Conditions: Estrogen Receptor Positive Breast Cancer Progesterone Receptor Positive Tumor Recurrent Breast Carcinoma Stage IA Breast Cancer Stage IB Breast Cancer Stage IIA Breast Cancer Stage IIB Breast Cancer Stage IIIA Breast Cancer
Keywords: tamoxifen ovarian function suppression + tamoxifen ovarian function suppression + exemestane
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 3066
Healthy volunteers: no

Brief summary:
RATIONALE: Estrogen can stimulate the growth of breast tumor cells. Ovarian function suppression combined with hormone therapy using tamoxifen or exemestane may fight breast cancer by reducing the production of estrogen. It is not yet known whether suppression of ovarian function plus either tamoxifen or exemestane is more effective than tamoxifen alone in preventing the recurrence of hormone-responsive breast cancer.

PURPOSE: This randomized phase III trial studies ovarian suppression with either tamoxifen or exemestane to see how well they work compared to tamoxifen alone in treating premenopausal women who have undergone surgery for hormone-responsive breast cancer.

Detailed description:
OBJECTIVES:

* Compare the disease-free survival, breast cancer-free interval, distant recurrence-free interval and overall survival of premenopausal women with endocrine-responsive breast cancer when treated with tamoxifen + ovarian function suppression (by triptorelin, oophorectomy, or ovarian irradiation) or exemestane + ovarian function suppression vs. tamoxifen alone. The primary comparison is ovarian function suppression with either tamoxifen or exemestane vs. tamoxifen alone.
* Compare the quality of life, including late side effects of early menopause, of patients treated with these regimens.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to participating center, prior adjuvant/neoadjuvant chemotherapy (yes vs no), and number of positive axillary and/or internal mammary lymph nodes (0 vs 1 or more) and intended initial method of ovarian function suppression (triptorelin vs oophorectomy vs ovarian irradiation). Treatment duration is 5 years. Patients are followed every 3 months for 1 year, every 6 months for 5 years, and then annually thereafter. Quality of life is assessed at baseline, every 6 months for 2 years, and then annually for 4 years.

Arms:
arm 1: Tamoxifen 20mg orally daily for 5 years arm 2: Tamoxifen 20mg orally daily for 5 years plus ovarian function suppression (OFS; triptorelin (GnRH analogue) 3.75 mg by im injection q28 days for 5 years; or surgical oophorectomy; or ovarian irradiation) arm 3: Exemestane 25mg orally daily for 5 years plus ovarian function suppression (OFS; triptorelin (GnRH analogue) 3.75 mg by im injection q28 days for 5 years; or surgical oophorectomy; or ovarian irradiation)

Interventions: intervention 1: Exemestane intervention 2: Laboratory Biomarker Analysis intervention 3: Oophorectomy intervention 4: Quality-of-Life Assessment intervention 5: Radiation Therapy intervention 6: Tamoxifen intervention 7: Triptorelin
Intervention descriptions: intervention 1: Exemestane 25mg orally daily for 5 years plus ovarian function suppression intervention 2: Correlative studies intervention 3: Undergo bilateral surgical oophorectomy intervention 4: Ancillary studies intervention 5: Undergo ovarian irradiation intervention 6: Tamoxifen 20mg orally daily for 5 years intervention 7: 3.75 mg by im injection q28 days for 5 years

Protocol document:
Prot_001.pdf: 
IBCSG 24-02 (SOFT: Suppression of Ovarian Function Trial)  
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V3.0 Amendment 2 14July11 Amendment 1: blue text; Amendment 2: green text   
 Coordinating Center Effingerstrasse 40 CH-3008 Bern Switzerland www.ibcsg.org  
  
INTERNATIONAL BREAST CANCER  
 STUDY GROUP  
  
IBCSG 24-02  
BIG 2-02  
  
Suppression of Ovarian Function Trial  
(SOFT)  
  
Amendment 2  
  
A Phase III Trial Evaluating the Role of Ovarian Function  
Suppression and the Role of Exemestane as Adjuvant Therapies for 
Premenopausal Women with Endocrine Responsive Breast Cancer  
  
tamoxifen versus  
ovarian function suppression + tamoxifen versus ovarian 
function suppression + exemestane  
  
Coordinating Group:   International Breast Cancer Study Group (IBCSG)  
  
EudraCT number: 2004-000166-13  
  
This protocol document includes information needed to conduct the study for 
all participating centers, with logistical details specific for IBCSG centers.  
  
  
Cover pages added to the front of this protocol and Appendix VII contain 
logistical details that are needed for non-IBCSG participating groups and 
centers, including group specific contact information, randomization 
procedures, data submission procedures, serious adverse event reporting 
procedures, drug supply information and country-specific regulations and 
procedures.  
  
IBCSG Coordinating Center, Effingerstrasse 40, CH-3008 Bern 
Phone: +41 31 389 93 91  
Fax: +41 31 389 93 92  
  
  
  
  
  
  
  
  
  


IBCSG 24-02 (SOFT: Suppression of Ovarian Function Trial)  
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Study Chairs  
Study Co-Chair  
Dr. Prue Francis  
Tel:  +61 3 96561701  
(BIG)  
Peter MacCallum Cancer Institute  
Fax:  +61 3 96561408  
 
St. Andrews Place  
E-mail: prue.francis@petermac.org   
 
East Melbourne 3002 Australia  
  
 
  
  
Study Co-Chair  
Dr. Gini Fleming  
Tel:  +001 773 702 6712  
(North American Intergroup)  
University of Chicago Medical Center  
Fax:  +001 773 702 0963  
 
Section of Hematology/Oncology  
E-mail: gfleming@medicine.bsd.uchicago.edu
 
5841 South Maryland Ave, MC 2115  
  
  
 
Chicago, IL 60637-1470  USA  IBCSG 
Centers and Contacts  
Coordinating Center  
Safety Office  
Drug Supply Office  
Quality of Life Office  
Medical Affairs  
Quality Assurance & Audit  
International Trial  
Activities  
Translational Research  
Coordinator   
 
Anita Hiltbrunner, IBCSG Director   
Dr. Barbara Ruepp  
Sonja Schlaepfer, Sabrina Ribeli-Hofmann  
Dr. Karin Ribi  
Dr. Manuela Rabaglio  
Dr. Petra Sicher  
Dr. Rudolf Maibach  
 
Rosita Kammler  
IBCSG Coordinating Center  
Effingerstrasse 40  
Email: anita.hiltbrunner@ibcsg.org  
Email: safetyoffice@ibcsg.org    
Email: drugsupply@ibcsg.org  
Email: karin.ribi@ibcsg.org  
Email: manuela.rabaglio@ibcsg.org  
Email: petra.sicher@ibcsg.org  
Email: rudolf.maibach@ibcsg.org  
Email: rosita.kammler@ibcsg.org  
 
Tel: +41 31 389 9391  
 
CH-3008 Bern, Switzerland  
Fax: +41 31 389 9392  
 
 
 
Data Management Center  
Lynette Blacher (Director of Data Management)  
Karolyn Scott (Data Management Section Head)  
Holly Shaw (Trial Coordinator)  
Renaye Hecker (Trial Coordinator)  
Adrianna Cesario (Data Manager)  
Monica Greco (Data Manager)  
Adriana Mora de Karausch (Data Manager)  
Jocelyn Swick (Data Manager)  
Email: ibcsg24-26_STP@fstrf.org  
Tel: +1 716 898-7500   
Fax: +1 716 836 6097  
 
FSTRF, 4033 Maple Rd.  
 
 
Amherst, NY  14226  USA  
 
 
 
 
Statistical Center  
Meredith M. Regan, ScD  
Prof. Richard D. Gelber  
Lynette Zickl, MS  
Karen Price  
Email: mregan@jimmy.harvard.edu   
Email: gelber@jimmy.harvard.edu   
Email: zickl@jimmy.harvard.edu  
Email: price@jimmy.harvard.edu    
 
Dept. of Biostatistics and Computational Biology  
Tel: +1 617 632 2458  


IBCSG 24-02 (SOFT: Suppression of Ovarian Function Trial)  
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Dana-Farber Cancer Institute  
Fax: +1 617 632 2444  
 
450 Brookline Ave.  
 
 
Boston, MA  02215 USA  
 
 
 
 
  
Scientific Committee Chairs  Prof. Aron Goldhirsch  
Tel: +41 91 985 12 11  
 
Clinica Sant‟ Anna 
via San Anna 1  
CH - 6924 Sorengo  
and  
Fax: +41 91 985 13 61  
Email: aron.goldhirsch@ibcsg.org 
 
European Institute of Oncology  
Via Ripamonti 435  
I-20141 Milan, Ital  
Fax: +39 02 57489212  
 
 
Prof. Alan Coates  
 
Tel: +61 2 9380 9022  
 
The Cancer Council Australia  
Fax: +61 2 9380 8233  
 
PO Box 4708  
Email: alancoates@cancer.org.au   
  
Sydney NSW 2001, Australia  
 
Central Pathology Office  
Prof. Giuseppe Viale  
University of Milan & European Institute of  
Oncology  
Via Ripamonti 435  
20141 Milan, Italy  
 
Tel: +39 02 5748 9419  
Fax: +39 02 5748 9417  
E-mail: giuseppe.viale@ieo.it   
  
 
Supported by Pfizer, Inc.  
 
  
  
GROUP SPECIFIC CONTACT INFORMATION  
  
Please refer to Section 1 of Appendix VII for group-specific contact information to direct 
your inquiries about participation/eligibility/treatment for this trial.  


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IBCSG 24-02 / BIG 2 
  
 Coordinating Center Effingerstrasse 40 CH-3008 Bern Switzerland www.ibcsg.org  
Protocol Amendment 2 Signature Page  
-02  
Suppression of Ovarian Function Trial (SOFT)  
  
  
  
Approved by:  
Director, Statistical and Data Management Center, International Breast Cancer Study Group 
Prof. R.D. Gelber  
  
Signature on file  
  
  
  
  
  
  
14 July 2011  
_________________________________________________  
______________  
  
  
                           
  
  
  
  
  
  
Date  
 


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IBCSG 24-02 / BIG 2 
  
 Coordinating Center Effingerstrasse 40 CH-3008 Bern Switzerland www.ibcsg.org  
Protocol Amendment 1 Signature Page  
-02  
Suppression of Ovarian Function Trial (SOFT).  
  
  
  
Approved by:  
CEO, International Breast Cancer Study Group  
Prof. Dr. med. M. Castiglione  
  
Signature on file  
  
  
  
  
  
  
07 October 2005  
__________________________________________________  
______________  
  
 
  
  
  
  
  
  
  
  
 
 
 
Approved by:  
Group Statistician, International Breast Cancer Study Group Prof. 
R.D. Gelber  
 
 
Date  
Signature on file  
  
  
  
  
  
  
07 October 2005  
__________________________________________________  
______________  
  
 
                           
  
  
  
  
  
 
Date  
Protocol Signature Page  


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IBCSG 24-02 / BIG 2 
  
 Coordinating Center Effingerstrasse 40 CH-3008 Bern Switzerland www.ibcsg.org  
-02  
Suppression of Ovarian Function Trial (SOFT).  
  
  
  
Approved by:  
CEO, International Breast Cancer Study Group  
Prof. Dr. med. M. Castiglione  
  
  
 
  
(Signature on file)  
17Apr03  
__________________________________________________  
______________  
 
  
 
 
 
 
 
Approved by:  
Group Statistician, International Breast Cancer Study Group Prof. 
R.D. Gelber  
 
 
 
Date  


IBCSG 24-02 (SOFT: Suppression of Ovarian Function Trial)  
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IBCSG 24-02 / BIG 2 
  
 Coordinating Center Effingerstrasse 40 CH-3008 Bern Switzerland www.ibcsg.org  
(Signature on file)  
17Apr03  
__________________________________________________  
______________  
 
  
 
Date  
  


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Principal Investigator Protocol Signature Page Amendment 
2  
  
IBCSG 24-02 / BIG 2-02  
  
Suppression of Ovarian Function Trial (SOFT).  
  
I have read the protocol and agree that it contains all necessary details for conducting this study. I 
will conduct the study as outlined in the following protocol and in compliance with GCP. I will 
provide copies of the protocol and all drug information relating to pre-clinical and prior clinical 
experience furnished to me by IBCSG to all physicians responsible to me who participate in 
this study. I will discuss this material with them to assure that they are fully informed 
regarding the drug and the conduct of the study. I agree to keep records on all patient information 
(Case Report Forms and patient's informed consent statement), drug shipment and return forms, 
and all other information collected during the study for a minimum period of 15 years.  
  
Name of Principal Investigator:  
 
 
  
  
  
  
  
  
  
  
  
  
 
 
 
  
  
  
Signature  
Date  
 


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Protocol Summary and Schema  
  
Suppression of Ovarian Function Trial (SOFT)  
  
A Phase III Trial Evaluating the Role of Ovarian Function Suppression and the Role of  
Exemestane as Adjuvant Therapies for Premenopausal Women with Endocrine Responsive  
Breast Cancer  
  
Patient Population: Premenopausal women (estradiol (E2) levels in the premenopausal range) 
with histologically proven, resected breast cancer with ER and/or PgR positive tumors who have 
received either no chemotherapy or remain premenopausal following completion of adjuvant 
and/or neoadjuvant chemotherapy.   
  
Entry:  Patients who do not receive chemotherapy should be randomized within 12 weeks after 
surgery; such patients must have estradiol (E2) levels in the premenopausal range following 
surgery.  Patients who have received adjuvant and/or neoadjuvant chemotherapy should be 
randomized within 8 months of the final dose of chemotherapy as soon as premenopausal status is 
confirmed; such patients must have estradiol (E2) levels in the premenopausal range between 2 
weeks and 8 months after the final dose of chemotherapy.    
  
Stratification Factors:  
-Institution  
-Prior adjuvant/neoadjuvant chemotherapy (no; yes)   
-Number of positive axillary and/or internal mammary lymph nodes (0 – including pN0(sn), 
pN0(i+)(sn) and pNx; 1 or more – including  pN1mi)  
-Intended initial method of ovarian function suppression (triptorelin for 5 years; surgical 
oophorectomy; ovarian irradiation)  
  
Sample Size: 3000 patients (600 per year for 5 years with 1.9 years of additional follow-up)  
  
Schema:  
*  
 
A 
 
Tamoxifen for 5 
years  
 Institution  
 Prior chemotherapy (no; 
yes)  
nodes (0; 1 ** 
 Number of positive 
 or more)  
 B  
OFS 
plus   
Tamoxifen for 5 years   
 Intended initial method 
of ovarian function suppression, 
if  
R  
A  
N  
D  
O  
M  
I  
Z  
E  
  
  
  
  
  
  
  
  
  
  
  
Primary   
Surgery    
Stratify:   
No chemotherapy  
stratum (randomize  
after surgery)*   
Chemotherapy  
s tratum (randomize  
within  eight   months  
after completing  
chemotherapy)*   


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assigned by randomization ** 
 
(triptorelin for 5 years; surgical C  
OFS plus   
oophorectomy; ovarian Exemestane for 5 years   
irradiation)  
*  Patients may have received tamoxifen or anti-aromatase agent prior to randomization  
**  OFS = ovarian function suppression (triptorelin for 5 years OR surgical oophorectomy OR ovarian irradiation)  
Treatment Schedules  
Radiotherapy:  
 
Radiation therapy to the conserved breast is required.  Radiation therapy to the 
chest wall following mastectomy is optional (if given, it may also include nodal 
fields).  Radiation therapy may be given either after all chemotherapy or 
integrated into chemotherapy (if regimen is considered safe by the investigator).  
Radiation therapy may be concurrent with trial hormonal therapy.   
Chemotherapy: Patients in the chemotherapy stratum must have completed adjuvant (and/or  
neoadjuvant) chemotherapy prior to randomization.  A planned duration of  2 
months if an anthracycline was included (e.g. 4 cycles of EC or AC) or  4 
months if no anthracycline was given (e.g. 6 cycles of CMF) is recommended.  
If an anthracycline was used, an epirubicin-containing regimen is 
recommended.  The final dose of chemotherapy must be less than 8 months 
prior to randomization.  
  
Adjuvant Endocrine Therapy:  
  
  
Tamoxifen:  
 
Tamoxifen 20 mg orally daily until 5 years from date of randomization, unless 
relapse or intolerance should occur earlier.  
Exemestane:  
 
Exemestane (Aromasin®) 25 mg orally daily, preferably after food, until 5 years 
from date of randomization, unless relapse or intolerance should occur earlier.  
Exemestane should begin after initiating ovarian function suppression.  
Triptorelin:  
 
Surgical  
Triptorelin (GnRH analogue) 3.75 mg by intramuscular injection every 28 days 
for 5 years from randomization, unless relapse or intolerance should occur 
earlier or surgical oophorectomy or ovarian irradiation is subsequently 
performed.  Triptorelin (Decapeptyl Depot® intramuscular or Trelstar Depot® 
intramuscular) will be supplied by the study for use as GnRH analogue.    
oophorectomy:  
 
Ovarian  
Bilateral surgical oophorectomy via laparotomy or laparoscopy.  
irradiation:  
Bilateral ovarian irradiation.  Biochemical verification of ovarian function 
cessation is required after two months (see Section 5.1.3).  


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TABLE OF CONTENTS   
  
Section  
Page  
  
  
1  
Introduction ...................................................................  12   
2 
 Trial objectives ..............................................................  16   
3  
Patient 
selection .............................................................  16  
  
  
  
  
  
  
3.1   
Criteria for patient eligibility ...........................................  16   
 
 
3.2   
Criteria for patient ineligibility ........................................  18  
  
  4  
Randomization and stratification ................................  20  
  
  
4.1   
Randomization timing .......................................................  20   
 
 
4.2  
Registration procedures ....................................................  20   
  
4.3 
 
Randomization help desk ..................................................  21   
  
4.4 
 
Randomized groups ...........................................................  22   
4.5  
Stratification 
.................................................................................  22  
  
  5  
Treatment details ..........................................................  23  
  
  
5.1   
Trial treatments .................................................................  23   
 
 
5.2   
Side effects of study drugs ................................................  25   
  
5.3  
 
Concomitant treatments ...................................................  26   
  
5.4  
Study 
drug supply..............................................................  27  
  
  6  
End points and definitions of treatment failure .........  28  
  
  
6.1   
Trial end points ..................................................................  28   
 
 
6.2   
Diagnosis of treatment failure ..........................................  28  
  
  7  
Study parameters ..........................................................  32  
  
  
7.1  
Table of study parameters................................................  32   
 
 
7.2  
Adverse event reporting ...................................................  34   
  
7.3 
 
Serious Adverse Event (SAE) reporting .........................  35   
  
7.4 
 
Exposure in utero reporting .............................................  37  
  
  8  
Data submission ............................................................  37  
  
  
8.1  
Case report forms schedule ..............................................  38 8.2  Data 
management ..............................................................  
40 
8.3 
Investigators' 
file  
.............................................................. 
40 
8.4 
Authorization 
log  


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.............................................................. 
41 
8.5 
Patient 
identification 
log  
.................................................. 41  
  
  9  
Statistical considerations ..............................................  41  
  
  
9.1  
Study design, objectives, and stratification .....................  42   
 
 
9.2  
Data analyses ......................................................................  42   
  
9.3 
 
Sample size considerations................................................  42   
  
9.4 
 
Interim monitoring ............................................................  45   
  
9.5  
Data 
and safety monitoring committee............................  
45  
  
 10  
Quality of life (see Appendix V)  .................................  45  11  Additional 
protocol-specific parameters ....................  46  
  
  
  
11.1  Hormone receptors ...........................................................  46   
 
 
11.2  Pathology and pathology material banking ....................  46 11.3  
Family 
history....................................................................  48  
  
 12  
Regulatory approval procedures and  
  
  
patient informed consent ..............................................   48  
12.1 Ethical Review Board/Ethics Committee ........................  
48 
12.2 
Regulatory approval procedures .....................................  48 
12.3 
Requirements for Center Activation ...............................  48 12.4 Protection of 
human subjects ...........................................  
48 12.5 Informed consent 
procedures……………………………  
49 
12.6 
Quality 
assurance………………………………………… 50  
  
 13  
Administrative considerations .....................................  50  
  
  
13.1 Insurance ............................................................................  
50  
  
 14  
References ......................................................................  51  
  
Appendices   
  
I.  
Requirements for Informed Consent  II.  NCI Common Terminology Criteria for 
Adverse Events (CTCAE), Version 3.0  
[available from the internet at:  http://ctep.cancer.gov/reporting/ctc.html]  
III.  
Hormone Receptor Guidelines  IV.  
Pathology Protocol V.  
Quality-of-
Life Protocol VI.  
Authorization Log VII.  
Participating Group Specific Logistical 
Information  
VIII. IBCSG Guidelines for Publication and Presentations  


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1   
Introduction  
  
1.1 Adjuvant therapy for premenopausal women with receptor positive breast 
cancer  
  
Chemotherapy, tamoxifen and ovarian ablation (by surgery or radiation) are individually effective 
adjuvant treatment modalities in women under 50 years of age with estrogen receptor positive 
(ER+) breast cancer [1,2].   
  
Chemotherapy plus 5 years of tamoxifen is more effective than chemotherapy alone in women 
under 50 with ER+ breast cancer.  The addition of 5 years of tamoxifen to adjuvant chemotherapy 
in this group results in an additional ~ 40% reduction in the odds of recurrence or death [3].  In 
women at relatively low risk for recurrence (NSABP B-20 trial in node negative ER+ breast 
cancer) chemotherapy plus tamoxifen resulted in a significant 44% reduction in the odds of 
recurrence compared to tamoxifen alone in women under 50 [4].  These data suggest that adjuvant 
combination chemo-endocrine strategies can improve results over single modality treatments.  
  
In women under 50 with hormone receptor positive breast cancer who receive both adjuvant 
chemotherapy and 5 years of tamoxifen, it is unclear whether any additional benefit is derived 
from suppression of ovarian function as no trial has addressed this question to date.   
  
Data from the Early Breast Cancer Trialists‟ Collaborative Group suggest that in the presence of 
chemotherapy the benefit from ovarian ablation appears smaller [2]. The magnitude of benefit 
from the addition of ovarian function suppression to chemotherapy may have been underestimated 
in previous trials due to inclusion of some women with ER-negative tumors and a predominance 
of women who would have been rendered permanently amenorrhoeic (postmenopausal) from the 
adjuvant chemotherapy alone.  The majority of premenopausal women with breast cancer are at 
least 40 years of age and more than 80% of these women will develop amenorrhea following 6 
cycles of classical CMF chemotherapy [5, 6].  By contrast, less than half of premenopausal women 
under age 40 develop amenorrhea with CMF.  The prognosis of women who develop amenorrhea, 
even temporarily, from CMF chemotherapy tends to be better than those who continue to 
menstruate [7].  Shorter anthracycline-based regimens such as 4 cycles of doxorubicin and 
cyclophosphamide (AC) result in less frequent premature menopause compared with classic CMF 
(34% versus 69%) [8]. A recent report on the Canadian NCI trial indicated that the incidence of 
amenorrhea was significantly higher in the CEF arm compared to CMF: 73.9 vs 61.9% (p=0.005).  
According to the reported findings amenorrhea did not affect relapse free survival (RFS). The 7-
year RFS was 53% and 49% for patients with and without amenorrhea, respectively (p=0.3 by log 
rank) [9].  It is unclear whether a subgroup analysis for women with endocrine responsive disease 
(excluding those with tumors not expressing hormone receptors) would have shown an association 
between amenorrhea and improved outcome.  
  
1.2  
The role of ovarian function suppression   
  


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This trial aims to focus the ovarian function suppression question on the subset of women who 
biologically would be most likely to benefit, i.e., women with hormone receptor positive breast 
cancer plus premenopausal status either following surgery alone or after completion of 
adjuvant/neoadjuvant chemotherapy.  These women are likely to be on average younger than the 
median age for premenopausal breast cancer and will mostly be under 40 years of age.  Analysis 
of women treated on IBCSG trials (I, II, V and VI) reveals that young women (under 35 years of 
age) with ER-positive tumors have a worse prognosis than premenopausal women > 35 years old 
[10].  Paradoxically in these trials, women < 35 years old with ER-positive disease treated with 
adjuvant chemotherapy alone have a worse prognosis than women with ER-negative tumors in the 
same age group [11].  This young group of women with ER-positive disease may potentially 
benefit from receiving “maximal” adjuvant endocrine therapy in addition to chemotherapy.  
  
Synthetic gonadotropin releasing hormone (GnRH) analogues administered by monthly injection 
have been shown to suppress ovarian function and result in a decline in estradiol levels to 
postmenopausal range with chronic administration [12].  GnRH analogues produce clinical 
responses in premenopausal women with advanced receptor positive breast cancer similar to those 
seen with conventional ovarian ablation and tamoxifen [13,14].  High levels of estradiol are known 
to occur in premenopausal women on tamoxifen alone [15] and the addition of a GnRH analogue 
can suppress these hormonal surges. GnRH analogues evaluated in breast cancer trials include 
goserelin, leuprorelin, buserelin and triptorelin.  
  
Triptorelin has been shown to be efficacious as a single agent in the metastatic breast cancer phase 
II trial setting [16].  Twenty-seven premenopausal hormone receptor positive breast cancer patients 
were treated with 3.75 mg Decapeptyl Depot® IM q 28 days until progression.  Tamoxifen was 
given for the first 4 weeks to cover a potential flare period induced by treatment stimulation of the 
pituitary gonadal axis by the LHRH.  Prior treatment consisted of adjuvant chemotherapy in 7, 
adjuvant tamoxifen in 1 and no adjuvant treatment in 19.  Six patients (18%) achieved CR, and a 
further 14 (52%) achieved PR for an overall response rate of 70%.  Four patients had SD and four 
progressed.  The median duration of response for CRs was 51 months and for PRs was 12 months; 
the median TTP for all patients was 15 months.  Side effects were minimal and the most common 
complaint was hot flushes.  
  
In a randomized study comparing the effect of goserelin with or without tamoxifen in 318 
premenopausal patients with advanced breast cancer there was a modest benefit in favor of 
combination endocrine therapy in time to progression (p=0.03) and a non-significant improvement 
in median survival (13 weeks longer with combination p=0.25) [17].  The EORTC randomized 
161 premenopausal patients to receive combination therapy with buserelin plus tamoxifen, 
compared to buserelin alone or tamoxifen alone, as first line treatment for metastatic breast cancer.  
The combined therapy arm resulted in a significant improvement in progression free survival 
(p=0.03) and overall survival (p= 0.01) compared with either single agent alone [18,19].  A meta-
analysis of four randomized trials in premenopausal advanced breast cancer addressing the 
question of GnRH analogue alone versus GnRH analogue combined with tamoxifen reported a 
significant survival benefit for the combined endocrine approach [20].  It is important to test 


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whether the advantage seen with combination endocrine therapy in the  advanced disease setting 
can be translated into meaningful differences for women in the adjuvant setting.    
  
In a U.S. Intergroup randomized trial in premenopausal women with hormone receptor-positive 
node-positive breast cancer, the combination of tamoxifen plus goserelin for 5 years after 
chemotherapy significantly reduced recurrences compared with chemotherapy alone or 
chemotherapy plus goserelin.  However, it remains unclear whether tamoxifen without goserelin 
after chemotherapy would have provided similar benefit as this treatment arm was not tested [21].  
  
Although ovarian function suppression by GnRH analogues is thought to be similar to other forms 
of ovarian ablation (surgery or radiation) in the advanced disease setting, this may not be true in 
the adjuvant setting, particularly if administered for a relatively short duration in very young 
women in whom menstrual function may resume after cessation.  Studies of efficacy of adjuvant 
endocrine therapy with tamoxifen suggest that duration is important [3] and this may also apply to 
GnRH analogues.  In this trial, GnRH analogues, oophorectomy or ovarian irradiation (with 
biochemical confirmation of cessation of ovarian function) are all allowed; the method will be 
documented in the case report forms.  There are case studies of failure of ovarian function 
suppression under GnRH analogue [22].  In such cases ovarian function suppression should be 
achieved by other means.  
  
1.3  
Anti-aromatase agents  
  
There are two classes of aromatase inhibitors. Agents such as anastrozole and letrozole act by 
reversibly binding to the aromatase enzyme, which is responsible for the production of estrogens 
in postmenopausal women. Exemestane is an oral irreversible inactivator of aromatase that 
depletes plasma estrogen by more than 90% and whole body aromatization by 98%. Unlike 
reversible aromatase inhibitors, it cannot be displaced from the aromatase enzyme. Exemestane 
has been shown to significantly increase both median survival and median time to progression 
when compared to megestrol acetate as second line hormonal therapy in postmenopausal women 
with advanced breast cancer [23].   
  
There is evidence in postmenopausal women with metastatic disease that aromatase inhibitors 
produce response rates and survival equivalent or superior to those seen with tamoxifen [24,25], 
and trials comparing aromatase inhibitors to tamoxifen for postmenopausal women in the adjuvant 
setting are awaiting maturity.  The updated results of the ATAC trial (anastrozole, tamoxifen and 
combination) in 9366 postmenopausal women with operable breast cancer were recently published 
after a median follow-up of 68 months. Among the 84% of patients with steroid hormone receptor 
positive disease, the hazard ratio for disease-free survival comparing anastrozole with tamoxifen 
was 0.83 (p=0.005) [26, 46]. In the Intergroup Exemestane Study  (IES), postmenopausal women 
with primary breast cancer who had received two to three years of adjuvant hormonal therapy with 
tamoxifen were randomized to either complete a total of 5 years of hormonal therapy with 
tamoxifen or to switch to exemestane for the remaining time.  After a median follow-up of 30.6 
months, switching to exemestane significantly improved the disease-free survival compared with 


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continuing tamoxifen (hazard ratio 0.68; p <0.001) [47,48]. The first results of the primary core 
analysis of the IBCSG 18-98/BIG 1-98 trial reported on 8010 postmenopausal women with 
endocrine-responsive breast cancer who were randomized to either tamoxifen or letrozole as 
adjuvant hormonal therapy.  After a median follow-up of 25.8 months, letrozole significantly 
prolonged disease-free survival compared with tamoxifen (hazard ratio = 0.81; p=0.003) [49].  
  
It is postulated that these promising results with aromatase inhibitors in postmenopausal women 
can also be obtained in premenopausal women who undergo ovarian function suppression.   
  
Aromatase inhibitors at safe doses do not fully inhibit ovarian enzymes, and are not likely to be 
effective in premenopausal women [27].  However it has been shown that the combination of an  
aromatase inhibitor plus a GnRH agonist in premenopausal women can produce lower estrogen 
levels than a GnRH agonist alone [28,29].  In a small study, the combination of goserelin plus an 
aromatase inhibitor was found to result in objective responses or stable disease in 89% of 
premenopausal women with advanced breast cancer who had previously received goserelin plus 
tamoxifen [30].  
  
Either the combination of a GnRH agonist (or oophorectomy or ovarian irradiation) with tamoxifen 
or the combination of a GnRH agonist with an aromatase inhibitor (exemestane) has the potential 
to improve survival in premenopausal women over that seen with tamoxifen alone.   
  
This trial will compare the two tamoxifen containing arms to assess the role of ovarian function 
suppression, will compare the two ovarian function suppression arms to assess the role of 
exemestane compared with tamoxifen, and will compare the exemestane regimen to tamoxifen 
alone in premenopausal women with estrogen or progesterone receptor positive invasive breast 
cancer who either do not receive chemotherapy or who remain premenopausal at the end of their 
chemotherapy. The duration of hormonal treatment will be five years.  
  
1.4   Bone mineral density  
  
In a study of the effect of tamoxifen on bone mineral density in healthy premenopausal and 
postmenopausal women, tamoxifen treatment was associated with a significant loss of bone 
mineral density in premenopausal women, whereas it prevents loss of bone mineral density in 
postmenopausal women [31].  In an adjuvant breast cancer study assessing bone mineral density 
in premenopausal women receiving GnRH analogue (goserelin) for 2 years, there was a significant 
reduction in bone mineral content, while addition of tamoxifen to goserelin appears to compensate 
for the demineralizing effects of GnRH analogue [32].  A pre-clinical trial by Goss et al. [33] 
showed that in the ovariectomized rat, exemestane prevented bone loss.  It is possible that the 
combination of exemestane and ovarian function suppression may result in less osteoporosis than 
the other hormonal therapies.  Data on the use of bisphosphonates will be collected to assess the 
potential for confounding of the overall results.   
2  
Trial objectives  
  


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This trial will evaluate the worth of ovarian function suppression (achieved by either long-term 
use of GnRH analogue or surgical oophorectomy or ovarian irradiation) plus tamoxifen compared 
with tamoxifen alone for premenopausal women with steroid hormone receptor positive early 
invasive breast cancer who either receive no adjuvant chemotherapy or remain premenopausal 
following adjuvant and/or neoadjuvant chemotherapy.  In addition, the worth of exemestane will 
be evaluated for this premenopausal patient population by comparing ovarian function suppression 
plus exemestane with tamoxifen alone and by comparing ovarian function suppression plus 
exemestane with ovarian function suppression plus tamoxifen.  
  
2.1  
Primary objectives  
  
2.1.1 To compare ovarian function suppression (OFS: GnRH analogue or oophorectomy or ovarian 
irradiation) plus tamoxifen vs. tamoxifen alone  
  
2.1.2 To compare OFS plus exemestane vs. tamoxifen alone (A secondary objective per 
Amendment 2)  
  
2.1.3 To compare OFS plus exemestane vs. OFS plus tamoxifen (This comparison will combine 
data with the IBCSG 25-02 TEXT trial as the primary analysis for the TEXT trial)  
   
2.2  
Primary endpoint  
  
2.2.1 Disease-free survival  
  
2.3  
Secondary endpoints  
  
2.3.1 Overall survival  
2.3.2 Systemic disease-free survival Breast cancer-free interval and distant recurrencefree 
interval  
2.3.3 Quality of life  
2.3.4 Sites of first treatment failure  
2.3.5 Late side effects of early menopause   
2.3.6 Incidence of second (non-breast) malignancies   
2.3.7 Causes of death without cancer event  
  
3  
Patient selection  
  
3.1  
Criteria for patient eligibility  
  
3.1.1  Premenopausal women [estradiol (E2) in the premenopausal range (according to institution 
parameters)] who meet the following criteria:  
  


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 Patients who did not receive chemotherapy should be randomized within 12 weeks after 
definitive surgery. Such patients should have estradiol (E2) in the premenopausal range 
following surgery; the only patients who do not require testing of estradiol (E2) to confirm 
premenopausal status are those who have been menstruating regularly during the 6 months 
prior to randomization and have not used any form of hormonal contraception or any other 
hormonal treatments during the 6 months prior to randomization.    
  
 Patients who received prior adjuvant and/or neoadjuvant chemotherapy should be randomized 
after completing chemotherapy and within 8 months of the final dose of chemotherapy as soon 
as premenopausal status is confirmed; all such patients should have premenopausal status 
confirmed by an estradiol (E2) in the premenopausal range between 2 weeks and 8 months after 
completing chemotherapy.    
  
Adjuvant trastuzumab (Herceptin ®) is allowable, and is not considered to be chemotherapy 
for eligibility timing determination.  
  
Patients with temporary chemotherapy-induced amenorrhea who regain premenopausal status 
within eight months of the final dose of chemotherapy are eligible. [Please note that some 
patients taking tamoxifen or aromatase inhibitors, even without evidence of menses, may have 
ovarian function recovery following chemotherapy and resume estradiol secretion.]   
Premenopausal levels of serum estradiol may persist after chemotherapy-induced amenorrhea 
despite prolonged amenorrhea [34].  Therefore in patients wishing to participate in the study, 
with postmenopausal hormone levels shortly after chemotherapy, it is recommended to recheck 
their estradiol level at a later timepoint within 8 months of completing chemotherapy, even in 
the absence of return of menses.   
  
3.1.2   Histologically proven, resected breast cancer.  Pathology material should be available for 
submission for central review as part of the quality control measures for this protocol.  
  
3.1.3 Patients must have hormone receptor positive tumors.  If there is more than one breast tumor, 
each tumor must be hormone receptor positive. Hormone receptors must be determined using 
immunohistochemistry.  ER and/or PgR must be greater than or equal to 10% of the tumor cells 
positive by immunohistochemical evaluation.  Biochemical determination alone is not acceptable.  
Detailed guidelines for assessments of ER and PgR are given in the Appendix III.  
  
3.1.4 The tumor must be confined to the breast and axillary nodes without detected metastases 
elsewhere, with the exception of tumor detected in internal mammary chain nodes by sentinel node 
procedure.  Patients who received neoadjuvant therapy must have had operable disease prior to 
neoadjuvant treatment to be eligible.  Patients who had a pathological evaluation with tru cut or 
core biopsy of invasive breast cancer prior to neoadjuvant therapy and were found to have no 
invasive tumor in the pathological specimen from definitive surgery are eligible.  For these 
patients, pre-neoadjuvant tumor characteristics will be used for defining eligibility.  In case of 
persistent disease, pathology findings from the definitive surgery should be used.  


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3.1.5 Patients must have had proper surgery for primary breast cancer with no known clinical 
residual loco-regional disease:    
• 
A total mastectomy.  Radiotherapy is optional after mastectomy.  
OR  
• 
A breast-conserving procedure (lumpectomy, quadrantectomy or partial mastectomy with 
margins clear of invasive cancer and DCIS).  The local pathologist must document negative 
margins of resection in the pathology report.  If all other margins are clear, a positive posterior 
(deep) margin is permitted, provided the surgeon documents that the excision was performed 
down to the pectoral fascia and all tumor has been removed.  Likewise, if all other margins are 
clear, a positive anterior (superficial; abutting skin) margin is permitted provided the surgeon 
documents that all tumor has been removed. Radiation therapy to the conserved breast is 
required; patients may be randomized before, during or after completion of radiation therapy 
to the breast.  
  
3.1.6 Either axillary lymph node dissection (pathological examination of at least 6 nodes 
recommended) or a negative axillary sentinel node biopsy [pN0(sn)] is required. Patients with 
negative or microscopically axillary positive sentinel nodes (pN1mi: micrometastasis none > 
2.0mm) do not require further axillary therapy. Those with positive sentinel nodes must have either 
an axillary dissection or radiation of axillary nodes.   
  
3.1.7 For IBCSG centers, patients must have completed baseline Quality of Life (QL) Forms prior 
to randomization.  The only exceptions are cognitive or physical impairment that interferes with 
QL assessment or inability to read any of the languages available on IBCSG QL forms.  For non-
IBCSG centers, extent of participation in the QL study is to be determined at the activation of the 
trial for each cooperative group (see Appendix VII for Group-specific guidelines).  
  
3.1.8 Written informed consent must be signed and dated by the patient and the investigator prior 
to randomization.  
  
3.1.9 Patients must be accessible for follow-up.  
  
3.1.10 Patients must be informed of and agree to data and tissue material transfer and handling, in 
accordance with national data protection guidelines.  
  
3.2  
Criteria for patient ineligibility  
  
3.2.1 Patients who are postmenopausal (i.e., do not have an estradiol (E2) level in the 
premenopausal range) after surgery or after chemotherapy, whichever is later.  
  
3.2.2a  Patients with distant metastatic disease.  
  


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3.2.2b  Patients with locally advanced inoperable breast cancer including inflammatory breast 
cancer or supraclavicular node involvement or with enlarged internal mammary nodes (unless 
pathologically negative) are not eligible. Patients with involved internal mammary nodes detected 
by sentinel node biopsy that are not enlarged are eligible.  
3.2.2c Patients with positive final margins (referring to only DCIS and invasive cancer, not LCIS), 
except as noted in section 3.1.5.  DCIS at a margin is permitted if a complete mastectomy has been 
performed.  
  
3.2.2d  Patients with clinically detectable residual axillary disease.   
  
3.2.3 Patients with a history of prior ipsilateral or contralateral invasive breast cancer. Patients with 
synchronous bilateral invasive breast cancer (diagnosed histologically within 2 months) are 
eligible if the bilateral disease meets all other eligibility criteria (see section 8.1.2 for data 
management for such patients).  
  
3.2.4 Patients with previous or concomitant invasive malignancy are not eligible. The exceptions 
are patients with the following (and only the following) malignancies (previous or concomitant) 
who are eligible if adequately treated:  
 basal or squamous cell carcinoma of the skin  in situ non-breast carcinoma without 
invasion  contra- or ipsilateral in situ breast carcinoma  non-breast invasive 
malignancy diagnosed at least 5 years ago and without recurrence: o stage I papillary 
thyroid cancer o stage Ia carcinoma of the cervix o stage Ia or b endometrioid 
endometrial cancer o borderline or stage I ovarian cancer  
  
3.2.5 Patients with other non-malignant systemic diseases (cardiovascular, renal, hepatic, lung, 
etc.) that would prevent prolonged follow-up.  Patients with previous thrombosis (e.g., DVT) 
and/or embolism can be included only if medically suitable.  
  
3.2.6 Patients who have had a bilateral oophorectomy or ovarian irradiation. Patients who will be 
recommended to undergo oophorectomy within 5 years (e.g., BRCA1 / 2 gene carriers) and 
therefore for whom randomization to a treatment arm without OFS is inappropriate.  
   
3.2.7 Patients with a history of noncompliance to medical regimens and patients who are 
considered potentially unreliable.  
  
3.2.8 Patients who are pregnant or lactating at the time of randomization or who desire a pregnancy 
within 5 years.  Patients planning to use additional hormonal therapy apart from the randomized 
treatment (see Section 5.3.1) during the next five years including all types of hormonal 
contraception. A pregnancy test is recommended for women of child-bearing potential who are 
sexually active and not using reliable contraceptive methods.  
  
3.2.9 Patients who received endocrine therapy (including neoadjuvant and adjuvant) for more than 
8 months after their breast cancer diagnosis. Patients who are receiving endocrine therapy at 


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randomization (and have received it for less than 8 months) may continue such therapy until 
protocol-specified tamoxifen/exemestane is initiated (see section 5.1).  
3.2.10 Patients who were taking tamoxifen or other SERM (e.g. Raloxifene) or hormone 
replacement therapy (HRT) within one year prior to their breast cancer diagnosis. Prior oral 
contraceptives are allowed.  
  
3.2.11 Patients who have received GnRH analogues as part of their breast cancer treatment prior 
to randomization.  
  
3.2.12 Patients with psychiatric, addictive, or any disorder that would prevent compliance with 
protocol requirements.  
  
4  
Randomization and stratification  
  
This trial will use a web-based randomization system.  Each Participating Group will determine 
how its centers will access the randomization system, either through a Group Randomization 
Center, or directly from the Participating Center.  The following procedures should be used in 
either case.  Specific details for randomizing are in the “IBCSG Registration/Randomization 
Procedures Manual,” which is available on the IBCSG website (www.ibcsg.org).  
  
4.1  
Randomization timing  
  
In principle, patients should be enrolled in the study and randomized as close as possible to the 
start of protocol treatment.  In this trial, patients who do not receive chemotherapy should be 
randomized within 12 weeks after surgery and those who receive adjuvant/neoadjuvant 
chemotherapy should be randomized between 2 weeks and 8 months after the last dose of 
chemotherapy, as soon as premenopausal status is confirmed, as described in Section 3.1.1.    
  
Adjuvant trastuzumab is allowable and is not considered to be chemotherapy for eligibility timing 
determination.  
  
  
4.2  
Registration procedures  
  
Complete the following steps to randomize a patient on this trial.  
  
4.2.1 Verify eligibility.  
  
4.2.2 Obtain informed consent form signed and dated by patient and investigator.  
  
4.2.3 Complete baseline Quality of Life (QL) Forms; QLC, QLM, and, for English speaking 
centers, Form QLS. (Required for IBCSG participating centers; for other Groups, participation in 


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the QL study is according to Group-specific guidelines, see Appendix VII.)  See Section 3.1.7 for 
exceptions.  
  
4.2.4 Complete Confirmation of Registration Form (A).  
  
4.2.5 Depending on your Group‟s choice, either   
 Telephone or fax your Randomization Center to review the eligibility and 
randomization information.  Your Randomization Center will access the IBCSG 
Registration/Randomization System.  
 Directly access the IBCSG Registration/Randomization System.  
  
In the former case, the Randomization Center will provide the Participating Center with 
the following information.  In the latter case the Randomization System will provide this 
information.  
Randomization number (patient ID)  
Treatment assignment  
Date of randomization  
  
4.2.6 When randomization is complete, fill in Confirmation of Registration Form (A) and fax Form 
A, and Forms QLC, QLM, and, for English speaking centers, Form QLS, to an IBCSG DataFax 
number.  This completed Form A is considered the essential document for regulatory purposes.  It 
should be filed at your institution.   
  
4.2.7 File your copy of the completed Confirmation Form (A) and Informed Consent Form.  Do 
not mail these forms.  
  
4.3  
Randomization help desk  
  
The IBCSG Data Management Center (located at FSTRF) is responsible for developing and 
maintaining the IBCSG Registration/Randomization System.   The Randomization Help Desk 
includes technical personnel and administrators of the randomization programs at the Data 
Management Center in Amherst, NY, USA.  
  
Normal Business Hours:  Monday – Friday 00:00-18:00 US Eastern Time  
  
FSTRF Randomization Help Desk  
Frontier Science & Technology Research Foundation (FSTRF)  
4033 Maple RD, Amherst, NY 14226 USA  
Phone: +1 716 898 7301  
Fax: +1 716 898 7082  Email: 
bc.helpdesk@fstrf.org  
  
  
  
  


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The telephone information may also be used after business hours for urgent issues.  
4.4  
Randomized groups  
  
Randomization (1:1:1) to 3 groups:  
  
4.4.1 Tamoxifen alone for 5 years.  
  
4.4.2 Ovarian function suppression (triptorelin for 5 years or surgical oophorectomy or ovarian 
irradiation) plus tamoxifen for 5 years.  
  
4.4.3 Ovarian function suppression (triptorelin for 5 years or surgical oophorectomy or ovarian 
irradiation) plus exemestane for 5 years.  
  
4.5  
Stratification  
  
4.5.1 Institution.  
  
4.5.2 
Prior adjuvant/neoadjuvant chemotherapy   
 No  
 Yes  
  
4.5.3 
Number of positive axillary and/or internal mammary lymph nodes   
0 (including  pN0(sn), pN0 (i+)(sn) and pNx)  
1 or more (including  pN1mi)  
  
Patients with less than 6 axillary lymph nodes dissected, all of which were negative and without a 
sentinel node assessment will be classified as pNx in secondary statistical analyses.  For purposes 
of stratification, disease will be regarded as node-negative if all examined axillary and/or internal 
mammary lymph nodes were proven to be pathologically negative or if a sentinel axillary and/or 
internal mammary lymph node biopsy result was negative. Isolated tumor cells (less than or equal 
to 0.2mm) in a sentinel node is classified as node negative [i.e., pN0(i+)(sn)]. Microscopic disease 
(pN1mi: > 0.2mm and less than or equal to 2.0mm) in a sentinel axillary and/or internal mammary 
node is categorized as node positive.   
  
4.5.4 Intended initial method of ovarian function suppression, in the event the patient is  
randomized to ovarian function suppression:  
 Triptorelin for 5 years  
 Surgical oophorectomy  
 Ovarian irradiation  
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5.1  
Trial treatments  
  
5.1.1 Triptorelin (GnRH analogue) 3.75 mg by intramuscular injection every 28 (+3) days for 5 
years from the date of randomization, unless relapse or intolerance should occur earlier or bilateral 
surgical oophorectomy or bilateral ovarian irradiation is subsequently performed.  (Triptorelin: 
Decapeptyl Depot® intramuscular or Trelstar Depot® intramuscular).  The responsible investigator 
may authorize another qualified person to administer triptorelin. Triptorelin will be supplied free 
of charge for patients randomized to ovarian function suppression in this study.  
  
In case of intolerance to triptorelin, goserelin (Zoladex®) 3.6 mg by subcutaneous injection every 
28 days may be used as an alternative to triptorelin but will not be provided by the study.  GnRH 
analogues administered at 3 monthly intervals are not approved in this trial due to uncertainty 
concerning the duration of ovarian function suppression in women with this schedule.  
  
There are case studies of failure of ovarian function suppression under GnRH analogue [22].  In 
such cases ovarian function suppression should be achieved by other means, providing the patient 
accepts an alternative method.   
  
5.1.2 Bilateral surgical oophorectomy via laparotomy or laparoscopy.  For patients randomized to 
an ovarian function suppression treatment group, oophorectomy may be performed initially, after 
GnRH analogue has been administered for some time, or not at all.   
  
5.1.3 Bilateral ovarian irradiation.  For patients randomized to an ovarian function suppression 
treatment group, ovarian irradiation may be performed initially, after GnRH analogue has been 
administered for some time, or not at all.  Target volume:  small pelvis (previous ultrasound pelvic 
examination with skin marks of the ovarian position is recommended).  Standard ovarian 
irradiation regimen is recommended, using megavoltage energy and scheduling as follows: 3 Gy 
per fraction in 4 fractions (total dose = 12 Gy) or 3 Gy per fraction in 5 fractions (total dose = 15 
Gy).  Biochemical verification of ovarian function cessation is required after two months by 
measurement of estradiol (E2).  If biochemistry shows that radiation was not successful in 
achieving ovarian function suppression, then this should be achieved by alternate means.  
  
5.1.4 Tamoxifen 20 mg orally daily until 5 years from date of randomization, unless relapse or 
intolerance should occur prior to 5 years.  
  
5.1.5 Exemestane (Aromasin®) 25 mg orally daily, preferably after food, until 5 years from date 
of randomization, unless relapse or intolerance should occur prior to 5 years. It is suggested that 
exemestane begin approximately 6 to 8 weeks after initiation of ovarian function suppression; 
however, it may begin immediately after, but no later than 10 weeks after, initiation of ovarian 
function suppression. [Note that exemestane administered to a premenopausal woman in the 
absence of ovarian function suppression (i.e., if GnRH analogue is discontinued) is not an effective 
treatment.]  Patients who were receiving tamoxifen therapy at the time of randomization may 
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5.1.6 Radiotherapy: The role of radiotherapy is not assessed in the present trial but radiotherapy 
should be used according to accepted guidelines. Radiation therapy to the conserved breast is 
required.   
 Radiation therapy to the chest wall following mastectomy is optional and nodal fields may 
be treated together with the conserved breast or the chest wall.   
 Radiation therapy may be given either after all chemotherapy or integrated into 
chemotherapy (if the combination is considered safe by the investigator).  
 Radiation therapy may be concurrent with trial hormonal therapy or given before starting 
tamoxifen or exemestane, according to institutional practice. A patient may be randomized 
prior to completing radiation therapy in order to meet the time frame for randomization 
(section 3.1.1) and then initiate oral trial hormonal therapy when radiation therapy is 
completed if this is institutional practice.  However, patients randomized to ovarian 
function suppression and planning to receive triptorelin (GnRH analogue) injections should 
commence those as soon as randomized.   
   
Radiation therapy is well documented to reduce the risk for local and regional recurrence and may 
decrease breast cancer mortality. These beneficial effects may be counteracted by increased 
morbidity and mortality from causes other than breast cancer. The morbidity (e.g. lymphedema 
and reduced mobility of the shoulder, and cardiac morbidity) should be minimized by stringent 
indications for chest wall and nodal irradiation and by careful planning of the treatment. It is 
recommended to restrict such treatment to patients who are at high risk of local recurrence (e.g. 
20% or more) such as those with breast-conserving surgery, four or more metastatic axillary lymph 
nodes, and some patients with tumors larger than 5 cm [35,36].  
  
Increased morbidity or mortality could occur after cardiac exposure to chest wall or breast 
irradiation, and there is a common feeling that this risk might be enhanced for anthracyclinetreated 
patients. Although the risk for cardiac morbidity and mortality in recent trials which use modern 
radiotherapy techniques appears to be less than in older studies, information on late adverse effects 
is limited. There is evidence that the risk is related to the volume of the irradiated heart [37]. It is 
therefore strongly advised to use 3-D-planning to avoid excessive cardiac exposure. If another 
system for treatment planning is used, the radiation oncologist should be aware that patients may 
receive anthracyclines and/or other cardiotoxic drugs as part of adjuvant chemotherapy.  
  
Tamoxifen may mediate enhancement of radiation-induced lung fibrosis [38]. The clinical 
relevance of the observed changes is unknown and is unlikely to be severe. No change in current 
practice is recommended and institutions are encouraged to further study lung and skin fibrosis in 
patients receiving tamoxifen or exemestane together with radiotherapy.  
  
5.1.7 Chemotherapy: Patients in the chemotherapy stratum must have completed adjuvant (and/or 
neoadjuvant) chemotherapy prior to randomization.  A planned duration of  2 months if an 
anthracycline was included (e.g. 4 cycles of EC or AC) or  4 months if no anthracycline was given 
(e.g. 6 cycles of CMF) is recommended.  If an anthracycline was used, an epirubicincontaining 


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regimen is recommended.  The final dose of chemotherapy must be less than 8 months prior to 
randomization.  
  
5.2  
Side effects of study drugs  
  
5.2.1 GnRH analogue:  The most common side effects are hot flushes, sweating, amenorrhea, 
fertility impairment, decreased libido and vaginal dryness and/or dyspareunia.  Less frequent side 
effects are headache, tiredness, mood changes, sleep disturbance, nausea, back or joint pain, local 
injection site reaction, weight gain and slight rise in cholesterol.  Loss of bone mineral density can 
occur.  
  
In clinical trials in advanced disease adverse events (AEs) were generally mild to moderate and 
rarely severe enough to require discontinuation of treatment.  Adverse experiences that have been 
seldom reported include: skin rash, allergic and anaphylactic reactions including angioedema, 
hypo- or hypertension, and elevated liver enzymes.  
  
GnRH analogue is contraindicated in pregnancy and lactation.  Cases of pregnancy have occurred 
in women receiving regular injections of GnRH analogue [22].  The role of nonhormonal 
contraception should therefore be discussed.  
  
Following a safety review of several published studies in men with prostate cancer receiving GnRH 
agonists, on 20 October 2010, the US FDA required manufacturers of GnRH agonists to add new 
safety information about increased risk of diabetes and certain cardiovascular diseases in men 
receiving GnRH agonist for the treatment of prostate cancer to the Warnings and Precautions 
section of the drug labels. The FDA‟s 3 May 2010 Drug Safety Communication, last updated 4 
January 2011, about the Ongoing Safety Review of GnRH Agonists noted, “There are no known 
comparable epidemiologic studies evaluating the risk of diabetes and cardiovascular disease in 
women 
taking 
GnRH 
agonists.” 
(http://www.fda.gov/Drugs/DrugSafety/ 
PostmarketDrugSafetyInformationforPatientsandProviders/ucm209842.htm; 
accessed 
21 
February 2011) Therefore, no changes are recommended concerning the management of patients 
on this study. Nevertheless, in addition to the cardiovascular and other targeted adverse events 
already collected, we will prospectively capture adverse event information specifically on 
hyperglycemia and glucose intolerance (diabetes) and the use of anti-diabetic drugs as concomitant 
medications.  
  
5.2.2 Tamoxifen:  The most common side effects are hot flushes, night sweating, vaginal 
discharge, irregular menses, vulvar itching and nausea.  Fluid retention and skin rash have been 
reported.  Tamoxifen is known to increase the risk of thromboembolic disease.  Ocular alterations 
such as corneal damage, cataract or retinopathy are rare.  Patients should avoid pregnancy as 
tamoxifen may cause fetal harm.  There may be an increased risk of endometrial cancer, polyps 
and hyperplasia associated with the estrogen agonist action of tamoxifen.  Rare cases of uterine 
sarcoma have been reported.  Tamoxifen may be associated with loss of bone mineral density in 
premenopausal women while it prevents bone mineral density loss in the low estrogen 


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(menopausal) state.  Modification of tamoxifen dosage is rarely indicated.  No standard dose 
modifications are prescribed.    
  
5.2.3 Exemestane:  The most common side effects seen with exemestane in clinical trials in 
advanced disease are hot flushes, nausea, increased sweating, fatigue, hair thinning, dizziness and 
skin rash. Exemestane lowers plasma estrogen levels, which may result in loss of bone mineral 
density. The best data for comparing the side effects of exemestane with tamoxifen comes from 
the Intergroup Exemestane Study (IES) in postmenopausal women receiving adjuvant hormonal 
therapy, in which exemestane was compared to tamoxifen for two to three years (after two to three 
years of prior tamoxifen).  The following adverse events were reported in similar percentages of 
patients: hot flushes and sweating, aches or pains, fatigue, insomnia, headaches, dizziness, 
depression, nausea and cardiovascular disease other than myocardial infarction.  Adverse events 
that were significantly more common with exemestane than tamoxifen included visual 
disturbances, arthralgias and diarrhea and there was a trend to an increase in osteoporosis.  Adverse 
events that were significantly more common with tamoxifen than exemestane were gynecologic 
symptoms and vaginal bleeding, muscle cramps and thromboembolic disease [47].  In a subsequent 
updated oral presentation of this trial [48], a nonsignificant excess of myocardial infarctions was 
noted in those treated with exemestane compared with tamoxifen in the population (mean age 64 
years).  
  
5.3  
Concomitant treatments  
  
5.3.1 Additional hormonal treatments (either oral or transdermal) including estrogen, 
progesterone, androgens, aromatase inhibitors, hormone replacement therapy, oral or other types 
of hormonal contraceptives (including implants and depot injections), raloxifene or other SERMS 
are not allowed while on study.  For women with vaginal dryness and/or dyspareunia, use of 
vaginal moisturizers and lubricants should be considered [39].  If these non-hormonal measures 
are insufficient to relieve symptomatic vaginal dryness then a local vaginal estrogen treatment, 
preferably with minimal systemic absorption, is allowed (e.g., Estring®).   
  
5.3.2 Women who are distressed by vasomotor symptoms (e.g., hot flushes and night sweats) 
requiring medical intervention should be treated with non-hormonal treatments (e.g., serotonin 
reuptake inhibitors) [40].  
  
5.3.3 Bisphosphonates are not allowed UNLESS bone density has been documented to be at least 
1.5 standard deviations below the young adult normal mean or the patient is participating in a 
randomized clinical trial testing bisphosphonates in the adjuvant breast cancer setting.  The  
administration of vitamin D3 and calcium supplements is allowed.  Considering the potential 
increased risk of osteoporosis in women in this study, patients should be advised about adequate 
calcium intake and weight bearing exercise.    
5.3.4 Patients for whom it is clinically indicated may receive neoadjuvant/adjuvant therapy with 
trastuzumab (Herceptin®) prior to and/or while on study.  When determining eligibility, 
trastuzumab should not be considered as chemotherapy.  


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5.3.5 Patients should be advised that a low risk of pregnancy remains despite GnRH analogue 
therapy [22].    
  
5.3.6 Patients will not receive other investigational agents while on study except as described in 
Section 5.3.3.  
  
5.4  
Study drug supply  
  
Exemestane will be provided by Pfizer.  Triptorelin will be provided by Pfizer in North and South 
America, and by Ipsen in all other areas.  
  
Tamoxifen, chemotherapy and goserelin will not be provided by the study and must be prescribed 
by the patient's physician.  The drugs should be obtained as if the patient were receiving standard 
treatment and not participating in a clinical trial.   
  
The coordination of the drug supply-related activities for all clinical centers in all countries will 
be performed by the IBCSG Coordinating Center in Bern, Switzerland. Exemestane and triptorelin 
will be provided via a central distribution mechanism.  The central clinical supply facility from 
Ipsen in France will be responsible for the distribution of both drugs in countries outside North 
and South America and a central clinical supply facility nominated by Pfizer in the United States 
will be responsible for the distribution in North and South America.  
  
Prior to the shipment of exemestane and triptorelin to a participating clinical center, the necessary 
ethics and regulatory approvals must be transmitted to the IBCSG Coordinating Center.  Upon 
approval by IBCSG, Ipsen and Pfizer will proceed with the shipment of a certain amount of drug 
as start up reserve in order to have medication on site before patients are randomized by the 
investigator. Shipment of additional Six-month to one-year supplies of exemestane and triptorelin 
will occur automatically based upon randomization assignment. Sixmonth to one-year supplies of 
exemestane and triptorelin will be re-supplied automatically on a continuous basis for patients 
continuing treatment.  New packages should only be dispensed to patients at the scheduled protocol 
visits.  
  
Logistics for transmitting ethics and regulatory approvals to the IBCSG Coordinating Center and 
for study drug supply for different parts of the world are described in detail in Appendix VII: 
Participating Group Specific Logistical Information.  
  
Destruction of drug: Expired or useless drugs at any clinical center may be destroyed on site and 
a certificate of destruction provided to IBCSG.  If this is not feasible, the expired or useless drugs 
should be sent back to the supplier for destruction. Any supplied study drug returned by patients 
at study completion may not be reused and should be destroyed or returned as above.  
  


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6  
End points and definitions of treatment failure  
  
6.1  
Trial end points  
  
6.1.1 Primary end point: First confirmation of relapse (local, regional, or distant), contralateral 
breast cancer, second (non-breast) primary tumor, and/or death.  
  
Disease-free survival (DFS) is defined as the time from randomization to local (including 
recurrence restricted to the breast after breast conserving treatment), regional or distant relapse, 
contralateral breast cancer, appearance of a second (non-breast) primary tumor, or death from any 
cause, whichever occurs first.  Appearance of DCIS or LCIS either in the ipsilateral or in the 
contralateral breast will not be considered as an event for DFS (but must be reported on the Follow-
Up Form).  See Section 6.2.7 for other exceptions.  
  
6.1.2 Secondary end points:  Overall survival (OS) is defined as the time from randomization to 
death from any cause.  
  
Systemic relapse is defined as any recurrent or metastatic disease in sites other than the local 
mastectomy scar/chest wall/skin, the ipsilateral breast in case of breast conservation, or the 
contralateral breast.   
  
Systemic disease-free survival (SDFS) is defined as the time from randomization to systemic 
relapse, appearance of second (non-breast) primary tumor, or death, whichever occurs first.  See 
Section 6.2.7 for exceptions.  
  
Breast cancer-free interval (BCFI) is defined as the time from randomization to the earliest time 
of invasive breast recurrence (local, regional or distant relapse) or a new invasive breast cancer in 
the contralateral breast. Deaths without a prior breast cancer event are censored. The appearance 
of a second (non-breast) primary tumor is not considered as an event.  
  
Distant recurrence-free interval (DRFI) is defined as the time from randomization to the earliest 
time of distant recurrence. Deaths without a prior breast cancer event are censored. The appearance 
of a second (non-breast) primary tumor is not considered as an event.  
  
Quality of life.   
Sites of first treatment failure.  
Late side effects of early menopause.  
Incidence of second (non-breast) primaries.  
Causes of death without cancer event.  
  
6.2  
Diagnosis of treatment failure  
  


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The diagnosis of first treatment failure depends on evidence of recurrent disease, which can be 
classified as either suspicious or acceptable.  In either case, this should be specified and reported.   
Acceptable evidence of treatment failure according to site is defined below.  Any events not 
included in this section are considered unacceptable as evidence of recurrent disease.  Treatment 
failures include: local, regional, contralateral breast, and distant failures, second (non-breast) 
primaries, and deaths without cancer events.  The date of treatment failure is the time of first 
appearance of a suspicious lesion, later proven to be a definitive recurrence or metastasis.  All 
events described below should be recorded on the Follow-up Form (E).  
  
6.2.1 Local failure   
Local failure is defined as a tumor recurrence in any soft tissues of the ipsilateral (or in the case of 
bilateral, either) conserved breast or the chest wall, mastectomy scar, and/or skin.  
  
Acceptable for recurrence in ipsilateral conserved breast:  positive cytology or histology  
  
Acceptable for recurrence in chest wall, mastectomy scar, and/or skin:  positive cytology or 
histology or evidence of new lesions (by CT or MRI) without any obvious benign etiology.  
  
Suspicious:  a visible or palpable lesion.  
  
Appearance of DCIS or LCIS either in the ipsilateral or in the contralateral breast is not considered 
a treatment failure.  
  
6.2.1.1 Treatment after local relapse for patients who received breast-conserving surgery. Patients 
may continue to receive the protocol treatment after resection of a relapse in the ipsilateral 
conserved breast, an option that reflects the controversy concerning therapy for reappearance of 
disease in the ipsilateral breast.  Continued treatment is only allowed when there is no evidence of 
loco-regional disease outside the breast or of distant disease at the time of breast relapse.  Details 
of the local treatment for the conserved breast relapse must be recorded on the Follow-up Form 
(E).  Patients who develop a local relapse other than a relapse in the ipsilateral conserved breast 
should change therapy.    
  
6.2.2 Regional failure  
Regional failure is defined as a tumor recurrence in the ipsilateral axillary lymph nodes, extranodal 
soft tissue of the ipsilateral axilla, ipsilateral internal mammary lymph nodes, and/or ipsilateral 
supraclavicular lymph nodes. For patients with bilateral breast cancer at randomization, failure in 
the previously-listed regional nodes should be recorded as regional failure (rather than distant) on 
the Follow-Up Form E.  The side (right or left) of the nodes should be recorded.  
  
Acceptable: positive cytology or histology or evidence of new lesions by CT or MRI without a 
benign etiology.  
Suspicious:  a visible or palpable lesion.  
  


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6.2.3 Contralateral breast failure  
Acceptable:  positive cytology or histology.  
Suspicious: a visible or palpable lesion, suspicious mammogram, ultrasound, or MRI.  
  
Appearance of DCIS or LCIS in the contralateral breast is not considered an event for DFS. For 
patients with bilateral breast cancer at randomization, contralateral breast failure cannot be 
defined.  
  
6.2.4 Distant failure  
Tumors in all areas other than those defined above are considered distant metastases.  The 
following criteria apply:  
  
6.2.4.1 Bone marrow  
Acceptable: positive cytology, aspiration or biopsy.  
Suspicious: unexplained depression of peripheral blood counts and/or a leucoerythroblastic blood 
picture.  
  
6.2.4.2 Lung  
Acceptable: positive cytology or histology or a positive CT or MRI without obvious benign 
etiology or evidence of progressive disease.  (Progressive disease is confirmed by  
two X-rays with the second showing worsening disease.) Suspicious:  
new radiological lesion(s).  
  
6.2.4.3 Pleura  
Acceptable:  positive cytology or histology.  
Suspicious:  new pleural effusion.  
  
6.2.4.4 Bone  
Acceptable: positive cytology or histology or a positive X-ray, MRI, or CT, one bone scan with 
new multiple lesions and no obvious benign etiology.  
Suspicious:  skeletal symptoms or positive scan showing only one new lesion (until confirmed by 
other imaging study).  
  
6.2.4.5 Liver  
Acceptable: positive cytology or histology, or positive CT or MRI without an obvious benign 
etiology, or evidence of progressive disease by ultrasound.  (Progressive disease in 
this case is confirmed by two ultrasounds with the second showing worsening 
disease).  
Suspicious: any two of the following: hepatomegaly on physical examination, equivocal 
ultrasound and abnormal liver function test.  
  


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6.2.4.6 Central nervous system  
Acceptable:  positive cytology or histology.  Positive MRI or CT when the clinical picture is 
suspicious.  
Suspicious:  any other clinical findings suggestive of this diagnosis.  
  
6.2.4.7 Distant lymph nodes, not including ipsilateral supraclavicular lymph nodes, or, for cases 
with bilateral invasive cancers,  supraclavicular or axillary nodes on either side.  
Acceptable: positive cytology or histology, or enlarged lymph nodes in CT or MRI, or progressive 
disease by physical exam without an obvious benign etiology. Suspicious:  evidence of enlarged 
lymph nodes by physical exam.  
  
For patients with bilateral breast cancer at randomization, failure in the axillary lymph nodes, 
extranodal soft tissue of the axilla, internal mammary lymph nodes, and/or supraclavicular lymph 
nodes on either the right or left side should be recorded as regional failure (rather than distant) on 
the Follow-Up Form E.  The side (right or left) of the recurrence should be recorded.  
  
6.2.4.8 Other sites  
Acceptable:  positive cytology or histology or evidence of progressive disease if only indirect 
means of diagnosis were used (e.g., X-ray).  
Suspicious:  clinical and radiological evidence of a tumor.  
  
6.2.5 Second (non-breast) primary  
Any positive diagnosis of a second (non-breast) primary other than basal cell or squamous cell 
carcinoma of the skin, cervical carcinoma in situ or bladder cancer in situ is considered a treatment 
failure. Patients may continue to receive the protocol treatment after a second (nonbreast) primary 
is diagnosed.  
  
6.2.6 Death without cancer event  
Any death without a prior cancer event described in 6.2.1 through 6.2.5 above is considered a 
treatment failure.   
  
6.2.7 Other noteworthy events  
The following events should be recorded on the Follow-up Form (E).  These events are NOT 
considered treatment failures, but must be recorded.  ipsilateral and contralateral breast cancer in 
situ  cervical carcinoma in situ, bladder cancer in situ  basal or squamous cell carcinoma of the 
skin  
7  
Study parameters  
  
7.1   Table of study parameters  
  


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Visit  
  
1A  2  
3  
4  
5  
6  
7  
8  
9  10  11  12  13  14  15  
Yearly 
until death  
Year  
1  1  
1  
1  
1  
2  
2  
3  
3  
4  
4  
5  
5  
6  
6  
  
Trial month  
0  3  
6  
9  12  18  24  30  36  42  48  54  60  66  72  
  
Informed consent  
x  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
Check of inclusion & 
exclusion criteria  
x  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
History*  
x  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
Physical examination 
including weight*  
x  
  
x  
 
x  
 
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
 
x  
EstradiolB   
x  
 
 
 
 
 
 
 
 
 
 
   
 
 
  
Adverse Events (AE)C  
x  x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
  
Late AEsD  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x  
Laboratory tests  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  HematologyE  
x  v  
v  
v  
v  
v  
v  
v  
v  
v  
v  
v  
v  
v  
v  
  
  Blood chemistryF   
x  v  
v  
v  
v  
v   
v
v  
v  
v  
v  
v  
v  
v  
v  
  
Investigations  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  MammogramG  
x  
 
 
 
y  
 
y  
 
y  
 
y  
 
y  
 
y  
  
  Chest-X-rayH  
  (PA and lateral views) or 
chest CT  
x  v  
v  
v  
v  
v  
v  
v  
v  
v  
v  
v  
v  
v  
v  
  
  Bone scanI  
y  v  
v  
v  
v  
v  
v  
v  
v  
v  
v  
v  
v  
v  
v  
  
  Abdominal US, CT or   
liver scanJ  
v  v  
v  
v  
v  
v  
v  
v  
v  
v  
v  
v  
v  
v  
v  
  
 Gynecological examK  
v  v  
v  
v  
v  
v  
v  
v  
v  
v  
v  
v  
v  
v  
v  
  
Bone mineral 
densitometryL  
y  
 
 
 
y  
 
y  
 
y  
 
y  
 
y  
 
y  
  
CRFsM  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
Quality of LifeN  
x  
 
x  
 
x  
x  
x  
 
x  
 
x  
 
x  
 
x  
  
Forms B,C,H,F,P  
x  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
Form F  
x  
and at disease relapse (Form RF)  
  
Form AE, CCM  
x  x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
  
Form E  
 x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
Form OFS, TE (while 
receiving OFS, tamoxifen 
or exemestane)   
 x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
 
 
  
Forms R, SAE, EIU, GYN  
as needed per protocol  
  
Forms BC, BF, BP and 
BR  
Submit for patients with synchronous bilateral breast cancer a 
required per protocol.  
s  
  
x = mandatory   
y =  recommended   
v = if medically indicated  


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*Physical exam and history may be completed up to two months prior to randomization. A pregnancy test is recommended for women of 
child-bearing potential who are sexually active and not using reliable contraceptive methods. 
Legend to Table 7.1   
  
A. The day of randomization is considered Day 0 for the purpose of follow-up.  
  
B. Estradiol must be in the premenopausal range within 12 weeks of surgery or for patients who have 
received chemotherapy between 2 weeks and 8 months after the final dose of chemotherapy (Section 
3.1.1). It is recommended to determine E2 level as close to randomization as possible. The only patients 
who do not require testing of estradiol (E2) to confirm premenopausal status are those who did NOT 
receive chemotherapy and who have been menstruating regularly during the 6 months prior to 
randomization and have not used any form of hormonal contraception or any other hormonal treatments 
during the 6 months prior to randomization.  
  
C. Adverse events should be graded using the NCI CTCAE version 3.0 (Appendix II).  The following list 
gives targeted adverse events that should be recorded on the CRF at any time:  
Vaginal dryness and/or treatment to alleviate  
Decreased libido (sexual interest)  
Urinary incontinence  
Vasomotor menopausal symptoms (hot flashes/flushes, night sweats) and/or treatment to alleviate 
Osteoporosis and/or treatment to prevent/alleviate  
Bone fracture   
Dyspareunia (pain or discomfort with intercourse) and/or treatment to alleviate  
Musculoskeletal symptoms (myalgia, arthralgia (joint pain), stiffness not including bone fractures) 
and/or treatment to alleviate  
Depression  
CNS cerebrovascular ischemia  
CNS hemorrhage  
Hypertension  
Cardiac ischemia/infarction  
Thrombosis and/or embolism   
Nausea  
Insomnia   
Sweating  
Fatigue  
Allergic reaction and/or hypersensitivity  
Injection site reaction  
Glucose Intolerance (Diabetes) and/or anti-diabetes treatment  
Hyperglycemia  
Other Grade 3 or higher adverse events  
  
D. Late adverse events (adverse events occurring after trial treatment is completed) should be recorded on 
Follow-up Form E.  
  
E. Hematology must be done within 2 months prior to randomization and whenever medically indicated.  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  


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F. Blood chemistry (includes liver function tests with alkaline phosphatase) must be done within 2 months 
prior to randomization and whenever medically indicated.  
Radiological assessments  
  
G. A bilateral mammography must be taken within one year prior to randomization.  A mammography of 
the conserved and contralateral breast is recommended at yearly intervals or should be done according 
to national standards or hospital specific requirements.  
  
H. A chest X-ray or chest CT is required within one year prior to randomization.  A chest X-ray must be 
performed any time it is medically indicated or according to specific local requirements.  Both PA view 
and lateral view should be done.  
  
I. A bone scan is recommended within one year prior to randomization.  A bone scan should be performed 
during treatment with trial drug if alkaline phosphatase is significantly elevated (e.g. > 3 x ULN) or if 
medically indicated otherwise (i.e. bone pain).  If the bone scan showed areas suspicious for tumor then 
these areas should be confirmed by X-ray or CT or MRI.  
  
J. Abdominal ultrasound or liver scan or abdominal CT is required prior to randomization or during 
treatment if liver function tests are significantly abnormal or if medically indicated or according to 
specific local requirements.  
  
Other procedures  
  
K. In the event of a pelvic complaint (i.e., abnormal vaginal bleeding), patients should have a 
gynecological examination because of increased risk of uterine cancer in patients receiving tamoxifen.  
It is recommended that all patients receive gynecological assessment according to standard local 
practice for patients on tamoxifen.  
  
L. Bone densitometry by DEXA is recommended within one year prior to randomization and then yearly 
for 6 years.  Bisphosphonates may be used for patients who demonstrate a BMD T-score at least 1.5 
standard deviations below the young adult normal mean.  
  
M. See Section 8 for details on CRF schedule and submission.  Details on CRF completion are available 
in the Trial 24-02 Data Management Manual.  
  
N. Quality of Life self-assessment forms must be completed and submitted according to guidelines in 
Appendix V.  
  
All patients must be followed every 3 months for the first year and every 6 months for years 2 to 6, and 
thereafter yearly for assessment of disease status and for survival data collection.  
  
  
7.2   Adverse event reporting  
  


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The main criterion for tolerability is the occurrence of toxicities and adverse events.  The severity 
and causality will be classified according to the NCI Common Terminology Criteria for Adverse 
Events (CTCAE).  The CTCAE should be labeled: CTCAE Version 3.0.  The CTCAE is available 
for downloading on the internet at (http://ctep.cancer.gov/reporting/ctc.html).  
  
An adverse event is defined as any untoward medical occurrence that occurs from the first dose of 
study medication until 30 days after the final dose, regardless of whether it is considered related 
to a medication.  
  
In addition, any known untoward event that occurs subsequent to the adverse event reporting 
period that the investigator assesses as possibly related to the protocol treatment should be 
considered an adverse event.  
  
Symptoms of the targeted cancer (if applicable) should not be reported as adverse events.  
  
The toxicity severity grade provides a qualitative assessment of the extent or intensity of an adverse 
event, as determined by the investigator or as reported by the subject.  The severity grade does not 
reflect the clinical seriousness of the event, only the degree or extent of the affliction or occurrence 
(e.g. severe nausea, mild seizure), and does not reflect the relationship to study drug.  
  
Severity grade for other adverse events, not covered in the toxicity grading scale:  
  
1 = Grade 1  
Mild  
2 = Grade 2  
Moderate  
3 = Grade 3  
Severe  
4 = Grade 4  
Life-threatening  
5 = Grade 5  
Fatal  
  
  
7.3  
Serious Adverse Event (SAE) reporting  
  
7.3.1 Definition  
  
A serious adverse event is defined in general as any undesirable medical occurrence/adverse drug 
experience that occurs during or within 4 weeks after stopping study treatment that, at any dose, 
results in any of the following:   


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is fatal (any cause) life-threatening,  
requires or prolongs inpatient hospitalization, results in 
persistent or significant disability/incapacity or  
is an unexpected grade 4 toxicity is a 
congenital anomaly or birth defect is 
a secondary cancer  
requires significant medical intervention  
  
Other significant/important medical events, which may jeopardize the patient, or may 
require significant medical intervention to prevent one of the other serious outcomes listed above, 
are also considered a serious adverse event.   
Serious adverse event also includes any other event that the investigator or company judges to be 
serious or which is defined as serious by the regulatory agency in the country in which the event 
occurred.  
  
An unexpected adverse event is one that is not listed as a known toxicity of the investigational 
drug in the package insert or the investigator‟s brochure.  
  
A related adverse event is one for which the investigator assesses that there is a reasonable 
possibility that the event is related to the investigational drug.  
  
7.3.2 Exceptions to the definition  
  
Any death or serious adverse event that occurs more than 4 weeks after stopping study treatment 
but is considered to be at least possibly related to previous study treatment is also considered an  
SAE.  All serious adverse events must also be reported for the period in which the study protocol  
interferes with the standard medical treatment given to the patient.  Cases of second primaries and 
congenital abnormalities are to be regarded as SAEs, regardless of whether they occur during or 
after study treatment.   
  
Events not considered to be serious adverse events are hospitalizations occurring under the 
following circumstances:   
elective surgery (planned before entry into the clinical study);  occur 
on an outpatient basis and do not result in admission;  are part of the 
normal treatment or monitoring of the studied treatment; progression 
of disease.  
  
7.3.3 Reporting SAEs  
  
Any serious adverse event occurring in a patient after providing informed consent must be 
reported. Information about all serious adverse events will be collected and recorded on the IBCSG 
Serious Adverse Event Report Form (Form 24-SAE).  
  
  
  
  
  
  
  
  
  
  
  
  
  


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To ensure patient safety, the IBCSG must learn of each SAE using the procedures described below:  
 The investigator/MD responsible for the patient must FAX a signed SAE Form in English 
within 24 hours to the DataFax data submission fax number for the participating center.  A 
copy is automatically forwarded to the IBCSG Coordinating Center for medical review.  
 Follow-up information should be completed on the original SAE Form within 15 days of the 
initial report and must be faxed to the DataFax data submission fax number for the participating 
center.  A copy is automatically forwarded to the IBCSG Coordinating Center.  
 The IBCSG Coordinating Center will inform Pfizer Corporation and all appropriate parties 
about all SAEs related to study medication (per either investigator or IBCSG medical review) 
within 24 hours of receipt at the IBCSG Coordinating Center.  
The original Serious Adverse Event Form and the fax confirmation sheet must be kept with the 
case report forms at the participating center.  
  
IBCSG Coordinating Center will medically review all SAEs with respect to seriousness, causality 
and expectedness.  The Safety Office will prepare and distribute notifications of those SAEs 
subject to expedited reporting (suspected, unexpected serious adverse reactions, SUSARs), to the 
appropriate persons and regulatory authorities.  
  
The IBCSG Coordinating Center will prepare a summary report of all SAEs received at the end of 
each month. Principal Investigators will receive the summary report on a monthly basis. These 
reports can also be found on the IBCSG web site (www.ibcsg.org).  
  
7.4  
Exposure in utero reporting  
  
If any trial subject becomes or is found to be pregnant while receiving protocol treatment or within 
4 weeks of discontinuing protocol treatment, the investigator must FAX an Exposure in Utero 
Form (Form 24-EIU) to the DataFax data submission fax number for the participating center.  This 
must be done irrespective of whether an adverse event has occurred and within 24 hours of 
awareness of the pregnancy.  The information submitted should include the anticipated date of 
birth or pregnancy termination.  A copy of the form is automatically forwarded to the IBCSG 
Coordinating Center for medical review and for transmission to Pfizer Corporation.  
The investigator will follow the subject until completion of the pregnancy and report the outcome 
within 5 days or as specified below by completing the follow-up portion of the initial Exposure in 
Utero Form.  The completed form must be faxed to the DataFax data submission fax number for 
the participating center.  A copy is automatically forwarded to the IBCSG Coordinating Center for 
medical review and for transmission to Pfizer Corporation.  
If the outcome of the pregnancy meets the criteria for classification as a serious adverse event (i.e., 
spontaneous abortion, stillbirth, neonatal death, or congenital anomaly [including that in an 
aborted fetus]), the investigator should follow the procedure for reporting serious adverse events 
as described in Section 7.3.3, and submit the follow-up Exposure in Utero Form as described 
above.  


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8  
Data submission  
  
We will conduct the trial according to the ICH Good Clinical Practice (GCP) guidelines.  Keeping 
accurate and consistent records is essential to a cooperative study.  The following forms are to be 
submitted at the indicated times by the participating institutions for each patient:  
8.1  Case report forms schedule—SOFT  
The Data Management Manual for this trial contains instructions for submitting forms using the DataFax system.  
  
RANDOMIZATION FORMS  
Form IC  
Informed Consent Form  
Obtain before randomization and keep with patient records.  
Forms 24QLC, 
24-QLM,  24-
QLS  
QL Core and QL Module Forms; 
QL Supplement Form (for  
English-speaking Centers only).  
DataFax baseline QL forms (see exceptions in Section 3.1.7).  
These forms are also required during follow-up (see instructions 
below).  
Form 24-A  
Confirmation of Registration Form  Fill in before contacting your Randomization Center or entering 
the IBCSG Registration/Randomization system to randomize.   
DataFax completed form for all patients randomized.  
BASELINE FORMS  
Form 24-B  
Clinical Form   
DataFax within 1 month of randomization.  
Form 24-C*  
Surgery Form  
DataFax within 1 month of randomization.  
Form 24-H  
Prior Treatment History Form  
DataFax within 1 month of randomization.  
Form 24-F*  
  
Hormone Receptor Form  
DataFax within 1 month of randomization with the hormone 
receptor report.   
Form 24-P*  
  
Pathology Form  
DataFax within 1 month of randomization with a copy of the 
original pathology report.   
Form 24-AE  
Adverse Event Form  
Complete prior to starting protocol treatment (tamoxifen, 
exemestane, OFS) and DataFax within 1 month of randomization.  
This form is also required at follow-up (see instructions below.)    
Form 24-CCM  Concomitant Medications Form  
Complete prior to starting protocol treatment (tamoxifen, 
exemestane, OFS) and DataFax within 1 month of randomization.  
This form is also required at follow-up (see instructions below.)    
FOLLOW-UP FORMS  
Form 24-E  
  
Follow-Up Form  
DataFax every 3 months in Year 1, every 6 months during Years 2-
6, and yearly thereafter.  
Form 24-OFS  
  
Ovarian Function Suppression 
Form  
DataFax at each follow-up period until completion of OFS.  
  
Form 24-TE  
  
Tamoxifen/Exemestane Form  
DataFax at each follow-up period until the completion of 
tamoxifen and/or exemestane.    
Form 24-AE  
Adverse Event Form  
DataFax at each follow-up period during protocol therapy 
(tamoxifen, exemestane, OFS), and with Form 24-E at 6 and 12 
months after the last dose of protocol therapy.  This form is also 
required at baseline.  
Form 24-CCM  Concomitant Medications Form  
DataFax at each follow-up period during protocol therapy 
(tamoxifen, exemestane, OFS), and with Form 24-E at 6 and 12 
months after the last dose of protocol therapy.  This form is also 
required at baseline.  


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Forms 24- 
QLC, 24-QLM  
QL Core and QL Module Forms  
DataFax on schedule in QL Appendix V:  months 6, 12, 18, 24, 36, 
48, 60, 72. These forms are also required at baseline.  
Form 24-QLS  
QL Supplement Form (for  
English-speaking Centers only)  
DataFax on schedule in QL Appendix V:  months 6, 12, 24.  This 
form is also required at baseline.  
Form 24-MQL  Missed QL Form  
DataFax if scheduled QL Core, Module and/or Supplement 
Form(s) is/are not obtained.  
8.1 Case report forms schedule—SOFT (continued on next page)  
  
  
8.1 Case report forms schedule—SOFT (continued from previous page)  
EVENT-DRIVEN FORMS  
Form 24-R*  
  
Radiotherapy Form  
DataFax after completion of radiotherapy, or if radiotherapy was 
planned but not given.    
Form 24-
SAEA  
Serious Adverse Event Form 
(Section A)  
DataFax within 24 hours when SAE occurs, see Section 7.3.  
Form 24-
SAEB  
Serious Adverse Event Form 
(Section B)  
DataFax within 15 days of the initial report and/or at the 
definitive SAE outcome, see Section 7.3.  
Form 24-EIU  
Exposure in Utero Form  
DataFax if patient becomes pregnant during protocol therapy 
(tamoxifen, exemestane, OFS), and when pregnancy outcome is 
known.  
Form 24-GYN  
  
Gynecologic Procedures Form  
Use to report gynecologic surgery, procedures and/or diagnostic 
imaging (excluding PAP smears and minor procedures related to 
diagnosis of cervical carcinoma in situ).  DataFax with the next 
scheduled Form 24-E.  
Form 24 RF  
Relapse Hormone Receptor Form  
DataFax if a hormone receptor analysis was done at relapse.  
* For patients with bilateral breast cancer Forms BC, BF, BP and BR should be submitted for the second breast/side (see section 
8.1.2)  
  
8.1.1 Signing and submitting forms  
All forms should be signed by the Principal Investigator or designee.  An authorization log (see 
Appendix VI.) should be completed at each participating center.  The Pathology Form (P) must be 
signed by the pathologist who reviewed the case or the Principal Investigator.  
  
For IBCSG Participating Centers: Forms should be faxed to an IBCSG DataFax number. SAE 
forms should also be faxed to an IBCSG DataFax number for automatic transmission to the IBCSG 
Coordinating Center.  Full instructions on submitting forms will be distributed to each participating 
center and are available on the IBCSG website (www.ibcsg.org).  Also available on the website is 
a list of fax numbers that are available for faxing case report forms.  
  
For non-IBCSG Participating Centers: Please consult your Participating Group Specific 
Logistical Information (Appendix VII) for special instructions about how to submit data from your 
center.  
  
8.1.2 Data submission for patients with synchronous bilateral breast cancer at 
randomization  


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Patients with synchronous bilateral breast cancer are eligible for the SOFT Trial providing both 
tumors meet the eligibility criteria.  Because of the presence of tumors in both breasts, information 
for both left and right breasts must be collected for these patients.  Report the information for one 
breast/side on the Surgery, Receptor, Pathology and Radiotherapy Forms, and the other breast/side 
on the following forms:  
 
  Bilateral Surgery Form BC  
Bilateral Hormone Receptor Form BF  
Bilateral Pathology Form BP  
Bilateral Radiotherapy Form BR  
All relevant pathology and Hormone Receptor Reports  
  
See section 11 for pathology material submission requirements.  
8.2  
Data management  
  
Data collected in this trial will be sent to the IBCSG Data Management Center in Amherst, NY 
USA.  The Data Management Center will process the data and will generate queries and forms 
requests.  The IBCSG Coordinating Center in Bern, Switzerland will provide medical review and 
summary of SAEs.  The IBCSG Statistical Center in Boston, MA USA will perform the data 
analysis.  
  
8.3  
Investigators’ file  
  
Each center should keep documentation about this trial in an investigators' file, which should 
include the following documents:  
  
  
  
  


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Protocol and appendices  
Amendments  
Signed Protocol Signature Pages  
Sample CRFs including blank SAE forms  
Data Management manual  
Quality-of-Life manual  
Randomization manual  
Patient information and Informed Consent templates approved by Ethical Committee 
Investigator's Brochure and updates  
Ethical Committee approval of protocol, Patient Information sheet and IC, amendments  
Ethical Committee review of SAE, investigators' alert, and other documents  
Correspondence with Ethical Committee  
Health Authority Approval  
Correspondence with Health Authority  
Malpractice insurance information  
Agreement with IBCSG  
Correspondence with IBCSG Coordinating Center, Data Management Center  
SAE reports from IBCSG Coordinating Center  
Accrual reports from IBCSG  
Normal laboratory values  
Laboratory Certifications  
CV of Principal Investigator and co-Investigators  
Authorization log  
Patient Identification log    
ICH GCP guidelines/Declaration of Helsinki and updates  
Audits/monitoring reports  
Obvious Corrections document   
  
  
8.4  
Authorization log  
  
The Principal Investigator (PI) should identify the other members of the Clinical Trial Team who 
are supervised by the PI and approved to provide information in CRFs, queries, etc. (See template 
in Appendix VI.).  
  
8.5  
Patient identification log  
  
As per GCP, patients have the right to confidentiality.  Therefore, no patients‟ names should be 
used in CRFs or any other documentation transmitted to IBCSG central offices.  Items that are 
used to identify a patient include initials of patient's name, date of birth, randomization number. 
When no names are used, at least 2 of the above are usually required to identify the patients‟ 
records.  It is, therefore, imperative that the local data manager keeps an identification log for all 
patients entered in this trial including:  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  


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 Patient's name  
Patient's initials  
Randomization number  
Date of birth  
Other items that could be included are date of randomization and treatment arm.  
9  
Statistical considerations   
  
9.1  
Study design, objectives, and stratification  
  
This study is a multi-national, Phase III, randomized clinical trial designed to evaluate five years 
of tamoxifen versus a combination of five years of tamoxifen plus ovarian function suppression 
(OFS: five years of GnRH analogue or surgical oophorectomy or ovarian irradiation) versus a 
combination of five years of exemestane plus OFS. The trial is designed to answer the following 
three questions for premenopausal patients with hormone-receptor positive breast cancer who 
either receive no adjuvant chemotherapy or who remain premenopausal after adjuvant and/or 
neoadjuvant chemotherapy:    
  
 Do results differ between five years of tamoxifen alone and ovarian function suppression 
(OFS: five years of GnRH analogue or surgical oophorectomy or ovarian irradiation) plus 
five years of tamoxifen?  
 Do results differ between five years of tamoxifen alone and OFS plus five years of 
exemestane?  
 Do results differ between OFS plus five years of tamoxifen and OFS plus five years of 
exemestane?  
  
The randomization will be stratified according to participating institution, use of 
adjuvant/neoadjuvant chemotherapy (no; yes), number of positive axillary and/or internal 
mammary lymph nodes (0 – including pN0(sn), pN0(i+)(sn) and pNx; 1 or more – including  
pN1mi) and intended method of ovarian function suppression (GnRH analogue x 5 years; surgical 
oophorectomy; ovarian irradiation).  
  
9.2  
Data analyses  
  
The treatment comparisons for primary objectives will be based on disease-free survival (DFS: 
Section 6.0) using two-sided stratified logrank tests to determine if the treatment groups are 
different, with an overall experiment-wise alpha level equal to at most 0.05. Kaplan-Meier 
estimates of the DFS distributions will be calculated for each of the treatment arms. Cox 
proportional hazards regression models will be used to investigate whether the a treatment 
comparison is modified by adjustments for various covariates.   
  
  
  
  


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Other factors will be used to characterize the patients enrolled in the study and to provide 
descriptive statistics of outcomes according to subgroups of the population.  These factors include 
age at randomization, type and schedule of initial chemotherapy, type of surgery, use of post 
mastectomy radiation, tumor size, tumor grade, hormone receptor proportion score, ER/PgR 
subgroup, use of trastuzumab, and Her2 subgroup.  These analyses will be considered as secondary 
and descriptive.  
  
The following additional secondary outcomes will be assessed: overall survival, breast cancer- free 
interval, distant recurrence-free interval, quality of life, sites of first recurrence, late side effects of 
early menopause, causes of death without recurrence, incidence of second (non-breast) 
malignancies.    
  
9.3   Sample size considerations  
  
The protocol allows the entry of patients who did not receive chemotherapy, but we do not expect 
to enroll many such patients. Hence our DFS estimates are based on a patient population receiving 
chemotherapy. From IBCSG Trial VIII (CMF x 6 arm: 355 patients), 15.6% of patients maintained 
menses following chemotherapy. The age distribution and the probability of maintaining menses 
are shown in Table 9.1.  
  
Table 9.1. Maintaining Menses following CMF x 6 in IBCSG Trial VIII  
  
 
 
Age Group  
Number of Patients  
Maintained Menses  
 
<=35  
  
27  
  
78%  
 
36-40  
  
55  
  
35%  
 
41-45  
  
120  
  
10%  
 
>45  
  
153  
  
2%  
 
  
Patients who remain premenopausal following chemotherapy are likely to have an outcome similar 
to that observed for patients <=35, as the majority of patients in this age group maintain menses.  
A recent review of data from IBCSG, NSABP, ECOG and SWOG indicated that women under age 
35 with ER-positive, node-positive disease who were treated with chemotherapy alone had about 
a 40% 5-year DFS [11].  Assuming a 40% reduction in risk of relapse by adding tamoxifen [3], the 
baseline 5-year DFS for patients with node-positive disease who receive chemotherapy plus 
tamoxifen is estimated to be 58%. This estimate agrees with the 59% 5-year DFS based on 109 
women in CALGB 9344 under age 35 with ER positive, nodepositive disease who received 
chemotherapy plus tamoxifen.  Premenopausal women with ERpositive, node-negative disease in 
IBCSG Trial V had a 70% 5-year DFS without tamoxifen (results were the same for either no 
chemotherapy or a single perioperative cycle of CMF).  Adding tamoxifen should improve this to 
81%.  If we assume that a little over 60% of the cases enrolled in this trial will be node-positive, 


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the baseline risk for the tamoxifen alone control group (with or without prior chemotherapy) is 
estimated to be 67%.  
  
The three treatment comparisons will be performed annually starting when 200 events have been 
observed in the three arms, for a total of 5 analyses over 6.9 years. Table 9.2 shows the operating 
characteristics of three alternative designs that would allow the detection of 20%, 25%, and 30% 
reduction in hazard by adding OFS to tamoxifen compared with tamoxifen alone.  
  
Table 9.2. Operating characteristics for the OFS + tamoxifen versus tamoxifen alone comparison.  
  
Reduction in hazard  
20%  
25%  
30%  
Tamoxifen alone 5-yr DFS  
67%  
67%  
67%  
OFS + tamoxifen 5-yr DFS  
72.6%  
74.1%  75.6%  
Two-sided alpha level  
.0167  
.0167  
.0167  
Power  
.80  
.80  
.80  
Required number of events for two arms*  
861  
522  
343  
Accrual rate for two arms (pts/year)  
400  
400  
400  
Total accrual time (yrs)  
5.5  
5  
4.5  
Sample size (two arms)  
2200  
2000  
1800  
Total study duration with 4 interim + 1 final analyses (yrs)*  9.8  
6.9  
5.4  
Total sample size (all 3 arms)  
3300  
3000  
2700  
* Under the alternative hypothesis with 4 interim analyses and 1 final analysis [41].  
  
For planning purposes, we will target a 25% reduction in hazard for each of the three comparisons. 
This will require recruitment for the three arms of 3000 patients (600 patients per year for 5 years 
with 1.9 years of additional follow-up).  Accrual of premenopausal patients with ER-positive 
tumors to IBCSG Trials VI (N+) and VIII (N-) averaged 222 per year. Applying the 15.6% rate of 
maintaining menses following chemotherapy to this cohort, we anticipate approximately 35 
patients per year from IBCSG institutions.  Global participation including the Breast International 
Group (BIG) and the US Intergroup is required to successfully complete this trial.  
  
The same operating characteristics apply to the second comparison (OFS plus exemestane versus 
tamoxifen alone) and to the third comparison (OFS + exemestane versus OFS + tamoxifen), when 
testing for an improvement in 5-year DFS from the baseline value of 67%. If one assumes a 25% 
reduction in hazard due to the addition of OFS to tamoxifen (and thus an estimated 74.1%  
5-year DFS for the OFS + tamoxifen arm), then a further 25% reduction in the hazard for OFS + 
exemestane compared with OFS + tamoxifen (to 79.8% 5-year DFS) would be detected with 68% 
power, if the final analysis is performed at 6.9 years from the activation of the study.  
  
The originally planned sample size was 3000. It was projected that 5 years of accrual, plus 1.9 
years of additional follow up would be sufficient to observe the 783 target number of DFS events 
(522 needed for each pairwise comparison). This number of events would provide 80% power to 
detect a hazard ratio of 0.75 for GnRH + tamoxifen versus tamoxifen alone (74.1% versus 67.0% 


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5-yr DFS, respectively) using a 2-sided, 0.0167 level test (adjusting for multiple tests). The study 
opened to enrollment in August 2003. In January 2011, enrollment was closed with 3066 patients 
randomized. Due to agreements with pharmaceutical partners and financial constraints, it is not 
possible to increase patient enrollment.   
  
As of October 2010, the overall DFS event rate was substantially lower than originally anticipated: 
approximately 2% per year compared with the protocol-specified 8% per year.  Consequently, at 
the October 2010 estimated event rate, an additional thirteen (13) years of follow up (end of 2023) 
would be required to observe the protocol-specified 783 target number of the DFS events (at which 
time the median follow up would be 15 years). The Steering Committee considered this delay in 
the reporting of the trial results (20 years after first enrollment compared with the originally 
anticipated 7 years) to be unacceptably long, and decided to revise the analysis plan so that the 
first results of the study could be reported within 3 years of completing enrollment (median follow 
up approximately 5 years). This decision was endorsed by the IBCSG Data and Safety Monitoring 
Committee (DSMC). Outcome according to treatment group was not available to either the 
Steering Committee or the DSMC.   
  
By revising the timing for the first report of results from an „event-driven‟ plan (783 DFS events 
in SOFT) to a „time-driven‟ plan (with a data cut-off defined for the fall of 2013), the Steering 
Committee recognized that the statistical power for the original three pairwise comparisons at the 
time of first report will be substantially reduced. Therefore, the Steering Committee decided to 
focus the primary analysis from the SOFT trial on the unique comparison: OFS + tamoxifen versus 
tamoxifen alone, and to test this comparison at the 2-sided 0.05 level with no interim analyses 
planned. We estimate that the power to detect hazard ratios of 0.80, 0.75, and 0.70 at the 2013 
timing of the first analysis to be 34%, 52%, and 69%, respectively. A hazard ratio of 0.665 for 
OFS + tamoxifen versus tamoxifen alone would be detected with power of 80%. The comparison 
of OFS + exemestane versus tamoxifen alone is considered of secondary importance in the SOFT 
patient population. The comparison of OFS + exemestane versus OFS + tamoxifen will be assessed 
primarily in the originally-planned combined analysis of SOFT and the Tamoxifen and 
Exemestane Trial (TEXT) described below.   
  
We prospectively plan to combine the data available for the two OFS-containing arms with the 
data available from the Tamoxifen and Exemestane Trial (TEXT: BIG 3-02; IBCSG 25-02) that 
is being conducted as a complementary study with SOFT.  We note that SOFT and TEXT differ 
with respect to patient selection and treatment for women who receive chemotherapy; SOFT 
enrolls patients who remain premenopausal following chemotherapy and initiates OFS (GnRH 
analogue, surgical oophorectomy or ovarian irradiation) following the completion of 
chemotherapy, while TEXT enrolls patients following surgery and uses concurrent GnRH 
analogue and chemotherapy. Nevertheless, the combined analysis will provide a statistically 
powerful comparison of exemestane versus tamoxifen as adjuvant therapy for premenopausal 
women. The two studies are scheduled to open simultaneously.  The power of such a combined 
analysis (at the 0.05 two-sided level) to detect a 20%, 25%, or 30% reduction in hazard with OFS 
+ exemestane versus OFS + tamoxifen would be at least 8863%, 9884%, and 9995%, respectively, 
assuming that both SOFT and TEXT recruit as planned and that the combined analysis is 


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performed 6.9 years from the opening of the two studies. are first reported based on data available 
in the fall of 2013 and the October 2010 estimated event rates in the two trials continue.  
  
Updates of efficacy results will be prepared and reported approximately every 2 years after the 
first report.  
  
9.4  
Interim monitoring  
  
A group sequential design with four interim analyses and one final analysis will be used [41]. 
Under the hypothesis of a 25% reduction in hazard between the tamoxifen alone arm and one of 
the two OFS arms, the target number of events for the final analysis is 783. Formal interim analyses 
are planned yearly starting when 200 events have been observed in the three arms. At each interim 
analysis and at the final analysis testing for each comparison will be performed using O'Brien-
Fleming boundaries [42].  
  
Originally the protocol included a group sequential design with four interim and one final efficacy 
analysis. Due to the lower than anticipated DFS event rate, no interim efficacy analysis has been 
performed. Because the number of events is so much lower than anticipated, the DSMC determined 
that the first analysis planned for 2013 would be sufficient, and that interim monitoring for efficacy 
was not required.  
  
9.5  
Data and Safety Monitoring Committee (DSMC)  
  
The study will be presented for review by the IBCSG Data and Safety Monitoring Committee 
(DSMC) at each of their semi-annual meetings. Accrual, toxicity, events, and deaths will be 
monitored. Analyses of efficacy according to randomization group will be presented only at the 
time points specified for formal interim analysis (annually from the 200th event).  The DSMC will 
also make recommendations concerning potential modifications to the design criteria for this study 
if the assumptions used in the design are found to be inaccurate.  A formal review of the accrual 
rate will be performed two years after study activation to assess whether modifications are 
required.  
  
  
10  
Quality of Life   
  
See Appendix V for a complete description of the quality-of-life study to be conducted in 
conjunction with this protocol.  See Appendix VII for non-IBCSG Group-specific guidelines 
for participating in the quality-of-life study.  
11  Additional protocol-specific parameters  
  
11.1 Hormone receptors  
  


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11.1.1  Hormone receptor determination  
Immunohistochemical measurements of estrogen receptor (ER) and progesterone receptor (PgR) 
of the invasive component of the tumor are required for this protocol.  The measurements should 
be expressed as percent of positive cells.  Patients with greater than or equal to 10% of cells 
positive are considered hormone receptor positive.  For this trial, only patients with either 
ERpositive and/or PgR-positive tumors are eligible. For patients with bilateral breast cancer, all 
tumors must meet the above criteria.  
  
The following items are required for all patients:  
  
1. Completed Hormone Receptor Form F  
2. Steroid Hormone Receptor Report   
  
For patients with bilateral breast cancer, the following items are required for the second breast/side:  
  
1. Completed Bilateral Hormone Receptor Form BF  
2. Steroid Hormone Receptor Report   
  
11.1.2 Quality assurance  
It is mandatory that all laboratories conducting immunohistochemical measurements participate in 
a program for quality assurance.  One such system is the NEQAS Scheme, which has been 
validated by the IBCSG pathologists.  
  
More information on immunohistochemical measures and the NEQAS system is available in the 
Hormone Receptor Guidelines (Appendix III).  
  
11.1.3  Central review  
Tissue bank material will be used for central review of hormone receptors.  The original 
histological report must be available.  
  
11.2 Pathology and pathology material banking  
  
11.2.1  Pathology requirements  
  
The work of the pathologist is basic to the success of all studies.  Each center should identify a 
pathologist responsible for study patients.  The pathologist determines the diagnosis, classification, 
and grading of the primary tumor; and evaluates the non-tumor breast tissue and local or regional 
spread as found in the biopsy and/or mastectomy specimen, including precise documentation of 
tumor size, margins of the primary, the total number of lymph nodes examined, and the number of 
nodes involved.  All lymph nodes must be examined from each patient.  If the patient has received 
a sentinel node biopsy, each sentinel node must be evaluated.  The central review pathologist will 
review the submitted specimens and complete the Central Pathology Review (CPR) form.  See 
Appendix IV, “Pathology Guidelines” for more information.  


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The following items are required for all patients:   
  
1. Completed Pathology Form P   
2. Pathology Report   
3. Tumor block for banking  
4. Normal tissue block for banking  
5. Representative H & E sections of the above blocks   
  
For patients with bilateral breast cancer, the following items are required for the second breast/side:  
1. Completed Bilateral Pathology Form BP   
2. Pathology Report   
3. Tumor block for banking  
4 Representative H & E section of the above block  
  
The tissue blocks, particularly in case of small tumors, may be returned to the participating center 
upon request.  If for some reason blocks can not be provided, 20 unstained slides of the primary 
tumor and 10 unstained slides of the normal tissue must be submitted.  
  
All reports, slides, and blocks must be marked with the randomization number.  If materials are 
not properly marked, we cannot guarantee that the slides will be forwarded to the Central 
Pathology Review Office.  The IBCSG Coordinating Center has received broken slides in the past 
and asks that they be sent in customized boxes especially made for slides.  They should be packed 
with tissue paper to prevent any movement.  The slides have not been packed securely enough if 
they move around when the box is shaken.  
  
11.2.2  
Pathology material banking  
  
The IBCSG has established a central repository for tissue blocks and slides from every patient 
enrolled in IBCSG clinical trials.  The required pathological material (described in the previous 
section) is submitted to, catalogued, and maintained in the IBCSG Central Pathology Office and 
IBCSG Tissue Bank in Milan Coordinating Center Office in Bern (IBCSG Central Pathology 
Office, European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy Coordinating 
Center, Effingerstrasse 40, CH-3008 Bern).  The Australia-New Zealand Group will maintain a 
tumor bank within Australia.  Immunohistochemistry characterization is done as part of The H&E 
section is sent for central pathology review, and the respective sections are stored in the central 
repository thereafter. then returned to Bern for storage.  Central pathology review reports will be 
available to institution pathologists who wish to see them. Central pathology review will include 
histopathological parameters (tumor type and grade, occurrence of peritumoral vascular invasion), 
hormone receptors (estrogen and progesterone receptors), HER2 status and the proliferative 
fractions (Ki-67 immunostaining).  Testing for genes which may be inherited is not a part of the 
central pathology review of this study. The blocks will be available for prospective and 


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retrospective studies approved by the Biological Protocols Working Group and by the IBCSG 
Ethical Committee.  
  
11.3 Family history   
  
Information on patients‟ family history of breast cancer is being collected on Clinical Form B to 
evaluate its impact on prognosis.  A positive family history of breast cancer has been shown to be 
associated with an increased risk of contralateral tumors [43] and second primaries [44].  In 
addition, research is ongoing to determine whether genetically-associated breast cancer responds 
differently to treatment [45].  
  
12. Regulatory approval procedures and patient informed consent  
  
12.1  Ethics Review Board/Ethics Committee  
All protocols and the patient informed consent (IC) Forms must have the approval of a properly 
constituted committee or committees responsible for approving clinical trials. The Ethical Review 
Board (ERB)/Institutional Review Board (IRB) written, signed approval letter/form must contain 
approval of the designated investigator, the institution, the protocol (identifying protocol title and 
version number), and of the patient IC template, as well as the composition of the Ethics 
Committee (names of members) that approved such documents. Documentation of ethics 
committee approval should be sent to the IBCSG Coordinating Center prior to enrollment of the 
first patient. The IBCSG Ethics Committee also approves the protocol and reviews it annually.   
  
12.2. Regulatory approval procedures  
The protocol, other protocol related documents including patient information and IC, and other 
documents as required locally must be submitted to and approved by health authorities according 
to national regulations.   
  
12.3. Requirements for Center Activation  
Prior to activation, the Centers have to submit all required regulatory documents as specified in 
the activation letter including Ethics Committee approval, Health authority approval, and approved 
patient information/IC to the IBCSG Coordinating Center.  
Logistics for transmitting regulatory documents and ethics and health authority approvals for 
participating groups are described in Appendix VII.  
  
12.4 Protection of human subjects  
The IBCSG has an Office for Human Research Protection (OHRP) assurance (#T-4777) and 
follows all of the policies and procedures that are part of that assurance. All potential subjects for 


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this trial will receive a full explanation of the trial, its purpose, treatments, risks, benefits, and all 
of the other items listed in Section 12.5. Additional institution-specific sections should be added 
to Appendix I as described in Section 12.5.  
The medical record must be available for review by the IBCSG audit team as described in Section 
12.6.  
SAE reports are distributed monthly. In addition they are available on the IBCSG website 
(www.ibcsg.org).  
IBCSG will promptly notify the appropriate persons of all SAE reports subject to expedited 
reporting. Investigators are responsible to forward such safety information to their Ethics 
Committee.  
  
12.5 Informed consent procedures  
  
Informed consent for each patient will be obtained prior to initiating any trial procedures in 
accordance with the statement entitled "Requirements for Informed Consent." (See Appendix I.)  
One signed and dated copy of the informed consent must be given to each patient and the original 
copy must be retained in the investigator's trial records.  The informed consent form must be 
available in the case of data audits.  There must be verification on Form A and in the randomization 
system that informed consent was obtained and the date obtained.  
  
The "Declaration of Helsinki" (http://www.wma.net/e/policy/b3.htm) and its updates recommend 
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 trial at any time.  The patient should be told that 
material from her tumor will be stored and potentially used for additional studies not described in 
this protocol.   
  
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 a minor, 
informed consent must be obtained from the parent, 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 Good Clinical Practice and the 
"Declaration of Helsinki."   
  
The IBCSG recognizes that each institution has its own local, national, and international guidelines 
to follow with regard to informed consent.  Therefore, we provide a template information sheet 
and informed consent form, available from the IBCSG website in Microsoft Word, which can be 
downloaded and edited to incorporate information specific to your institution (www.ibcsg.org).  
The final version should receive the Institutional Review Board/ Local Ethical Committee 
approval in advance of its use.  
  


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The template Patient Information Sheet and Informed Consent has been written according to ICH 
guidelines which state the Informed Consent should adhere to GCP and to the ethical principles 
that have origin in the “Declaration of Helsinki.”  
Following the ICH-GCP guidelines, the Informed Consent should contain information about the 
following items:  
The trial involves research  
Purpose of the trial  
Trial treatment (s) and the probability of random assignment  
The subject‟s responsibilities  
The aspects of the trial that are experimental  
Risks  
Benefits  
Alternative treatments available  
Compensation/Expenses  
Subject‟s participation is voluntary/right to withdraw  
Confidentiality  
Information about course of the trial  
Circumstances under which trial may be terminated  
Contact persons for further information or in case of injury  
The approximate number of subjects involved in the trial  
Duration of subject‟s participation in the trial  
  
The template has been designed to cover the above items. If the IRB/Local Ethical Committee 
requires modifications, none of the above items should be completely excluded, nor should the 
meaning of the highlighted areas be modified.  
  
12.6 Quality assurance  
  
The IBCSG conducts trials according to the ICH Good Clinical Practice (GCP) guidelines.  The  
Study Data Manager reviews each Case Report Form as they are received.  In addition, the Study 
Chair and/or IBCSG Medical Reviewer reviews each case at specific timepoints.  The IBCSG 
conducts periodic audit visits to ensure proper trial conduct, verify compliance with GCP, and 
perform source data verification.  
  
Data Management manuals are available from the IBCSG website (www.ibcsg.org).  
  
13  Administrative considerations  
  
13.1 Insurance  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  


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IBCSG as the Sponsor of the Study, contracts adequate Clinical Trial Insurance, in accordance 
with all relevant legal requirements, laid down 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.  
14  References  
  
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34:632-640, 1998.  
8. Cobleigh MA, Bines J, Harris D, et al: Amenorrhea following adjuvant chemotherapy for 
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9. Parulekar W, Trudeau ME, Shepherd L, et al: Incidence and prognostic impact of amenorrhea 
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Am Soc Clin Oncol 20:A97, 2001 (abstr).  
10. Aebi S, Gelber S, Castiglione-Gertsch M, Gelber RD, Collins J, Thürlimann B, et al. for the 
International Breast Cancer Study Group (IBCSG): Is chemotherapy alone adequate for young 
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11. Goldhirsch A, Gelber RD, Yothers G, Gray RJ, Green S, Bryant J, Gelber S, 
CastiglioneGertsch M, Coates AS: Adjuvant therapy for very young women with breast cancer: 
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13. Blamey RW, Jonat W, Kaufmann M, et al: Goserelin depot in the treatment of premenopausal 
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14. Taylor CW, Green S, Dalton WS et al: Multicenter randomized clinical trial of goserelin versus 
surgical ovariectomy in premenopausal patients with receptor-positive metastatic breast 
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15. Lum SS, Woltering EA, Fletcher WS et al: Changes in serum estrogen levels in women during 
Tamoxifen therapy. Am J Surg 173:399-402, 1997.  
16. E. Garcia-Giralt et al.  Phase II trial of Decapeptyl (D-TRP-6), a potent Luteinizing Hormone-
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17. Jonat W, Kaufmann M, Blamey RW, et al: A randomised study to compare the effect of the 
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1995.  
18. Klijn JGM, Beex L, Mauriac L et al: Combined treatment with the LHRH-agonist buserelin 
and tamoxifen vs single treatment with each drug alone in premenopausal metastatic breast 
cancer. Final results of EORTC study 10881. Ann Oncol 4 (9):11 [meeting abstract 540], 1998.  
19. Klijn JGM, Beex L, Mauriac L et al: Combined treatment with buserelin and tamoxifen in 
premenopausal metastatic breast cancer: a randomized study. J Natl Cancer Inst 92:903-911, 
2000.  
20. Klijn JGM, Blainey RW, Boccardo F et al: Combined tamoxifen and Luteinizing 
HormoneReleasing Hormone (LHRH) agonist versus LHRH agonist alone in premenopausal 
advanced breast cancer: A meta-analysis of four randomized trials.  J Clin Oncol 19:343-353, 
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21. Davidson N, O‟Neill A, Vukov A et al: Effect of chemohormonal therapy in premenopausal 
node (+) receptor (+) breast cancer: An Eastern Cooperative Oncology Group phase III 
intergroup trial (E5188, INT-0101).  Proc Am Soc Clinic Oncol 18: A249, 1999 (abstr).   
22. Jimenez-Gordo AM, de las Heras B, Zamora P, et al: Failure of goserelin ovarian ablation in 
premenopausal women with breast cancer: two case reports. Gynecol Oncol 76:126-7, 2000  
23. Kaufman M, Bajetta E, Dirix LY, et al: Exemestane is superior to megestrol acetate after 
tamoxifen failure in postmenopausal women with advanced breast cancer: Results of a phase 
III randomized double-blind trial. J Clin Oncol 18:1399-1411, 2000.  


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24. Pritchard KI. Current and future directions in medical therapy for breast carcinoma: endocrine 
treatment. Cancer 88(12 Suppl):3065-3072, 2000.    
25. Mouridsen H, Gershanovich M, Sun Y, et al: Superior efficacy of letrozole versus tamoxifen 
as first-line therapy for postmenopausal women with advanced breast cancer: results of a phase 
III study of the International Letrozole Breast Cancer Group. J Clin Oncol 19:25962606, 2001.  
26. The ATAC Trialists‟ Group.  Anastrazole alone or in combination with Tamoxifen versus 
tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer; 
the first results of the ATAC randomized trial.  The Lancet 359: 2131-2139, 2002.  
27. Santen RJ, Samojlik E, Wells SA. Resistance of the ovary to blockade of aromatization with 
aminoglutethimide. J Clin Endocrinol Metab 51:473-477, 1980.  
28. Dowsett M, Doody D, Miall S, et al. Vorozole results in greater oestrogen suppression than 
formestane in postmenopausal women and when added to goserelin in premenopausal women 
with advanced breast cancer. Breast Cancer Res Treat 56:25-34, 1999.    
29. Celio L, Martinetti A, Ferrari L, et al: Premenopausal breast cancer patients treated with a 
gonadotropin-releasing hormone analog alone or in combination with an aromatase inhibitor: 
a comparative endocrine study. Anticancer Res 16:2261-2268, 1999.  
30. Forward D, Cheung KL, Jackson JF, et al: Combined use of goserelin and anastrazole 
(Arimidex) in premenopausal women with metastatic breast cancer. Proc Am Soc Clin Oncol 
19:A582, 2000 (abstr).  
31. Powles TJ, Hickish T, Kanis JA, Tidy A, Ashley S: Effect of tamoxifen on bone mineral 
density measured by dual-energy x-ray absorptiometry in healthy premenopausal and 
postmenopausal women. J Clin Oncol 14:78-84, 1996.  
32. Sverrisdottir A, Fornander T and Rutquist L: Bone mineral density in premenopausal patients 
in a randomized trial of adjuvant endocrine therapy (ZIPP-Trial). Proc Am Soc Clinical 
Oncology 20: 2001 abstract #96.   
33. Goss PE, Grynpas MD, Qi S, et al. The effects of exemestane on bone and lipids in the 
ovariectomized rat. Breast Cancer Res Treat 69:224, 2001 (Abstract 132).  
34. Braverman AS, Sawhney H, Tendler A et al. Premenopausal serum estradiol levels may persist 
after chemotherapy induced amenorrhea in breast cancer. Proc Am Soc Clin Oncol 12;2002 
(Abstract 164).  
35. Goldhirsch, A., et al., Meeting highlights: International Consensus Panel on the Treatment of 
Primary Breast Cancer. Seventh International Conference on Adjuvant Therapy of Primary 
Breast Cancer. J Clin Oncol, 2001. 19(18): p. 3817-27.  
36. Recht, A., et al., Postmastectomy radiotherapy: clinical practice guidelines of the American 
Society of Clinical Oncology. J Clin Oncol, 2001. 19(5): p. 1539-69.  
37. Rutqvist, L.E., et al., Cardiovascular mortality in a randomized trial of adjuvant radiation 
therapy versus surgery alone in primary breast cancer. Int J Radiat Oncol Biol Phys, 1992. 
22(5): p. 887-96.  


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38. Bentzen SM, Skocxylas JZ, Overgaard M, Overgaard J., Radiotherapy-related lung fibrosis 
enhanced by tamoxifen. J Natl Cancer Inst. 1996; 88:918-922.  
39. Loprinzi C, Abu-Ghalzaleh S, Sloan J, et al. Phase III randomized double blind study to 
evaluate the efficacy of a polycarbophil-based vaginal moisturizer in women with breast 
cancer. J Clin Oncol 15:969-973,1997.  
40. Loprinzi C, Kugler J, Sloan J, et al. Venlafaxine alleviates hot flashes: An NCCTG trial. Proc 
Am Soc Clin Oncol 19:A4, 2000 (abstr).  
41. EaSt 2000 (Early Stopping) statistical software package. Cytel Corporation, Cambridge, MA, 
USA, 2000.  
42. O‟Brien PC, Fleming TR: A multiple testing procedure for clinical trials.  Biometrics 
35:549556, 1979.  
43. Chabner E, Nixon A, Gelman R, Hetelekidis S, Recht A, Bornstein B, Connolly J, Schnitt S, 
Silver B, Manola J, Harris J, Garber J:  Family history and treatment outcome in young women 
after breast-conserving surgery and radiation therapy for early-stage breast cancer.  J Clin 
Oncol 16:2045-2051, 1998.  
44. Brekelmans CT, Voogd AC, Botke G, van Geel BN, Rodrigues P, Rutgers EJ, Klijn JG, 
Coebergh JW:  Family history of breast cancer and local recurrence after breast-conserving 
therapy.  The Dutch Study Group on Local Recurrence after Breast Conservation (BORST).  
Eur J Cancer 35:620-626, 1999.  
45. Phillips KA, Andrulis IL, Goodwin PJ:  Breast carcinomas arising in carriers of mutations in 
BRCA1 or BRCA2:  are they prognostically different?  J Clin Oncol 17:3653-3663, 1999.  
46. Howell A, Cuzick J, Baum M, Buzdar A, Dowsett M, Forbes JF, Hoctin-Boes G, Houghton  
J, Locker GY, Tobias JS, ATAC Trialists‟ Group. Results of the ATAC (Arimidex, Tamoxifen 
Alone or in Combination) trial after completion of 5 years‟ adjuvant treatment for breast 
cancer. Lancet 2005;365(9453):60-62.  
47. Coombes RC, Hall E, Gibson LJ, et al; Intergroup Exemestane Study.  A randomized trial of 
exemestane after 2 to 3 years of tamoxifen therapy in postmenopausal women with primary 
breast cancer. N Engl J Med 350;1081-1092, 2004.  
48. Coombes RC, Hall E, Snowdon CF, et al; A randomized trial in postmenopausal patients with 
early breast cancer who remain disease-free after 2 to 3 years of tamoxifen: updated survival 
analysis.  27th Annual San Antonio Breast Cancer Symposium; December 8-11, 2004; San 
Antonio, TX (oral presentation). Breast Cancer Res and Treat Vol 88 suppl 1, 2004 pS7.  
49. Thurlimann BJ, Keshaviah A, Mouridsen H, Mauriac L, Forbes JF, Paridaens R, 
CastiglioneGertsch M, Gelber RD, Smith I, Goldhirsch A. BIG 1-98: Randomized double-
blind phase III study to evaluate letrozole vs. tamoxifen as adjuvant endocrine therapy for 
postmenopausal women with receptor-positive breast cancer. Proc Am Soc Clin Oncol 
2005;23(16S):6s (suppl, abstr 511).  
  


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Appendices   
  
I.  
Requirements for Informed Consent  II.  NCI Common Terminology Criteria for 
Adverse Events (CTCAE), Version 3.0  
[available from the internet at:  http://ctep.cancer.gov/reporting/ctc.html]  
III.  
Hormone Receptor Guidelines  IV.  
Pathology Protocol V.  
Quality-of-
Life Protocol VI.  
Authorization Log VII.  
Participating Group Specific Logistical 
Information  
VIII. IBCSG Guidelines for Publication and Presentations  
  

SAP_000.pdf: 
TEXT & SOFT 2017 Update SAP: Working version November 2017 
 
1 
 
 
 
 
 
 
 
 
 
International Breast Cancer Study Group Statistical Center 
 
 
TEXT (Trial 25-02/BIG 3-02) and SOFT (Trial 24-02/BIG 2-02)  
Statistical Analysis Plan 
 
2017 Update  
 
 
Meredith Regan, ScD 
May 2017 
Complete for efficacy, AE, protocol treatment 
red text reflects changes for the update analyses since the first analyses 
blue text reflects edits/notes since the analysis started 
Nov 2017 
For non-protocol therapy notes (noted in blue) 
 
 
 


TEXT & SOFT 2017 Update SAP: Working version November 2017 
 
2 
 
1. Introduction 
1.1 Background 
In 2003 IBCSG initiated a suite of three complementary tailored treatment investigations, the SOFT, 
TEXT and PERCHE trials, designed to answer questions concerning adjuvant treatment for 
premenopausal women with endocrine-responsive early breast cancer: 1) What is the role of ovarian 
function suppression (OFS) for women who remain premenopausal and are treated with tamoxifen? 2) 
What is the role of aromatase inhibitors for women treated with OFS? 3) What is the role of 
chemotherapy for women treated with OFS plus oral endocrine therapy? 
The conduct of these randomized phase III trials required world-wide participation through collaboration 
of the Breast International Group (BIG) network and the North American Breast Cancer Groups. Pfizer 
is the primary pharmaceutical industry partner and Ipsen provides triptorelin outside of North America.  
Over a 7.5-year period from 2003 to 2011, 5742 premenopausal women were enrolled at over 500 
centers in 27 countries on 6 continents in:  
 
TEXT (Tamoxifen and Exemestane Trial): designed to determine the role of AIs for women who 
receive OFS from the start of adjuvant therapy; 
 
SOFT (Suppression of Ovarian Function Trial): designed to determine the role of OFS and the role 
of AIs for women who remain premenopausal after completion of (neo)adjuvant chemotherapy, or 
who are premenopausal following surgery and tamoxifen alone is a reasonable treatment option;  
 
PERCHE (Premenopausal Endocrine-Responsive Chemotherapy): designed to determine the 
value of adding chemotherapy to combined endocrine therapy with OFS plus oral endocrine 
therapy.  
TEXT and SOFT successfully enrolled the targeted number of patients. PERCHE closed prematurely in 
2006 with only 29 patients enrolled (25 of 29 were co-enrolled in TEXT; (Regan et al., Ann Onc 2008).  
Completion of TEXT and SOFT enrollment was anticipated within 5 years and first reporting about 7 
years after the trials’ initiation. However the characteristics of the enrolled patients differ from those 
anticipated in the protocols, and patients’ outcomes are better than expected, necessitating an 
adaptation of the trials’ analysis plans, in protocol amendments released in 2011. The original designs 
of TEXT and SOFT and the adaptations to overcome these challenges and ensure timely answers to 
questions concerning adjuvant treatment for premenopausal women with endocrine-responsive early 
breast cancer were described recently (Regan et al., Breast 2013). 
1.2 Trial Designs 
The designs of TEXT and SOFT are summarized below. 
 
 


TEXT & SOFT 2017 Update SAP: Working version November 2017 
 
3 
 
TEXT (IBCSG 25-02 / BIG 3-02) 
Title: 
Tamoxifen and Exemestane Trial (TEXT): A phase III trial evaluating the 
role of exemestane plus GnRH analogue as adjuvant therapy for 
premenopausal women with endocrine responsive breast cancer. 
Patient 
Population: 
Premenopausal women (estradiol (E2) levels in the premenopausal range) 
with histologically proven, resected breast cancer with ER and/or PgR 
positive tumors (ER and/or PgR ≥ 10%). 
Entry: 
Patients should be randomized within 12 weeks after surgery prior to 
commencing any adjuvant systemic therapy. 
Activation Date: 
04Aug03 (First patient randomized 7Nov03) 
Target Accrual:  
2639 patients 
Closure Date: 
11Mar11 (Last patient randomized 7Apr13) 
Final Accrual: 
2672 patients 
 
TEXT Schema: 
*
Primary 
Surgery  
Stratify: 
• 
Institution 
• 
Chemotherapy 
(no; yes) 
• 
Number of 
positive nodes   
(0; 1 or more) 
R 
A 
N 
D 
O 
M 
I 
Z 
E 
(+/- CT)** 
Triptorelin for 5 years plus 
Tamoxifen*** for 5 years 
A 
B 
(+/- CT)** 
Triptorelin for 5 years plus 
Exemestane*** for 5 years 
* Randomization prior to receiving any adjuvant systemic therapy 
**CT (chemotherapy) is determined by investigator/patient choice and if used, should begin at the same 
time as triptorelin.  
***Tamoxifen or exemestane should start after adjuvant chemotherapy has been completed or 
approximately six to eight weeks after the initiation of triptorelin, whichever is later. 
 
IBCSG 25-02 (TEXT) is an international, non-blinded, randomized phase III trial designed to investigate 
the efficacy the aromatase inhibitor (AI) exemestane with OFS, achieved by long-term use of GnRH 
analogue, compared with tamoxifen+OFS. TEXT focuses the AI question on premenopausal patients 
whom the physician feels OFS is most appropriate from the start of adjuvant therapy. Eligibility required 
enrollment within 12 weeks of definitive surgery and excluded patients who had already received any 
(neo)adjuvant chemotherapy or endocrine therapy. Randomization used 1:1 allocation and stratified by 
whether adjuvant chemotherapy was planned (no; yes), and number of positive nodes (0; 1 or more). 
Patients would either receive no chemotherapy or commence chemotherapy at the same time as GnRH 
analogue is initiated. Patients had to use GnRH analogue for at least 6 months and then could change 
to permanent OFS with surgery or radiation at any time thereafter.  
 
 


TEXT & SOFT 2017 Update SAP: Working version November 2017 
 
4 
 
SOFT (IBCSG 24-02 / BIG 2-02) 
Title: 
Suppression of Ovarian Function Trial (SOFT): A phase III trial evaluating 
the role of OFS and the role of exemestane as adjuvant therapies for 
premenopausal women with endocrine-responsive breast cancer. 
Patient 
Population: 
Premenopausal women (estradiol (E2) levels in the premenopausal range†) 
with histologically proven, resected breast cancer with ER and/or PgR 
positive tumors (ER and/or PgR ≥ 10%) who have received either no 
chemotherapy or remain premenopausal following completion of adjuvant 
and/or neoadjuvant chemotherapy. 
Entry: 
Patients who do not receive chemotherapy should be randomized within 12 
weeks after surgery; such patients must have E2 levels in the 
premenopausal range following surgery. Patients who have received 
adjuvant and/or neoadjuvant chemotherapy should be randomized within 8 
months of the final dose of chemotherapy as soon as premenopausal status 
is confirmed; such patients must have E2 levels in the premenopausal range 
between 2 weeks and 8 months after the final dose of chemotherapy. 
Activation Date: 04Aug03 (First patient randomized 17Dec03) 
Target Accrual:  3000 patients 
Closure Date: 
31Jan11 (Last patient randomized 27Jan11) 
Final Accrual: 
3066 patients 
 
SOFT Schema: 
 
IBCSG 24-02 (SOFT) is an international, three-arm, non-blinded, randomized phase III trial designed to 
investigate the role of OFS and the role of the AI exemestane, originally planned with three primary 
comparisons: tamoxifen+OFS versus tamoxifen alone; exemestane+OFS versus tamoxifen alone; and 
exemestane+OFS versus tamoxifen+OFS. SOFT focuses the OFS question on those who biologically 
would be most likely to benefit, i.e., women with endocrine-responsive breast cancer with 
premenopausal status either after completion of (neo)adjuvant chemotherapy or following surgery 
alone.  


TEXT & SOFT 2017 Update SAP: Working version November 2017 
 
5 
 
Eligibility required enrollment either: (a) within 8 months of the final dose of chemotherapy once 
premenopausal status was confirmed by estradiol levels (e.g., patients with temporary chemotherapy-
induced amenorrhea who regained premenopausal status within 8 months were eligible); or (b) within 
12 weeks of definitive surgery if no adjuvant chemotherapy was to be given. Patients could have 
received adjuvant oral endocrine therapy (but not GnRH analogues) for up to 8 months prior to 
randomization. The 8-month criterion was an early protocol amendment (from 6 months) to overcome 
logistical challenges of enrolling a patient who presented after regaining premenopausal status at a 6-
months post-chemotherapy standard-of-care visit. 
Randomization used 1:1:1 allocation, and was stratified according to prior (neo)adjuvant chemotherapy 
(yes;no), lymph node status (0; 1+) and intended method of OFS (GnRH analogue, oophorectomy; 
ovarian irradiation). For patients randomized to receive OFS, the use of GnRH analogue, bilateral 
oophorectomy or bilateral ovarian irradiation was by patient preference and patients who began with 
GnRH analogue could opt to undergo surgery or irradiation at any time.  
1.2.1 Design Commonalities 
As a planned suite of trials, a majority of trial design features were common to both trials. Briefly, the 
trials enrolled premenopausal women with histologically-proven, resected, hormone receptor-positive 
(defined as ER≥10% and/or PgR≥10%) early invasive breast cancer. Premenopausal status was 
defined by estradiol levels in the premenopausal range according to institutional parameters. The tumor 
was to be confined to the breast and axillary lymph nodes without detected metastases elsewhere. 
Patients must have had proper local-regional treatment for primary breast cancer with no known 
residual loco-regional disease. Study visits were every 3 months during year one, every 6 months 
during the next 5 years, and yearly follow-up thereafter.  
The oral endocrine therapy was either tamoxifen or the steroidal AI exemestane. OFS was by GnRH 
analogue triptorelin administered 4-weekly for 5 years, bilateral surgical oophorectomy, or bilateral 
ovarian irradiation (with biochemical confirmation of cessation of ovarian function after 2 months). 
1.2.2 Original statistical design assumptions and sample size considerations 
TEXT planned enrollment was 1845 patients. The design projected that 4.5 years of uniform accrual, 
plus 2.4 years of additional follow-up, would be sufficient to observe the target of 396 DFS events, 
which would provide 80% power to detect 25% reduction in hazard with exemestane+OFS versus 
tamoxifen+OFS (HR=0.75; 79.8% versus 74.1% 5-year DFS, respectively) using a 2-sided 0.05 α-level 
logrank test and assuming exponential distribution of DFS. Four interim analyses prior to the final 
analysis were planned. By November 2007, 2039 of the planned 1845 patients had enrolled, and 
enrollment was suspended. Because of the faster-than-expected enrollment rate and lower-risk 
characteristics of enrolled patients than anticipated, Amendment 2 (Jul08) re-opened enrollment with an 
increased target sample size of 2639 patients. A revised estimate of 80% 5-year DFS in the 
tamoxifen+OFS control group (with corresponding 25% reduction in hazard to 84.6% 5-year DFS for 
exemestane+OFS) was hypothesized based on the 2007 overview analysis of GnRH analogues in 
which the 5-year breast cancer recurrence was around 18% among patients treated with GnRH 
analogue plus tamoxifen. With the observed enrollment pattern and revised hazard rates, the increased 
sample size was projected to reach the target of 396 DFS events within 0.5 years of the original design, 
or 7.4 years since first enrollment. 


TEXT & SOFT 2017 Update SAP: Working version November 2017 
 
6 
 
SOFT planned enrollment was 3000 patients for the 3 arms. The design projected that 5 years of 
uniform accrual, plus 1.9 years of additional follow-up would be sufficient to observe the target of 783 
DFS events (522 per pairwise comparison) to have 80% power to detect a 25% reduction in hazard 
relative to control 5-year DFS of 67% (HR=0.75; 74.1% versus 67.0% 5-year DFS; 2-sided α=0.0167). 
If tamoxifen+OFS would result in a 25% reduction in hazard to 74.1% 5-year DFS, then power was 
68% to detect a further 25% reduction with exemestane+OFS to 79.8% 5-year DFS. Four interim 
analyses prior to the final analysis were planned. 
From the outset, the protocols planned to combine the data of TEXT with the two arms of SOFT 
comparing exemestane+OFS versus tamoxifen+OFS. Differences in the two trials with respect to 
selection and treatment for women who received chemotherapy (i.e., TEXT enrolled patients following 
surgery and used concurrent GnRH analogue and chemotherapy, while SOFT enrolled patients who 
remained premenopausal following chemotherapy and initiated OFS after completion of chemotherapy) 
were taken into account in the combined analysis plan. The statistical power of such a combined 
comparison (at the two-sided α=0.05 level) would be at least 88%, 98% and 99% to detect a 20%, 25%, 
and 30% reduction in hazard, respectively, with exemestane+OFS versus tamoxifen+OFS under the 
protocol assumptions about accrual duration and additional follow-up. 
1.2.3 Adaptations in the statistical design and analysis plans 
As of October 2010, the overall DFS event rates—blinded to treatment assignment—were substantially 
lower than originally anticipated: approximately 1.7% and 2% per year versus the protocol-specified 6% 
and 8% per year in TEXT and SOFT, respectively. IBCSG projected an additional 7 and 13 years of 
follow-up to observe the targeted 396 and 783 DFS events in TEXT and SOFT, respectively (at median 
follow-up of 10.5 and 15 years). Increasing the sample size could hasten reaching the required events, 
but finances constrained this possibility. 
The Steering Committee considered this delay to be unacceptably long (reporting 14 and 20 years after 
first enrollment versus 6.9 years originally-anticipated). The Committee decided to change the timing of 
analysis from “event-driven” to “time-driven” with a planned data cut-off during the third quarter of 2013, 
when the median follow-up should be at least 6 and 5 years in TEXT and SOFT, respectively. It was 
recognized that an analysis with fewer events than targeted would substantially reduce statistical power 
for the original protocol-planned primary objectives (approximately 60% in TEXT and 35% in SOFT to 
detect 25% reductions in hazards, assuming the October 2010 event rates continued). Therefore 
amendments of the TEXT and SOFT protocols (July 2011) revised the analysis plans for the first 
reporting of the trial objectives: 
1. AI Question: the primary analysis comparing exemestane+OFS versus tamoxifen+OFS would 
implement the originally-planned combined analysis of TEXT and SOFT. The power of such a 
combined comparison (two-sided α=0.05 level) would be at least 95%, 84% and 63% to detect a 
30%, 25% and 20% reduction in hazard, respectively, with exemestane+OFS. 
2. OFS Question: the primary analysis from SOFT would focus on the unique comparison of 
tamoxifen+OFS versus tamoxifen alone, tested at the two-sided α=0.05 level. IBCSG estimated 
power to be at least 80%, 69%, 52% and 34% to detect 33.5%, 30%, 25% and 20% reductions in 
hazard, respectively, with tamoxifen+OFS.  


TEXT & SOFT 2017 Update SAP: Working version November 2017 
 
7 
 
These power calculations assumed a data cut-off in the third quarter of 2013 and persistence of the 
October 2010 DFS event rates, which project 250 DFS events in TEXT and 280 DFS events in SOFT 
(about 93 per group under the null hypothesis) at the time of data cut-off. The revised analysis plans 
removed planned interim efficacy analyses. The revised analysis plans removed planned interim 
efficacy analyses.  
The Steering Committee’s decision was endorsed by the IBCSG DSMC. These committees did not 
receive, nor did the IBCSG Statistical Center have knowledge of, outcome data according to treatment 
group prior to this decision. The first report of the combined analysis of the AI Question is anticipated 
in mid-2014. The report of the OFS Question from SOFT is anticipated in late 2014 after about 6 
additional months of follow-up and a median follow-up of at least 5 years is reached.  
Patient follow-up will continue and updates of efficacy results are planned approximately every two 
years after the first reports. 
1.3 First Results 
1.3.1 AI Question 
After a median follow-up of 68 months (5.7 years), DFS events were reported for 514 (11%) of 4690 
patients in the ITT population. Patients assigned E+OFS had statistically significantly reduced hazard of 
a DFS event vs. patients assigned T+OFS (HR=0.717; 95% CI, 0.602 to 0.855; P=0.0002). The 
estimated 5-year DFS was improved at 91.1% vs. 87.3% among patients assigned E+OFS vs. T+OFS. 
The reduction in hazard with E+OFS vs. T+OFS was consistently observed for secondary endpoints of 
breast cancer-free interval and distant recurrence-free intervals, although at this point in follow-up a 
reduction in hazard of death was not observed. 
In this analysis, 30.2% of patients continue on protocol-assigned treatment. 30.6% and 29.4% of 
patients assigned to E+OFS and T+OFS have had grade 3-4 targeted AEs reported, of which hot 
flashes/flushes, musculoskeletal symptoms and hypertension were the most frequently reported 
1.3.2 OFS Question 
After a median follow-up of 67 months (5.6 years), DFS events were reported for 299 (14.7%) of 2033 
patients in the ITT population. T+OFS non-significantly reduced hazard of a DFS event vs. T (HR=0.83; 
95% CI, 0.66 to 1.04; P=0.10). The estimated 5-year DFS among patients assigned T+OFS was 86.6% 
(95% CI, 84.2% to 88.7%) versus 84.7% (95% CI, 82.2% to 86.9%) among patients assigned T. The 
relative effects of T+OFS vs. T were consistent between the two chemotherapy strata; as expected, the 
absolute difference at 5 years was more notable among patients who received prior chemotherapy. The 
reduction in hazard with T+OFS vs. T was consistently observed for the secondary endpoints of breast-
cancer-free interval and distant recurrence-free interval. 106 (5.2%) deaths were reported, and on 
average there was a non-significantly reduced hazard of death; with all except 10 deaths among 
patients who received prior chemotherapy, the reduction in hazard was more apparent among this 
cohort of patients 
At the time of the analysis, 26% of patients continued on protocol-assigned treatment. 31% and 24% of 
patients assigned to T+OFS and T have had grade 3-5 targeted AEs reported, of which hot 
flashes/flushes, musculoskeletal symptoms and hypertension were the most frequently reported. 
1.3.3 Numbers of DFS events, deaths and median follow-up by trial 


TEXT & SOFT 2017 Update SAP: Working version November 2017 
 
8 
 
For the AI Question analysis, the TEXT ITT population had 285 DFS events and 101 deaths reported, 
after median follow-up of 6 years (data cut-off, 31Aug13). 
At the time of the OFS Question analysis, the 3 arms of the SOFT ITT populations had 412 DFS events 
and 164 deaths reported, after median follow-up of 5.6 years (data cut-off, 31Mar14). 
 
2. Efficacy Analysis Plans 
2.1 Protocol Objectives 
Based on revised statistical analysis plans in the 2011 amendments (i.e., SOFT Amendment 2 
(24Aug11); and TEXT Amendment 3 (24Aug11)): 
2.1.1 Primary Objective 
AI Question: To evaluate the efficacy of exemestane+OFS compared with tamoxifen+OFS, across both 
trials combined, as adjuvant endocrine therapy for premenopausal women with endocrine-responsive 
early invasive breast cancer.  
OFS Question: To evaluate the role of OFS+tamoxifen compared with tamoxifen alone, as adjuvant 
endocrine therapy for premenopausal women with endocrine-responsive early invasive breast cancer. 
2.1.2 Secondary Objectives 
• 
Assess overall survival, breast cancer-free interval, and distant recurrence-free interval  
• 
Assess quality of life (see separate analysis plan) 
• 
Investigate sites of first treatment failure 
• 
Assess late side effects of early menopause 
• 
Assess the incidence of second (non-breast) malignancies and causes of death without cancer 
event 
• 
TEXT: Investigate patient and tumor features that may contribute to inter-individual variability of 
responsiveness to GnRH analogue plus exemestane and GnRH analogue plus tamoxifen (see 
separate analysis plan) 
 
2.2 Updated Analyses 
Rather than presenting results by trial, the analyses will continue to be organized as: 
• 
AI Question (E+OFS vs T+OFS), jointly for  the two trials; 
o Summarize by 4 cohorts 
o Summarize by trial also 
• 
OFS Question (T+OFS vs T), reporting all three arms  
The analysis will secondarily focus on the subgroup of HER2-negative disease. The main reason is the 
clinical relevance of separating the subgroups of HER2-negative and positive disease in current 
practice and trial design. We also previously observed heterogeneity of treatment effects according to 
HER2 status, and the HER2-postiive subgroup presents challenges because HER2-directed therapy 
changed during the conduct of the trials and HER2-directed therapy had different timing in TEXT and 


TEXT & SOFT 2017 Update SAP: Working version November 2017 
 
9 
 
SOFT chemotherapy cohorts (starting after randomization in TEXT, starting and mostly completing prior 
to randomization in SOFT). 
 
2.2 Analysis Populations 
The updated analysis will continue to use an intention-to-treat (ITT) approach. During the first analyses, 
there was one SOFT T+OFS patient who was included in the AI Question ITT population, but then 
excluded from the OFS Question ITT population (243007). In updated analyses, this patient will remain 
in the ITT populations as previously analyzed. 
AI Question: The AI Question ITT population will include 
• 
All patients randomized in TEXT (exemestane+OFS and tamoxifen+OFS); 
• 
SOFT 
patients 
randomized 
to the 
two OFS-containing 
arms 
(exemestane+OFS 
and 
tamoxifen+OFS). 
OFS Question: The OFS Question ITT population will include 
• 
SOFT patients randomized to the two tamoxifen-containing arms (tamoxifen+OFS and tamoxifen 
alone). 
• 
SOFT patients randomized to exemestane+OFS. 
 
2.3 Endpoint Definitions 
Endpoint definitions remain the same as in the first report. 
Per IBCSG standard, the date of DFS event is the date a proven recurrence was first suspected. Since 
the first trial report, the 2425-RC Form SOP was clarified that in cases with multiple proven sites of first 
recurrence (within 2 months of each other), that the date first suspected should be the earliest of 
suspected dates from among those proven sites (which may not necessarily correspond to the site with 
the earliest proven date).  
 
2.4 Follow-up 
As in the first analysis, median follow-up is calculated from the Kaplan-Meier estimate of overall 
survival, with the event/censoring indicator inverted (i.e. alive as event and dead as censored).  
In the first analysis, the visit cut-offs were 31Aug13 and 31Mar14. Updated results were anticipated to 
be presented every two years thereafter until the last patient enrolled has been followed for at least 10 
years. 
For the first update, concurrent visit cut-offs (of 31Dec16) and database locks (04May17)  are planned. 
The visit cut-off is selected because almost all patients will have at least 6 years follow-up (except 
those final patients randomized during Q1 2011). 
 


TEXT & SOFT 2017 Update SAP: Working version November 2017 
 
10 
 
2.5 Tests and Estimates 
As in the first analysis, the primary objectives will be investigated by comparing DFS between two 
treatment groups using two-sided stratified logrank test (H0: DFS1=DFS2; Ha: DFS1≠DFS2), with an 
overall experiment-wise α=0.05 (i.e., α=0.05 for AI Question analysis; and α=0.05 for OFS Question 
analysis). The test statistic and p-value will be taken from the stratified Cox PH model score test. 
Hazard ratios (AI Question: E+OFS / T+OFS; OFS Question: OFS+T / T) will be estimated from a 
stratified Cox PH model, with two-sided Wald 95% CIs. Kaplan-Meier estimates of the DFS distributions 
will be calculated for each of the treatment arms, with reporting of the 8yr DFS (MFU is 7.9y in SOFT 
and 9.1y in TEXT so 8yr estimates appropriate for both trials); the SEs will use Greenwood’s formula 
and the pointwise 95% CIs will be obtained using complementary log-log transformation of the SDF.  
The E+OFS vs T comparison will be included with estimation of HR (95% CI) for E+OFS / T, but no 
hypothesis testing is planned. The 8yr DFS would also be summarized.  
In the first OFS Question analysis, the primary analysis model included only the 2 treatment groups; it 
is now planned that the model for HR estimates will include all 3 treatment groups, using contrasts to 
obtain the pairwise score tests. 
We will check the proportional hazards assumption by visually assessing the plot of log(-log(survival)) 
versus log of survival time for parallelism. This will be done overall, and according to strata. 
2.5.1 Stratification variables for logrank tests and HRs 
AI Question analysis: 
• 
Trial (TEXT; SOFT); 
• 
Prior/Intended chemotherapy (no; yes); 
• 
Number of positive nodes (0; 1+). 
OFS Question analysis: 
• 
Prior chemotherapy (no;yes); 
• 
Number of positive nodes (0; 1+), and  
The analyses will use the originally-defined strata variables, even if the actual value on the A form has 
been changed within the database since the first analysis (any such changes will be noted). 
Since the first trial report, it was determined that the TEXT chemo strata hadn’t paid adequate attention 
to value of patients enrolled in PERCHE whose chemo receipt was by random assignment. Upon 
review, those randomized to yes-chemo were all 12/12 in the yes-chemo strata, though only 11/13 of 
those randomized to no-chemo were in the no-chemo strata. As above, we will use the originally-
defined strata variables but the observed adj_ct variable now says “no chemo” for all 13 pts. 
Note about the stratification of OFS Question analysis: the two methods of ovarian ablation, 
oophorectomy and ovarian irradiation, were planned to be grouped as the third stratification factor 
because few patients had specified irradiation. Even grouped, having the 3 stratification factors (for 8 
strata total) resulted in some small strata sizes with sparse events especially once considering the 
chemotherapy cohorts separately or other subgroups and once looking at outcomes with fewer events. 
As such, the outcome analyses will NOT include the third stratification factor, but the endpoint analyses 
in the overall ITT population will be repeated with the third stratification factor included to understand 
ramifications of this decision. 


TEXT & SOFT 2017 Update SAP: Working version November 2017 
 
11 
 
2.5.2 Cohorts 
The TEXT and SOFT trial populations include four cohorts of patients: 
• 
Patients in TEXT who were randomized within 12 weeks of surgery and for whom 
chemotherapy was not planned; 
• 
Patients in SOFT who did not receive chemotherapy and were randomized within 12 weeks of 
surgery; 
• 
Patients in TEXT who were randomized within 12 weeks of surgery and for whom 
chemotherapy was planned to begin after randomization, concurrently with GnRH analogue;  
• 
Patients in SOFT who are premenopausal after prior (neo)adjuvant chemotherapy and are 
randomized within 8 months of completion chemotherapy. 
Therefore in addition to having trial and chemotherapy as stratification factors, it is of interest to 
estimate the treatment effect within cohorts of the trials’ patient populations. Note, the two cohorts of 
TEXT and SOFT who will not receive chemotherapy may differ, considering that in TEXT all patients 
would receive OFS whereas in SOFT the patients may have been randomized not to receive OFS.  
(n.b., We will use the chemotherapy stratification factor, which in TEXT is intended chemotherapy and 
therefore may be different from actual chemotherapy receipt, in a few patients). 
AI Question: In addition to the overall treatment comparison, the HRs (95% CI) will be estimated within 
each of the 4 trial-by-chemotherapy cohorts separately. The 4 cohort HR estimates will be obtained 
from adding the cohort-by-treatment interaction and using contrasts to estimate HRs and CIs within 
each of the 4 cohorts. 
The HRs (95% CI) will also be estimated by trial. To obtain these estimates, we will refit the primary 
Cox model with a trial-by-treatment interaction and using contrasts to estimate HRs and CIs within each 
of the trials. 
OFS Question: In addition to the overall treatment comparison, the HRs (95% CI) will be estimated 
within each of the chemotherapy cohorts separately (SOFT prior chemo; SOFT no prior chemo) as 
described above. 
 
2.6 Analysis Components 
2.6.1 CONSORT 
For the CONSORT flow diagram. Any changes (except WC/LFU) from first analysis will be noted. 
Tables: 
• 
CONSORT diagram content numbers by treatment assignment 
o Number of patients randomized 
o Number of patients included vs excluded from analysis population (noting any difference 
from first report) 
o Number in analysis population who never started protocol treatment (noting any 
difference from first report) 
o Number in analysis population who WC/LFU 


TEXT & SOFT 2017 Update SAP: Working version November 2017 
 
12 
 
o Number of patients analyzed in analysis population [same/as number included] 
2.6.2 Follow-up compliance and WC/LFU 
This section summarizes follow-up compliance, according to trial, in the ITT populations. 
Tables: 
• 
Institutional follow-up compliance group/country (rows); by trial and overall  
• 
Withdrawn consent and lost to follow-up status 
2.6.2 Stratification factors and patient characteristics 
2.6.2.1 Stratification factors 
Any patients for whom values of the stratification factors are determined to be different from those 
originally analyzed will be listed. 
2.6.2.2 Characteristics 
Because some of the values of characteristics may have changed since the first trial report, tables of 
characteristics of the analysis populations to be used in subgroup analyses will be re-summarized 
overall and by trial, cohort and treatment group. Continuous variables are summarized as mean, SD, 
min/max, and quartiles. Categorical variables are summarized as N(%); for variables with unavailable 
(missing, unknown, not done) values, the default approach is to list the number of unknowns as a 
category, but calculate percentages excluding these unknowns from the denominator; however there 
will be some variables that are frequently not assessed and in those cases the percentages will be 
calculated with and without the unknown category.  
Table of:  
• 
Patient: age group 
• 
Disease: HR status, HER2 status/treatment; N status, T size, T grade  
• 
Treatment: local therapy (surgery/RT), chemotherapy regimen  
2.6.3 Primary efficacy analysis 
The primary efficacy analysis will proceed as summarized in Section 2.4 above. The data cut-off and 
database lock dates used for the analyses and the median follow-up duration will be reported (MFU 
also by trial & treatment group).  
2.6.3.1 Subgroup Analyses and Covariate-adjusted HR Estimates 
Same as first analysis. 
2.6.3.2 Tables and Figures 
Tables: 
• 
AI Question (E+OFS vs T+OFS), stratified by cohort & nodal stratum 
o Primary treatment comparison: N events and patients, HR, 95% CI, log-rank test statistic 
and p-value, 8yr DFS, SE and 95% CI 
o By-trial (2) and by-cohort (4) treatment comparisons: N events and patients, HR, SE, 
95% CI, 8yr DFS, SE and 95% CI 


TEXT & SOFT 2017 Update SAP: Working version November 2017 
 
13 
 
o Treatment effects within subgroups: N events and patients within each subgroup, 
treatment HR, 95% CI, 8yr DFS, SE and 95% CI 
o Adjusted model: parameter estimate ± SE, HR, 95% CI for each model covariate 
o TEXT adjusted model (stratified by chemo & nodal strata): parameter estimate ± SE, 
HR, 95% CI for each model covariate 
• 
OFS Question (T+OFS vs T), stratified by chemo & nodal strata 
o Primary treatment comparison: N events and patients, HR, 95% CI, log-rank test statistic 
and p-value, 8yr DFS, SE and 95% CI 
o By-chemo cohort (2) treatment comparisons: N events and patients, HR, SE, 95% CI,8yr 
DFS, SE and 95% CI 
o Treatment effects within subgroups: N events and patients within each subgroup, 
treatment HR, 95% CI, 8yr DFS, SE and 95% CI 
• 
E+OFS vs T, stratified by chemo & nodal strata 
o Primary treatment comparison: N events and patients, HR, 95% CI, log-rank test statistic 
and p-value, 8yr DFS, SE and 95% CI 
o By-chemo cohort (2) treatment comparisons: N events and patients, HR, SE, 95% CI,8yr 
DFS, SE and 95% CI 
o Treatment effects within subgroups: N events and patients within each subgroup, 
treatment HR, 95% CI, 8yr DFS, SE and 95% CI 
• 
SOFT adjusted model (3-arms; stratified by chemo & nodal strata): parameter estimate ± SE, 
HR, 95% CI for each model covariate; T as reference group for reporting T+OFS vs T and 
E+OFS vs T treatment comparisons  
Figures: 
• 
AI Question (E+OFS vs T+OFS) 
o KM plot of DFS, by treatment group, for entire analysis population (y-axis: Percent Alive 
and Disease-Free; x-axis: Time since Randomization (yearly intervals); x-axis limited to 
9 years (min SOFT/TEXT MFU plus 1 yr) and numbers at risk at yearly intervals) 
o KM plots of DFS, by treatment group, for each trial, and for each of 4 cohorts 
o Forest plot of DFS, overall and for trials & for cohorts 
o Forest plot of DFS, overall and for subgroups 
2.6.4 Secondary efficacy analyses 
Breast cancer-free interval, distant recurrence-free interval and overall survival will be summarized as 
described for DFS. Forest plots for BCFI; DRFI and OS depend on # events. 
Sites of first treatment failure will be summarized overall and by treatment group, by trial & treatment 
group, and by cohort(or chemo strata) & treatment group as N (%). 
Second (non-breast) malignancies as site of first failure, and deaths without prior cancer event will be 
summarized overall and by treatment group.  
Tables: 
• 
Primary treatment comparison for each of the 3 endpoints: N events and patients, HR, 95% CI, 
log-rank test statistic and p-value, 8yr DFS, SE and 95% CI 


TEXT & SOFT 2017 Update SAP: Working version November 2017 
 
14 
 
• 
Cohort treatment comparisons (4) for each of the 3 endpoints: N events and patients, HR, SE, 
95% CI,8yr DFS, SE and 95% CI 
• 
Sites of first failure, overall and by treatment group 
• 
Types of second non-breast malignancies, as site of first failure, overall and by treatment group.  
Figures: 
• 
KM plots of BCFI, by treatment group, for entire analysis population and for each of the 4 
cohorts (y-axis: Percent Free from Breast Cancer; x-axis) 
• 
KM plots of DRFI, by treatment group, for entire analysis population and for each of the 4 
cohorts (y-axis: Percent Free from Distant Recurrence) 
• 
KM plot of OS, by treatment group, for entire analysis population and for each of the 4 cohorts 
(y-axis: Percent Alive) 
2.6.5 Adverse Events / Safety 
2.6.5.1 AE population 
The AE population is the subset of patients in the ITT analysis population who started protocol 
treatment (and have at least 1 post-baseline AE form submitted). This population will be updated from 
the first analysis using updated information, as necessary, and any such changes will be included in the 
report. 
2.6.5.2 AE analysis 
Targeted AEs, and other grade 3-5 AEs, are collected on CRFs, until 1 year after the cessation of all 
protocol treatment. The grade and causality attribution are recorded according to the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 3.0. In TEXT, chemotherapy-related AEs are 
collected separately. 
The targeted AEs will be summarized by AE type and maximum grade over time, regardless of 
causality attribution. The maximum grade consolidates the reports of a given type of AE for a patient 
over time since randomization (i.e., baseline reports are excluded) by taking the maximum across time 
(i.e., a patient appears only once for a given type of AE). Patients with reports of multiple AEs of 
different types are reported multiple times under the relevant AE categories. Maximum grade 0 
indicates that the AE type has not been reported.  
Note, during a period of trial conduct, the IBCSG audit team was asking sites to record grade 3+ weight 
gain and obesity as other AEs; discussed among StatC/DMC/CC that CRFs record weight serially on E-
form and any analysis of weight changes and/or obesity [in these or other IBCSG adjuvant trials] would 
use the actual weight, not the AE; as a result the audit team changed their practice. Therefore the 
weight change and obesity “other grade 3+” AEs will be deleted from dataset before summarizing other 
grade 3+ AEs because the incidence will not be interpretable. 
Tables: 
• 
AI Question (E+OFS vs T+OFS) 
o Targeted AEs reported according to treatment group (N; %) 
o Targeted AEs reported according to trial & treatment group (N;%) 
o Targeted AEs reported according to cohort & treatment group (N;%) 


TEXT & SOFT 2017 Update SAP: Working version November 2017 
 
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o Tables above repeated for the subset of events deemed possibly, probably or definitely 
related to study treatment(s) 
• 
SOFT (E+OFS vs T+OFS vs T) 
o Targeted AEs reported according to treatment group (N; %) 
o Targeted AEs reported according to chemo strata & treatment group (N;%) 
o Tables above repeated for the subset of events deemed possibly, probably or definitely 
related to study treatment(s) 
Other grade 3 or higher AEs are also requested on CRFs, by write-in text. All will be tabulated, similarly 
according to max grade, but the intention is to focus on those deemed possibly, probably or definitely 
related to study treatment(s), which will also be tabulated.  
2.6.5.3 Post-treatment AEs 
The follow-up (E) form collects some events occurring after protocol treatment has ended (which aren’t 
reported on the AE form): clinically-significant cardiovascular and/or cerebrovascular events, bone 
fractures, and other severe (≥ grade 3) AEs. These will not be part of the update clinical trial report. 
2.6.6 Treatment 
2.6.6.1 Protocol treatment 
Data are from the internal Treatment Summary form; see SDMC Treatment Summary Form Guidelines 
for details of how data are recorded. There is some inconsistency, relevant primarily for TEXT, among 
patients who completed 5 years of oral ET with whether any oral ET that continued after 5y since 
randomization but stopped within year 5-6 was recorded on the protocol treatment page or non-protocol 
treatment page (i.e., though protocol said 5 yrs since randomization, patients sometimes received 5 yrs 
since oral ET start; goal is to separate completion of 5 yrs of oral ET from extended adjuvant ET). 
Guidelines originally said put it all on non-protocol treatment page but this was changed so that up to 6 
additional months stayed on protocol treatment page, and if it continued beyond 6 months then protocol 
treatment ended on day rando+5y and non-protocol treatment started on day rando+5y+1d until actual 
stop date. So need to be careful in analysis of time until oral ET stop that everything is consistently 
truncated at 5 yrs.   
As of the clinical data cut-off, all patients would have ceased protocol treatment (there are a few 
patients for whom final confirmation of cessation not received and/or final date of cessation not 
documented).  Protocol treatment status will be summarized, overall and by treatment assignment, and 
also by trial and/or cohort. The variables are the same as in the original trial report (see original SAP for 
details), with the exception of the “continuing protocol treatment” category vs. “last known on protocol 
treatment” categories.  
2.6.6.2 Non-protocol treatment    
This will not be part of the update clinical trial report. A preliminary analysis will be conducted after 
compiling the update clinical trial report to get a sense of what is going on; a full analysis of protocol 
and non-protocol treatment is planned to follow separately). We will plan to describe 
• 
Non-protocol ET to complete 5 years (if protocol-assigned T/E is stopped early);  
• 
[OFS question] Use of OFS within 5 years of randomization among patients assigned 
tamoxifen-alone 


TEXT & SOFT 2017 Update SAP: Working version November 2017 
 
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• 
Concomitant bisphosphonates use 
• 
Extended adjuvant ET use, including oophorectomy/ovarian irradiation after 5 years. 
As noted above, among those who completed 5 yrs of protocol-assigned oral ET, need to be careful 
about an extra few months up to 1 yr of protocol-assigned oral ET, which could be reflected either in the 
protocol treatment variables or non-protocol treatment variables. And need to be careful not to consider 
these few extra months as extended adjuvant ET.   
Recall, protocol treatment is considered as completed per-protocol at the time of any DFS event. In the 
case of local recurrence and second (non-breast) cancer, the protocol allowed treatment to continue. 
The Treatment Summary form non-protocol therapy page captures the therapy after local recurrence 
and second (non-breast) cancer (as during the trial we clarified that we considered protocol therapy as 
ended at the DFS event in such cases as well); such therapy is not considered as non-protocol therapy 
for these analyses. 
Also in SOFT, if a patient had been on tamoxifen and was randomized to Exe+OFS, the tam was 
allowed to continue until the exe was started, 6-8 weeks after OFS was initiated; this is also captured 
on the Treatment Summary form non-protocol therapy page and such therapy is not considered as non-
protocol therapy for these analyses. 
With regard to non-protocol OFS: 
• 
At the time of this database lock, there was no record of non-protocol ovarian irradiation use; 
• 
Any use of GnRH agonist is considered, of any type, and for any duration (as long as not after 
DFS event); 
• 
Any ooph reported >5yrs for any reason is recorded, as long as it’s not after DFS event; 
• 
The timing of non-protocol OFS was segmented as 0 to 4.5yr since randomization vs. ≥4.5yr 
since randomization; this is in parallel with protocol therapy, for which triptorelin through 4.5yr 
was considered as completed per protocol. 
With regard to non-protocol ET: 
• 
As noted, it can be difficult to differentiate competing 5 yrs of oral ET from extended oral ET use 
from the 66 month visit; the plan is to identify number of patients on oral ET at ≥6 yrs since 
rando; look at 2 denominators, ITT, and patients who are DFS event-free & in follow-up at 6 yrs 
since rando. 
• 
There is just one record of toremifene, which is just being lumped with tamoxifen 
• 
 
2.6.6.3 Tables and Figures 
Tables: 
• 
Treatment status, overall and by treatment group and trial and/or cohort 
Figures: 
• 
Cumulative incidence of early treatment discontinuation, by treatment group, and secondarily by 
cohort and/or trial and treatment group; without and with competing risk of DFS event that leads 
to treatment cessation. 


TEXT & SOFT 2017 Update SAP: Working version November 2017 
 
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2.6.7 GYN and fertility-related issues 
During and after protocol treatment, the follow-up (E) form routinely collects menstrual status, 
pregnancy, and GYN procedures. In addition, after protocol treatment has ended we collect pregnancy 
attempts. These will not be part of the update clinical trial report. Research projects are planned.