up examinations are carried out at yearly intervals (+/- 6 
months) for a period of 8 years in Arm A and 5 years in Arm B. 
1. 
Clinical examinations 
2. 
Bilateral mammogram (unilateral mammogram in the case of mastectomy) 
3. 
Serious adverse events (see 9.1 and 9.2.4) 
Amended text: 
7.3.  
Follow-up 
After the therapy is complete, follow-up examinations are carried out at 36, 48 and 60 months 
in Arm A analogously to the therapy examinations in the Arm B. After the 60th monthly visits, 
the standardised follow-up examinations are carried out at yearly intervals (+/- 6 months) 
over a period of 5 years for both arms. 
1. 
Physical examination 
2. 
Bilateral mammogram (unilateral mammogram in the case of mastectomy) 
3. 
Serious adverse events (see 9.1 and 9.2.4) 
Affected protocol point: 
1.2. Flow chart (page 12) 
Old text: 
1. Separate specification for patient history and clinical examination 
2. No detailed information for gynaecological examination 
Amended text: 
1. Change to physical examination 
2. Gynaecological examination with asterisk * in screening: * Including ultrasound 
(exception: status post hysterectomy) or ** at the therapy visits: ** "Follow-up 
examination in accordance with the current state of scientific knowledge" 






Clinical Study Protocol Amendment Number 1 
Study Code 1033AU/0003, 
ABCSG Protocol 16, S.A.L.S.A. 
SOP-00008-G T02 Clinical Study Protocol Amendment Template 
Version 6, Date: 1 May 2004 
11(12) 
 
Agreement for Protocol Amendment No. 1 
Title: 
A Prospective, Randomised, Open, Multicentre Phase III Study to Assess the 
Efficacy of Secondary Adjuvant Endocrine Anastrozole Therapy for 2 Further 
Yrs vs 5 Further Yrs in Patients With HR +ve Breast Cancer After 5-yr 
Primary Adjuvant Endocrine Therapy 
Study no.: 
1033AU/0003 
Version: 
Final version 1.0 dated 21/03/2005 
I agree with the contents of this protocol amendment. 
 
 . . . . . . . . . . . . .  
 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   
Date 
   
 
 
 
 
Responsible statistician 
Special Facility for Medical Statistics and Information Technology 
 
Institute of Clinical Biometrics 
 
Medical University of Vienna 
 
Spitalgasse 23 
1090 Vienna, Austria 
 
 






Clinical Study Protocol Amendment Number 2 
Study Code 1033AU/0003, 
ABCSG Protocol 16, S.A.L.S.A.  
SOP-00008-G T02 Clinical Study Protocol Amendment Template 
Version 6, Date: 1 May 2004 
2(15) 
Old text: 
Inclusion criteria: 
1. 
Postmenopausal patients with histologically verified invasive or minimally invasive 
breast cancer that has been radically treated locally with or without previous 
chemotherapy and/or radiotherapy 
2. 
Aged 80 years  
3. 
No distant metastasis at randomisation  
4. 
No recurrence at randomisation  
5. 
TNM-classification at the time of diagnosis: T1-3, N0-1, M0 
6. 
Oestrogen and/or progesterone receptor-positive before the start of primary 
endocrine therapy  
7. 
Endocrine therapy for 5 years (maximum deviation ± 12 months) 
8. 
Therapy break (from the preliminary therapy) maximum 12 months  
9. 
Informed consent prior to randomisation 
Amended text: 
Inclusion criteria: 
1. 
Postmenopausal patients with histologically verified invasive or minimally invasive 
breast cancer that has been radically treated locally with or without previous 
chemotherapy and/or radiotherapy 
2. 
No distant metastasis at randomisation  
3. 
No recurrence at randomisation  
4. 
TNM-classification at the time of diagnosis: T1-3, N0 and N+, M0 
5. 
Oestrogen and/or progesterone receptor-positive before the start of primary 
endocrine therapy  
6. 
Endocrine therapy for 5 years (maximum deviation ± 12 months) 
7. 
Therapy break (from the preliminary therapy) maximum 12 months  
8. 
Informed consent prior to randomisation 
Old text: 
Exclusion criteria:  
1. 
Premenopausal patients or patients with non-determinable menopausal status at 
randomisation 
2. 
Manifest secondary malignancy or status post secondary malignancy  
3. 
General contraindications and/or hypersensitivity to anastrozole  
4. 
Carcinoma in situ of any size with or without Paget's disease of the nipple or T4 
tumours at the time of initial diagnosis  
5. 
Receptor determination unknown or negative at the time of diagnosis or at the start 
of the primary endocrine therapy 
6. 
Age > 80 years  
7. 
Known hepatic and/or renal impairment 
8. 
Performance index >2 as per WHO 
9. 
Regular use of hormone products and hormone replacement therapy (HRT) for 
more than 6 months since the primary breast cancer surgery 
10. Serious concomitant disease preventing implementation of adjuvant therapy in line 
with the protocol and/or controlled follow-up 
11. Lack of patient cooperation 


Clinical Study Protocol Amendment Number 2 
Study Code 1033AU/0003, 
ABCSG Protocol 16, S.A.L.S.A.  
SOP-00008-G T02 Clinical Study Protocol Amendment Template 
Version 6, Date: 1 May 2004 
3(15) 
12. Legal 
incapacity 
and/or 
other 
circumstances 
preventing 
the 
patient  
from understanding the nature, significance and implications of the clinical trial 
13. Existing psychiatric disease as per ICD at study enrolment (especially alcohol 
dependency) 
Amended text: 
Exclusion criteria:  
1. 
Premenopausal patients or patients with non-determinable menopausal status at 
randomisation 
2. 
Manifest secondary malignancy or status post secondary malignancy (exceptions: 
simultaneous bilateral breast cancer, oestrogen and/or progesterone 
receptor-positive on both sides, at the time of diagnosis; cervical carcinoma 
in situ and basal cell skin cancer)  
3. 
General contraindications and/or hypersensitivity to anastrozole  
4. 
Carcinoma in situ of any size with or without Paget's disease of the nipple or T4 
tumours at the time of initial diagnosis  
5. 
Receptor determination unknown or negative at the time of diagnosis or at the start 
of the primary endocrine therapy 
6. 
Known hepatic and/or renal impairment 
7. 
Performance index >2 as per WHO 
8. 
Regular use of hormone products and hormone replacement therapy (HRT) for 
more than 6 months since the primary breast cancer surgery 
9. 
Serious concomitant disease preventing implementation of adjuvant therapy in line 
with the protocol and/or controlled follow-up 
10. Lack of patient cooperation 
11. Legal incapacity and/or other circumstances preventing the patient from 
understanding the nature, significance and implications of the clinical trial 
12. Existing psychiatric disease as per ICD at study enrolment (especially alcohol 
dependency) 
Affected protocol point: 
Point 1.1. Study summary/study schedule (protocol, page 11) and point 4. Design 
(protocol, page 21.) 
Old text: 
Planned recruitment end: 
 
 
 
 
December 2008 
Planned end of the maximum treatment phase: 
 
December 2013 
Planned end of follow-up: 
 
 
 
 
December 2018 
Amended text: 
Planned recruitment end: 
 
 
 
 
December 2009 
Planned end of the maximum treatment phase: 
 
December 2014 
Planned end of follow-up: 
 
 
 
 
December 2019 
Affected protocol point: 
Point 1.2. Flow chart (protocol, page 12)


Clinical Study Protocol Amendment Number 2 
Study Code 1033AU/0003, 
ABCSG Protocol 16, S.A.L.S.A.  
SOP-00008-G T02 Clinical Study Protocol Amendment Template 
Version 6, Date: 1 May 2004 
4(15) 
Old flow chart 
 
1.2. 
Flow chart 
 
Parameter 
Screening 
6 months 
12 
months 
24 
months 
36 
months 
48 
months 
60 
months 
6 years 
7 years 8 years 
9 years 
10 years 
Verification of 
inclusion and 
exclusion criteria 
x 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
 
x 
 
 
 
 
 
 
 
 
 
 
 
Clinical examination 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Gynaecological 
examination 
x 
 
x 
x 
x 
x 
x 
 
 
 
 
 
Ultrasound or  
CT of abdomen 
x 
 
x 
x 
x 
x 
x 
 
 
 
 
 
Chest x-ray or CT 
x 
 
x 
x 
x 
x 
x 
 
 
 
 
 
Bilateral or unilateral 
mammogram 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Measurement of bone 
density (optional) 
x 
 
x 
x 
x**** 
x**** 
x**** 
 
 
 
 
 
Survey of fracture rate 
 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
LFP* 
x 
 
x 
x 
x 
x 
x 
 
 
 
 
 
RFP** 
x 
 
x 
x 
x 
x 
x 
 
 
 
 
 
TU marker*** 
(optional) 
x 
 
x 
x 
x 
x 
x 
 
 
 
 
 
SAE/AE  
 
See point 9 
See point 9 
 
Legend: * LFP: GOT,GPT, AP, total bilirubin;** RFP: Serum creatinine; *** TU marker: CEA, CA 15-3;****only for patients in Arm B (5 years of anastrozole) 


Clinical Study Protocol Amendment Number 2 
Study Code 1033AU/0003, 
ABCSG Protocol 16, S.A.L.S.A.  
SOP-00008-G T02 Clinical Study Protocol Amendment Template 
Version 6, Date: 1 May 2004 
5(15) 
New flow chart 
 
1.2. 
Flow chart 
 
 
Legend: *   
Including assessment of general status to record WHO status 
**  Including ultrasound 
***  Follow-up examination according to the current state of scientific knowledge 
 
****  TU marker: CEA, CA 15-3 
 
 
Parameter 
Screening 
6 
months 
12 
months 
24 
months 
36 
months 
48 
months 
60 
months 
6 
years 
7 
years 
8 
years 
9 
years 
10 
years 
Verification of inclusion and 
exclusion criteria 
x 
 
 
 
 
 
 
 
 
 
 
 
Physical examination * 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Gynaecological examination 
x** 
 
x*** 
x*** 
x*** 
x*** 
x*** 
 
 
 
 
 
Ultrasound or CT of abdomen 
x 
 
x 
x 
x 
x 
x 
 
 
 
 
 
Chest x-ray or CT 
x 
 
x 
x 
x 
x 
x 
 
 
 
 
 
Bilateral or unilateral mammogram 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Measurement of bone density 
(optional) (thoracic/lumbar spine) 
x 
 
x 
x 
x 
x 
x 
 
 
 
 
 
Survey of fracture rate 
 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
TU marker**** (optional) 
x 
 
x 
x 
x 
x 
x 
 
 
 
 
 
SAE/AE  
 
See Chapter 9 of the protocol 
See Chapter 9 of the protocol 




Clinical Study Protocol Amendment Number 2 
Study Code 1033AU/0003, 
ABCSG Protocol 16, S.A.L.S.A.  
SOP-00008-G T02 Clinical Study Protocol Amendment Template 
Version 6, Date: 1 May 2004 
7(15) 
11.2. Data collection / documentation sheets 
 
11.2.1. Documentation 
At the study sites, all data required by the study protocol as well as objective and 
subjective information must be entered directly into the relevant medical files/original 
patient documentation before documentation in the CRF. 
All data collected during the study is entered into the designated documentation forms 
(CRFs) by the investigator or a person who has previously been authorised in writing. 
These provide a mirror image of the requirements according to the protocol.  
 
If an examination has not been completed, this will be indicated with "n.d.". If information 
is not available, this will be documented with "n.a.". 
 
The IntTrial® system allows the investigator to document study data electronically  
("on-screen"; "e-CRF") or conventionally on a paper CRF. The study CRF is made 
available on CD-ROM. The CD-ROM contains all CRF pages both in the form of fillable 
PDF documents (e-CRF) and as a print version, which can be printed out and completed 
by hand. 
After completion on computer, the CRF pages are sent to Data Management by email. 
Alternatively, the pages can also be printed out and either faxed or sent by mail. A copy  
of each page sent is kept at the site, either in electronic or paper form. 
In the case of conventional documentation, the print template of the CRF is used. Fully 
completed pages are sent by post or faxed to Data Management. All entries must be 
made in permanent black or blue ballpoint pen to ensure the legibility of all copies.  
It is important that documentation is completed soon after therapy. Documentation should 
therefore be completed and sent to Data Management within 7 days of a visit. 
The completed CRF pages are sent to: 
ABCSG Data Management 
FAO 
 
Theresiengasse 32 
1180 Vienna, Austria 
Study fax: 
 
 
Study email: 
 


Clinical Study Protocol Amendment Number 2 
Study Code 1033AU/0003, 
ABCSG Protocol 16, S.A.L.S.A.  
SOP-00008-G T02 Clinical Study Protocol Amendment Template 
Version 6, Date: 1 May 2004 
8(15) 
11.2.2. Subsequent corrections to documentation 
Once a CRF page has been completed on the computer and forwarded to Data 
Management, the page can no longer be corrected by the investigator and resubmitted to 
Data Management. The CRF page is entered into the preliminary database and further 
adjustments may only be carried out again during SDV.  
If a CRF page is accidentally sent to Data Management twice, the second page will not be 
input, but simply archived. SDV is performed on the first version of the respective CRF 
page. 
The same rules apply to paper CRFs. Since in this case, entries are made by hand, 
corrections made during documentation are made in accordance with the usual rules. An 
incorrect entry is crossed out, however, the deleted entry must remain recognisable. The 
corrected value should be written next to it. The date of the change and signature/initials 
of the investigator or authorised person must be added to each correction. The use of 
correction fluid is prohibited. 
11.3. Data acquisition 
 
Data acquisition is carried out by the person responsible for data management. Data entry 
takes place on an ongoing basis, in parallel with the clinical trial. 
11.3.1. Data entry / obvious corrections / queries 
CRFs received by Data Management are included in the preliminary study database. A 
system consisting of the Cardiff Teleform Reader, the Teleform Verifier and MS-SQL is 
used for the input process with IntTrial®. The input process is divided into automatic data 
acquisition, followed by a manual check by the data entry staff, with each value being 
checked subsequently. 
A copy of each CRF page is automatically archived in electronic format as an indexed 
PDF. Corrections of obvious mistakes in the documentation (obvious corrections) are 
made immediately during input by the input staff and the changes are logged in the 
database. Missing, contradictory or illegible entries are also logged as queries in the 
database. 
11.3.2. Creating an electronic copy of CRFs for source data verification (SDV) 
To enable the study data to be monitored, the data from each CRF page included in the 
preliminary study database is exported into a blank CRF form. The obvious corrections 
made as well as the queries logged in the database are exported into the form. 
These CRF pages are then made available to the competent monitor for source data 
adjustment. During SDV, queries already listed are processed and the CRF page is 
signed by the investigator after any corrections are made. A copy of the signed CRF 
remains at the site and the original is given to the monitor. 


Clinical Study Protocol Amendment Number 2 
Study Code 1033AU/0003, 
ABCSG Protocol 16, S.A.L.S.A.  
SOP-00008-G T02 Clinical Study Protocol Amendment Template 
Version 6, Date: 1 May 2004 
9(15) 
11.3.3. Data entry / database validation / database lock 
The signed CRF pages are forwarded by the monitor to Data Management and then 
entered into the database again from there. This data is then validated by a final query 
process, based on checks for validity, consistency and plausibility. 
Query forms to clarify any queries are passed on to the investigator for processing  
via the monitor. After processing, these are sent back to Data Management, and  
a copy is retained at the site. 
After clarification of all possible queries using query forms, the database is closed. The 
analysis and statistical analysis is carried out using SAS® (Statistical Analysis Software) 
version 8. 
11.4.  Original data in the CRF 
 
All data collected within this protocol must be available as original data in the respective 
medical history. Direct entries in the CRF are not considered to be source data. 
 
11.5.  Storage of CRFs 
 
Once the study is completed, the documentation remains with the ABCSG. The originals 
of all central study documents including the documentation sheets are stored at the study 
site for at least 15 years after the end of the study. CRFs can also be stored on image 
carriers or other data storage devices.  
 
During the study, one copy of the CRF remains with the respective investigator. The 
investigator also retains the administrative documents produced (correspondence with the 
Ethics Committee, BUMI, AstraZeneca, study site etc.), the patient identification list, 
signed informed consent forms, copies of documentation sheets and the general study 
documentation (protocol, amendments) for the period of time stated above. 
Original data on study patients (medical files) must be stored in accordance with the 
archiving term applicable to the study sites, however, for a minimum of 15 years. 
 
If the investigator does not stay at the study site for whatever reason (e.g. retirement, 
appointment elsewhere), the retention of the documents must be handed over to a 
successor, who consequently takes on the responsibility, and this must be documented in 
writing. Both AstraZeneca and the ABCSG must be informed of such a transfer in writing. 


Clinical Study Protocol Amendment Number 2 
Study Code 1033AU/0003, 
ABCSG Protocol 16, S.A.L.S.A.  
SOP-00008-G T02 Clinical Study Protocol Amendment Template 
Version 6, Date: 1 May 2004 
10(15) 
Amended text: 
11.  DATA MANAGEMENT 
 
Data is managed by the ABCSG using the "Macro" (InferMED) data management system 
via the "DATAPORT" web portal. "MACRO" is a piece of software developed for use in 
controlled single or multi-centre clinical studies of all phases (I-IV). Documentation is web-
based (eCRF) and is supported by active online support. 
System compliance with the requirements of international guidelines such as "ICH Good 
Clinical Practice" and "FDA 21 CFR Part 11" is essential for "MACRO". An audit trail is 
created for the entire course of the study, which shows any changes e.g. in terms of the 
data entered, the date and time of entry and the added comments. 
"MACRO" also provides the possibility for easy detection of discrepancies in the individual 
data sets (e.g.implausibilities selected by Edit Check programming, missing values etc.) 
through the use of various marks (icons). This allows the employees from Monitoring and 
Data Management to generate queries (=discrepancies) quickly, which in turn can be 
processed by the investigator in a timely manner. Through automatic assignment of 
specific "marks" (icons) by the system, the processing status of the queries  
(= discrepancies) is visible and can be tracked up to final completion. 
Employees from Monitoring also have the option to use other "marks" (= icons) to indicate 
the status of source data verification (SDV) (e.g. planned, completed, pending, 
discontinued). 
Due to the web-based processing, all entries, changes, queries etc. are visible to 
authorised persons immediately after implementation. This reduces the processing time 
and means that all data is available more quickly for statistical evaluation. 
 
11.1. Patient identification list 
 
 
All patient-related data will be recorded in anonymous form. Each patient is assigned a 
patient number at randomisation that uniquely identifies them together with their initials. 
The investigator will keep a confidential patient list, in which the identifying data is linked 
to the patients’ full name and optionally the insurance number. 
 
11.2. Data collection / documentation sheets 
 
11.2.1. Documentation 
At the study sites, all data required by the study protocol as well as objective and 
subjective information must be entered directly into the relevant medical files/original 
patient documentation before documentation in the web-based CRF (eCRF). 


Clinical Study Protocol Amendment Number 2 
Study Code 1033AU/0003, 
ABCSG Protocol 16, S.A.L.S.A.  
SOP-00008-G T02 Clinical Study Protocol Amendment Template 
Version 6, Date: 1 May 2004 
11(15) 
Patient data that is relevant for the study is collected in the "MACRO" data management 
system via the "DATAPORT" web portal directly at the site by the investigator or by study 
personnel with documentation authorisation. Only in exceptional cases will a hard-copy 
CRF be provided for the site. In this case, entries must be made in block letters or in 
easily legible script using a black or blue pen. The data documented on hard-copy CRFs 
is recorded in "MACRO" by data entry staff from the ABCSG using "double data entry". 
Correct collection and input of data is checked by the competent monitor via the Internet 
and is marked accordingly in the system using a designated icon. Any queries 
(=discrepancies) are generated by the monitor via the internet and are immediately visible 
to both the investigator and Data Management as soon as they are created on the system. 
 
11.3. Data management (data review) 
The eForms marked as source data verified by Monitoring are checked for consistency 
and plausibility by Data Management. Any queries (=discrepancies) are generated via the 
Internet and are therefore visible to both the investigator and monitor as soon as they are 
created in the system by means of "marks" (icons). Data Management locks all eForms 
that it finds to be fully correct, meaning they are protected from further processing. 
"Marks" indicate this processing status. 
The individual working steps carried out by Data Management are specified in SOPs (= 
standard operating procedures) and WIs (= working instructions). 
Justification for the amendment:  
- 
The age limit in the inclusion and exclusion criteria is being raised (reason: there 
are a number of sprightly patients who will tolerate the study follow-up phase well 
and can remain compliant. The primary objective of the study will not be affected 
by a potential increase in the incidence of deaths that are not breast cancer 
related.) 
- 
Correction of the permitted N-stages of the tumour from N1 to N+ (reason: it is 
expected that all patients, regardless of their N-stage at the time of diagnosis will 
benefit from extending the therapy with anastrozole beyond 5 years)  
- 
Addition to the exclusion criterion: "Manifest secondary malignancy or status post 
secondary malignancy" with the following exceptions: a) simultaneous bilateral 
breast cancer, oestrogen and/or progesterone receptor-positive on both sides at 
the time of diagnosis (reason: because of the simultaneity of the tumour 
occurrence, such a carcinoma is interpreted as a multi-centric carcinoma); b) in-
situ carcinoma of the cervix and basal cell carcinoma of the skin, is a correction of 
the data in the CRF and protocol, as these exceptions were defined in the CRF 
(reason: the probability of relapse in these carcinomas is minimal.) 
- 
Extension of the recruitment phase for 1 year (reason: the annual recruitment rate 
was overestimated in the study planning phase.)  






Clinical Study Protocol Amendment Number 2 
Study Code 1033AU/0003, 
ABCSG Protocol 16, S.A.L.S.A. 
SOP-00008-G T02 Clinical Study Protocol Amendment Template 
Version 6, Date: 1 May 2004 
14(15) 
 
Agreement for Protocol Amendment No. 2 
Title: 
A Prospective, Randomised, Open, Multicentre Phase III Study to Assess 
the Efficacy of Secondary Adjuvant Endocrine Anastrozole Therapy for 2 
Further Yrs vs 5 Further Yrs in Patients With HR +ve Breast Cancer After 
5-yr Primary Adjuvant Endocrine Therapy 
Study no.: 
1033AU/0003 
Version: 
Final version dated 30/10/2008 
I agree with the contents of this protocol amendment. 
 
 . . . . . . . . . . . . .   
 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   
Date 
   Assoc. Univ. 
 
 
 
 
Responsible statistician 
Special Facility for Medical Statistics and Information Technology 
Institute of Clinical Biometrics 
Medical University of Vienna 
Spitalgasse 23 
1090 Vienna, Austria 
 


Clinical Study Protocol Amendment Number 2 
Study Code 1033AU/0003, 
ABCSG Protocol 16, S.A.L.S.A. 
SOP-00008-G T02 Clinical Study Protocol Amendment Template 
Version 6, Date: 1 May 2004 
15(15) 
 
Agreement for Protocol Amendment No. 2 
Title: 
A Prospective, Randomised, Open, Multicentre Phase III Study to Assess 
the Efficacy of Secondary Adjuvant Endocrine Anastrozole Therapy for 2 
Further Yrs vs 5 Further Yrs in Patients With HR +ve Breast Cancer After 
5-yr Primary Adjuvant Endocrine Therapy 
Study no.: 
1033AU/0003 
Version: 
Final Version dated 30/10/2008 
I agree with the contents of this protocol amendment. 
 
 . . . . . . . . . . . . .   
 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   
Date 
  
 
 
 
Medical Director at AstraZeneca Österreich  
Schwarzenbergplatz 7 
1037 Vienna, Austria 
 








Clinical Study Protocol Amendment Number 3 
Study Code: 1033AU/003, 
ABCSG Protocol 16, S.A.L.S.A. 
SOP-00008-G T02 Clinical Study Protocol Amendment Template 
Version 6, Date: 1 May 2004 
4(5) 
 
Agreement for Protocol Amendment No. 3 
Title: 
A Prospective, Randomised, Open, Multicentre Phase III Study to Assess 
the Efficacy of Secondary Adjuvant Endocrine Anastrozole Therapy for 2 
Further Yrs vs 5 Further Yrs in Patients With HR +ve Breast Cancer After 
5-yr Primary Adjuvant Endocrine Therapy 
Study no.: 
1033AU/0003 
Version: 
Final version dated 27/11/2009 
I agree with the contents of this protocol amendment. 
 
 . . . . . . . . . . . . .   
 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   
Date 
   
 
 
 
, 
ABCSG statistician 
Austrian Breast and Colorectal Cancer Study Group 
Nußdorfer Platz 8 
1190 Vienna, Austria 


Clinical Study Protocol Amendment Number 3 
Study Code: 1033AU/003, 
ABCSG Protocol 16, S.A.L.S.A. 
SOP-00008-G T02 Clinical Study Protocol Amendment Template 
Version 6, Date: 1 May 2004 
5(5) 
 
Agreement for Protocol Amendment No. 3 
Title: 
A Prospective, Randomised, Open, Multicentre Phase III Study to Assess 
the Efficacy of Secondary Adjuvant Endocrine Anastrozole Therapy for 2 
Further Yrs vs 5 Further Yrs in Patients With HR +ve Breast Cancer After 
5-yr Primary Adjuvant Endocrine Therapy 
Study no.: 
1033AU/0003 
Version: 
Final version dated 27/11/2009 
I agree with the contents of this protocol amendment. 
 
 . . . . . . . . . . . . .   
 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   
Date 
  
 
 
 
Medical Director 
AstraZeneca Österreich GmbH 
Schwarzenbergplatz 7 
1037 Vienna, Austria 
 

SAP_001.pdf: 


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ABCSG Statistics 
Confidential 
Page 2 of 15 
ABCSG 16 – v1.0 
SOP ABCSG-ST 02 SUDO 05/01 
Date: 2017-08-28 
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2.1.
Study design ............................................................................................................ 4
2.1.1.
Study duration ..................................................................................................... 5
2.2.
Study objectives ...................................................................................................... 5
2.2.1.
Primary objective ................................................................................................ 5
2.2.2.
Secondary objectives .......................................................................................... 5
2.3.
Randomization and stratification criteria ................................................................ 6
2.4.
Number of subjects - sample size estimation .......................................................... 7
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3.1.
Data handling conventions ...................................................................................... 7
3.1.1.
Data entry errors and potential outliers .............................................................. 7
3.1.2.
Missing data ........................................................................................................ 7
3.1.3.
Stratification errors ............................................................................................. 9
3.1.4.
Original eCRF pages and amended eCRF pages ................................................ 9
3.2.
Types and time points of analyses ........................................................................... 9
3.2.1.
Interim analysis ................................................................................................... 9
3.2.2.
Advanced analysis .............................................................................................. 9
3.2.3.
Final analysis ...................................................................................................... 9
3.3.
Definition of populations for analyses .................................................................... 9
3.3.1.
Per-protocol (PP) population .............................................................................. 9
3.3.2.
Intention to Treat (ITT) population .................................................................. 10
3.3.3.
Safety (SAF) population ................................................................................... 10
3.4.
Description of study population ............................................................................ 10
3.4.1.
Disposition of patients ...................................................................................... 10
3.4.2.
Important Protocol Deviations (IPDs) .............................................................. 10
3.4.3.
Baseline demographic and disease characteristics ........................................... 10
3.5.
Primary endpoint evaluation ................................................................................. 11
3.5.1.
Primary endpoint .............................................................................................. 11
3.5.2.
Efficacy analysis for primary endpoint ............................................................ 11
3.6.
Secondary endpoint evaluation ............................................................................. 12
3.6.1.
Overall survival (OS) ........................................................................................ 12
3.6.2.
Time to new contralateral breast cancer ........................................................... 12
3.6.3.
Time to secondary carcinoma ........................................................................... 12
3.6.4.
Time to first clinical fracture ............................................................................ 13
3.7.
Safety evaluation ................................................................................................... 13
3.8.
Exploratory analyses ............................................................................................. 13
3.8.1.
Subgroup analyses ............................................................................................ 13
3.8.2.
Multivariable analyses ...................................................................................... 13
3.9.
Software ................................................................................................................. 14

&KDQJHVRIDQDO\VLVFRPSDUHGWRVWXG\SURWRFRO
4.1.
Interim analysis ..................................................................................................... 14
4.2.
Advanced analysis ................................................................................................. 14
4.2.1.
Data set for advanced analysis .......................................................................... 14
4.2.2.
Primary and secondary endpoints in advanced analysis ................................... 14
4.2.3.
Exploratory objectives in advanced analysis .................................................... 15





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ABCSG Statistics 
Confidential 
Page 3 of 15 
ABCSG 16 – v1.0 
SOP ABCSG-ST 02 SUDO 05/01 
Date: 2017-08-28 
Glossary of abbreviations 

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ABCSG Statistics 
Confidential 
Page 4 of 15 
ABCSG 16 – v1.0 
SOP ABCSG-ST 02 SUDO 05/01 
Date: 2017-08-28 
 ,QWURGXFWLRQ
The Austrian Breast & Colorectal Cancer Study Group (ABCSG) is a cooperative institution 
that was set up to conduct controlled clinical trials in breast and colorectal cancer and to 
facilitate communication and the dissemination of knowledge among scientists and others 
dedicated to the cancer problem. Since its establishment in 1984, more than 15,000 patients 
have been enrolled in ABCSG investigations. In certain patient risk groups, ABCSG is 
currently recruiting up to 40 per cent of all Austrian breast cancer patients to their clinical 
trials. The ultimate goal of the ABCSG is to enhance the standard of cancer treatment in this 
country and abroad by developing innovative approaches and testing increasingly more 
effective therapeutic strategies. 
Prospectively randomized clinical investigations have come to be seen as the only instrument 
to generate valid and reliable clinical data, to gain insights into significant prognostic and 
predictive factors, and thus to enhance all aspects of evidence-based medicine. As a target of 
oncological research and practice, the ABCSG has selected two of the most common 
malignancies affecting women and men in the present-day western world: carcinoma of the 
breast and bowel. 
As a whole, the ABCSG collaborates toward the common goal of controlling, effectively 
treating, and ultimately curing cancer by means of large, multicenter cancer trials in the (neo-) 
adjuvant setting. Research results are provided to the medical community through scientific 
publications and professional meetings. 
This Statistical Analysis Plan (SAP) is based on the Amended Clinical Study Protocol for 
ABCSG study 16 (1033AU/0003) and gives a detailed description of all statistical analyses 
planned to be conducted within this trial at predefined time points.   

 6WXG\GHWDLOV
ABCSG-16 is a prospective, randomized, open-label, multicenter Phase III study in 
endocrine-responsive postmenopausal women with early breast cancer who have already 
received their standard 5 years of adjuvant endocrine treatment 
Patients aged 80 years, who are recurrence-free 60 months after the operation and who have 
completed a primary 5-year endocrine treatment, are being randomized to receive a further 2 
(arm A) or 5 (arm B) years of treatment with anastrozole. 

6WXG\GHVLJQ
All patients free of recurrence 60 (±12) months after operation are randomized following a 
primary 5-year endocrine therapy with therapy intervals of maximal 12 months (e.g. from 
studies 8 and 9) as follows: 
x Arm A: 2-year anastrozole therapy (Arimidex£)
x Arm B: 5-year anastrozole therapy (Arimidex£)


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Confidential 
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ABCSG 16 – v1.0 
SOP ABCSG-ST 02 SUDO 05/01 
Date: 2017-08-28 
 6WXG\GXUDWLRQ
The duration of therapy is 2 or 5 years respectively. The follow-up period will last 8 years for 
arm A and 5 years for arm B.  
Scheduled study start: December 2003 
Scheduled end of recruitment: original protocol: December 2008 
 
protocol amendment 3: June 2010 

(QGRIWUHDWPHQW
Scheduled end of max. treatment phase: original protocol: December 2013 
 
protocol amendment 3: December 2015 

(QGRIVWXG\
Scheduled end of follow-up:  original protocol: December 2018 
 
protocol amendment 3: December 2020 


6WXG\REMHFWLYHV
 3ULPDU\REMHFWLYH
The primary objective is the assessment of the effect of 2 further years of anastrozole 
treatment vs. further 5 years of anastrozole treatment on disease-free survival (DFS), 
following a five-year adjuvant endocrine therapy. 
 6HFRQGDU\REMHFWLYHV
x Assessment of the effect of further 2 years of anastrozole treatment vs. 5 further years 
of anastrozole treatment on the overall survival (OS) following five years of adjuvant 
endocrine therapy. 
x Comparison of the respective rates of fracture occurrence in the two groups
x Comparison of the occurrence of secondary carcinoma in the two groups 
R Comparison of the occurrence of contra-lateral breast cancer in the two groups, 
respectively  
R Comparison of the occurrence of secondary carcinoma except the contra-lateral 
mammary carcinoma in the two groups respectively 


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ABCSG Statistics 
Confidential 
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ABCSG 16 – v1.0 
SOP ABCSG-ST 02 SUDO 05/01 
Date: 2017-08-28 

5DQGRPL]DWLRQDQGVWUDWLILFDWLRQFULWHULD
Stratification criteria: 
The following stratification criteria are applied: 
1) pT-Stadium: 
i) - pT1(d 2 cm) 
ii) - pT2 (> 2 - 5 cm) 
iii)- pT3(> 5 - 10 cm) 
2) pN-Stadium:
i) no lymph node metastasis 
ii) 1 - 3 lymph node metastasis 
iii)4 - 9 lymph node metastasis 
LY t 10 lymph node metastasis
3) Adjuvant primary hormone therapy : 
i) 5 years of anti-estrogen 
ii) 2 years of anti-estrogen + 3 years anastrozole 
iii)Another, comparable endocrine therapy 
4) Adjuvant chemotherapy :-  
i) Chemotherapy containing anthracycline 
ii) Chemotherapy containing taxane 
iii)Other chemotherapy 
iv)No chemotherapy 
5) Participation in a clinical study: 
i) Study 8 (ABCSG) 
ii) Study 9 (ABCSG) 
iii)None
6) Receptor status: 
i) ER+PgR+ 
ii) ER+PgR- 
iii)ER-PgR+ 
7) Federal states:  
(I) Vienna
(II)Lower Austria 
(III)Burgenland 
(IV)Styria 
(V)Carinthia
(VI)Upper Austria 
(VII)Salzburg 
(VIII)Tyrol
(IX)Vorarlberg 


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ABCSG Statistics 
Confidential 
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ABCSG 16 – v1.0 
SOP ABCSG-ST 02 SUDO 05/01 
Date: 2017-08-28 

1XPEHURIVXEMHFWVVDPSOHVL]HHVWLPDWLRQ
As of randomization, all patients receive the same therapy for 2 years. After that, one group 
will continue the therapy for 3 further years. Therefore, differences between the groups are 
only to be expected 2 years after randomization. Therefore, the most relevant point in time 
regarding evaluation of the data will be 2 years after randomization (i.e. change of therapy) 
for each patient. 
It is to be expected that 700 patients can be recruited per year. Considering that 5% of patients 
will drop out of the study within the first 2 years due to recurrence, an effective rate of 
recruitment of 665 remains. 
A difference between the therapy group and the control group of 0.916 and 0.937 3 years after 
change of therapy at exponential survival (corresponding to a hazard quotient of 1.35) can be 
uncovered with 85% power at a two-sided level of significance of 5%, if 433 events are 
observed. This is feasible, if 665 patients are recruited annually for 5 years and followed up 
for another 2.7 years, amounting to a case number of 3,500, and of these 3325 evaluable 
patients. The expected total duration of the study is 9.7 years. 
With an exponential drop-out rate of 7%, the power would be reduced to 80%. 

 6WDWLVWLFDOPHWKRGV

'DWDKDQGOLQJFRQYHQWLRQV
 'DWDHQWU\HUURUVDQGSRWHQWLDORXWOLHUV
Patients may have potential outliers for particular observations. Observations will be checked 
for correctness by the study team before data freeze and at the time point of data freeze all 
data should be correct. Remaining potential outliers based on correct values will be included 
in analysis. Values found to be incorrect due to data entry error after data freeze will be 
excluded from all analyses as missing values. 
 0LVVLQJGDWD
Subjects may have missing specific data points for a variety of causes.  In general, data may 
be missing due to a missed visit, non-evaluability of a specific clinical measurement at its 
planned clinical visit or a subject's early withdrawal from study. The general procedures 
outlined below describe what will be done when a data point is missing. 

,PSXWDWLRQVRIPLVVLQJGDWD
Generally, only evaluable measurements are considered for the analyses. No values are 
imputed for missed or non-evaluable visits. In case of primary and secondary efficacy 
endpoints possible specific requirements are stated in the according analysis sections. 


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ABCSG Statistics 
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ABCSG 16 – v1.0 
SOP ABCSG-ST 02 SUDO 05/01 
Date: 2017-08-28 

3DUWLDOGDWHV
Partially incomplete dates (day or day/month missing) will be imputed for dates of 
progression as well as for therapy begin and/or end dates. Completely missing dates and 
missing years will not be imputed.  
Imputation Rules for Partial Progression Dates  
 
Missing 
Impute 
Exception 
Oncological
Event Date 
Day 
01 
Default to the Randomization date if the 
imputed date is before the Randomization date. 
Day 
/Month 
01JAN
Death Date 
Day 
01 
Default to the Randomization date if the 
imputed date is before the Randomization date. 
Day 
/Month 
01JAN
Fracture Date 
Day 
01 
Default to the Randomization date if the 
imputed date is before the Randomization date. 
Day 
/Month 
01JAN

Imputation Rules for Partial Therapy Dates  
 
Missing 
Impute 
Exception 
Therapy
Examination* 
Date 
Day 
15 
Default to the Randomization date if the 
imputed date is before the Randomization date. 
Default to the EOS date if the imputed  date is 
after the EOS date 
Day 
/Month 
Visit due date or 
1st July 
Primary 
Surgery Date 
Day 
15 
 
Day 
/Month 
1st July 
 
AI Start Date 
Day 
1 
Default to the Randomization date if the 
imputed date is before the Randomization date. 
Day 
/Month 
01JAN
AI End Date 
Day 
Last day of the 
month 
Default to the Randomization date if the 
imputed date is before the Randomization date. 
Default to the EOS date if the imputed date is 
after the EOS date  
Day/Mon
th
31DEZ

Imputation Rules for Follow Up and End of Study Dates  
 
Missing 
Impute 
Exception 
Follow Up 
Examination 
Date 
Day 
15 
Default to the EOS date if the imputed therapy 
stop date is after the EOS date 
Day 
/Month 
Follow up visit 
due date window 
lower bound 
Default to the EOS date if the imputed therapy 
stop date is after the EOS date 
End of Study 
Date 
Day 
15 
10,5 Years after Randomization Date if the 
imputed  date is after the EOS date 
Day 
/Month 
10,5 Years after 
Randomization 
Date 


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ABCSG Statistics 
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ABCSG 16 – v1.0 
SOP ABCSG-ST 02 SUDO 05/01 
Date: 2017-08-28 
 6WUDWLILFDWLRQHUURUV
Stratification errors defined as different values in the stratification factors compared between 
the randomization system and actual patient values from the electronic case report forms 
(eCRF) will be tabulated. 
 2ULJLQDOH&5)SDJHVDQGDPHQGHGH&5)SDJHV
If different data were entered on the same data field on the original eCRF page and on the 
amended eCRF page, the data of the amended eCRF will be chosen and the data on the 
original eCRF will be discarded. 

7\SHVDQGWLPHSRLQWVRIDQDO\VHV
According to the protocol, the final analysis of the study should take place after a follow-up 
of 10 years for each patient. End of 2016 similar studies with prolonged endocrine therapy 
were presented to the scientific community. At this time, the required number of events was 
long since been reached. Therefore, the ABCSG presidium decided in January 2017 to submit 
an abstract for the presentation at the San Antonio Breast Cancer Symposium (SABCS) in 
December 2017 based on an advanced analysis. The final analysis should take place 
approximately after 1 additional year. AstraZeneca agreed to these changes in April 2017. 
 ,QWHULPDQDO\VLV
After recruitment of two thirds of the required number of patients an interim analysis will take 
place. A significance level of 0.001 will be used, according to the guidelines of Geller and 
Pocock (1987). If an unexpectedly high effect of the therapy should occur, the study can be 
terminated early. 
 $GYDQFHGDQDO\VLV
The advanced analysis for the presentation at SABCS 2017 will be based on the cleaned data 
with cutoff date June 30th, 2016. 
 )LQDODQDO\VLV
The final analysis will be performed after the last visit of each patient occurring until June 
30th, 2017 and subsequent data cleaning.

'HILQLWLRQRISRSXODWLRQVIRUDQDO\VHV
 3HUSURWRFRO33SRSXODWLRQ
Primary endpoint analysis will be based on the PP; that is, all patients who were randomized, 
signed the Informed Consent, comply with inclusion and exclusion criteria and have had at 
least one follow-up examination after randomization and who survived without recurrence for 
two years. All subjects will be analyzed according to the therapy arm to which they have been 


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ABCSG Statistics 
Confidential 
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ABCSG 16 – v1.0 
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randomized. Subjects who terminate the study before their scheduled final study visits will be 
censored. 
 ,QWHQWLRQWR7UHDW,77SRSXODWLRQ
Secondary endpoint analyses and all sensitivity analyses (including sensitivity analyses for 
the primary endpoint) will be based on the ITT population; that is, all patients who were 
randomized and signed the Informed Consent. All subjects will be analyzed according to the 
therapy arm to which they have been randomized. Subjects who terminate the study before 
their scheduled final study visits will be censored. 

 6DIHW\6$)SRSXODWLRQ
Safety analyses will be based on the SAF population and include all enrolled and treated 
patients. Hence, all patients who were randomized and received at least one dose of study 
treatment. 


'HVFULSWLRQRIVWXG\SRSXODWLRQ
The description of the study population is based on the ITT population. 
 'LVSRVLWLRQRISDWLHQWV
Recruitment, discontinuation from study including reasons for discontinuation, as well as 
patient disposition and discontinuation from treatment including reasons for discontinuation 
will be summarized overall and by treatment arm. 
 ,PSRUWDQW3URWRFRO'HYLDWLRQV,3'V
IPDs include inclusion and exclusion criteria, as well as selected variables related to 
additional relevant screening assessments, study treatment administration/dispensation,
concomitant 
medication, 
primary 
endpoint, 
study 
treatment/randomization, 
study 
procedures/assessments, withdrawal/termination criteria and safety reporting. The IPDs are 
defined in a separate document listing all IPDs, their classification and additional details. 
IPDs will be summarized in total and by treatment arm.  
 %DVHOLQHGHPRJUDSKLFDQGGLVHDVHFKDUDFWHULVWLFV
Demographic and tumour characteristics data at baseline will be summarized descriptively per 
treatment arm and in total. Demographic and anamnestic data at baseline include age, tumour 
stage, nodal status, tumour grade, hormone receptor status (estrogen and progesterone), type 
of surgery, prior radiotherapy, prior chemotherapy and type of prior endocrine therapy. 



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ABCSG Statistics 
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ABCSG 16 – v1.0 
SOP ABCSG-ST 02 SUDO 05/01 
Date: 2017-08-28 

3ULPDU\HQGSRLQWHYDOXDWLRQ
 3ULPDU\HQGSRLQW
Disease-free survival (DFS) is defined as the time from randomization or from two years after 
randomization (depending on the type of analysis, see below) to the earliest occurrence of 
loco-regional recurrence, distant recurrence, contralateral new breast cancer, second cancer or 
death, from any cause. Patients who have not had a disease recurrence or died will be right-
censored at the date of their last assessment of their DFS status.  
 (IILFDF\DQDO\VLVIRUSULPDU\HQGSRLQW
For the primary endpoint, a 2-sided log-rank test (unstratified) will be used to test for 
differences between 2 additional years anastrozole versus 5 additional years anastrozole at an 
overall alpha level of 0.05. 
7\SHVRIDQDO\VHVIRUWKHSULPDU\HQGSRLQW
Main analysis: 
Start time for DFS: 2 year after randomization 
Population: PP 
Sensitivity analysis 1: 
Start time for DFS: 2 year after randomization 
Population: ITT 
Sensitivity analysis 2: 
Start time for DFS: randomization 
Population: ITT 
(YDOXDWLRQRIFHQVRULQJGDWHIRU')6DQDO\VLV
In case of no events and no early study termination, patients will be censored after 10.5 years. 
The last DSF event free day is evaluated as the maximum of the last treatment visit date and 
last follow up visit date including only visits with cancer status evaluation. In case of follow-
up visits with documented cancer status but without a documented visit date, the lower bound 
of the due visit date window will be used. Follow-up visits with information whether patient 
is alive but without cancer status evaluation will not be used.
$GGLWLRQDOVSHFLILFDWLRQV
It was possible to document the location of successive events after the first events within the 
event categories ‘distant metastases’ (‘Fernmetastasen’) and ‘secondary carcinoma’ 
(‘Zweitkarzinome’) in the eCRF. In these cases, the text “[Folge-Event”] in notes related to 
the location data entry fields indicate that the affected location does not belong to the first 
event within the respected event category. These locations will be excluded from listings of 
affected locations for the first events within the respective event category. 


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ABCSG Statistics 
Confidential 
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ABCSG 16 – v1.0 
SOP ABCSG-ST 02 SUDO 05/01 
Date: 2017-08-28 

6HFRQGDU\HQGSRLQWHYDOXDWLRQ
All secondary endpoint analyses will be based on the ITT population. For all secondary 
endpoints, 2-sided log-rank tests (unstratified) will be used to test for differences between 2 
additional years anastrozole versus 5 additional years anastrozole at an overall alpha level of 
0.05. No multiplicity adjustment will be applied for the secondary endpoints. 
 2YHUDOOVXUYLYDO26
This is defined as the time from randomization or from two years after randomization to death 
due to any cause. Patients who have not died will be right-censored at the last date when they 
were known to be alive (date of their last assessment). 
Main analysis 
Start time for OS: 2 year after randomization 
Sensitivity analyses 
Start time for OS: randomization 
 7LPHWRQHZFRQWUDODWHUDOEUHDVWFDQFHU
This is defined as the time from randomization or from two years after randomization to first 
occurrence of new contralateral breast cancer. Subjects without contralateral breast cancer 
event would be censored at last date when they were known to be contralateral breast cancer 
free.

Main analysis 
Start time for time until new contralateral breast cancer: 2 year after randomization 
Sensitivity analyses 
Start time for time until new contralateral breast cancer: randomization 

 7LPHWRVHFRQGDU\FDUFLQRPD
This is defined as the time from randomization or from two years after randomization to first 
occurrence of new secondary cancer without new breast cancer (local or contralateral). 
Subjects without secondary cancer event would be censored at last date when they were 
known to be secondary cancer free. 
Main analysis 
Start time for time until new second cancer: 2 year after randomization 
Sensitivity analyses 
Start time for time until new second cancer: randomization 


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ABCSG 16 – v1.0 
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 7LPHWRILUVWFOLQLFDOIUDFWXUH
This is defined as the time from two years after randomization to first clinical fracture. 
Patients without clinical fractures where censored at their last therapy visit (maximum 
approximately 5 years after randomization). 

6DIHW\HYDOXDWLRQ
Analyses of the safety data are based on the SAF population. Only serious adverse events 
(SAEs) and adverse events (AEs) leading to discontinuation of the therapy are collected in 
this trial. Frequencies of serious adverse events will be summarized descriptively per 
treatment arm and in total. Patient listings of SAEs and of AEs leading to discontinuation of 
the therapy will be given. Change in tumor markers CEA and CA 15-3 will be descriptively 
summarized (e.g., means, median, standard deviations, ranges). 

([SORUDWRU\DQDO\VHV
Exploratory analyses will be based on the ITT population. 
 6XEJURXSDQDO\VHV
DFS will be analyzed using Cox proportional hazard models within each of following 
subgroups:
x Age group: age  60, age > 60
x Tumor stage: T1, T2 and T3 
x Histological grade: Grade I, Grade II, Grade IIIs 
x Hormone receptor status: ER+/PgR+, any negative 
x Previous hormone therapy: Tamoxifen, Tamoxifen+AI, AI  
x Previous chemotherapy: any chemotherapy, no chemotherapy 
 0XOWLYDULDEOHDQDO\VHV
To adjust for the possible effect of demographic or prognostic factors on the primary and the 
secondary endpoints, multivariable analyses will be performed. To avoid multi-collinearity 
between the covariates, prior correlation analyses will be performed. Depending on the 
statistical results and the clinical relevance, highly correlated covariates may be excluded 
from multivariable analyses. 
The following stratification factors will be used as covariates to explore the relationship to the 
primary and secondary endpoints (the stratification factor ‘Federal states’ will not be 
included):


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ABCSG Statistics 
Confidential 
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ABCSG 16 – v1.0 
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Date: 2017-08-28 
x pT-stage
x pN-stage
x Histologic grade  
x Hormone Receptor status 
x Previous hormone therapy 
x Previous chemotherapy 
x Previous radiotherapy 
x Participation in a clinical study 
In addition, age will be in included in the multivariable analysis. 
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All analyses will be done using SAS version 9.3 or higher. 
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According to the protocol, an interim analysis was planned to take place after the recruitment 
of two thirds of the required number of patients. Because the number of events was to low (67 
DFS events) at the time when 2333 patient had been recruited, no interim analysis was 
performed.  
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The advanced analysis for the presentation at SABCS 2017 will be based on the cleaned data 
with cutoff date June 30th, 2016. 
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According to the protocol, the final analysis will follow the principle of intent-to-treat of all 
randomized patients who comply with inclusion and exclusion criteria and have had at least 
one follow-up examination after randomization and who survived without recurrence for two 
years. This population will be used for the final analysis for consistency with the protocol. As 
this definition of an ITT population is outdated, the up-to-date definition of ITT as described 
in section 3.3.2. will be used for the advanced analysis. 
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According to the protocol, two years after randomization will be used as starting point for the 
calculation of the time until the occurrence of an event. 


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ABCSG Statistics 
Confidential 
Page 15 of 15 
ABCSG 16 – v1.0 
SOP ABCSG-ST 02 SUDO 05/01 
Date: 2017-08-28 
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In addition to analyses according to protocol (starting two years after randomization) time-to-
event analyses will be conducted with the starting point being the date of randomization. 
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Additional exploratory objectives were added for the advanced analyses: 
x Influence of adherence to prescribed therapy on DFS
x The effect of the proportion of the treatment duration with anastrozole compared to 
the total duration of endocrine treatment in previous therapy on disease-free survival 
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Adherence is defined as the consistency of taking protocol treatment. Treatment duration will 
be calculated on the basis of documented start and end of therapy. Early/Late end of therapy is 
defined as departure from prescribed duration of arm therapy for more than or less than 6 
months.
Patient is adherent if duration of therapy is not shorter than 6 month and not longer than 6 
month then prescribed therapy for therapy group or has an early end of therapy with reason 
recurrence or death. 
Patient with an early/late end of therapy with reason for end of therapy different from 
recurrence/death are defined as non-adherent. Patients who died during treatment period and 
do not have reported treatment discontinuation before their death are considered adherent. 
Patients who never started therapy treatment are consider non-adherent. 
The adherent population consists of all patients from the ITT population who are adherent to 
prescribed treatment. Analyses for the primary and for all secondary endpoints will be 
repeated based on the adherent population with time at randomization as start point. 
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The effect of the proportion of the treatment duration with anastrozole compared to the total 
duration of endocrine treatment in previous therapy on disease-free survival will be analyzed 
using Cox proportional hazard models with therapy group, type of previous endocrine therapy 
and their interactions as covariates.