Primary Operation in SYnchronous meTastasized InVasivE Breast Cancer, a Multicenter Prospective Randomized Study to Evaluate the Use of Local Therapy
Phase: NA
Conditions: Synchronous Metastasized Breast Cancer, Circulating Tumor Cells
Sponsor: Austrian Breast & Colorectal Cancer Study Group

 
 
NCT01015625 
 
ABCSG 28 / POSYTIVE 
 
Study Title: 
Primary Operation in SYnchronous meTastasized InVasivE breast cancer, a multicenter prospective 
randomized study to evaluate the use of local therapy 
 
 
Protocol version 4.0 (06.09.20119 
 
 
Involved Local Ethics committees and their approvals: 
 
• 
Federal State Salzburg 
27 October 2011 
• 
Medical University Innsbruck 
18 November 2011 
• 
Federal State Upper Austria 
12 January 2012 
• 
Hospital Sisters of Mercy Linz 
13 January 2012 
• 
Federal State Burgenland 
16 January 2012 
• 
Medical University Graz 
20 January 2012 
• 
Federal State Vorarlberg  
25 January 2012 
• 
Medical University Vienna 
10 February 2012 
• 
Federal State Carinthia 
February 2012 

ABCSG 28, POSYTIVE 
 
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Protocol version_4.0 (final) 06.09.2011 
 
 
 
 
Primary Operation in SYnchronous meTastasized InVasivE 
breast cancer, a multicenter prospective randomized study 
to evaluate the use of local therapy 
 
 
 
 
ABCSG 28 / POSYTIVE 
 
 
 
 
 
Protocol version 4.0 (final) 06.09.2011 
 
 
 
 
 
A Study conducted by the 
Austrian Breast & Colorectal Cancer Study Group 
(ABCSG) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL: Information and data included in this protocol contain trade secrets and privileged or 
confidential information which is the property of the sponsor. No person is authorized to make it public 
without written permission of the sponsor. These restrictions on disclosure will apply equally to all 
future information supplied to you which is indicated as privileged or confidential. This material may be 
disclosed to and used by your staff and associates as may be necessary to conduct the clinical study. 
 

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Protocol version_4.0 (final) 06.09.2011 
 
TABLE OF CONTENTS 
 
Protocol Number ..................................................................................................... 4 
Sponsor and Coordination ...................................................................................... 4 
A
 ...................................................................................... 4 
Coordinating Investigator ........................................................................................ 4 
Experts of the trial ................................................................................................... 4 
Signatures .................................................................................................................. 6 
Investigator`s Agreement ............................................................................................ 7 
Study Summary .......................................................................................................... 8 
Title ......................................................................................................................... 8 
Objective ................................................................................................................. 8 
Studydesign ............................................................................................................ 8 
Treatment regimens ................................................................................................ 8 
Therapy arm A, surgical therapy ......................................................................... 8 
Therapy arm B, surgery on demand .................................................................... 8 
Radiation therapy ................................................................................................ 9 
Systemic therapy ................................................................................................. 9 
Number of patients .............................................................................................. 9 
Inclusion and exclusion criteria ............................................................................... 9 
General inclusion criteria ..................................................................................... 9 
Disease specific inclusion criteria ........................................................................ 9 
Exclusion criteria ............................................................................................... 10 
Stratification .......................................................................................................... 10 
Efficacy evaluation............................................................................................. 10 
Timetable .............................................................................................................. 10 
Introduction ............................................................................................................... 11 
Background and preliminary data ......................................................................... 11 
Hypothesis ............................................................................................................ 12 
Aim ........................................................................................................................ 12 
Study objectives .................................................................................................... 12 
Patients ..................................................................................................................... 12 
Sample Size Considerations ................................................................................. 12 
Study design (Appendix 1) ........................................................................................ 13 
Inclusion and Exclusion Criteria ............................................................................ 13 
General inclusion criteria ................................................................................... 13 
Disease specific inclusion criteria ...................................................................... 13 
Exclusion criteria ............................................................................................... 14 
Stratification .......................................................................................................... 14 
Outcome measurements and statistical analyses ................................................. 14 
Primary Endpoint ............................................................................................... 14 
Secondary endpoints ............................................................................................ 15 
Surgical Therapy ................................................................................................... 16 
Surgery on demand............................................................................................... 16 
Radiation therapy .................................................................................................. 16 
Systemic therapy .................................................................................................. 16 
Follow up (Appendix 4) ......................................................................................... 17 
Blood specimens in pre-selected centers (Appendix 6) ........................................ 17 
Tissue specimens in pre-selected centers ............................................................ 17 
Measurements of VEGF and TGF beta in pre-selected centers ........................... 17 

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Protocol version_4.0 (final) 06.09.2011 
 
Assessment of circulating tumor cells (CTC) and breast cancer stem cells in pre-
selected centers .................................................................................................... 18 
Stopping rules (End of Study) ............................................................................... 18 
Risks and Benefits for the patients ........................................................................ 18 
ADMINISTRATIVE REQUIREMENTS ...................................................................... 19 
Good Clinical Practice ........................................................................................... 19 
Ethical Considerations .......................................................................................... 20 
Patient Information and Informed Consent ............................................................ 20 
Patient data protection .......................................................................................... 20 
Data management ................................................................................................ 20 
On-site Monitoring ................................................................................................. 21 
Publication Policy .................................................................................................. 21 
Appendix 1: Flow chart randomization and groups ................................................... 22 
Appendix 2: Union against cancer (UICC 1987) breast cancer stages ..................... 23 
Appendix 3: Eastern Cooperative Oncology Group (ECOG) Performance Status .... 24 
Appendix 4: Follow up Flowchart .............................................................................. 25 
Appendix 5: EORTC QLQ-C30 (version 3.0), QLQ BR 23........................................ 27 
Appendix 6: Blood specimen Flow chart in pre-selected centers .............................. 31 
Appendix 7: Declaration of Helsinki .......................................................................... 32 
References ............................................................................................................... 36 

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Protocol version_4.0 (final) 06.09.2011 
 
Protocol Number 
ABCSG 28 / P O S Y T I V E 
 
Primary Operation in SYnchronous meTastasized InVasivE breast 
cancer, a multicenter prospective randomized study to evaluate the use 
of local therapy 
 
Sponsor and Coordination 
 
AUSTRIAN BREAST & COLORECTAL CANCER STUDY GROUP 
ABCSG Trial Office 
 
 
 
office@abcsg.at  
Nussdorfer Platz 8, A-1190 Vienna, Austria 
 
T: +43 1 408 92 30 
 
Academic project directors 
Univ. Prof. Dr. Florian Fitzal 
florian.fitzal@meduniwien.ac.at 
Univ. Prof. Dr. Michael Gnant 
michael.gnant@meduniwien.ac.at 
Dept. of Surgery - Division of General Surgery 
T: +43 1 40400/5621 
Univ. Prof. Dr. Günther Steger 
guenther.steger@meduniwien.ac.at 
Dept. of Internal Medicine I/Division of Oncology 
T: +43 1 40400/5459 
Medical University Vienna 
Währinger Gürtel 18-20 
A-1090 Vienna, Austria 
 
Coordinating Investigator 
Univ. Prof. Dr. Florian Fitzal 
Medical University Vienna – Dep Surgery 
Experts of the trial 
Prim. Univ. Prof. Dr. Richard Greil 
r.greil@salk.at 
Paracelsus University Salzburg - St. Johanns-Spital 
T: +43 662 4482/2879 
Head of Dept. of Internal Medicine III/Division of Oncology 
Müllner Hauptstraße 48, A-5020 Salzburg, Austria 
 
Univ. Prof. Dr. Hellmut Samonigg 
hellmut.samonigg@meduni-graz.at 
Medical University Graz 
 
T: +43 316 385/3115 
Dept. of Internal Medicine/Division of Oncology 
Auenbruggerplatz 15, A-8036 Graz, Austria 
 
Univ. Prof. Dr. Christian Marth 
christian.marth@uklibk.ac.at 
Medical University Innsbruck 
christian.marth@i-med.ac.at 
Head of Department of Gynecology 
T: +43 512 504/23051 
Innrain 52, A-6020 Innsbruck, Austria 
 
OA Dr Marija Balic 
 
 
Marija.Balic@klinikum-graz.at 
Medical University Graz 
 
T: +43 316 385/3115 
Dept. of Internal Medicine/Division of Oncology 
Auenbruggerplatz 15, A-8036 Graz, Austria 
 
 

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Protocol version_4.0 (final) 06.09.2011 
 
OA Dr Vesna Bijelic -Radisic   
Vesna.Bjelic-Radisic@klinikum-graz.at 
Medical University Graz 
 
T: +43 316 385/0 
Dept. of Gynecology 
Auenbruggerplatz 15, A-8036 Graz, Austria 
 

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Protocol version_4.0 (final) 06.09.2011 
 
Signatures 
 
 
Study title:  
Primary Operation in SYnchronous meTastasized InVasivE 
breast cancer, a multicenter prospective randomized study to 
evaluate the use of local therapy 
 
 
 
Protocol Number:   
ABCSG 28 / POSYTIVE 
 
 
 
Academic project directors: 
 
[+ Coordinating Investigator]  ________________________________ 
_____________ 
Florian Fitzal, Prof. MD 
Date 
Medical University of Vienna 
Dept. of Surgery – Division of General Surgery 
Währinger Gürtel 18-20, A-1090 Vienna 
Phone: +43 1 40400 5621 
Fax: +43 1 40400 5641 
Email: florian.fitzal@meduniwien.ac.at 
 
 
 
 
 
________________________________ 
_____________ 
Michael Gnant, Prof. MD 
Date 
Medical University of Vienna 
Dept. of Surgery – Division of General Surgery 
Währinger Gürtel 18-20, A-1090 Vienna 
Phone: +43 1 40400 5646 
Fax: +43 1 40400 7603 
Email: michael.gnant@meduniwien.ac.at 
 
 
 
 
 
________________________________ 
_____________ 
Günther Steger, Prof. MD 
Date 
Medical University of Vienna 
Dept. of Internal Medicine I - Oncology 
Währinger Gürtel 18-20, A-1090 Vienna 
Phone: +43 1 40400 5459 
Fax: +43 1 40400 6081 
Email: guenther.steger@meduniwien.ac.at 
 
 
 
 
Biostatistics: 
________________________________ 
_____________ 
Christian Fesl, PhD 
Date 
ABCSG Senior Statistician 
Phone: +43 1 408 92 30 - 27 
Fax: +43 1 409 09 90 
Email: christian.fesl@abcsg.at 

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Protocol version_4.0 (final) 06.09.2011 
 
Investigator`s Agreement 
 
 
I have read the preceding protocol entitled “Primary Operation in SYnchronous 
meTastasized InVasivE breast cancer, a multicenter prospective randomized study to 
evaluate the use of local therapy”, and agree to abide by all provisions set forth therein.  
 
 
I agree to comply with the International Conference on Harmonisation Tripartite Guideline on 
Good Clinical Practice (ICH-GCP), Declaration of Helsinki, applicable European Union 
Guidelines and national regulations. 
 
 
I agree to ensure that Financial Disclosure Statements will be completed by  
 
 
myself and/or 
 
my sub investigators  
 
before study initiation or during the study if there are changes that affect my financial 
disclosure status. 
 
 
I agree to ensure that the confidential information contained in this document will not be used 
for any purpose other than the evaluation or conduct of the clinical investigation without prior 
written consent of ABCSG. 
 
 
 
 
 
 
_____________________________________ 
_________________ 
Signature 
Date 
 
 
 
 
 
 
_____________________________________________________________ 
Name of Investigator (in capital letters or typewrite) 
 

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Protocol version_4.0 (final) 06.09.2011 
 
 
Study Summary 
Title 
Primary Operation in SYnchronous meTastasized InVasivE breast cancer, a 
multicenter prospective randomized study to evaluate the use of local therapy 
Objective 
The primary objective is to evaluate the median survival of patients with synchronous 
metastasized breast cancer and the primary tumor in place comparing arm A with 
local therapy to the primary tumor versus arm B without local therapy. 
 
The secondary objectives are to evaluate time to distant and local progression as 
well as in pre-selected centers circulating tumor cells and growth factors in the 
peripheral blood within the two groups. 
Studydesign 
This study is a prospective, randomized, multicenter study concerning the influence 
of local treatment on patients with synchronous metastasized breast cancer. Patients 
will be stratified at inclusion according to the geographic region, the hormone-
receptor status (ER-/PR-/not determinable; any PR and/or ER+), the HER-2 status 
(positive vs. negative/not determinable), the grading (G1/G2/not determinable vs. 
G3), location of metastases (visceral ± vs bone only) and use of first line therapy 
(anthracyclin-based ± any other, except taxan, vs. taxan-based ± any other vs. other 
therapies, e.g. antihormonal therapy alone). Thereafter patients will be randomly 
assigned to receive either local therapy of the breast (lumpectomy or mastectomy + 
axillary surgery /± radiotherapy) versus no local therapy. Surgery of the metastases is 
not allowed in both treatment regimens and may only be performed on demand. This 
will be considered as protocol deviation. Systemic therapy will be administered at the 
centers policy. 
Treatment regimens 
Therapy arm A, surgical therapy 
Local therapy consists of lumpectomy or mastectomy with or without radiotherapy 
(according to center tumorboard decision) with a resection free margin of at least 
1 mm or more demonstrated on paraffin embedded histological sections. 
Intraoperative frozen sections are allowed but not definitive for margin assessment. 
For axillary surgery, either axillary dissection level I and II or sentinel node biopsy has 
to be performed (mandatory) which has only to be followed by axillary dissection in 
case of macrometastasis of at least one sentinel lymph node..  
Therapy arm B, surgery on demand 
In arm B (no local therapy) it may be necessary to perform local therapy on demand 
(surgery, radiotherapy). Reasons may be uncontrolled bleeding or infected 
exulcerations with a septic component and no treatment benefit from conservative 
therapy. This will be considered as protocol deviation. However, the patient’s follow 
up is recorded and data are available for analyses as intention to treat. 

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Protocol version_4.0 (final) 06.09.2011 
 
Radiation therapy 
Local radiation therapy of the breast may be given according to center policy in 
therapy arm A. Radiation therapy of the metastases is allowed according to center 
policy in both arms. 
Systemic therapy 
Chemotherapy or anti-hormone therapy is used according to center policy. The 
following recommendations should be followed: 
1. In cases of radiotherapy and chemotherapy (arm A), radiotherapy should not 
be given later than 6 months after surgery. Radiotherapy is allowed in parallel 
to anti-hormonal treatment. 
2. In premenopausal patients anti-hormonal treatment - if indicated - should 
always be coupled with ovarian ablation (surgical resection or systemic 
endocrine treatment, e.g. with goserelin) to ensure complete hormonal 
blockade. 
3. In postmenopausal patients the primary anti-hormonal treatment - if indicated - 
should be an aromatase inhibitor (if there are no contraindications). 
4. Chemotherapy – if indicated - should precede anti-hormonal treatment – if 
indicated. 
Number of patients 
254 patients (127 in each group) including a drop out rate of 5% 
Inclusion and exclusion criteria 
Females whose conditions satisfy all of the following criteria are the only patients 
eligible for this study. 
General inclusion criteria 
1. Written informed consent must be obtained and documented prior to beginning 
any protocol specific procedures and according to local regulatory 
requirements. 
2. Patients age ≥ 18 years 
3. Eastern Cooperative Oncology Group Performance Status is 0 -2 (Appendix 3) 
4. Able to comply with the protocol requirements during the treatment and follow-
up period. 
Disease specific inclusion criteria 
5. Untreated synchronous metastasized invasive carcinoma of the breast with 
the primary tumor in situ (bilateral synchronous metastasized breast cancer 
patients are eligible). 
6. The primary tumor must be identified and may be any size, however, primary 
resection with resection free margins must be possible. 
7. Invasive adenocarcinoma of the breast on histological examination. 
8. The metastatic site must be identified by radiological assessment (Computer 
Tomography of the chest and the abdomen OR ultrasound and chest x ray for 
visceral metastases; bone scan AND/OR computer tomography AND/OR 
magnetic resonance for bone metastases). A biopsy is not necessary. 

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Exclusion criteria 
 
1. Patients in whom a R0 resection (microscopic free margins) is clinically 
questionable 
2. Inflammatory cancer 
3. Patients with brain metastases 
4. Patients who are not eligible for general anesthesia and operations 
5. Patients without metastatic breast cancer (patients with a tumor marker value 
(CEA, CA15-3) above normal levels without the radiological proven evidence 
of metastases are not eligible for the study) 
6. Patients with a second untreated malignancy 
7. Any previous malignancy treated with curative intent and the patient has not 
been disease-free for 5 years – exceptions are: 
a. carcinoma in situ of the cervix 
b. squamous carcinoma of the skin 
c. basal cell carcinoma of the skin 
8. Patients with any recurrent cancer disease 
9. Pregnant or lactating women 
10. Patients are not allowed to be part of another local therapy trial 
Stratification 
 
 
o 
versus
 
 Receptor status 
o 0/0 versus any positive 
 Her2neu status 
o FISH amplified/IHC+++ versus negative 
 Location of metastases 
o visceral ± versus bone only 
 Planned first line therapy 
o Anthracycline-based ± any other except taxane versus taxane-based ± 
any other versus any other therapy 
Efficacy evaluation 
Median survival 
Time to local progression 
Time to distant progression 
Circulating tumor cells and growth factors in pre-selected centers 
Quality of life 
Timetable 
Planned start date 
 
Q1/10 
Planned end enrollment date 
Q1/14 
Expected follow up end date 
Q1/19 

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Introduction 
Background and preliminary data 
Overall survival for patients with metastasized breast cancer (stage IV) is limited. 
Most recent data report about a median survival between 11 and 23 months 
depending on prognostic factors and systemic therapy 1-6. As cancer cells have 
already spread throughout the systemic circulation in stage IV breast cancer disease 
it is generally believed that systemic therapy may be the only life prolonging 
treatment. Even in stage I and II breast cancer patients more aggressive local 
therapy did not improve overall survival 7,8. 
 
Recently a meta-analysis by the Early Breast and Colorectal Trial Collaborative 
Group (EBCTCG) in 2002 updated in 2005 has shown that the prevention of local 
recurrence by local therapy significantly correlates with an improvement in overall 
survival in stage I and II breast cancer patients 9 suggesting an important role of local 
therapy for overall survival. The first clinical evidence that local therapy may be of 
benefit in stage IV disease arises from renal-cell cancer patients. Case reports about 
metastasis shrinkage after primary tumor resection in renal-cell cancer patients were 
followed by two randomized trials demonstrating that removal of the primary tumor in 
metastasized renal-cell cancer significantly improved survival 10,11. 
 
Regarding stage IV breast cancer patients Khan et al 4 evaluated 9162 patients 
accounting for 4.1% of all breast cancer patients entered into the National Cancer 
Data Base (NCDB) between 1990 and 1993. 43% had systemic treatment only while 
57% underwent additional local surgery due to salvage treatment, patients wish or 
local complications. Local therapy consisted of partial or total mastectomy with or 
without axillary surgery. The use of radiotherapy has not been evaluated due to lack 
of data. Patients with surgical removal of the primary tumor had a significant 
increased 3-year survival rate (17% vs. 35%) with a hazard ratio of 0.61. Similar the 
Geneva Cancer Registry report from Rapiti et al 5 demonstrated a 40% reduced risk 
of death with the surgical removal of the primary tumor in 300 stage IV breast cancer 
patients. A significant improvement in progression free survival by this treatment has 
been demonstrated in 224 patients with stage IV breast cancer at the MD Anderson 
Cancer Center 1 and Blanchard et al 2 suggested a significant increase in median 
survival from 17 to 27 months for the surgical removal of the primary in 427 stage IV 
breast cancer patients at the Baylor College of Medicine. A retrospective analysis of 
the Surveillance, Epidemiology and End Results (SEER) program data of 9734 
patients also demonstrated a 37% improvement for overall survival in patients with 
stage IV breast cancer and removal of the primary tumor 6. These data together 
strongly suggest an important role for local therapy in stage IV cancer disease. 
However, this has to be proven in prospective studies. More over the reason for a life 
extending role of local therapy in metastasized patients is unclear. 
 
Theoretically there are some unproven speculative explanations. The primary tumor 
may act as a source for ongoing systemic spreading of chemoresistant cancer cells 
(circulating tumor cells, stem cells) 12-15 or metastases proliferation factors (TGFbeta 
16-18, VEGF 19-24) supporting systemic tumor growth and further metastases 
proliferation. Resection of the primary tumor may thus down regulate the constant 
release of circulating tumor cells/stem cells and/or proliferating factors 25,26 reducing 
the capacity to produce new metastases and decreasing proliferation of metastases. 

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The reduction of chemoresistant systemic stem cells by resection of the primary 
tumor may render metastatic cells chemosensitive. Clinically there is evidence that 
resection of the primary tumor may enhance the response to systemic therapy 11,27,28 
Hypothesis 
We first hypothesize that the removal of the primary tumor in stage IV breast cancer 
patients followed by systemic therapy improves median survival compared with no 
local therapy. In case that this main thesis proves true we secondly hypothesize that 
the ultimate reason for the improved survival by local therapy may be due to the 
reduction of stem cells or circulating proliferation factors such as VEGF or TGF beta 
in the peripheral system as these cells and factors may origin from the primary 
cancer. This may reduce metastatic growth kinetics and increase chemosensitivity of 
visceral and non-visceral metastases and prolong median and progression free 
survival. 
Aim 
The aim of the study is to investigate the effect of local therapy to the primary tumor 
in synchronous metastasized breast cancer patients and to evolve the role of 
circulating tumor cells and growth factors in the peripheral blood. 
Study objectives 
The primary study objective is 
 
1. to demonstrate that the resection of the primary breast cancer in synchronous 
metastasized breast cancer patients increases the median survival. 
 
The secondary study objectives are 
 
1. to investigate the role of the primary breast cancer resection in terms of local 
and distant time to progression  
2. to evaluate the role of peripheral circulating tumor cells and growth factors in 
synchronous metastasized breast cancer patients and whether there is any 
association between their detection and the median survival in pre-selcted 
centers 
3. to examine whether the resection of the primary breast cancer influences 
peripheral circulating tumor cells and growth factors in pre-selcted centers 
4. to investigate the quality of life in both groups 
Patients 
Sample Size Considerations 
A sample of 254 patients will be enrolled in this trial (127 in each group) including a 
drop out rate of 5%. This assumes that there will be a 48-month accrual period. The 
median survival of patients with local therapy to the primary tumor should be 
increased by 50% in comparison to patients without local therapy to have 80% power 
to detect a hazard ratio of 0.666 with a two-sided significance level of 0.05. The 
recruitment period is assumed with 4 years. The maximum study duration should be 
9 years. 

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Study design (Appendix 1) 
This is a prospective multicenter national randomized study. Patients with a 
histological verified breast cancer are first screened for any metastatic disease. In 
cases of visceral or non visceral metastatic spreading (International Union against 
Cancer UICC M1 = stage IV; Appendix 2) the patient is eligible for the study taking 
into consideration all inclusion and exclusion criteria listed below. After signed 
informed consent the patient is randomized to either arm A (local treatment) or Arm B 
(no local treatment, only on demand). In arm A therapy consists of either breast 
conserving surgery or mastectomy. For axillary surgery, either axillary dissection 
level I and II or sentinel node biopsy has to be performed (mandatory) which has only 
to be followed by axillary dissection in case of macrometastasis of at least one 
sentinel lymph node, followed by radiotherapy (on centers preference). Surgery of the 
metastases is not allowed in both treatment arms and may only be performed on 
demand. This will be considered as protocol deviation. Systemic therapy follows 
surgery on the centers preference. In arm B only systemic therapy is given on the 
centers preference. Follow up should be done every 3 months during the first 2 years 
and from then on every 6 months and should include clinical, radiological and 
laboratory exams. The median survival is the primary endpoint, while the time to local 
or distant progession are definded as secondary endpoints. 
 
Additional we measure circulating tumor cells and growth factors in the peripheral 
blood at pre-selcted centers. Therefore 15ml of blood are drawn before surgery and 
1-3 days after surgery (arm A only), as well as before first application of systemic 
therapy, 3-6 months and 12 months after first application of systemic therapy in both 
arms. 
 
Quality of life questionnaires are handed out to all patients before surgery or first 
application of systemic therapy as well as every 6 months after enrollment until 42 
months visit.  
 
Inclusion and Exclusion Criteria 
 
Females whose conditions satisfy all of the following criteria are the only patients 
eligible for this study. 
General inclusion criteria 
1. Written informed consent must be obtained and documented prior to beginning 
any protocol specific procedures and according to local regulatory 
requirements. 
2. Patients age ≥ 18 years 
3. Eastern Cooperative Oncology Group Performance Status is 0 -2 (Appendix 3) 
4. Able to comply with the protocol requirements during the treatment and follow-
up period. 
Disease specific inclusion criteria 
5. Untreated synchronous metastasized invasive carcinoma of the breast with 
the primary tumor in situ (bilateral synchronous metastasized breast cancer 
patients are eligible). 

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Protocol version_4.0 (final) 06.09.2011 
 
6. The primary tumor must be identified and may be any size, however, primary 
resection with resection free margins must be possible. 
7. Invasive adenocarcinoma of the breast on histological examination. 
8. The metastatic site must be identified by radiological assessment (Computer 
Tomography of the chest and the abdomen OR ultrasound and chest x ray for 
visceral metastases; bone scan AND/OR computer tomography AND/OR 
magnetic resonance for bone metastases). A biopsy is not necessary. 
Exclusion criteria 
1. Patients in whom a R0 resection (microscopic free margins) is clinically 
questionable 
2. Inflammatory cancer 
3. Patients with brain metastases 
4. Patients who are not eligible for general anesthesia and operations 
5. Patients without metastatic breast cancer (patients with a tumor marker value 
(CEA, CA15-3) above normal levels without the radiological proven evidence 
of metastases are not eligible for the study) 
6. Patients with a second untreated malignancy 
7. Any previous malignancy treated with curative intent and the patient has not 
been disease-free for 5 years – exceptions are: 
a. carcinoma in situ of the cervix 
b. squamous carcinoma of the skin 
c. basal cell carcinoma of the skin 
8. Patients with any recurrent cancer disease 
9. Pregnant or lactating women 
10. Patients are not allowed to be part of another local therapy trial 
Stratification 
 
 
o 
versus
 
 Receptor status 
o 0/0 versus any positive 
 Her2neu status 
o FISH amplified/IHC+++ versus negative 
 Location of metastases 
o visceral ± versus bone only 
 Planned first line therapy 
o anthracyclinebased ± any other except taxane versus taxane based ± any 
other versus any other therapy 
Outcome measurements and statistical analyses 
Primary Endpoint 
Median survival 
Median survival of both groups (Arm A local therapy and Arm B no local therapy) will 
be compared. Patients are evaluated as intention to treat (thus, patients with surgery 
on demand are on group B). The median survival is the time point at which 50% of all 
randomized patient died. For this primary endpoint, the 2-sided log-rank test 

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Protocol version_4.0 (final) 06.09.2011 
 
(unstratified) will be used to test for differences between local therapy versus no local 
therapy at an overall alpha level of 5%. A stratified version of the 2-sided log-rank 
test will be performed with the stratification factors used for randomization except 
geographic region. Kaplan-Meier curves and estimates will be provided for each 
treatment group. Potential confounding effects of the impact of other variables 
(grading, age, her2-neu expression and so on) will be assessed with the multiple 
Cox-Regression analysis. Data analysis for the primary endpoint is performed on an 
intention-to-treat basis (ITT). The ITT population includes all randomized subjects 
who withdraw informed consent and the permission to use their data collected by 
then. All subjects will be analyzed according to the treatment to which they have 
been randomized. Subjects who terminate the study before their scheduled final 
study visits will be censored. 
 
Sample size considerations:  
The sample size calculation is based on the following assumptions: 
 4 years recruitment period and a maximum study duration of 9 years 
 Control Arm – systemic therapy alone: median survival is 24months 
 Experimental Arm – surgery plus systemic therapy: median survival is 
36 months (assuming a hazard ratio of 0.666 compared to arm A)  
 Overall alpha level of 5% and a power of 80% 
 One interim analyses when 50% of the total number of events (death) have 
occurred 
Based on these assumptions and taking into consideration a potential drop-out rate 
of 5%, 254 patients (127 in each treatment arm) need to be enrolled in order to 
observe 192 events which should be sufficient to yield 80% power for a two-sided 
log-rank test at an overall alpha level of 5%. 
 
In order to control the overall type one error at the 5% level, the interim analyses will 
follow a Lan-DeMets alpha spending approach, using an O’Brien-Fleming boundary 
function. According to this approach, the study will be stopped after 50% of the total 
number of events (96 events) due to efficacy (median survival in experimental arm 
greater than in the control arm) or due to futility ( median survival in experimental arm 
less than in the control arm) at a 2-sided alpha = 0.00306. 
 
Secondary endpoints 
Time to distant progression (TTPd) 
Time to treatment change due to systemic progression. 
Time to local progression (TTPl) 
Increase in size >25% of the primary tumor in arm B (no local therapy). 
Local recurrence in arm A (local therapy). 
 
For the secondary endpoint, TTPd and TTPl, the 2-sided log-rank test (unstratified) 
will be used to test for differences between local versus no local therapy at an overall 
alpha level of 5%. A stratified version of the 2-sided log-rank test will be performed 

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Protocol version_4.0 (final) 06.09.2011 
 
with the stratification factors used for randomization except geographic region. 
Kaplan-Meier curves and estimates will be provided for each treatment group. The 
multiple analysis will be conducted with a Cox regression model. The local 
recurrence in arm A (local therapy) will be assessed with univariate and multiple 
logistic regression analysis. 
Reduction of growth factors, circulating tumor cells, stem cells in pre-
selected centers 
For the secondary endpoint growth factors, circulating tumor cells, stem cells, post 
intervention measurements are compared with baseline values and tested with the 
repeated measures ANOVA. Correlations between initial or late drop of growth 
factors, circulating tumor cells, stem cells and median survival or TTP, respectively, 
will be calculated with the Spearman rank order correlation test. The stem cell and 
growth factors in the tumor will be correlated with the stem cell and growth factor 
release into the peripheral circulation and known prognostic factors such as her2neu 
expression and grading as well as survival time. The association with her2neu 
expression and grading and categorical variables will be assessed by an ANOVA. 
The association with the survival time will be analysed with a Cox regression. 
Surgical Therapy 
Local therapy consists of lumpectomy or mastectomy with a resection free margin of 
at least 1 mm or more demonstrated on paraffin embedded histological sections. 
Intraoperative frozen sections are allowed but not definitive for margin assessment. 
For axillary surgery, either axillary dissection level I and II or sentinel node biopsy has 
to be performed (mandatory) which has only to be followed by axillary dissection in 
case of macrometastasis of at least one sentinel lymph node.  
 
Surgery on demand 
In the arm B (no local therapy) it may be necessary to perform local therapy on 
demand (surgery, radiotherapy). Reasons may be uncontrolled bleeding or infected 
exulcerations with a septic component and no treatment benefit from conservative 
therapy. This will be considered as protocol deviation. However, the patient’s follow 
up is recorded and data are available for retrospective analyses as intention to treat. 
Radiation therapy 
Local radiation therapy of the breast may be given according to center policy in 
therapy arm A. In arm B this will be considered as protocol deviation. Radiation 
therapy of the metastases is allowed according to center policy in both arms. 
Systemic therapy 
Chemotherapy or anti-hormone therapy is used according to center policy. The 
following recommendations should be followed: 
1. In cases of radiotherapy and chemotherapy (arm A), radiotherapy should not 
be given later than 6 months after surgery. Radiotherapy is allowed in parallel 
to anti-hormonal treatment. 
2. In premenopausal patients anti-hormonal treatment - if indicated - should 
always be coupled with ovarian ablation (surgical resection or systemic 
endocrine treatment, e.g. with goserelin) to ensure complete hormonal 
blockade. 

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3. In postmenopausal patients the primary anti-hormonal treatment - if indicated - 
should be an aromatase inhibitor (if there are no contraindications). 
4. Chemotherapy – if indicated - should precede anti-hormonal treatment – if 
indicated. 
 
Follow up (Appendix 4) 
Routine laboratory tests for safety assessment of palliative systemic therapy and 
radiological follow up are performed according to the centers’ guidelines with the 
recommended procedures as follows: 
 Clinical examination and laboratory tests (red and white blood cells, Tumor 
marker CA15-3 and CEA) before and every 2-4 months after randomization. 
After two years examinations should be done every 5-7 months. 
 CT scan of the liver and the lung before and every 2-4 months after 
randomization. Alternatively a PET-CT scan can be performed. Ultrasound of 
the liver or chest X-ray is only recommended in cases of contraindication for 
CT. After two years examinations should be done every 5-7 months. 
 CT scan or alternatively PET-CT scan of bone metastases (if diagnosed) 
before and in case of pre-randomization diagnosed bone metastases every 2-
4 months after randomization or in case of suspect new bone metastases 
anytime after randomisation for diagnostic imaging. After two years 
examinations should be done every 5-7 months. 
 EORTC QLQ-C30 and QLQ-BR23 quality of life (Appendix 5) sheets before 
and every 6 months after treatment until 24 months visit, then every 12 months 
until 48 months visit. 
 
Blood specimens in pre-selected centers (Appendix 6) 
15ml of blood are drawn before surgery and 1-3 days after surgery (arm A only), as 
well as before first application of systemic therapy, 3-6 months and 12 months after 
first application of systemic therapy in arm A and arm B. 
Tissue specimens in pre-selected centers 
Tumor tissue from core needle biopsies before systemic therapy (arm B no local 
therapy group) or from surgical resections (arm A local therapy group) are used for 
further immunhistochemical and flow cytometry analyses. Only in pre-selected 
centers with experimental background. 
 
Measurements of VEGF and TGF beta in pre-selected centers 
Blood 
Blood (7.5 ml) is drawn into pre-chilled CTAD-tubes, kept on ice and further 
processed within 30 min: After an initial centrifugation step at 1000 x g and 4ºC for 10 
min, plasma is transferred to microtubes and subjected to further centrifugation at 
10000 x g and 4ºC for 10 min (to remove “contaminating” platelets). The supernatant 
is stored in aliquots at -70ºC to avoid repeated cycles of freezing / thawing prior to 
analysis. Samples are transported to the University of Vienna surgical research 
laboratories for further examinations immediately under dry ice. Plasma samples are 

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analyzed in duplicate by ELISA to determine the concentration of circulating 
angiogenic factors. Commercially available ELISA tests are applied for VEGF-A, -C, -
D (Quantikine, R&D Systems, Minneapolis, MN) and TGF-beta,-beta 1,-beta 2 and-
beta 3 (R&D System). 
Tumor 
Specimens from core needle biopsies (arm B) or surgical resected tumors (arm A) 
are fixed in formaldehyde and sent to the Medical University of Vienna together with 
the plasma samples. Thereafter blocks are stained with anti-VEGF and anti-TGF beta 
(R&D Systems) for immunhistochemistry and paraffin blocks are analysed.  
Assessment of circulating tumor cells (CTC) and breast cancer 
stem cells in pre-selected centers 
Blood 
Peripheral blood (7.5 ml) will be drawn in EDTA-tubes to which a cell preservation 
solution is added. Probes are shipped to the Medical University of Vienna right away 
at 4°C. The cells are subjected to immunostaining with appropriate isotype controls 
or a set of antibodies for evaluation of CTCs (anti-human CK8+, 18+ and 19+ and 
CD45-) or breast cancer stem cells (anti-human ESA+ CD44+ CD24- lineage-) within 
72 hours. Lineage markers antibodies are anti-CD2, -CD3, -CD10, -CD16, -CD18, -
CD31, -CD64, -CD140b. Samples will be analyzed with an EPICS XL-MCL flow 
cytometer and with acquisition of at least 100000 cells per sample to yield an 
informative number of events for CTCs (anti-human CK8+, 18+ and 19+ and CD45-) 
and endothelial progenitors (CD3-, CD19-, CD33-, KDR+, CD133+). 
Tumor 
Tumor specimens are minced and kept in RPMI medium 1640 under sterile 
conditions for a maximum of 72 hours. During that time, specimens are shipped to 
the Medical University of Vienna together with other specimens. Thereafter the tumor 
pieces are mixed with ultra-pure collagenase III in medium 199 and allowed to 
incubate at 37°C for 3-4 hours. After incubation, cells are filtered through a 46µl nylon 
mesh and washed with RPMI/20% FSB, then washed twice with HBSS. Cell are 
counted and transferred to a 5 ml tube, washed with HBSS and HICS and incubated 
with Sandoglobin solution for 10 min. After another washing step with HBSS and 
HICS, antibodies are added. The antibodies are the same as for blood specimen. 
Stopping rules (End of Study) 
1. Withdrawal of informed consent 
2. Death 
3. Lost to Follow Up 
Risks and Benefits for the patients 
Risk of biopsy 
Core needle biopsies are routinely performed to preoperatively diagnose breast 
cancer. Morbidities are bleeding or infections which usually may be treated 
conservatively. Cell seeding has been demonstrated but the clinical impact is only 
minor 29. 

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Risk of blood withdraw 
Usually there are no complications with venous blood withdraw, however, a 
thrombophlebitis or local pain and red skin may result from this invasive diagnostic 
procedure. The risk is between 1 and 5%. Local cooling packs and sometimes 
antibiotics and bandages may be necessary to reduce the pain and the infection. 
Risks of local treatment 
The main risk for the patient is for women in the treatment group A (local therapy) 
who undergo operation under general anesthesia. In general the local treatment 
(surgical removal of the primary tumor) has been done throughout more than 100 
years in metastasized and non-metastasized patients with excellent results. Recently 
El-Tamer et al published morbidity and mortality rates of mastectomy and 
lumpectomy in 3107 patients 30. 
30-day mortality was 0 – 0.24% and 30-day morbidity was between 1.8 and 5.7% 
showing higher numbers for mastectomized patients. The highest morbidity rate was 
due to superficial wound infections with 3% in the mastectomy group. Wound 
infection was associated with adipositas (BMI >30). Sever events such as cardiac 
arrest or pulmonalembolia were seen in 0.06% or 0.24%, respectively. 
Thrombophlebitis and systemic infections have been seen in 0.07 – 0.24% and 0.07 - 
0.3%, respectively. Acute renal insufficiency has been observed in 0.06% of patients 
undergoing mastectomy.  
Bleedings as well as seroma productions are rare and may be observed in 1 to 2% of 
patients. Most bleedings and hematoma formations may be treated conservatively 
while only a minority may need to undergo a second operation. 
There is, however, a small risk to need a second operation due to positive resection 
margins. This risk is reduced by the use of intraoperativen frozen section analyses to 
6% (Fitzal et al; data submitted). 
Benefit for the patients 
The benefit for the patient may be a 10% absolute increase in median survival from 
24 to 36 months. More over if the hypothesis is true that the resection of the primary 
tumor in metastasized patients increases overall survival, the knowledge about 
carcinogenesis increases substantially. If we are able to demonstrate that circulating 
tumor cells and/or growth factors released from the primary tumor may be at least in 
part responsible for this improvement, the doors are open to investigate new 
therapeutic strategies in these patients such as anti-growth factor antibodies or 
systemic therapies destroying tumor stem cells. No trial has been published so far 
answering these important questions which may, in fact, guide us to new aspects of 
cancer therapy. 
ADMINISTRATIVE REQUIREMENTS 
Good Clinical Practice 
 The study will be conducted in accordance with the International Conference 
on Harmonisation (ICH) for Good Clinical Practice (GCP) and the appropriate 
regulatory requirement(s). Essential clinical documents will be maintained to 
demonstrate the validity of the study and the integrity of the data collected. 

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Ethical Considerations 
 The study will be conducted in accordance with ethical principles founded in 
the Declaration of Helsinki (see Appendix 5). The IEC will review all 
appropriate study documentation in order to safeguard the rights, safety and 
well-being of the patients.  
Patient Information and Informed Consent 
The principal investigators at each center will ensure that the patient is given full and 
adequate oral and written information about the nature, purpose, possible risk and 
benefit of the study. Patients must also be notified that they are free to discontinue 
from the study at any time. The patient should be given the opportunity to ask 
questions and allowed time to consider the information provided. 
The patient’s signed and dated informed consent must be obtained prior to 
undertaking any trial-related procedure which is not part of the routine clinical 
management of the patient (i.e. would not be indicated outside the study). 
Additionally all consent forms have to be signed and dated by the investigator or 
authorised delegate. If the patient is unable to read or write, the consent forms 
should be signed and dated by the investigator and an independent witness, to 
indicate that the patient apparently understood the information and consented freely. 
The written subject information must not be changed without prior release by ABCSG 
and the approval by IRB/IEC. 
The principal investigator(s) must store the original, signed Informed Consent Form. 
A copy of the signed Informed Consent Form must be given to the patient. 
Patient data protection 
The Informed Consent Form will incorporate wording that complies with relevant data 
protection and privacy legislation. Pursuant to this wording, patients 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. 
The Informed Consent Form will explain that study data will be stored electronically, 
maintaining confidentiality in accordance with national data legislation. All data 
computer processed by ABCSG will be identified by randomization code / study code. 
The Informed Consent Form will also explain that for data verification purposes, 
authorized representatives of ABCSG, a regulatory authority, an IEC may require 
direct access to parts of the hospital or practice records relevant to the study, 
including patients’ medical history. 
Data management 
Data management is carried out by ABCSG by the use of the MACRO, InferMed's 
web based electronic data collection system for clinical trials. MACRO has been 
designed to support the requirements of internationally recognised ICH Good Clinical 
Practice and FDA 21 CFR Part 11. 

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On-site Monitoring 
The ABCSG Monitor is responsible for verifying the CRFs at regular intervals 
throughout the study to verify adherence to the protocol, completeness, accuracy and 
consistency of the data and adherence to local regulations on the conduct of clinical 
research. The monitor should have access to subject medical records and other 
study-related records needed to verify the entries in the eCRF. 
Publication Policy 
Authorship of any publications resulting from this study will be determined on the 
basis of the Uniform Requirement for Manuscripts Submitted to Biomedical Journals 
(International Committee of Medical Journal Editors, 2004), which states: 
 Authorship credit should be based on (1) substantial contributions to 
conception and design, acquisition of data, or analysis and interpretation of 
data; (2) drafting the article or revising it critically for important intellectual 
content; (3) final approval of the version to be published. Authors should meet 
conditions 1, 2, and 3. 
 When a large, multicenter group has conducted the work, the group should 
identify the individuals who accept direct responsibility for the manuscript.  
These individuals should fully meet the criteria for authorship defined above. 
 Acquisition of funding, collection of data, or general supervision of the 
research group, alone, does not justify authorship. 
 All persons designated as authors should qualify for authorship, and all those 
who qualify should be listed. 
 Each author should have participated sufficiently in the work to take public 
responsibility for appropriate portions of the content. 
 

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Appendix 1: Flow chart randomization and groups 
Flow chart randomisation and groups 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SYNCHRONOUS METASTASIZED BREAST CANCER 
biopsy of the primary for verification 
RANDOMIZATION 
LOCAL THERAPY  
• lympectomy or mastectomy 
with negative margins (R0) 
• Axillary dissection I/II or 
sentinel node biopsy ± axillary 
dissection 
• Radiotherapy 
NO LOCAL 
THERAPY 
• local therapy only on demand 
bleeding, infection 
SYSTEMIC THERAPY 
FOLLOW UP 
clinical, blood and radiological examination 
every 2-4 months 

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Appendix 2: Union against cancer (UICC 1987) breast 
cancer stages 
 
Stage 0 
Tis 
N0 
M0 
Stage I 
T1 
N0 
M0 
Stage II 
 
 
 
Stage IIa 
T0 
N1 
M0 
 
T1 
N1 
M0 
 
T2 
N0 
M0 
Stage IIb 
T2 
N1 
M0 
 
T3 
N0 
M0 
Stage III 
 
 
 
IIIa 
T3 
N1 
M0 
 
T1,T2,T3 
N2 
M0 
IIIb 
T4 
Any N 
M0 
 
Any T 
N3 
M0 
Stage IV 
Any T 
Any N 
M1 
 

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Appendix 3: Eastern Cooperative Oncology Group (ECOG) 
Performance Status 
 
Grade ECOG 
0 
Fully active, able to carry on all pre-
disease performance without 
restriction 
1 
Restricted in physically strenuous 
activity but ambulatory and able to 
carry out work of light or sedentary 
nature, e.g., light house work, office 
work 
2 
Ambulatory and capable of all self-care 
but unable to carry out any work 
activities. Up and about more than 50% 
of waking hours 
3 
Capable of only limited self-care, 
confined to bed of chair more than 
50% of waking hours 
4 
Completely disabled. Cannot carry on 
any self-care. Totally confined to bed 
or chair 
5 
Dead 
 
Oken et al Am J Clin Oncol 5:649-655, 1982 
 

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Appendix 4: Follow up Flowchart 
recommended 
Assessments & 
Investigations 
YEAR 1 
YEAR 2 
YEAR 3 
YEAR 4 
YEAR 5 
RELAPSE/ 
PROGRESSION 
Months ( 1 month) 
3 
6 
9 
12 
15 
18 
21 
24 
30 
36 
42 
48 
54 
60 
History and Clinical 
Examination 
 
Intercurrent Medical 
History 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
General and Physical 
Examination 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Quality of Life 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Laboratory (incl CEA, CA 
15-3)  
According to systemic therapy but at least every 2-4 
months 
every 5-7 months 
Imaging 
Breast Imaging (check 
guidance) 
(○) 
(○) 
(○) 
 
(○) 
(○) 
(○) 
 
(○) 
 
(○) 
 
(○) 
 
 
CT1 Thorax/Abdomen 
(US/chest X-ray) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bone Imaging 
In cases of pre-randomized diagnosed bone 
metastases every 2-4 months, in case of suspected 
bone metastases for staging 
In cases of pre-randomized 
diagnosed bone metastases every 5-7 
months, in case of suspected bone 
metastases for staging  
 
Pregnancy Test 2 
in pre/perimenopausal women according to local policy 
 

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1 Alternatively a PET-CT scan can be performed 
2 Pregnancy tests have to be performed in pre/perimenopausal women during screening phase and at regular intervalls throughout the trial according to 
local policy 

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Appendix 5: EORTC QLQ-C30 (version 3.0), QLQ BR 23 
 

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Appendix 6: Blood specimen Flow chart in pre-selected centers 
 
 
 
 
 

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Appendix 7: Declaration of Helsinki 
 
 
Adopted by the 18th WMA General Assembly Helsinki, Finland, June 1964 and amended by 
the 29th WMA General Assembly, Tokyo, Japan, October 1975 35th WMA General 
Assembly, Venice, Italy, October 1983 41st WMA General Assembly, Hong Kong, 
September 1989 48th WMA General Assembly, Somerset West, Republic of South Africa, 
October 1996 and the 52nd WMA General Assembly, Edinburgh, Scotland, October 2000 
A. 
INTRODUCTION 
1. 
The World Medical Association has developed the Declaration of Helsinki as a 
statement of ethical principles to provide guidance to physicians and other participants in 
medical research involving human subjects.  Medical research involving human subjects 
includes research on identifiable human material or identifiable data. 
2. 
It is the duty of the physician to promote and safeguard the health of the people.  The 
physician's knowledge and conscience are dedicated to the fulfillment of this duty. 
3. 
The Declaration of Geneva of the World Medical Association binds the physician with 
the words, "The health of my patient will be my first consideration," and the International 
Code of Medical Ethics declares that, "A physician shall act only in the patient's interest 
when providing medical care which might have the effect of weakening the physical and 
mental condition of the patient." 
4. 
Medical progress is based on research which ultimately must rest in part on 
experimentation involving human subjects. 
5. 
In medical research on human subjects, considerations related to the well-being of 
the human subject should take precedence over the interests of science and society. 
6. 
The primary purpose of medical research involving human subjects is to improve 
prophylactic, diagnostic and therapeutic procedures and the understanding of the aetiology 
and pathogenesis of disease.  Even the best proven prophylactic, diagnostic, and therapeutic 
methods must continuously be challenged through research for their effectiveness, 
efficiency, accessibility and quality. 
7. 
In current medical practice and in medical research, most prophylactic, diagnostic and 
therapeutic procedures involve risks and burdens. 
8. 
Medical research is subject to ethical standards that promote respect for all human 
beings and protect their health and rights.  Some research populations are vulnerable and 
need special protection.  The particular needs of the economically  
and medically disadvantaged must be recognized.  Special attention is also required for 
those who cannot give or refuse consent for themselves, for those who may be subject to 
giving consent under duress, for those who will not benefit personally from the research and 
for those for whom the research is combined with care. 
9. 
Research Investigators should be aware of the ethical, legal and regulatory 
requirements for research on human subjects in their own countries as well as applicable 
international requirements.  No national ethical, legal or regulatory requirement should be 

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allowed to reduce or eliminate any of the protections for human subjects set forth in this 
Declaration. 
B. 
BASIC PRINCIPLES FOR ALL MEDICAL RESEARCH 
1. 
It is the duty of the physician in medical research to protect the life, health, privacy, 
and dignity of the human subject. 
2. 
Medical research involving human subjects must conform to generally accepted 
scientific principles, be based on a thorough knowledge of the scientific literature, other 
relevant sources of information, and on adequate laboratory and, where appropriate, animal 
experimentation. 
3. 
Appropriate caution must be exercised in the conduct of research which may affect 
the environment, and the welfare of animals used for research must be respected. 
4. 
The design and performance of each experimental procedure involving human 
subjects should be clearly formulated in an experimental protocol.  This protocol should be 
submitted for consideration, comment, guidance, and where appropriate, approval to a 
specially appointed ethical review committee, which must be independent of the investigator, 
the sponsor or any other kind of undue influence.  This independent committee should be in 
conformity with the laws and regulations of the country in which the research experiment is 
performed.  The committee has the right to monitor ongoing trials.  The researcher has the 
obligation to provide monitoring information to the committee, especially any serious adverse 
events.  The researcher should also submit to the committee, for review, information 
regarding funding, sponsors, institutional affiliations, other potential conflicts of interest and 
incentives for subjects. 
5. 
The research protocol should always contain a statement of the ethical considerations 
involved and should indicate that there is compliance with the principles enunciated in this 
Declaration. 
6. 
Medical research involving human subjects should be conducted only by scientifically 
qualified persons and under the supervision of a clinically competent medical person.  The 
responsibility for the human subject must always rest with a medically qualified person and 
never rest on the subject of the research, even though the subject has given consent. 
7. 
Every medical research project involving human subjects should be preceded by 
careful assessment of predictable risks and burdens in comparison with foreseeable benefits 
to the subject or to others.  This does not preclude the participation of healthy volunteers in 
medical research.  The design of all studies should be publicly available. 
8. 
Physicians should abstain from engaging in research projects involving human 
subjects unless they are confident that the risks involved have been adequately assessed 
and can be satisfactorily managed.  Physicians should cease any investigation if the risks are 
found to outweigh the potential benefits or if there is conclusive proof of positive and 
beneficial results. 
9. 
Medical research involving human subjects should only be conducted if the 
importance of the objective outweighs the inherent risks and burdens to the subject.  This is 
especially important when the human subjects are healthy volunteers. 
10. 
Medical research is only justified if there is a reasonable likelihood that the 
populations in which the research is carried out stand to benefit from the results of the 
research. 
11. 
The subjects must be volunteers and informed participants in the research project. 

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12. 
The right of research subjects to safeguard their integrity must always be respected.  
Every precaution should be taken to respect the privacy of the subject, the confidentiality of 
the patient's information and to minimize the impact of the study on the subject's physical 
and mental integrity and on the personality of the subject. 
13. 
In any research on human beings, each potential subject must be adequately 
informed of the aims, methods, sources of funding, any possible conflicts of interest, 
institutional affiliations of the researcher, the anticipated benefits and potential risks of the 
study and the discomfort it may entail.  The subject should be informed of the right to abstain 
from participation in the study or to withdraw consent to participate at any time without 
reprisal.  After ensuring that the subject has understood the information, the physician should 
then obtain the subject's freely-given informed consent, preferably in writing.  If the consent 
cannot be obtained in writing, the non-written consent must be formally documented and 
witnessed. 
14. 
When obtaining informed consent for the research project the physician should be 
particularly cautious if the subject is in a dependent relationship with the physician or may 
consent under duress.  In that case the informed consent should be obtained by a well-
informed physician who is not engaged in the investigation and who is completely 
independent of this relationship. 
15. 
For a research subject who is legally incompetent, physically or mentally incapable of 
giving consent or is a legally incompetent minor, the investigator must obtain informed 
consent from the legally authorized representative in accordance with applicable law.  These 
groups should not be included in research unless the research is necessary to promote the 
health of the population represented and this research cannot instead be performed on 
legally competent persons. 
16. 
When a subject deemed legally incompetent, such as a minor child, is able to give 
assent to decisions about participation in research, the investigator must obtain that assent in 
addition to the consent of the legally authorized representative. 
17. 
Research on individuals from whom it is not possible to obtain consent, including 
proxy or advance consent, should be done only if the physical/mental condition that prevents 
obtaining informed consent is a necessary characteristic of the research population.  The 
specific reasons for involving research subjects with a condition that renders them unable to 
give informed consent should be stated in the experimental protocol for consideration and 
approval of the review committee.  The protocol should state that consent to remain in the 
research should be obtained as soon as possible from the individual or a legally authorized 
surrogate. 
18. 
Both authors and publishers have ethical obligations.  In publication of the results of 
research, the investigators are obliged to preserve the accuracy of the results.  Negative as 
well as positive results should be published or otherwise publicly available.  Sources of 
funding, institutional affiliations and any possible conflicts of interest should be declared in 
the publication.  Reports of experimentation not in accordance with the principles laid down 
in this Declaration should not be accepted for publication. 
C. 
ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH 
MEDICAL CARE 
1. 
The physician may combine medical research with medical care, only to the extent 
that the research is justified by its potential prophylactic, diagnostic or therapeutic value.  
When medical research is combined with medical care, additional standards apply to protect 
the patients who are research subjects. 
2. 
The benefits, risks, burdens and effectiveness of a new method should be tested 
against those of the best current prophylactic, diagnostic, and therapeutic methods.  This 

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does not exclude the use of placebo, or no treatment, in studies where no proven 
prophylactic, diagnostic or therapeutic method exists. 
3. 
At the conclusion of the study, every patient entered into the study should be assured 
of access to the best proven prophylactic, diagnostic and therapeutic methods identified by 
the study. 
4. 
The physician should fully inform the patient which aspects of the care are related to 
the research.  The refusal of a patient to participate in a study must never interfere with the 
patient-physician relationship. 
5. 
In the treatment of a patient, where proven prophylactic, diagnostic and therapeutic 
methods do not exist or have been ineffective, the physician, with informed consent from the 
patient, must be free to use unproven or new prophylactic, diagnostic and therapeutic 
measures, if in the physician's judgment it offers hope of saving life, re-establishing health or 
alleviating suffering.  Where possible, these measures should be made the object of 
research, designed to evaluate their safety and efficacy.  In all cases, new information should 
be recorded and, where appropriate, published.  The other relevant guidelines of this 
Declaration should be followed. 
 
 

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References 
1. Babiera GV, Rao R, Feng L, et al. Effect of primary tumor extirpation in breast 
cancer patients who present with stage IV disease and an intact primary 
tumor. Ann Surg Oncol 2006;13(6):776-82. 
2. Blanchard DK, Bhatia P, Hilsenbeck SG, Elledge RM. Does surgical management 
of stage IV breast cancer effect outcome? SABCC 2006, San Antonio. 
3. Carmichael AR, Anderson ED, Chetty U, Dixon JM. Does local surgery have a role 
in the management of stage IV breast cancer? Eur J Surg Oncol 
2003;29(1):17-9. 
4. Khan SA, Stewart AK, Morrow M. Does aggressive local therapy improve survival 
in metastatic breast cancer? Surgery 2002;132(4):620-6; discussion 626-7. 
5. Rapiti E, Verkooijen HM, Vlastos G, et al. Complete excision of primary breast 
tumor improves survival of patients with metastatic breast cancer at diagnosis. 
J Clin Oncol 2006;24(18):2743-9. 
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