Assessment of Vascular Endothelial Growth Factor (VEGF), Soluble Her2 Protein (NRP, Neu-Related Protein), and Vascular Cellular Adhesion Molecule-1 (VCAM-1) in Serum Samples of Patients Participating in Trial IBCSG 22-00
Phase: NA
Conditions: Breast Cancer
Sponsor: ETOP IBCSG Partners Foundation

IBCSG 22-00 Serum Substudy Ver 1.0 June02; Amendment 1: Ver 2.0 26Nov02; Amendment 2: Ver 3.0 01Nov05 
Working protocol: Amendment 1 in blue, Amendment 2 in green 
 Coordinating Center Effingerstrasse 40 CH-3008 Bern Switzerland www.ibcsg.org 
 
1
 
 
 
INTERNATIONAL BREAST CANCER
STUDY GROUP 
Trial 22-00 
 
Maintenance Chemotherapy in Hormone 
Non-Responsive Breast Cancer 
 
SERUM SUBSTUDY 
AMENDMENT 2 
 
 
 
 
 
Assessment of Vascular Endothelial Growth Factor (VEGF), 
Soluble Her2 Protein (NRP, HER2-ECD) and Vascular Cellular 
Adhesion Molecule-1 (VCAM-1) in Serum Samples 
 
 
 
 
 
Division of Medical Oncology, European Institute of Oncology, Milan, Italy 
Division of Pathology, European Institute of Oncology, Milan, Italy 
 
 
Principal Investigators:   Prof. A. Goldhirsch   
 
 
Prof. G. Viale 
 
Participants: 
Dr. M. Colleoni 
 
 
Dr. L. Orlando 
 
 
Dr. M. Sandri 
 
Statistician: 
Ms. S. Gelber
 
 
 
 
Data management:  
Ms. S. Lippert 
 
Coordinator, Samples 
Collection Center: 
Dr. G. Peruzzotti 
 

IBCSG 22-00 Serum Substudy Ver 1.0 June02; Amendment 1: Ver 2.0 26Nov02; Amendment 2: Ver 3.0 01Nov05 
Working protocol: Amendment 1 in blue, Amendment 2 in green 
 Coordinating Center Effingerstrasse 40 CH-3008 Bern Switzerland www.ibcsg.org 
 
2
 
Protocol Signature Page – Amendment 2 
 
IBCSG Trial 22-00 Serum Substudy 
Assessment of Vascular Endothelial Growth Factor (VEGF), Soluble Her2 
Protein (NRP, HER2-ECD) and Vascular Cellular Adhesion Molecule-1 
(VCAM-1) in Serum Samples 
 
Approved by: 
CEO, International Breast Cancer Study Group 
Prof. M. Castiglione 
 
 
 
 
(Signature on file) 
01 November 2005 
___________________________________________________ ______________ 
 
 
 
Date 
 
 
Approved by: 
Group Statistician, International Breast Cancer Study Group 
Prof. R.D. Gelber 
 
 
(Signature on file) 
01 November 2005 
_______________________________ 
_____________ 
______________ 
 
 
 
Date 

IBCSG 22-00 Serum Substudy Ver 1.0 June02; Amendment 1: Ver 2.0 26Nov02; Amendment 2: Ver 3.0 01Nov05 
Working protocol: Amendment 1 in blue, Amendment 2 in green 
 Coordinating Center Effingerstrasse 40 CH-3008 Bern Switzerland www.ibcsg.org 
 
3
 
Protocol Signature Page 
 
IBCSG Trial 22-00 Serum Substudy 
Assessment of Vascular Endothelial Growth Factor (VEGF), Soluble Her2 
Protein (NRP, HER2-ECD) and Vascular Cellular Adhesion Molecule-1 
(VCAM-1) in Serum Samples 
 
Approved by: 
CEO, International Breast Cancer Study Group 
Prof. M. Castiglione 
 
 
 
 
(Signature on file) 
26 Nov 2002 
___________________________________________________ ______________ 
 
 
 
Date 
 
 
Approved by: 
Group Statistician, International Breast Cancer Study Group 
Prof. R.D. Gelber 
 
 
 
26 Nov 2002 
(Signature on file) 
_______________________________ 
_____________ 
______________ 
 
 
 
Date 
 

IBCSG 22-00 Serum Substudy Ver 1.0 June02; Amendment 1: Ver 2.0 26Nov02; Amendment 2: Ver 3.0 01Nov05 
Working protocol: Amendment 1 in blue, Amendment 2 in green 
 Coordinating Center Effingerstrasse 40 CH-3008 Bern Switzerland www.ibcsg.org 
 
4
 
Principal Investigator and Co-investigator Protocol Signature 
Page 
 
IBCSG Trial 22-00 Serum Substudy 
Assessment of Vascular Endothelial Growth Factor (VEGF), Soluble Her2 
Protein (NRP, HER2-ECD) and Vascular Cellular Adhesion Molecule-1 
(VCAM-1) in Serum Samples 
 
I have read this protocol and agree to conduct this trial in accordance with all stipulations of 
the protocol and in accordance with the Declaration of Helsinki. 
 
 
Name of Principal Investigator: 
 
Signature: 
______________________________________________________ 
______________ 
 
 
 
Date 
 
Name of Co-investigator: 
 
Signature: 
______________________________________________________ 
______________ 
 
 
 
Date 
 
 
Name of Co-investigator: 
 
Signature: 
______________________________________________________ 
______________ 
 
 
 
Date 
 
Name of Co-investigator: 
 
Signature: 
______________________________________________________ 
______________ 
 
 
 
Date 
 
Name of Co-investigator: 
 
Signature: 
______________________________________________________ 
______________ 
 
 
 
Date 

IBCSG 22-00 Serum Substudy Ver 1.0 June02; Amendment 1: Ver 2.0 26Nov02; Amendment 2: Ver 3.0 01Nov05 
Working protocol: Amendment 1 in blue, Amendment 2 in green 
 Coordinating Center Effingerstrasse 40 CH-3008 Bern Switzerland www.ibcsg.org 
 
5
 
1 
Introduction 
 
1.1 
VEGF   
 
Angiogenesis, the process leading to the formation of new blood vessels, plays a central role 
in tumor progression of solid neoplasia. The switch from the avascular to the vascular phase 
is generally accompanied by rapid primary tumor growth and local invasiveness (1,2). 
Furthermore, angiogenesis is also necessary both at the beginning and end of the 
development of distant metastasis and is implicated in the phenomenon of dormant 
micrometastases (3). 
 
Tumor cells may induce angiogenesis via release of numerous growth factors and by their 
attraction of inflammatory cells, which in turn release multiple angiogenic stimuli. The 
angiogenic response can be blocked by inhibitory modulation of individual steps of capillary 
growth following an angiogenic stimulus. (2). Antiangiogenic peptides may be altered in the 
serum or urine of cancer patients.  In a study of 144 breast cancer patients, angiogenic protein 
basic fibroblast growth factor was abnormally elevated in the urine in 29% of cases and in the 
serum in 10%. Another angiogenic protein, vascular endothelial factor (VEGF), was 
abnormally elevated in the serum in over 70% of these breast cancer patients (4).  Since 
platelets bind VEGF, platelet values will also be assayed.   
 
1.2 
HER2-ECD   
 
The c-erbB2 oncogene (HER2/neu) encodes a type I trans-membrane tyrosine kinase family 
of receptors.  Amplification and overexpression of this gene, leading to an abnormal 
activation of HER2 signalling pathways, has been linked to higher transforming activity, 
increased metastatic potential, angiogenesis and drug resistance in breast tumor experimental 
models (5). Moreover its over-expression is thought to be associated with a poorer prognosis 
in breast cancer and to correlate with different responsiveness to chemotherapy and hormonal 
treatment. Immunohistochemical detection of the oncogene HER/neu (protein p185) product 
is the standard method of evaluating the amplification and/or overexpression of the gene, 
present in 20-40% of breast cancers. A soluble form of the extracellular domain of HER/neu 
can be shed from the surface of tumor cells (6).  No data are available regarding the presence 
of serum HER2-ECD (NRP) levels in c-erbB2 negative tumors, but the extracellular domain 
of the c-erbB2 oncogene product (NRP) is detectable in sera of 30-60% of patients with c-
erbB2 positive tumors.  Many reports have correlated the elevated serum levels of the c-
erbB2 with gene amplification and c-erbB2 overexpression in tumor.  These data support the 
hypothesis that the level of NRP protein can reflect the presence of c-erbB2 positive cells and 
that modification of the factor can predict a decrease of c-erbB2 positive cells during standard 
adjuvant chemotherapy.  Moreover, change in the detectable NRP during the maintenance 
phase can suggest a possible modification in the biology and/or behaviour of hypothetic 
micrometastasis.  
 
1.3 
VCAM-1   
 
The activation of endothelial adhesion molecules facilitates the local entry of inflammatory 
cells, which in turn promotes tissue neovascularization during tumor growth and wound 
repair.  Soluble forms of several adhesion molecules are known to be shed from the cell 
surface. In tumors, endothelial VCAM-1 play a major role in the adhesion of leukocytes to the 

IBCSG 22-00 Serum Substudy Ver 1.0 June02; Amendment 1: Ver 2.0 26Nov02; Amendment 2: Ver 3.0 01Nov05 
Working protocol: Amendment 1 in blue, Amendment 2 in green 
 Coordinating Center Effingerstrasse 40 CH-3008 Bern Switzerland www.ibcsg.org 
 
6
 
endothelium, suggesting a relationship between cellular adhesion and angiogenesis. Soluble 
VCAM-1 has been implicated in the mediation of angiogenesis and some studies support the 
hypothesis that VCAM-1 provides surrogate markers for endothelial activation and 
angiogenesis occurring during cancers. Recently, VCAM-1 serum levels have been associated 
with microvessel density and response to endocrine therapy (7) 
 
2 
Objectives 
 
2.1 
To evaluate differences from baseline (after completion of induction chemotherapy 
but before commencement of CM Maintenance for patients randomized to CM Maintenance) 
to 18 months after the start of induction chemotherapy in serum VEGF, VCAM-1 and NRP 
protein values between patients in the Observation Group and those in the low dose 
Cyclophosphamide Methotrexate (CM) Maintenance Group. 
  
2.2 
Secondary objectives 
 
2.2.1 To compare the differences from baseline to 12 and 36 months after the start of 
induction chemotherapy of serum VEGF, VCAM-1 and NRP values in the two randomized 
groups. 
 
2.2.2 To compare VEGF, VCAM-1 and NRP values before and after progression in the two 
randomized groups. 
 
3 
Patient selection 
 
3.1 
Inclusion criteria 
3.1.1. Patient must be randomized to the core protocol. Written informed consent for the 
serum substudy must be signed and dated by the patient and investigator. 
3.1.2 Patient must not have begun CM maintenance (if randomized to CM maintenance). 
 
4 
Clinical laboratory evaluation 
 
4.1 
Design    
 
Blood samples will be collected at: 
1. 
Baseline, (after the completion of induction chemotherapy and, if randomized to CM 
maintenance, before start of CM maintenance.) 
2.  
Months 12, 18 and 36 after start of induction chemotherapy
3.  
At time of confirmatory evidence of progression  
 
4.2  
Sample shipping  
 
Serum and plasma samples will be stored at -80 °C and sent with dry ice. The delivery to the 
IEO laboratory must be organized when three cryogenic boxes are filled and at a minimum of 
once a year.  To plan the delivery, Dr. L. Zorzino should be informed in advance by email 
(laura.zorzino@ieo.it) or by fax (+390257489417). The samples may be shipped Monday 
through Thursday to: Laboratory Medicine Unit 

IBCSG 22-00 Serum Substudy Ver 1.0 June02; Amendment 1: Ver 2.0 26Nov02; Amendment 2: Ver 3.0 01Nov05 
Working protocol: Amendment 1 in blue, Amendment 2 in green 
 Coordinating Center Effingerstrasse 40 CH-3008 Bern Switzerland www.ibcsg.org 
 
7
 
European Institute of Oncology 
Via Ripamonti 435, 20141 – Milan – Italy 
 
 
 
 
4.3  
Sample collection and evaluation  
 
4.3.1 Sample Collection.  
Fifteen milliliters of native blood will be collected and divided into 3 tubes (five milliliters 
per tube); two plain tubes and one containing citrate solution, all of them labeled with 
protocol number (22-00), IBCSG patient identification number, patient’s initials and date of 
collection. A Transporting Form 2002-TP (Section 12) must be filled out and submitted with 
each set of samples.  
 
The tubes must be treated as follows: 
1. The two PLAIN TUBES should be allowed to clot for two hours at room temperature, 
centrifuged at 3000 rpm for 10 min, and then separated.  
2. The CITRATATED TUBE should be immediately centrifuged at 3000 rpm for 10 min and 
then separated. 
3. The serum and the plasma must be separated in 500 µl aliquots (at least 6 for serum and 4 
for plasma), and put into cryogenic tubes on which the following information must be 
reported:  
a.   Protocol number: 22-00 
b. IBCSG patient’s identification number (randomization number) and the patient’s 
initials. 
c. Type of sample: S= serum or  P= citrated plasma 
d. Date of collection 
The cryogenic vials should be put into the appropriate cryogenic box, and a precise box map 
must be completed (Form 2002-BM, Section 12). Each box must be identified by a 
progressive letter (the first box will be box “A”, the second box, box “B”, and so on), and the 
same letter must be reported on the Box Map form, (Form 2002-BM, Section 12). 
 
The cryogenic box must be stored in a – 80 °C freeze. 
4.3.2 Sample evaluation 
1. VEGF will be assayed with the use of commercial microplate ELISA kit. 
2. VCAM will be assayed with the use of commercial microplate ELISA kit. 
3. HER2 ECD. A magnetic particle separation immunoassay designed for the automated 
analyzer “Immuno 1” and provided by Bayer Diagnostics will be utilized.  
 
4.3.3 The platelet count from the same day as the submitted blood draws (described above) 
should be recorded on the Transporting Form.  
 
5 
Patient registration and data management 
 
Patients must register for the Serum Substudy at the time of randomization to the core 
protocol, IBCSG 22-00.  The Confirmation of Registration Form for eligible patients on the 
core protocol (Form A) must indicate that the patient will be enrolled into the Serum 
Substudy.  In addition, the serum substudy informed consent form must be signed and dated 
by the patient and the investigator. One copy must be given to the patient and the original 
retained in the investigator’s trial records and available for data audits. 
 

IBCSG 22-00 Serum Substudy Ver 1.0 June02; Amendment 1: Ver 2.0 26Nov02; Amendment 2: Ver 3.0 01Nov05 
Working protocol: Amendment 1 in blue, Amendment 2 in green 
 Coordinating Center Effingerstrasse 40 CH-3008 Bern Switzerland www.ibcsg.org 
 
8
 
The Transporting Form must be submitted along with each submission of drawn blood 
described in Section 4.3. 
 
6 
Treatment details 
 
 
Detailed information on the treatment regimens can be found in Section 5 of the core 
protocol. 
 
7  
Study parameters 
 
7.1 
Table of study parameters 
 
7.1.1 Observation Group and CM Maintenance Group 
 
 
 
Baseline* 
 
Months 12, 18,  
36** 
at 
Progression*** 
VEGF 
X 
 
X 
X 
VCAM-1 
X 
 
X 
X 
NRP  
X 
 
X 
X 
Platelet count  
X 
 
X 
X 
 
* After completion of the induction chemotherapy and, if randomized to CMM, before the start of CMM. 
** Day 0 is defined as the day induction chemotherapy begins.  
***Blood to be drawn at time of confirmatory evidence of progression 
 
8 
Statistical methods 
 
8.1 
Endpoints   
 
The primary objective of this biological study is to evaluate differences from baseline to 18 
months in serum VEGF, VCAM-1 and NRP values between the Observation and CM 
Maintenance groups. 
 
The secondary objectives are: 
 
• To compare the differences from baseline to 12 and 36 months in serum VEGF, VCAM-1 
and NRP values in the two randomized groups. 
• To compare VEGF, VCAM-1 and NRP values before and after progression in the two 
randomized groups. 
 
8.2 
Data analyses   
 
For each analysis time point (12, 18, 36 months and at progression) the following analyses 
will be performed: 
1. 
The 95% confidence interval for the percent change from baseline will be presented 
for the two randomized groups for each serum level.  

IBCSG 22-00 Serum Substudy Ver 1.0 June02; Amendment 1: Ver 2.0 26Nov02; Amendment 2: Ver 3.0 01Nov05 
Working protocol: Amendment 1 in blue, Amendment 2 in green 
 Coordinating Center Effingerstrasse 40 CH-3008 Bern Switzerland www.ibcsg.org 
 
9
 
2. 
The Wilcoxon two-sample rank sum test will be used to compare the percentage 
change from baseline in the serum levels between the two groups.  
 
8.3 
Sample size considerations   
 
Previous data in the metastatic setting with similar cytotoxic agents (cyclophosphamide and 
methotrexate) yielded a mean decrease of 20% in VEGF levels with standard deviation of 
38% (8).  Based on a two-sided test with a type I error of 5% and a power of 80% this study 
is designed to detect a 20% difference from baseline to 18 months post randomization in the 
mean percentage decrease of VEGF, VCAM-1, and NRP and for the CM Maintenance Group 
compared with the Observation Group. We assume that the patients not receiving 
maintenance CM will have no change in their VEGF, VCAM-1, and NRP serum levels.  59 
patients per group are required to detect this 20% difference, but to account for a 30% non 
accessible rate at 18 months due to either disease recurrence or patient drop out, 85 patients 
per randomized arm will be enrolled into the substudy, for a total accrual of 170 patients. 
 
8.4 
Data and Safety Monitoring Committee (DSMC)   
 
The core study will be presented for review by the IBCSG Data and Safety Monitoring 
Committee (DSMC) at each of their semi-annual meetings.  The DSMC may also request to 
review data from this serum evaluation substudy.  
 
9 
Ethics committee review and patient informed consent 
 
9.1 
Ethical Review Board/Ethics   
 
All protocols and the patient informed consent forms must have the approval of a properly 
constituted committee or committees responsible for approving clinical trials.  The ERB/IRB 
written, signed approval letter/form must contain approval of the designated investigator, the 
protocol substudy (identifying protocol title and version number), and of the patient informed 
consent. Documentation of ethical committee approval must be sent to the IBCSG 
Coordinating Center prior to each participating center’s first patient’s serum evaluation. 
 
9.2 
Informed consent    
 
A separate informed consent form for each patient must be obtained prior to initiating any 
serum investigational procedures (see Appendix Ia, revised). The informed consent form is 
signed in duplicate by the Investigator and the Patient.  The Investigator must retain an 
original signed informed consent form for Trial records.  The Patient also retains one of the 
signed informed consent forms for her personal records. 
 
The "Declaration of Helsinki" recommends that consent be obtained from each potential 
patient in biomedical research trials after the aims, methods, anticipated benefits, and 
potential hazards of the trial, and discomfort it may entail, are explained to the individual by 
the physician.  The potential patient should also be informed of her right to not participate or 
to withdraw from the substudy at any time.  
 

IBCSG 22-00 Serum Substudy Ver 1.0 June02; Amendment 1: Ver 2.0 26Nov02; Amendment 2: Ver 3.0 01Nov05 
Working protocol: Amendment 1 in blue, Amendment 2 in green 
 Coordinating Center Effingerstrasse 40 CH-3008 Bern Switzerland www.ibcsg.org 
 
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If the patient is in a dependent relationship to the physician or gives consent under duress, the 
informed consent should be obtained by an independent physician.  If the patient is legally 
incompetent (i.e., mentally incompetent), informed consent must be obtained from the legal 
guardian, or legal representative in accordance with the law of the country in which the trial 
is to take place.  By signing this protocol, the investigator agrees to conduct the trial in 
accordance with the "Declaration of Helsinki."  
 
10 
Administrative considerations 
 
10.1 Insurance   
 
IBCSG as the Sponsor of the Study contracts adequate Clinical Trial Insurance, in accordance 
with all relevant legal requirements, mandated by local regulations where the Study takes 
place. This insurance provides compensation to participants of the study.  
 
Patients who suffer injuries due to the trial should report them immediately to their doctor.  
 
The local group must report all alleged claims immediately to IBCSG. 
 
11 
References 
 
1. Folkman J. The influence of angiogenesis research on management of patients with breast 
cancer. Breast Cancer Res Treat 36(2): 109-18, 1995 
2. Kern FG, Lippman ME. The role of angiogenic growth factors in breast cancer 
progression. Cancer Metastasis Rev 15: 213-9, 1996  
3. Gasparini G. Clinical significance of the determination of angiogenesis in human breast 
cancer: update of the biological background and overview of the Vicenza studies. Eur J 
Cancer 32A: 2485-93, 1996 
4. Salven P, Maenpaa H. Serum vascular endothelial growth factor is often elevated in 
disseminated cancer.  Clin Cancer Res 3: 647-651, 1997 
5. Hynes N. The biology of erbB2/neu/HER2 and its role in cancer. Biochim Biophis Acta 
1198:165-184, 1994  
6. Revillion F. Plasma c-erbB2 concentrations in relation to chemotherapy in breast cancer 
patients  Eur J Cancer 32A:231-234, 1996 
7. Byrne GJ, Ghellal A, Iddon J, et al. Serum soluble vascular cell adhesion molecule-1: role 
as a surrogate marker of angiogenesis. J Natl Cancer Inst 92:1329-36, 2000 
8. Colleoni M, Rocca A, Sandri MT, et al.  Low-dose oral methotrexate and 
cyclophosphamide in metastatic breast cancer: antitumor activity and correlation with 
vascular endothelial growth factor levels.   Ann of Oncol 13: 73-80, 2002 

IBCSG 22-00 Serum Substudy Ver 1.0 June02; Amendment 1: Ver 2.0 26Nov02; Amendment 2: Ver 3.0 01Nov05 
Working protocol: Amendment 1 in blue, Amendment 2 in green 
 Coordinating Center Effingerstrasse 40 CH-3008 Bern Switzerland www.ibcsg.org 
 
11
 
12 
Study Forms 
 
IBCSG TRIAL 22-00 SERUM SUBSTUDY 
Transporting FORM (Form 2002-TP) 
 
 
Patient’s Date of Birth  
 
 
 
 
D 
M 
Y 
 
Patient’s Initials (f, m, fl, sl)   
 
Participating Center Name ____________ Affiliate _________________ 
 
Center Code     
 
 
IBCSG Patient Randomization Number 
 
 
Three Tubes of Blood must be submitted:  
Fifteen milliliters of native blood will be collected and divided into 3 tubes (five milliliters 
per tube); two plain tubes and one containing citrate solution, all of them labeled with 
protocol number (22-00), IBCSG patient identification number, patient’s initials and date of 
collection.  
 
 
Express Mailing: 
 
Serum and plasma samples must be stored at -80 °C and sent on dry ice with this form by 
express mail to Laboratory Medicine Unit, European Institute of Oncology, Via Ripamonti 
435, Milano, Italy. 
 
DATE OF BLOOD DRAW 
 
 
 
 
D 
M 
Y 
 
 
PLATELET COUNT (x109/l) 
2
2

IBCSG 22-00 Serum Substudy Ver 1.0 June02; Amendment 1: Ver 2.0 26Nov02; Amendment 2: Ver 3.0 01Nov05 
Working protocol: Amendment 1 in blue, Amendment 2 in green 
 Coordinating Center Effingerstrasse 40 CH-3008 Bern Switzerland www.ibcsg.org 
 
12
 
 
 
 
IBCSG TRIAL 22-00 SERUM SUBSTUDY 
Box Map Form - Form 2002-BM      
 
Participating Center:  
 
 
 
 
  Affiliate:  
 
 
 
  
 
Center Code                                                                           Box:   
  (page 1) 
 
Note: All 2002-TP forms must be included with this shipment 
Position 
in box 
Date of 
Blood 
Draw 
Patient ID 
Patient 
Initials 
Patient Date 
of Birth 
Sample 
Type     
(S or P)* 
Notes 
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* S = serum, P = citrated plasma 

IBCSG 22-00 Serum Substudy Ver 1.0 June02; Amendment 1: Ver 2.0 26Nov02; Amendment 2: Ver 3.0 01Nov05 
Working protocol: Amendment 1 in blue, Amendment 2 in green 
 Coordinating Center Effingerstrasse 40 CH-3008 Bern Switzerland www.ibcsg.org 
 
13
 
 
 
 
IBCSG TRIAL 22-00 SERUM SUBSTUDY 
Box Map Form - Form 2002-BM      
 
Participating Center:  
 
 
 
 
  Affiliate:  
 
 
 
  
 
Center Code                                                                                                Box:  
 
  (page 2) 
 
Note: All 2002-TP forms must be included with this shipment 
Position 
in box 
Date 
Patient ID 
Patient 
Initials 
Patient Date 
of Birth 
Sample 
Type     
(S or P)*
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* S = serum, P = citrated plasma