Conditions: Breast Cancer Invasive Nos
Keywords: Premenopausal patients ER-positive PgR+ (>50%) HER2-negative or not amplified
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 51
Healthy volunteers: no

Brief summary:
The purpose of the this study is to investigate the anti-tumor activity and tolerability of the study medications Degarelix and Triptorelin in premenopausal women receiving preoperative treatment with Letrozole.

Detailed description:
RATIONALE Preoperative chemotherapy enables breast-conserving surgery for some patients with breast cancer, and it might be advantageous in several other ways. For example, the response to primary treatment may be used as a prognostic marker, since it has been demonstrated to be associated with a longer disease-free survival (DFS) compared with no response. In particular the degree of response (pathological complete remission (pCR)) predicts overall outcome in terms of DFS.

However, pCR can be achieved only in a minority of patients with estrogen receptor (ER)-positive disease. Studies in the medical literature indicate that pCR rates range from 2% to 10% in those patients whose tumors express ER suggesting that objective response and decrease of Ki67 must be considered within this subset of tumors.

The results of phase II studies and randomized phase III trials have clearly shown that preoperative endocrine therapy is a feasible and safe option among patients with hormone-receptor positive tumors. Letrozole has been shown to induce greater rates of clinical responses and of breast-conserving surgery in postmenopausal women as compared with tamoxifen.

In premenopausal women with ER and progesterone receptor (PgR) positive breast cancer, the preoperative endocrine therapy includes a combination of a gonadotropin-releasing hormone analogue (GnRH) plus tamoxifen. Recent studies suggest that neoadjuvant endocrine therapy with a combination of GnRH analogue and aromatase inhibitors (AIs: letrozole or anastrozole) is effective in selected premenopausal patients. The GnRH analogue, also known as a luteinizing hormone-releasing hormone agonist (LHRH agonist) or LHRH analogue, is a synthetic peptide drug modeled after the human hypothalamic gonadotropin-releasing hormone (GnRH). A GnRH analogue is designed to interact with the GnRH receptor and modify the release of pituitary gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) for therapeutic purposes. Upon administration of a GnRH analogue, an initial stimulating action of the hypophysis occurs - termed a "flare" effect - which eventually causes a paradoxical and sustained drop in gonadotropin secretion. This second effect has been termed "downregulation" and can be observed after about 10 days. While this phase is reversible following cessation of medication, it can be maintained when GnRH agonists' use is continued for a long time. For a select group of patients, there is a delay of approximately 2-4 months before downregulation of the gonadotropins is observed.

Degarelix (INN) or degarelix acetate (USAN) (tradename: Firmagon) is a hormonal therapy approved for the treatment of prostate cancer. Since testosterone, a male hormone, promotes the growth of many prostate tumors, reduction of circulating testosterone to very low (castration) levels is often the treatment goal in the management of advanced prostate cancer. Degarelix, an antagonist of GnRH, has immediate onset of action through binding to GnRH receptors in the pituitary gland and blocking their interaction with GnRH. The result is a fast and profound reduction in LH, FSH and in turn, testosterone suppression. Its activity in suppressing the ovaries of premenopausal women might therefore be faster than other GnRH analogues, possibly by several weeks. The probable difference in onset of action could have significant clinical value for patients who are candidates for short-term neoadjuvant endocrine treatment.

TRANSLATIONAL RESEARCH A tumor block from the diagnostic core biopsy and one from final surgery will be collected and banked for central review and future translational research at the IBCSG Tissue Bank hosted by the European Institute of Oncology in Milan, Italy.

PATIENT-REPORTED SYMPTOMS The patient-reported symptoms (PRS) will be assessed using the Functional Assessment of Cancer Therapy Endocrine Subscale (FACT-ES) comprising 18 items (each has score range from 0 to 4) with a possible maximum total score of 72. Functional Assessment of Chronic Illness Therapy (FACIT) guidelines will be used for scoring and interpretation of the FACT-ES total score. Patients will be asked to complete a PRS Form at baseline (prior to randomization), at day 1 of cycle 2, at day 1 of cycle 4, and prior to surgery.

The objectives are

* To assess the differences in PRS score over time between the two treatment arms
* To correlate the estradiol (E2) levels and total PRS score measured on day 1 of cycle 2 and day 1 of cycle 4 of triptorelin or degarelix administration
* To summarize each of the 18 individual (endocrine symptom) items of the FACT-ES descriptively over time as the proportion of patients with "clinically significant" symptoms (those scoring 3 or 4)

STRATIFICATION Stratification will be performed according to:

\- Age(in years): less than or equal to 39 versus 40 or more

STATISTICAL CONSIDERATIONS To achieve the primary objective, E2 levels will be determined centrally from samples taken at day 1 of the first treatment cycle before the administration of the first dose of degarelix or triptorelin (baseline), and thereafter at 24 and 72 hours, 7 days and 14 days after the first injection, and on day 1 of cycles 2 to 6 before the administration of degarelix or triptorelin.

For sample size calculation, we assume that the cumulative percentages of patients in the triptorelin arm achieving optimal ovarian function suppression (defined as E2 ≤2.72 pg/mL or ≤10 pmol/L) will be 30% within 2 weeks, 60% within 4 weeks and 75% within 8 weeks, and that degarelix will provide more rapid suppression (i.e., 60% within 2 weeks, 95% within 4 weeks and 100% within 8 weeks). Enrollment of 25 patients in each treatment arm will provide at least 90% power to detect a difference in time to optimal ovarian function suppression between the two groups, using a two sample log-rank test with a two-sided significance level of 0.05.

Randomized patients who receive at least one injection of triptorelin or degarelix will be included in the primary analysis. The primary endpoint will be compared between the two treatment arms using a stratified two-sample log-rank test, with age as stratification factor. The distribution of the primary endpoint will be summarized using the method of Kaplan-Meier and the two-sided 95% confidence interval (CI) for the difference in proportion of patients who achieve optimal ovarian function suppression between the two treatment arms at the end of the 1st, 2nd and 4th cycle will also be provided.

The toxicity, changes in Ki67 expression levels, the Preoperative Endocrine Prognostic Index (PEPI) score at the time of surgery, disease response, node-negative disease status at surgery and breast-conserving surgery (BCS) rate will also be summarized and differences assessed between treatment arms with confidence intervals.

The primary endpoint for patient-reported symptoms (PRS) analysis is the total PRS score measured at baseline, day 1 of cycle 2 and day 1 of cycle 4 of triptorelin or degarelix administration, and prior to surgery. The differences in PRS measurements between the two treatment arms over time will be explored using the repeated measures analysis based on generalized estimating equation (GEE) model.

Arms:
arm 1: Arm A: Triptorelin 3.75 mg i.m. on day 1 every 28 days for 6 cycles + letrozole 2.5 mg/day orally for 6 cycles arm 2: Arm B: Degarelix 240 mg s.c. on day 1 of cycle 1, followed by 80 mg s.c. on day 1 of cycles 2 to 6 + letrozole 2.5 mg every day orally for 6 cycles

Interventions: intervention 1: triptorelin intervention 2: degarelix intervention 3: letrozole
Intervention descriptions: intervention 1: Triptorelin 3.75 mg injected into the muscle on day 1 every 28 days for 6 cycles (1 cycle= 28 days) intervention 2: Degarelix 240 mg injected under the skin given as two injections of 120 mg on the first day of treatment, followed by injection of 80 mg on day 1 of cycles 2 to 6 (1 cycle=28 days) intervention 3: Letrozole 2.5 mg orally every day for 6 cycles

Protocol document:
Prot_001.pdf: 
IBCSG 41-13 TREND 
 
1 
V1.0 20 Dec 12 
 
 
 
A randomized phase II trial evaluating the endocrine activity 
and efficacy of neoadjuvant degarelix versus triptorelin in 
premenopausal patients receiving letrozole for primary 
endocrine responsive breast cancer 
 
 
EudraCT number: 
2012-005326-29 
NCT Number: 
NCT02005887 
 
 
Sponsor:   
International Breast Cancer Study 
Group (IBCSG) 
 
 
IBCSG Coordinating Center, Effingerstrasse 40, CH- 3008 Bern 
Phone: +41 31 389 93 91 
Fax: +41 31 389 93 92 
 
 
 
 
 
 
 
 
 
 
 
 
 
INTERNATIONAL BREAST 
CANCER STUDY GROUP 
IBCSG 41-13 
 
TREND 
 
(TRial on the Endocrine activity of 
Neoadjuvant Degarelix)  
 


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Trial Specific Contacts 
 
Study Chair 
Dr. Silvia Dellapasqua  
European Institute of Oncology 
Via Ripamonti 435 
20141 Milan, Italy 
 
E-mail: silvia.dellapasqua@ibcsg.org 
Tel: +39 02 574 89 243 
Fax: +39 02 57489457 
Study Co-Chair 
Dr. Marco Colleoni  
European Institute of Oncology 
Via Ripamonti 435 
20141 Milan, Italy 
E-mail: marco.colleoni@ieo.it 
Tel: +39 02 574 89 439 
Fax: +39 02 574 89 581 
 
 
 
 
Trial Statistician 
Dr. Kathryn P. Gray 
Dept. of Biostatistics and 
Computational Biology, CLSB 11007 
Dana-Farber Cancer Institute 
450  Brookline Ave  
Boston, MA 02215  USA 
E-mail: pkruan@jimmy.harvard.edu 
Tel: +1 617-582-7145 
Fax: +1 617-632-5444 
 
 
 
Trial Data Managers 
 
Lead Trial Coordinator 
Trial Coordinator 
Adrianna Cesario 
Amy Dickinson 
Holly Shaw 
Vanessa Palermo 
IBCSG Data Management Center 
 
E-mail: ibcsg41_TREND@fstrf.org 
Tel : +1 716-898-7500 (general) 
Fax :  +1 716-836-6097 
IBCSG Central Pathology Office 
Rosita Kammler 
Stefania Andrighetto/Elvira Benini        
 
E-mail: rosita.kammler@ibcsg.org 
E-mail: pathology.ibcsg@ieo.it 
Tel: +39 0257 489 928 
 
 Central Laboratory 
Dr. Harriet Johansson 
Division of Cancer Prevention and 
Genetics 
European Institute of Oncology 
Via Ripamonti 435, 20141 Milan, Italy 
 
E-mail: harriet.johansson@ieo.it 
Tel : +39 (02) 57 48 93 68 
Fax : +39 (02) 94 37 92 25 
 
IBCSG Contacts 
 
Coordinating Center 
 
 
Anita Hiltbrunner 
Dr. Barbara Ruepp 
Dr. Manuela Rabaglio 
Dr. Rudolf Maibach 
Sonja Schläpfer / Sabrina Ribeli-
Hofmann  
Rosita Kammler 
IBCSG Coordinating Center 
Effingerstrasse 40 
CH-3008  Bern, Switzerland 
E-mail: anita.hiltbrunner@ibcsg.org  
E-mail: barbara.ruepp@ibcsg.org 
E-mail: manuela.rabaglio@ibcsg.org 
E-mail: rudolf.maibach@ibcsg.org 
E-mail: drugsupply@ibcsg.org 
 
E-mail: rosita.kammler@ibscg.org 
Tel: +41 31 389 9391 
Fax: +41 31 389 9392 
 
 
 
Quality of Life Office 
Dr. Karin Ribi 
Dr. Jürg Bernhard 
IBCSG Coordinating Center 
E-mail: karin.ribi@ibcsg.org 
E-mail: juerg.bernhard@ibcsg.org 
 
 
 


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Data Management Center 
Lynette Blacher 
Tara Scolese 
Karolyn Scott 
FSTRF, 
4033 Maple Rd.  
Amherst, NY  14226 USA 
E-mail: blacher.lynette@fstrf.org 
E-mail: scolese.tara@fstrf.org 
E-mail: scott.karolyn@fstrf.org 
Tel: +1 716 898 7500 
Fax: +1 716 836 6097 
IBCSG Contacts (continued) 
 
 
Data Quality Control Office 
 
Main Contact:  Kimberly Lupejkis 
IBCSG Data Management Center 
 
 
E-mail: ib.dqc@fstrf.org 
 
Center Training Office 
 
Main Contact:  Jennifer Shepard 
IBCSG Data Management Center 
E-mail: ibcsg.training@fstrf.org 
 
 
 
 
Statistical Center 
Prof. Richard D. Gelber 
Dr. Meredith M. Regan 
E-mail: gelber@jimmy.harvard.edu 
E-mail: mregan@jimmy.harvard.edu 
 
Dept. of Biostatistics and 
Computational Biology, CLSB 11007 
Dana-Farber Cancer Institute 
450 Brookline Ave. 
Boston, MA 02215  USA 
Tel: +1 617-632-3012 
Fax: +1 617-632-5444 
 
 
 
Central Pathology Office 
Prof. Giuseppe Viale 
University of Milan & European 
Institute of Oncology 
Milan, Italy 
E-mail: giuseppe.viale@ieo.it 
Tel: +39 02 5748 9419 
Fax: +39 02 5748 9417 
 
 
 
 
Scientific Committee Chairs 
Prof. Aron Goldhirsch 
European Institute of Oncology 
Milan, Italy 
E-mail: aron.goldhirsch@ibcsg.org 
Tel: +39-02-57489439 
Fax: +39-02-94379273 
 
and 
Ospedale Regionale di Lugano (ORL) 
Sede: Ospedale Italiano 
Via P. Capelli 
6962 Viganello-Lugano, Switzerland 
 
 
 
Prof. Alan Coates 
Centennial Park NSW 2021 
Australia 
E-mail: alan.coates@ibcsg 
Tel: +61 2 9331 3521 
Fax: +61 2 9380 8233 
 
 
Dr. Marco Colleoni  
European Institute of Oncology 
Milan, Italy 
E-mail: marco.colleoni@ieo.it 
Tel: +39 02 574 89 439 
Fax: +39 02 574 89 581 
 
 
 
Ferring Pharmaceuticals 
 
Degarelix Advisor 
Tine Kold Olesen 
Global Project Director 
International PharmaScience Center 
Ferring Pharmaceuticals A/S 
Kay Fiskers Plads 11, DK-2300 
Copenhagen S 
Denmark 
Tel: +4588338834 
Fax: +4528176489 
E-mail: tine.kold.olesen@ferring.com 
 
 
 


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Protocol Signature Page 
 
IBCSG 41-13 
TREND 
 
 
 
 
 
 
Approved by: 
Group Statistician, International Breast Cancer Study Group 
Dr. M. M. Regan 
 
 
 
 
 
___________________________________________________ 
______________ 
 
 
 
Date 
 
 
 
Approved by: 
Director, International Breast Cancer Study Group 
Anita Hiltbrunner 
 
 
 
 
 
___________________________________________________ 
______________ 
 
 
 
Date 


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Principal Investigator Protocol Signature Page 
 
IBCSG 41-13 
TREND 
 
I have read the protocol and agree that it contains all necessary details for conducting this 
trial. I will conduct the trial 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 trial. I will discuss this material with them to assure that 
they are fully informed regarding the drugs and the conduct of the trial. 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 
trial for a minimum period of 15 years. 
 
Name of Principal Investigator:___________________________________________ 
 
 
_____________________________________________________ ______________ 
 
 
Signature 
Date 
 


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TABLE OF CONTENTS  
 
Section 
Page 
1. 
Protocol Summary and Schema ............................................................................ 9 
2. 
Trial schedule ...................................................................................................... 16 
3. 
Introduction ......................................................................................................... 18 
3.1. 
The role of primary systemic therapy in breast cancer ........................................ 18 
3.2. 
Primary endocrine therapy in postmenopausal breast cancer patients ................ 18 
3.3. 
Primary endocrine therapy in premenopausal breast cancer patients .................. 20 
3.4. 
GnRH agonist and GnRH antagonist ................................................................... 20 
3.5. 
Plasma estradiol levels during endocrine therapy with AI .................................. 22 
3.6. 
Rationale of the trial ............................................................................................ 22 
4. 
Trial objectives and endpoints ............................................................................ 22 
4.1. 
Primary endpoint ................................................................................................. 22 
4.2. 
Secondary endpoints ............................................................................................ 22 
5. 
Trial design, duration and termination ................................................................ 23 
5.1. 
Trial schema ........................................................................................................ 23 
5.2. 
Sample size and trial duration ............................................................................. 23 
6. 
Patient selection .................................................................................................. 24 
6.1. 
Criteria for patient eligibility ............................................................................... 24 
6.2. 
Criteria for patient ineligibility ............................................................................ 25 
7. 
Randomization and stratification ........................................................................ 26 
7.1. 
Protocol requirements before randomization ...................................................... 26 
7.2. 
Registration and randomization procedures ........................................................ 27 
7.3. 
Randomization Help Desk ................................................................................... 28 
7.4. 
Randomized arms ................................................................................................ 28 
7.5. 
Stratification ........................................................................................................ 28 
8. 
Study drugs formulation and handling ................................................................ 28 
8.1. 
Triptorelin ............................................................................................................ 28 
8.2. 
Degarelix ............................................................................................................. 29 
8.3. 
Letrozole .............................................................................................................. 30 
9. 
Treatment ............................................................................................................ 30 
9.1. 
Trial treatments .................................................................................................... 30 
9.2. 
Criteria for stopping neoadjuvant treatment ........................................................ 31 
9.3. 
Timing of surgery ................................................................................................ 31 
9.4. 
Dose modifications and delays ............................................................................ 31 
10. 
Determination of objective response ................................................................... 31 
10.1. 
Tumor measurements .......................................................................................... 31 
10.2. 
Response criteria .................................................................................................. 32 
10.3. 
Best overall response ........................................................................................... 32 
10.4. 
Treatment in case of progression ......................................................................... 33 
11. 
Clinical and laboratory evaluations ..................................................................... 33 
11.1. 
Before randomization .......................................................................................... 33 
11.2. 
During first cycle of trial treatment ..................................................................... 34 
11.3. 
Day 1 of every treatment cycle ............................................................................ 34 
11.4. 
After three cycles of trial treatment ..................................................................... 34 
11.5. 
At visit prior to surgery ....................................................................................... 34 
11.6. 
At visit 30 days after surgery ............................................................................... 35 
12. 
Safety .................................................................................................................. 35 


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12.1. 
Adverse effects of degarelix ................................................................................ 35 
12.2. 
Drug interactions with degarelix ......................................................................... 37 
12.3. 
Adverse effects of triptorelin ............................................................................... 37 
12.4. 
Adverse effects of letrozole ................................................................................. 38 
13. 
Adverse event and serious adverse event reporting ............................................ 39 
13.1. 
Adverse event reporting ....................................................................................... 39 
13.2. 
Targeted adverse events ....................................................................................... 40 
13.3. 
Abnormal Laboratory Values .............................................................................. 42 
13.4. 
Serious adverse event (SAE) reporting ............................................................... 42 
13.5. 
Pregnancy ............................................................................................................ 44 
13.6. 
Safety review of degarelix ................................................................................... 44 
14. 
Data submission .................................................................................................. 44 
14.1. 
Case report forms schedule .................................................................................. 45 
14.2. 
Signing and submitting forms.............................................................................. 46 
14.3. 
Data management ................................................................................................ 46 
14.4. 
Investigators’ file ................................................................................................. 46 
14.5. 
Authorization log ................................................................................................. 47 
14.6. 
Patient identification log ...................................................................................... 47 
15. 
Statistical considerations ..................................................................................... 47 
15.1. 
Primary endpoint ................................................................................................. 47 
15.2. 
Secondary objectives ........................................................................................... 48 
15.3. 
Stopping Rules and Data Monitoring .................................................................. 50 
15.4. 
Accrual ................................................................................................................. 50 
16. 
Patient-reported symptoms (PRS) ....................................................................... 50 
16.1. 
Introduction ......................................................................................................... 50 
16.2. 
PRS Objectives .................................................................................................... 51 
16.3. 
PRS Patient selection ........................................................................................... 51 
16.4. 
PRS design ........................................................................................................... 51 
16.5. 
PRS assessment ................................................................................................... 51 
16.6. 
PRS statistical considerations .............................................................................. 52 
16.7. 
PRS Timing requirements ................................................................................... 52 
16.8. 
PRS data collection and local data management ................................................. 52 
17. 
Additional protocol-specific evaluations ............................................................ 53 
17.1. 
Pathology and pathology material banking ......................................................... 53 
17.2. 
Submitting pathology material to IBCSG ........................................................... 53 
17.3. 
Banking biological material ................................................................................. 54 
17.4. 
Blood samples...................................................................................................... 54 
18. 
Ethical aspects, regulatory approval, and patient informed consent ................... 54 
18.1. 
Ethical Review Board/Ethics Committee ............................................................ 55 
18.2. 
Regulatory approval procedures .......................................................................... 55 
18.3. 
Protection of human subjects ............................................................................... 55 
18.4. 
Informed Consent ................................................................................................ 55 
18.5. 
Premature withdrawal .......................................................................................... 56 
19. 
Governance and Administrative Considerations ................................................. 56 
19.1. 
Insurance .............................................................................................................. 56 
19.2. 
Steering Committee ............................................................................................. 57 
19.3. 
Data and Safety Monitoring Committee (DSMC) ............................................... 57 
19.4. 
Premature discontinuation of the trial ................................................................. 57 
19.5. 
Quality Assurance................................................................................................ 57 
19.6. 
Data protection .................................................................................................... 58 


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19.7. 
Record Retention ................................................................................................. 58 
20. 
Confidentiality .................................................................................................... 58 
21. 
References ........................................................................................................... 58 
22. 
List of abbreviations............................................................................................ 62 
Appendices  
I. 
Requirements for Informed Consent  
II. 
NCI Common Terminology Criteria for Adverse Events v4.0 (available from the 
internet at: http://evs.nci.nih.gov/ftp1/CTCAE/About.html) 
 


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1. 
Protocol Summary and Schema 
 
 
TITLE 
A randomized phase II trial evaluating the endocrine activity and 
efficacy of neoadjuvant degarelix versus triptorelin in premenopausal 
patients receiving letrozole for primary endocrine responsive breast 
cancer (TREND) 
SPONSOR 
International Breast Cancer Study Group (IBCSG) 
PHARMA 
PARTNER 
Ferring 
INDICATION 
Primary breast cancer 
CLINICAL 
PHASE 
Phase II 
POPULATION 
Premenopausal patients with histologically confirmed primary breast 
cancer and with primary tumor which is ER+ and PgR+ (>50%) and 
HER2-negative or not amplified 
TREATMENT 
Patients will be randomized to one of two treatment arms. Cycles last 28 
days: 
Arm A: Triptorelin 3.75 mg i.m. on day 1 of every cycle + letrozole 2.5 
mg/day orally for 6 cycles 
Arm B: Degarelix 240 mg s.c. given as two subcutaneous injections of 
120 mg on day 1 of cycle 1, followed by 80 mg s.c. on day 1 of 
cycles 2 to 6 + letrozole 2.5 mg/day orally for 6 cycles 
Arms A and B: Letrozole 2.5 mg/day orally should be started on day 1, 
concurrently with triptorelin or degarelix. 
 
 


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STUDY SCHEMA 
 
RATIONALE 
Preoperative chemotherapy enables breast-conserving surgery for some 
patients with breast cancer, and it might be advantageous in several 
other ways. For example, the response to primary treatment may be 
used as a prognostic marker, since it has been demonstrated to be 
associated with a longer disease-free survival (DFS) compared with no 
response. In particular the degree of response (pathological complete 
remission (pCR)) predicts overall outcome in terms of DFS. 
However, pCR can be achieved only in a minority of patients with 
estrogen receptor (ER)-positive disease. Studies in the medical literature 
indicate that pCR rates range from 2% to 10% in those patients whose 
tumors express ER suggesting that objective response and decrease of 
Ki67 must be considered within this subset of tumors. 
The results of phase II studies and randomized phase III trials have 
clearly shown that preoperative endocrine therapy is a feasible and safe 
option among patients with hormone-receptor positive tumors. 
Letrozole has been shown to induce greater rates of clinical responses 
and of breast-conserving surgery in postmenopausal women as 
compared with tamoxifen. 
In premenopausal women with ER and PgR positive breast cancer, the 
preoperative endocrine therapy includes a combination of a 
gonadotropin-releasing hormone analogue (GnRH) plus tamoxifen. 
Recent studies suggest that neoadjuvant endocrine therapy with a 
combination of GnRH analogue and aromatase inhibitors (AIs: letrozole 
or anastrozole) is effective in selected premenopausal patients. The 
GnRH analogue, also known as a luteinizing hormone-releasing 
hormone agonist (LHRH agonist) or LHRH analogue, is a synthetic 
peptide drug modeled after the human hypothalamic gonadotropin-
releasing hormone (GnRH). A GnRH analogue is designed to interact 
Premenopausal
breast cancer
cT2-4b, M0, any N, 
ER>50%, 
PgR>50%
HER2 neg.
Stratify:
Age ≦39
vs 40+
R
A
N
D
O
M
I
Z
E
A
B
FFPE block 
from diagnostic
core biopsy
Translational research:
Cycle   1        2        3        4        5         6
Surgery 
Surgery 
treatments:
triptorelin 
degarelix
degarelix
Letrozole
3.75mg i.m. 
240mg s.c.
80mg s.c.
2.5mg/day
every 28 days
day 1
every 28 days
FFPE 
block


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with the GnRH receptor and modify the release of pituitary 
gonadotropins, follicle-stimulating hormone (FSH) and luteinizing 
hormone (LH) for therapeutic purposes. Upon administration of a 
GnRH analogue, an initial stimulating action of the hypophysis occurs – 
termed a “flare” effect – which eventually causes a paradoxical and 
sustained drop in gonadotropin secretion. This second effect has been 
termed “downregulation” and can be observed after about 10 days. 
While this phase is reversible following cessation of medication, it can 
be maintained when GnRH agonists’ use is continued for a long time. 
For a select group of patients, there is a delay of approximately 2-4 
months before downregulation of the gonadotropins is observed. 
Degarelix (INN) or degarelix acetate (USAN) (tradename: Firmagon) is 
a hormonal therapy approved for the treatment of prostate cancer. Since 
testosterone, a male hormone, promotes the growth of many prostate 
tumors, reduction of circulating testosterone to very low (castration) 
levels is often the treatment goal in the management of advanced 
prostate cancer. Degarelix, an antagonist of GnRH, has immediate onset 
of action through binding to GnRH receptors in the pituitary gland and 
blocking their interaction with GnRH. The result is a fast and profound 
reduction in LH, FSH and in turn, testosterone suppression. Its activity 
in suppressing the ovaries of premenopausal women might therefore be 
faster than other GnRH analogues, possibly by several weeks. The 
probable difference in onset of action could have significant clinical 
value for patients who are candidates for short-term neoadjuvant 
endocrine treatment. 
ELIGIBILITY 
Inclusion criteria: 
 Female gender 
 Premenopausal status determined locally: 
Estradiol (E2) must be above 54 pg/mL (or above 198 pmol/L), 
measured within 14 days prior to randomization. 
 Age ≥ 18 years 
 Performance Status – Eastern Cooperative Oncology Group 
(ECOG) 0-1 
 Histologically confirmed invasive breast cancer: 
- Primary tumor greater than 2 cm diameter, measured by 
clinical examination  and mammography or echography 
(cT2-4b) 
- Any nodal stage 
- No evidence of metastasis (M0)  
 Primary tumor must have ER and PgR >50% of the cells 
 Primary tumor must be HER2-negative (by IHC and/or ISH)  
 Hematopoietic status: 
- Absolute neutrophil count ≥ 1.5 × 109/L 
- Platelet count ≥ 100 × 109/L 
- Hemoglobin ≥ 9 g/dL 
 Hepatic status: 
- Serum total bilirubin ≤ 1.5 × upper limit of normal (ULN). In 
the case of known Gilbert’s syndrome, a higher serum total 


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bilirubin (< 2 × ULN) is allowed. 
- AST and ALT ≤ 2.5 × ULN 
- Alkaline phosphatase ≤ 2.5 × ULN 
 Renal status: Creatinine ≤ 1.5 ×ULN 
 Negative serum pregnancy test, within 2 weeks (preferably 7 
days) prior to randomization. Pregnancy test has to be repeated 
before treatment start if treatment does not start within 15 days 
of the previous test. 
 The patient must be willing to use effective non-hormonal 
contraception (barrier method – condoms, diaphragm – also in 
conjunction with spermicidal jelly, or total abstinence) after the 
pregnancy test and up to surgery. Oral, injectable, or implant 
hormonal contraceptives or medicated IUD are not allowed 
within 2 months prior to randomization and during the trial. 
 Prior fertility treatment is allowed but must have been stopped at 
least 12 months before randomization. 
 The patient has completed the baseline patient-reported 
symptoms questionnaire. 
 Written Informed Consent (IC) must be signed and dated by the 
patient and the Investigator prior to randomization. 
 The patient has been informed of and agrees to data transfer and 
handling, in accordance with national data protection guidelines. 
 The patient accepts blood samples to be taken according to the 
schedule in section 17.4 for the determination of the primary 
endpoint. 
 The patient agrees to make tumor (diagnostic core biopsy and 
surgical specimen) available for submission for central 
pathology review and to conduct translational studies as part of 
this protocol. 
NOTE: Central Pathology Review on the primary tumor is 
mandatory for this trial, but patients will evaluated for eligibility 
according to tumor characteristics as determined by the local 
Pathologist. Both the diagnostic breast core biopsy specimen and 
the final breast surgical specimen must be submitted for Central 
Pathology Review. 
Exclusion criteria: 
 Postmenopausal 
 Any hormonal treatment (e.g., oral, injectable, implant, or 
medicated IUD) in the previous 2 months 
 Presence of HER2 overexpression or amplification  
 Received any prior treatment for primary invasive breast cancer 
 Received any GnRH analog or SERM or AI within 12 months 
prior to randomization 
 A history of malignant neoplasms within the past 10 years, 
except for curatively treated 
- Basal and squamous cell carcinoma of the skin 
- Carcinoma in situ of the cervix 
- Carcinoma in situ of the bladder 


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 Previous ipsilateral breast cancer (invasive or in situ) at any time 
 Inflammatory breast cancer 
 Bilateral invasive breast cancer 
 Known history of uncontrolled or symptomatic angina, clinically 
significant arrhythmias, congestive heart failure, transmural 
myocardial infarction, uncontrolled hypertension (≥ 180/110), 
unstable diabetes mellitus, dyspnea at rest, or chronic therapy 
with oxygen 
 Concurrent disease or condition that would make the subject 
inappropriate for study participation or any serious medical 
disorder that would interfere with the subject’s safety 
 Unresolved or unstable, serious adverse events from prior 
administration of another investigational drug 
 Active or uncontrolled infection CTCAE v.4 grade 2 or higher 
 Dementia, altered mental status, or any psychiatric condition 
that would prevent the understanding or rendering of Informed 
Consent 
 Treatment with an investigational agent must have stopped at 
least 30 days before randomization. 
 Pregnant or lactating women; lactation has to stop before 
randomization. 
STUDY 
OBJECTIVES 
AND 
ENDPOINTS 
Primary objective 
The primary objective is to compare the endocrine activity of 
neoadjuvant degarelix and triptorelin in premenopausal patients 
receiving letrozole for primary endocrine responsive breast cancer. The 
endocrine activity is measured by time to optimal ovarian function 
suppression. 
Primary endpoint:  
Time to optimal ovarian function suppression: time from the first 
injection of degarelix or triptorelin to the first assessment of centrally 
assessed 17--estradiol (E2) level in the range of optimal ovarian 
function suppression (≤2.72 pg/mL or  ≤10 pmol/L) during the 6 cycles 
of neoadjuvant treatments. Time for patients who do not reach the 
targeted E2 level will be censored at the last E2 assessment date. 
Secondary endpoints: 
 Tolerability: adverse events according to CTCAE version 4 
 Ki67 proliferation marker changes 
 The Preoperative Endocrine Prognostic Index (PEPI) score 
determined after completion of neoadjuvant therapy or at the 
time of surgery 
 Best overall (disease) response: defined as best response 
recorded from the start of treatment across all time points until 
disease progression. Confirmation of partial or complete 
response by an additional scan is not required in this trial. Best 
overall response will be determined by a team consisting of the 
study chair, co-chair and IBCSG Head of Medical Affairs. 


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Tumor assessment will use WHO response criteria. 
 Node-negative disease at surgery 
 Breast-conserving surgery (BCS) rate 
 Patient-reported symptoms (PRS) outcomes 
TRANSLA-
TIONAL 
RESEARCH 
A tumor block from the diagnostic core biopsy and one from final 
surgery will be collected and banked for central review and future 
translational research at the IBCSG Tissue Bank hosted by the 
European Institute of Oncology in Milan, Italy (Prof. G. Viale). 
PATIENT-
REPORTED 
SYMPTOMS 
The patient-reported symptoms (PRS) will be assessed using the 
Functional Assessment of Cancer Therapy Endocrine Subscale (FACT-
ES) comprising 18 items (each has score range from 0 to 4) with a 
possible maximum total score of 72. Functional Assessment of Chronic 
Illness Therapy (FACIT) guidelines will be used for scoring and 
interpretation of the FACT-ES total score. Patients will be asked to 
complete a PRS Form at baseline (prior to randomization), at day 1 of 
cycle 2, at day 1 of cycle 4, and prior to surgery.  
The objectives are: 
 To assess the differences in PRS score over time between the 
two treatment arms 
 To correlate the estradiol (E2) levels and total PRS score 
measured on day 1 of cycle 2 and day 1 of cycle 4 of triptorelin 
or degarelix administration 
 To summarize each of the 18 individual (endocrine symptom) 
items of the FACT-ES descriptively over time as the proportion 
of patients with “clinically significant” symptoms (those scoring 
3 or 4) 
STRATIFI-
CATION 
Stratification will be performed according to: 
 Age (in years): less than or equal to 39 versus 40 or more 
STATISTICAL 
CONSIDE-
RATIONS 
To achieve the primary objective, E2 levels will be determined centrally 
from samples taken at day 1 of the first treatment cycle before the 
administration of the first dose of degarelix or triptorelin (baseline), and 
thereafter at 24 and 72 hours, 7 days and 14 days after the first injection, 
and on day 1 of cycles 2 to 6 before the administration of degarelix or 
triptorelin. 
For sample size calculation, we assume that the cumulative percentages 
of patients in the triptorelin arm achieving optimal ovarian function 
suppression (defined as E2 ≤2.72 pg/mL or ≤10 pmol/L) will be 30% 
within 2 weeks, 60% within 4 weeks and 75% within 8 weeks, and that 
degarelix will provide more rapid suppression (i.e., 60% within 2 
weeks, 95% within 4 weeks and 100% within 8 weeks).  Enrollment of 
25 patients in each treatment arm will provide at least 90% power to 
detect a difference in time to optimal ovarian function suppression 
between the two groups, using a two sample log-rank test with a two-
sided significance level of 0.05. 


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Randomized patients who receive at least one injection of triptorelin or 
degarelix will be included in the primary analysis. The primary endpoint 
will be compared between the two treatment arms using a stratified two-
sample log-rank test, with age as stratification factor. The distribution of 
the primary endpoint will be summarized using the method of Kaplan-
Meier and the two-sided 95% confidence interval (CI) for the difference 
in proportion of patients who achieve optimal ovarian function 
suppression between the two treatment arms at the end of the 1st, 2nd and 
4th cycle will also be provided.  
The toxicity, changes in Ki67 expression levels, the Preoperative 
Endocrine Prognostic Index (PEPI) score at the time of surgery, disease 
response, node-negative disease status at surgery and breast-conserving 
surgery (BCS) rate will also be summarized and differences assessed 
between treatment arms with confidence intervals. 
The primary endpoint for patient-reported symptoms (PRS) analysis is 
the total PRS score measured at baseline, day 1 of cycle 2 and day 1 of 
cycle 4 of triptorelin or degarelix administration, and prior to surgery. 
The differences in PRS measurements between the two treatment arms 
over time will be explored using the repeated measures analysis based 
on generalized estimating equation (GEE) model. 
NUMBER OF 
PATIENTS 
50 patients will be enrolled: (Arm A: 25; Arm B: 25)  
DURATION OF 
TRIAL 
Recruitment will last approximately 24 months with an additional 7 
months follow up after the last patient is enrolled. The end of the trial 
will be approximately 31 months after randomization of the first patient. 
 
 


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2. 
Trial schedule 
 
 
≤14 days 
prior to 
rando 
Day 1 of every 28 days cycle 
Prior to 
surgery 
30 days 
after 
surgery 
Cycle 
 
1 
2 
3 
4 
5 
6 
 
 
Informed consent 
x 
 
 
 
 
 
 
 
 
History 
x 
 
 
 
 
 
 
 
 
Physical examination, 
ECOG PS 
x 
x 
x 
x 
x 
x 
x 
x 
 
Serum pregnancy test1 
x 
 
 
 
 
 
 
 
 
Baseline symptoms 
x 
 
 
 
 
 
 
 
 
Adverse events 
 
x 
x 
x 
x 
x 
x 
x 
x 
Concomitant medications 
……………………….continuously………………………… 
Tumor evaluation 
(clinical) 
x 
x 
x 
x 
x 
x 
x 
x 
 
PRS 
x 
 
x 
 
x 
 
 
x 
 
Neoadjuvant Treatment 
 
 
 
 
 
 
 
 
 
GnRH agonist2  (arm A) or 
GnRH antagonist
3(arm B)
 
 
x 
x 
x 
x 
x 
x 
 
 
Letrozole
4 
 
 ....…….continuously……….. 
 
 
Laboratory tests 
 
 
 
 
 
 
 
 
 
Hematology
5 
x 
 
 
 
x 
 
 
x 
 
Blood chemistry
6 
x 
 
 
 
x 
 
 
x 
 
CEA and Ca 15.37 
x 
 
 
 
x 
 
 
x 
 
Estradiol8 
x 
x 
x 
x 
x 
x 
x 
x 
 
Tumor Evaluation 
 
 
 
 
 
 
 
 
 
Mammography9 
x 
 
 
 
x 
 
 
x 
 
Breast Ultrasound9 
x 
 
 
 
x 
 
 
x 
 
Chest x-ray10 
x 
 
 
 
 
 
 
 
 
Abdominal US or CT11 
√ 
 
 
 
 
 
 
 
 
Bone scan12 
√ 
 
 
 
 
 
 
 
 
Other tests 
 
 
 
 
 
 
 
 
 
ECG 
√ 
 
 
 
 
 
 
 
 
Echocardiography 
√ 
 
 
 
 
 
 
 
 
Pathology eval (local) 
x 
 
 
 
 
 
 
 
x 
Biological samples 
 
 
 
 
 
 
 
 
 
FFPE sample13 
x 
 
 
 
 
 
 
 
x 
Serum sample14 
x 
x14 
x 
x 
x 
x 
x 
 
 
x = mandatory √ = if medically indicated 
Legend for trial schedule: 
1. Pregnancy test has to be repeated before treatment start, if treatment does not start 
within 15 days of the previous test. 
 
 


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Neoadjuvant treatment: 6 cycles of 28 days each 
2. Triptorelin 3.75 mg i.m. on day 1 of every cycle 
3. Degarelix, Firmagon®  
- Day 1 of cycle 1: 240 mg s.c. given as two subcutaneous injections of 120 mg  
- Day 1 of cycles 2-6: 80 mg s.c.  
4. Letrozole 2.5 mg/day orally, continuously for 6 cycles 
Laboratory tests 
5. Hematology (Hemoglobin, platelet count, white blood cell count including 
differential (absolute neutrophil count)) must be done within 14 days prior to 
randomization, before the start of cycle 4 treatment and at the visit prior to surgery.  
6. Blood chemistry (blood urea nitrogen, creatinine, alkaline phosphatase, AST and 
ALT, total bilirubin, calcium,  urea, total cholesterol, LDL and HDL cholesterol, 
tryglycerides) must be done within 14 days prior to randomization, before the start of 
cycle 4 treatment and at the visit prior to surgery. 
7. CEA and CA 15.3 must be done within 14 days prior to randomization, beginning of 
cycle 4 and at the visit prior to surgery. 
8. 17--estradiol (E2) must be done within 14 days prior to rando, at baseline (day 1 of 
cycle 1, before treatment start), and then at the start of cycles 2 to 6, prior to injection 
of GnRH agonist or GnRH antagonist, and before surgery. Menopausal status will be 
assessed by the Investigator according to local laboratory estradiol level for 
menopausal status. Refer to section 9.2 for criteria for stopping neoadjuvant treatment 
in case of insufficient ovarian function suppression. 
NOTE: For the trial primary endpoint, estradiol levels will be assessed centrally, see 
note 14 below. 
Tumor evaluation 
9. A bilateral mammography, breast ultrasound and caliper measurement must be done 
prior to randomization, after 3 cycles of treatment (denoted as day 1 of cycle 4 in the 
schedule) and prior to surgery.  
Other procedures 
10. A chest X-ray is not required in patients who have undergone a PET scan.  
11. Abdominal ultrasound or CT scan is required if alkaline phosphatase or AST is 
>2.5×ULN; not required in patients who have undergone a PET scan. 
12. Bone scan is required if alkaline phosphatase is >2.5×ULN or if the patient has 
unexplained bone pain; not required in patients who have undergone a PET scan. 
Biological studies 
13. Two formalin-fixed, paraffin-embedded (FFPE) tumor blocks, one from the 
diagnostic core biopsy and one from the surgical specimen must be submitted for 
central pathology review and stored in the IBCSG Tissue Bank for future 
translational research studies.  
14. For determination of FSH, LH, E2 by a central laboratory, serum samples must be 
taken and stored at -80°C at day 1 of treatment before the administration of the 
first dose, thereafter at 24 and 72 hours, 7 days and 14 days after first injection, and 
on day 1 of cycles 2 to 6 before the administration of the next dose of the GnRH 
agonist or antagonist. 
 


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3. 
Introduction 
3.1. 
The role of primary systemic therapy in breast cancer 
Primary systemic therapy (PST) for operable breast cancer has been evaluated in a number 
of trials (1,2). So far the only demonstrated benefit related to treatment effect is sufficient 
tumor shrinkage to enable breast-conserving surgery, although the theoretical likelihood of 
decreasing the spreading of micrometastasis after surgical resection and minimizing the 
potential drug resistance have been hypothesized. The response to the primary treatment 
may be used as a prognostic marker, since it was demonstrated to be associated with a 
longer DFS compared with no response (3,4). The effect of treatment on the clinical and 
biological characteristics of the tumor may represent an objective assessment of its 
responsiveness, thus allowing any further treatment to be tailored according to the results 
observed. Moreover, the achievement of pathological complete remission (pCR) can predict 
overall outcome in terms of disease free survival (DFS) and overall survival (OS) (4). 
3.2. 
Primary endocrine therapy in postmenopausal breast cancer patients 
Preoperative treatment of endocrine responsive tumors represents a challenge for medical 
oncologists. Although chemotherapy is able to induce a high number of objective responses, 
the chance of obtaining a pCR is from 2 to 7-fold lower than in hormone receptor negative 
tumors and usually ranges from 6% to 14% (5,6,7). It is reasonable to speculate that these 
tumors might benefit from an endocrine treatment. 
Endocrine therapy has been historically limited to patients who were not suitable for 
chemotherapy and surgery. Earlier phase II studies with tamoxifen focused primarily on 
elderly and/or frail patients, often unselected for hormone receptor status of the tumor and 
showed a response rate ranging from 49% to 68% (8). The proven superiority of third-
generation aromatase inhibitors in the advanced disease stimulated the investigation of these 
agents in the preoperative (neoadjuvant) setting among post-menopausal women with 
hormone receptor positive tumors (9). Initially, phase II studies showed a response rate up to 
80% for letrozole and prompted comparison studies of aromatase inhibitors with tamoxifen 
(8). 
In a phase III study including 330 postmenopausal women, letrozole was shown to increase 
the response rate (55% vs 36% p<.001) and the breast-conserving surgery rate (45% vs 
35%, p=.022) as compared with tamoxifen (10). Interestingly, subgroup analyses showed 
that patients with HER1 and/or HER2 overexpressing tumors benefited from letrozole (RR= 
88% vs 21%), while in tumors not overexpressing HER1 and/or HER2, response rate was 
similar between the two treatments (54% vs 42%) (11). 
The second randomized trial, the IMPACT trial, comparing anastrozole vs tamoxifen vs the 
combination of the two agents,  failed to show any difference regarding response rate among 
treatments (37% vs 36% vs 39%), although patients receiving anastrozole were significantly 
more likely to undergo breast-conserving surgery (46% vs 22% vs 26% with anastrozole, 
tamoxifen, and combination therapy, respectively). In this study, again, patients with HER2 
overexpressing tumors presented a higher response rate with  the aromatase inhibitor when 
compared with tamoxifen although the difference was not statistically significant (58% vs 
22% vs 31% with anastrozole, tamoxifen, and combination therapy, respectively) (12). 
In a third trial, the PROACT trial, anastrozole and tamoxifen yielded a similar response rate. 
In the subgroup of patients who did not receive concurrent chemotherapy, anastrozole 
produced a higher response rate (36.2% vs 26.5% p=.09) (13). 


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The aromatase inhibitor exemestane has been compared with tamoxifen in a randomized 
study including 151 postmenopausal women with ER and/or PgR-positive breast cancer 
(15). The aromatase inhibitor significantly increased the clinical response rate (76% vs 40% 
p=.05) and the rate of breast-conserving surgery (36.8% vs 20% p=.05) (14). 
Endocrine therapy with aromatase inhibitors has been compared with four courses of 
doxorubicin and paclitaxel in a randomized study including 121 postmenopausal patients 
with ER-positive breast cancer. The preliminary results showed that four courses of 
chemotherapy yielded comparable response rate and pCR rate if compared with exemestane 
and anastrozole (15).  
Conflicting results have been reported in the literature on the value of factors predictive of 
response in the neoadjuvant setting in particular in the subset of patients with ER-positive 
tumors.  
The presence of elevated Ki67 before neoadjuvant therapy has been found to predict 
response to chemotherapy in locally advanced breast cancer. In particular higher Ki67 levels 
after preoperative chemotherapy significantly and independently correlate with poorer DFS 
(16,17). 
Recent results indicate that Ki67 might represent a valid surrogate of outcome in patients 
with ER-positive breast cancer treated with neoadjuvant endocrine therapy. In fact tumor 
Ki67 levels determined during neoadjuvant endocrine treatment were found to be a marker 
of treatment efficacy and to have significant prognostic value. 
Moreover, Ki67 data have been integrated into a post-treatment model (PEPI score) which 
also includes pathologic stage and ER levels. The model was found to be useful in 
identifying subsets of patients for whom adjuvant treatment without chemotherapy could be 
considered after a neoadjuvant endocrine treatment. In particular, in the IMPACT trial no 
relapses were recorded among patients with small node-negative tumors and a PEPI score of 
0 (residual tumor with low Ki67 index and with maintained ER expression) (18). 
The PEPI score (19) is based on a post neoadjuvant treatment model that integrates central 
pathology review (CPR) results of pathological features and biomarkers (tumor size, node 
status, Ki67 expression level and ER status by Allred score). The risk points associated with 
recurrence free survival (RFS) will be used in this trial to calculate the PEPI Score (see table 
below). 
 
RFS 
Pathology, biomarker status 
HR 
Points 
Tumor size: 
 
T1/2 
 
T3/4 
 
 
2.8 
 
0 
3 
Nodal status 
 
Negative 
 
Positive 
 
 
3.2 
 
0 
3 
Ki67 level 
 
0 – 2.7%  
(0 – 1 a) 
 
>2.7 – 7.3%  
(1 – 2 a) 
 
>7.3 – 19.7%  
(2 – 3 a) 
 
>19.7 – 53.1% 
(3 – 4 a) 
 
>53.1% 
(>4 a) 
 
 
1.3 
1.7 
2.2 
2.9 
 
0 
1 
1 
2 
3 
ER status, Allred score 
 
0 – 2 
 
3 – 8 
 
2.8 
 
3 
0 
aThe natural logarithm interval corresponding to the per cent Ki67 values on the original percentage scale. 


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In the adjuvant setting, a body of evidence also suggests that the level of both ER and PgR 
may play a crucial role in predicting response to treatment. In a study of the Edinburgh 
group, 83 postmenopausal women were treated with neoadjuvant letrozole for 3 months. 
Tumors were subdivided according to their ER Allred scores and of these, 60 tumors were 
scored 8 while 23 were scored as Allred 6 or 7. Although response rates were similar in both 
groups, a significantly greater reduction in tumor volume was observed in patients whose 
tumors had the highest ER levels (20). 
3.3. 
Primary endocrine therapy in premenopausal breast cancer patients 
Limited data are available on neoadjuvant treatments administered in premenopausal 
patients. In a study focused on 13 premenopausal women with endocrine responsive disease, 
neoadjuvant therapy with a gonadotropin-releasing hormone (GnRH) analogue induced a 
54% rate of clinical response after 3 months of treatment (21). Torrisi et al. analyzed the 
efficacy of letrozole in combination with GnRH analogues and revealed among its 32 
evaluable patients a median duration of therapy of 5.2 months for letrozole. A single patient 
(3%) obtained a complete clinical response, which was confirmed as by pCR upon 
pathological examination, whereas 15 patients (47%) obtained a partial response that 
produced an overall response rate of 50%; no patients progressed during treatment (22).  
The STAGE study randomized 204 premenopausal women with ER-positive, HER2-
negative breast cancer to receive goserelin 3·6 mg/month plus either anastrozole and 
tamoxifen placebo or tamoxifen and anastrozole placebo for 24 weeks before surgery. More 
patients in the anastrozole group had a complete or partial response than did those in the 
tamoxifen group during the 24 weeks of neoadjuvant treatment (70.4% vs. 50.5%, 
respectively) (23).  
3.4. 
GnRH agonist and GnRH antagonist 
3.4.1. 
GnRH agonist 
GnRH or LHRH (luteinizing hormone-releasing hormone agonist) analogues or agonists are 
synthetic peptide drugs modeled after the human hypothalamic gonadotropin-releasing 
hormone (GnRH). GnRH agonists are designed to interact with the GnRH receptor and 
modify the release of pituitary gonadotropins, follicle-stimulating hormone (FSH) and 
luteinizing hormone (LH), for therapeutic purposes. Upon administration of GnRH agonists 
an initial stimulating action of the hypophysis occurs – termed a «flare» effect - which 
eventually causes a paradoxical and sustained drop in gonadotropin secretion. This second 
effect was termed «downregulation» and can be observed after about 10 days. While this 
phase is reversible upon stopping the medication, it can be maintained when GnRH agonist 
use is continued for a prolonged period of time. For some patients, there can be a delay of 
approximately 2-4 months until downregulation of the gonadotropins occurs. 
3.4.2. 
GnRH agonist and antagonist in prostate cancer 
Degarelix (tradename: Firmagon), a new GnRH receptor blocker (antagonist), was 
developed as a novel therapy for patients with prostate cancer. Degarelix binds to and 
blocks the GnRH receptors in the anterior pituitary gland, resulting in decreased secretion of 
both LH and FSH. This leads directly to a rapid decrease in the production of testosterone. 
Testosterone suppression to castration levels (≤0.5 ng/mL) (24) is achieved within 1–3 days 
of administration.  


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In two phase II dose-finding clinical trials, a starting dose of 240 mg degarelix and 
maintenance doses of 160 mg or 80 mg were shown to effectively suppress testosterone 
levels in patients with prostate cancer, with no evidence of testosterone surge or inducement 
of clinical flare (25,26).  
In a dose-finding study CS07, patients were allocated to one of eight single doses. These 
were: 120 mg (40 mg/mL); 120 mg (20 mg/mL); 160 mg (40 mg/mL); 200 mg (40 mg/mL); 
200 mg (60 mg/mL); 240 mg (40 mg/mL); 240 mg (60 mg/mL); and 320 (60 mg/mL). The 
single 240 mg (40 mg/mL) dose was identical to the starting dose being proposed for 
registration. Based on the results for the primary and secondary endpoints relating to serum 
testosterone suppression, doses of 200 mg (40 mg/mL) and 240 mg (40 mg/mL) were the 
most efficacious as measured by response rates ≥ 95%. The study provides supportive 
evidence for the efficacy of the proposed initial dose of 240 mg (40 mg/mL) (27). 
A pivotal study compared the efficacy and safety of two s.c. degarelix treatment regimens 
and an i.m. leuprolide (L) 7.5 mg treatment regimen administered every 28 days for up to 12 
months in patients with prostate cancer. The two degarelix regimens were both initiated with 
a dose of 240 mg (40 mg/mL) followed 28 days later by a maintenance dose of either 160 
mg (40 mg/mL) or 80 mg (20 mg/mL) repeated every 28 days. The results for the primary 
analysis showed that both D240/160 and D240/80 treatment regimens were effective in 
suppressing testosterone from Day 28 to Day 364. The results also showed that both 
D240/160 and D240/80 treatment regimens were non-inferior to L7.5 in suppressing 
testosterone from Day 28 to Day 364 (28).  
A phase III study was conducted to compare the efficacy of monthly administrations of the 
luteinizing hormone releasing hormone agonists triptorelin and leuprolide to induce and 
maintain castrate levels of serum testosterone in men with advanced prostate cancer. Men 
with advanced prostate cancer were randomly assigned to receive triptorelin 3.75 mg or 
leuprolide 7.5 mg. In all, 284 men received either triptorelin (140) or leuprolide (144). The 
percentage of men with castrate levels of serum testosterone was lower at 29 days for 
triptorelin than for leuprolide (91.2% vs 99.3%; point estimate - 8.0, 95% confidence 
interval - 16.9% to - 1.4%), but equivalent at 57 days (97.7% vs 97.1%). The mean (98.8% 
vs 97.3%) and cumulative (96.2% vs 91.2%) castration maintenance rates between 29 and 
253 days were equivalent between the treatment groups (29). 
3.4.3. 
GnRH agonist and antagonist in breast cancer 
Triptorelin administered at a dose of 3.75 mg was shown to induce strong estradiol 
suppression among premenopausal patients with breast cancer (30). Moreover, letrozole in 
combination with triptorelin at the dose of 3.75 mg q 28 days induces a more intense 
estrogen suppression than tamoxifen + triptorelin in premenopausal patients with early 
breast cancer. Prospectively collected hormonal data were available in a study that included 
81 premenopausal women, of whom 30 were assigned to receive tamoxifen + triptorelin 
whereas 51 were assigned letrozole + triptorelin +/- zoledronate with a median age of 44 
years for both groups of patients. Letrozole + triptorelin (+/- zoledronate) induced stronger 
suppression of median E2 serum levels (P = .0008), LH levels (P = .0005), and cortisol 
serum levels (P < .0001) compared with tamoxifen + triptorelin (31). 
It therefore seems reasonable to compare the GnRH agonist triptorelin at the dose of 3.75 
mg every 28 days with the GnRH antagonist degarelix at the initial dose of 240 mg s.c., 
followed by 80 mg s.c. on day 1 of subsequent 28 day cycles. 


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3.5. 
Plasma estradiol levels during endocrine therapy with AI 
The guidelines of Smith et al. for the use of adjuvant AIs after chemotherapy-induced 
amenorrhea (32) recommend caution in the situation where estradiol levels determined by 
highly sensitive/specific methods such as GC-MS/MS are >10 pmol/L (>2.72 pg/mL) while 
on an AI, because this indicates that the AI is not exerting its full effectiveness. Thus 
optimal suppression will be defined as E2 levels ≤2.72 pg/mL or ≤10 pmol/L. 
3.6. 
Rationale of the trial 
Despite the advances achieved with primary therapy, novel treatment approaches are still 
necessary to increase disease control. Neoadjuvant endocrine therapy with a combination of 
GnRH agonist and AIs is effective for a select group of premenopausal patients.  
Degarelix induces a fast and profound reduction in LH, FSH and in turn, testosterone 
suppression. Its activity in suppressing ovarian function of premenopausal women might 
therefore be faster than that of the GnRH agonists, and for some patients this might mean 
shortening time to ovarian suppression by several weeks. A difference in onset of action 
might have significant clinical value in patients who are candidates for short-term 
neoadjuvant endocrine treatment.  
4. 
Trial objectives and endpoints 
The primary objective is to compare the endocrine activity of neoadjuvant degarelix and 
triptorelin in premenopausal patients receiving letrozole for primary endocrine responsive 
breast cancer. The endocrine activity is measured by time to optimal ovarian function 
suppression. 
4.1. 
Primary endpoint 
Time to optimal ovarian function suppression: time from the first injection of degarelix or 
triptorelin to the first assessment of centrally assessed 17--estradiol (E2) level in the range 
of optimal ovarian function suppression (≤2.72 pg/mL or  ≤10 pmol/L) during the 6 cycles 
of neoadjuvant  treatments. Time for patients who do not reach the targeted E2 level will be 
censored at the last E2 assessment date. 
4.2. 
Secondary endpoints 
 
 Tolerability: adverse events according to CTCAE version 4 
 Ki67 proliferation marker changes 
 The Preoperative Endocrine Prognostic Index (PEPI) score determined after 
completion of  neoadjuvant therapy or at the time of surgery 
 Best overall (disease) response: defined as best response recorded from the start of 
treatment across all time points until disease progression. Confirmation of partial or 
complete response by an additional scan is not required in this trial. Best overall 
response will be determined by a team consisting of the study chair, co-chair and 
IBCSG Head of Medical Affairs. Tumor assessment will use WHO response criteria. 
 Node-negative disease at surgery 
 Breast-conserving surgery (BCS) rate 
 Patient-reported symptoms (PRS) outcomes (see Section 16.5) 


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5. 
Trial design, duration and termination 
5.1. 
Trial schema 
 
 
Randomization allocation 1:1 to one of the two arms  
5.2. 
Sample size and trial duration 
 Neoadjuvant endocrine therapy of letrozole with either degarelix or triptorelin in 28 
days cycle for a total of 6 cycles. 
 Total of 50 patients (Arm A: 25 and Arm B: 25) will be enrolled. 
 Estradiol (E2) levels will be determined centrally from samples taken at day 1 of 
first treatment cycle before the administration of the first dose (baseline), thereafter 
at 24 and 72 hours, 7 days and 14 days after first injection, and on day 1 of cycles 2 
to 6. 
 Tumor evaluation will be at baseline (within 14 days prior to randomization) and at 
the end of 3rd and 6th cycles of treatment (denoted as day 1 of cycle 4 and prior to 
surgery). 
The randomization of 50 patients is expected to occur over approximately 24 months. The 
treatment and post-surgery evaluation will occur within 7 months. Thereafter patients will 
have no further follow-up. The end of the trial therefore will be approximately 31 months 
after randomization of the first patient. 
The trial will be conducted in 7 Centers in Italy. 
 
 
Premenopausal
breast cancer
cT2-4b, M0, any N, 
ER>50%, 
PgR>50%
HER2 neg.
Stratify:
Age ≦39
vs 40+
R
A
N
D
O
M
I
Z
E
A
B
FFPE block 
from diagnostic
core biopsy
Translational research:
Cycle   1        2        3        4        5         6
Surgery 
Surgery 
treatments:
triptorelin 
degarelix
degarelix
Letrozole
3.75mg i.m. 
240mg s.c.
80mg s.c.
2.5mg/day
every 28 days
day 1
every 28 days
FFPE 
block


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6. 
Patient selection 
6.1. 
Criteria for patient eligibility 
6.1.1. 
Female gender 
6.1.2. 
Premenopausal status determined locally: 
Estradiol (E2) must be above 54 pg/mL (or above 198 pmol/L), measured within 14 
days prior to randomization. 
6.1.3. 
Age ≥ 18 years 
6.1.4. 
Performance Status – Eastern Cooperative Oncology Group (ECOG) 0-1 (see chart 
at end of section*) 
6.1.5. 
Histologically confirmed invasive breast cancer: 
- Primary tumor greater than 2 cm diameter, measured by clinical examination  
and mammography or echography (cT2-4b) 
- Any nodal stage 
- No evidence of metastasis (M0)  
6.1.6. 
Primary tumor must have ER and PgR >50% of the cells 
6.1.7. 
Primary tumor must be HER2 negative (by IHC and/or ISH)  
6.1.8. 
Hematopoietic status: 
- Absolute neutrophil count ≥ 1.5 × 109/L 
- Platelet count ≥ 100 × 109/L 
- Hemoglobin ≥ 9 g/dL 
6.1.9. 
Hepatic status: 
- Serum total bilirubin ≤ 1.5 × upper limit of normal (ULN). In the case of known 
Gilbert’s syndrome, a higher serum total bilirubin (< 2 × ULN) is allowed 
- AST and ALT ≤ 2.5 × ULN 
- Alkaline phosphatase ≤ 2.5 × ULN 
6.1.10. Renal status: Creatinine ≤ 1.5 ×ULN 
6.1.11. Negative serum pregnancy test, within 2-weeks (preferably 7 days) prior to 
randomization. Pregnancy test has to be repeated before treatment start if treatment 
does not start within 15 days of the previous test. 
6.1.12. The patient must be willing to use effective non-hormonal contraception (barrier 
method – condoms, diaphragm – also in conjunction with spermicidal jelly, or total 
abstinence) after the pregnancy test and up to surgery. Oral, injectable, or implant 
hormonal contraceptives or medicated IUD are not allowed within 2 months prior 
to randomization and during the trial. 
6.1.13. Prior fertility treatment is allowed but must have been stopped at least 12 months 
before randomization 


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6.1.14. The patient has completed the baseline patient-reported symptoms questionnaire 
6.1.15. Written Informed Consent (IC) must be signed and dated by the patient and the 
Investigator prior to randomization 
6.1.16. The patient has been informed of and agrees to data transfer and handling, in 
accordance with national data protection guidelines 
6.1.17. The patient accepts blood samples to be taken according to the schedule in section 
17.4 for the determination of the primary endpoint 
6.1.18. The patient agrees to make tumor (diagnostic core biopsy and surgical specimen) 
available for submission for central pathology review and to conduct translational 
studies as part of this protocol 
NOTE: Central Pathology Review on the primary tumor is mandatory for this trial, 
but patients will be evaluated for eligibility according to tumor characteristics as 
determined by the local Pathologist. Both the diagnostic breast core biopsy 
specimen and the final breast surgical specimen must be submitted for Central 
Pathology Review. 
* ECOG Performance Status: 
PS 0 
Fully active, able to carry on all pre-disease performance without restriction 
PS 1 
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature, e.g., light housework, office work 
PS 2 
Ambulatory and capable of all self-care but unable to carry out any work activities. 
Up and about more than 50% of waking hours 
PS 3 
Capable of only limited self care, confined to bed or chair more than 50% of waking 
hours 
PS 4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 
6.2. 
Criteria for patient ineligibility 
6.2.1. 
Postmenopausal patients 
6.2.2. 
Any hormonal treatment (e.g., oral, injectable, implant, or medicated IUD) in the 
previous 2 months. 
6.2.3. 
Presence of HER2/neu overexpression or amplification  
6.2.4. 
Received any prior treatment for primary invasive breast cancer 
6.2.5. 
Received any GnRH analog or SERM or AI within 12 months prior to 
randomization 
6.2.6. 
A history of malignant neoplasms within the past 10 years, except for curatively 
treated 
- Basal and squamous cell carcinoma of the skin 


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- Carcinoma in situ of the cervix 
- Carcinoma in situ of the bladder 
6.2.7. 
Previous ipsilateral breast cancer (invasive or in situ) at any time 
6.2.8. 
Inflammatory breast cancer 
6.2.9. 
Bilateral invasive breast cancer 
6.2.10. Known history of uncontrolled or symptomatic angina, clinically significant 
arrhythmias, 
congestive 
heart 
failure, 
transmural 
myocardial 
infarction, 
uncontrolled hypertension (≥ 180/110), unstable diabetes mellitus, dyspnea at rest, 
or chronic therapy with oxygen 
6.2.11. Concurrent disease or condition that would make the subject inappropriate for 
study participation or any serious medical disorder that would interfere with the 
subject’s safety 
6.2.12. Unresolved or unstable, serious adverse events from prior administration of another 
investigational drug 
6.2.13. Active or uncontrolled infection CTCAE v.4 grade 2 or higher 
6.2.14. Dementia, altered mental status, or any psychiatric condition that would prevent the 
understanding or rendering of Informed Consent 
6.2.15. Treatment with an investigational agent must have stopped at least 30 days before 
randomization 
6.2.16. Pregnant or lactating women; lactation has to stop before randomization. 
7. 
Randomization and stratification 
This trial will use a web-based randomization system. Specific details for randomizing are 
in the “IBCSG Registration/Randomization Procedures Manual” which is available on the 
IBCSG website (www.ibcsg.org). 
7.1. 
Protocol requirements before randomization 
7.1.1. 
Pathology material from the diagnostic breast biopsy of the primary tumor has to 
be available for submission for central review as part of the quality control 
measures for this protocol.  
NOTE: Central Pathology Review (CPR) on the primary tumor is mandatory for 
this trial, but patients may be included based on tumor characteristics as determined 
by the local Pathologist. 
NOTE: An FFPE block with a specimen of the final breast surgery will have to be 
submitted for CPR as well. Please notify the pathologist of this requirement in 
advance. 


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7.1.2. 
Check current and concomitant medications 
NOTE: Additional hormonal treatments (oral or transdermal) including estrogen, 
progesterone, androgens, aromatase inhibitors, hormone replacement therapy, oral 
or other types of hormonal contraceptives (including implants and depot injections 
and medicated IUD), 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. 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®). 
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). 
Concomitant medication needs to be documented on the Form 41-CCM for the 14 
days prior to randomization and throughout the trial until 30 days after surgery. 
7.1.3. 
Patient needs to complete baseline PRS questionnaire. 
7.2. 
Registration and randomization procedures 
Complete the following steps to register and randomize a patient on this trial. 
7.2.1. 
Verify eligibility (see section 0) 
7.2.2. 
Make sure that the information needed for registration is available: 
- E2 level used to determine premenopausal status 
- Type of surgery intended to be performed upon completion of neoadjuvant 
treatment 
- Patient age in years 
- Prior fertility treatment yes/no, date of last such treatment 
- Date of most recent pregnancy test 
7.2.3. 
Obtain written Informed Consent both for the clinical trial and biological material 
submission, signed and dated by the patient and Investigator. Informed consent 
must be obtained prior to any trial-specific screening procedure or intervention.  
7.2.4. 
Directly access the IBCSG Registration/Randomization System and provide the 
requested information as indicated on the Confirmation of Registration (41-A) 
Form.  The date the Informed Consent Form and the Biological Material Consent 
was signed by the patient and the date signed by the Investigator are both required 
to complete randomization. 
The IBCSG Registration/Randomization System will provide the following 
information via e-mail: 
 Patient ID (randomization number)  
 Treatment assignment 
 Date of randomization 


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7.2.5. 
Submit the Confirmation of Registration (41-A) electronic case report form (eCRF) 
via iDataFax. The patient binder of eCRFs will be available in iDataFax within 24 
hours of successful randomization.  
7.3. 
Randomization Help Desk 
The IBCSG Data Management Center (located at Frontier Science and Research 
Technology Foundation (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. 
Business Hours:  00:00-18:00 US Eastern Time Monday through Friday 
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  
E-mail: bc.helpdesk@fstrf.org  
This telephone information may also be used after business hours for urgent issues. 
7.4. 
Randomized arms 
Randomization (1:1) to 2 arms; cycles last 28 days: 
Arm A: Triptorelin 3.75 mg i.m. on day 1 of every cycle + letrozole 2.5 mg/day orally for 6 
cycles 
Arm B: Degarelix 240 mg s.c. given as two subcutaneous injections of 120 mg on day 1 of 
cycle 1, followed by 80 mg s.c. on day 1 of cycles 2 to 6 + letrozole 2.5 mg/day 
orally for 6 cycles 
7.5. 
Stratification 
For randomization, patients will be stratified by age (in years): less than or equal to 39 vs 40 
or more. 
Dynamic institution balancing will be used in order to balance randomized assignments 
within institutions. 
8. 
Study drugs formulation and handling 
Triptorelin, degarelix and letrozole are the investigational drugs used in this trial; all will be 
supplied. 
Complete details of the study drug logistics, distribution, packaging, labeling and handling 
are described in a separate drug supply manual. 
8.1. 
Triptorelin 
Triptorelin is a synthetic decapeptide analogue of the natural gonadotropin-releasing 
hormone (GnRH). GnRH is a decapeptide synthesized in the hypothalamus and regulates 
the biosynthesis and release of the gonadotropins: LH (luteinizing hormone) and FSH 
(follicle stimulating hormone) by the pituitary. The increase of LH and FSH levels will 


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initially lead to an increase of the serum estrogen concentration in women, however chronic 
administration results in an inhibition of pituitary LH- and FSH-secretion. This inhibition 
leads to a reduction in steroidogenesis, through which the serum estradiol concentration in 
women fall into the postmenopausal range. 
Dose: 3.75 mg i.m. every 28 days for 6 cycles. 
In Italy, triptorelin has marketing authorization for the use in breast cancer, presurgical 
treatment before myomectomy/hysterectomy, uterine fibromyomas, and endometriosis. 
8.1.1. 
Packaging and labeling 
Both the box label and vial label will fulfill all requirements specified by governing 
regulations.  
8.1.2. 
Storage and handling 
Instructions for proper handling and disposal of triptorelin should be followed. All drugs 
will be stored as per the current version of the product’s SPC’s (Summary of Product 
Characteristics) and the standard hospital procedures. Pharmacy will maintain temperature 
logs of all storage conditions and comply with hospital pharmacy standard operating 
procedures. 
8.2. 
Degarelix 
Degarelix (Firmagon®) is a gonadotropin releasing hormone (GnRH) receptor blocker and 
the chemical structure is a linear decapeptide amide containing seven unnatural amino acids, 
five of which are D-amino acids.  
Degarelix is a selective gonadotropin releasing-hormone (GnRH) antagonist that 
competitively and reversibly binds to the pituitary GnRH receptors, thereby rapidly reducing 
the release of the gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone 
(FSH).  
Degarelix is registered in the European Union for treatment of adult male patients with 
advanced hormone-dependent prostate cancer. In women, degarelix has been safely 
administered for the treatment of infertility. 
Degarelix is supplied as a powder and solvent for solution for injection. The reconstitution 
procedure needs to be carefully followed. 
Dose: 240 mg s.c. given as two subcutaneous injections of 120 mg on day 1 of trial 
treatment, followed by 80 mg s.c. every 28 days for cycles 2-6. 
8.2.1. 
Packaging and labeling  
Both the box label and vial label will fulfill all requirements specified by governing 
regulations.  
8.2.2. 
Storage and handling 
Instructions for proper handling and disposal of degarelix should be followed. All drugs will 
be stored as per the current version of the product’s SPC’s (Summary of Product 
Characteristics) and the standard hospital procedures. Pharmacy will maintain temperature 
logs of all storage conditions and comply with hospital pharmacy standard operating 
procedures. This medicinal product does not require any special storage conditions. 


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8.3. 
Letrozole 
Letrozole is a potent, orally active non-steroidal competitive inhibitor of the aromatase 
enzyme system. As a non-steroidal aromatase inhibitor, letrozole effectively inhibits the 
conversion of androgens to estrogens both in vitro and in vivo.  
Letrozole is registered for the following indications:  
 Treatment of advanced breast cancer in postmenopausal women with disease 
progression following anti-estrogen therapy 
 First-line treatment of postmenopausal women with hormone receptor positive 
or hormone receptor unknown locally advanced or metastatic breast cancer 
 Extended adjuvant treatment of early breast cancer in postmenopausal women 
who have received 5 years of adjuvant tamoxifen therapy 
 Adjuvant treatment of postmenopausal women with hormone receptor positive 
early breast cancer 
 Pre-operative therapy in postmenopausal women with localized hormone 
receptor positive breast cancer, to allow subsequent breast-conserving surgery 
for women not originally considered as appropriate surgical candidates.  
Letrozole is supplied as film-coated tablet containing 2.5 mg letrozole. 
Dose: 2.5 mg / day orally. 
8.3.1. 
Packaging and labeling  
Both the box label and blister label will fulfill all requirements specified by governing 
regulations.  
8.3.2. 
Storage and handling 
Procedures for proper handling and disposal of letrozole should be followed. All drugs will 
be stored as per the current version of the products SPC’s (Summary of Product 
Characteristics) and the standard hospital procedures. Pharmacy will maintain temperature 
logs of all storage conditions and comply with hospital pharmacy standard operating 
procedures. 
Do not store above 30°C or outside original package. 
9. 
Treatment 
9.1. 
Trial treatments 
Six cycles of 28 days each: 
Arm A: Triptorelin 3.75 mg i.m. on day 1 of every cycle + letrozole 2.5 mg/day orally for 6 
cycles 
Arm B: Degarelix 240 mg s.c. given as two subcutaneous injections of 120 mg on day 1 of 
cycle 1, followed by 80 mg s.c. on day 1 of cycles 2 to 6 + letrozole 2.5 mg/day 
orally for 6 cycles 
Letrozole 2.5 mg/day orally should be started on day 1, concurrently with triptorelin or 
degarelix. 


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Trial treatment should start as soon as possible, and no later than 14 days after 
randomization. 
NOTE: Treatment can be started at any time during the menstrual cycle. 
Trial treatment stops at surgery. 
If the patient has to continue endocrine treatment with an LHRH analogue after surgery, she 
should wait at least 6 weeks from the date of last administration of degarelix in order to 
avoid drug interactions. 
9.2. 
Criteria for stopping neoadjuvant treatment 
In the following cases neoadjuvant treatment should be stopped, and the patient should 
undergo surgical intervention: 
 If ovarian function suppression is not achieved within 56 days after start of treatment 
according to local laboratory limits 
 In the case of an adverse event grade ≥ 3, judged by the Investigator to be at least 
possibly related to study drugs. 
9.3. 
Timing of surgery 
Definitive surgery should be performed within 2 to 3 weeks after the last administration of 
triptorelin or degarelix.  
9.4. 
Dose modifications and delays 
No dose modifications are allowed for the drugs used in this trial (triptorelin/degarelix and 
letrozole). 
Compliance with the protocol endocrine treatment should be strictly observed.  
 Delays in the administration of triptorelin/degarelix should not exceed 2 days.  
 Interruptions in the administration of letrozole should not exceed 2 days. 
In the case of adverse event(s) grade ≥ 3, judged by the Investigator to be at least possibly 
related to study drugs, treatment will be stopped and patient will undergo surgical 
intervention. 
10. 
Determination of objective response 
Objective response will be assessed using the WHO tumor measurement and response 
criteria. 
10.1. 
Tumor measurements 
Bilateral mammography and breast ultrasound are required at baseline, after 3 treatment 
cycles and prior to surgery. 
Breast ultrasound and mammography are mandatory.  
The technique(s) used for measurement of the tumor will be left to the discretion of the 
Investigator, however, for each patient the same technique(s) should be used throughout the 
study treatment period. Whenever possible, measurements should be made by the same 
Investigator or reporter for all assessments for each patient. 


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All measurements (bi-dimensional) should be recorded in metric notations (centimeters and 
tenths of centimeters) using a ruler or calipers. 
In the case of multifocal or multicentric disease, only the lesion with the largest dimensions 
will be considered.  
Primary tumor diameters as well as nodal status must be reported in the appropriate sections 
of the eCRF. 
All measurable lesions with diameter(s) that decrease to < 0.5 cm will continue to be 
recorded as having a diameter of 0.5 cm until the lesion is completely resolved or until the 
diameter increases to > 0.5 cm. When the diameter increases to > 0.5 cm, the actual 
measured diameter will again be recorded. When the lesion is completely resolved, record 
as: 0.0 x 0.0 cm. 
10.2. 
Response criteria 
To determine response, changes in tumor size from baseline to the assessments after 3 and 
after 6 cycles as measured physically by caliper or ruler and as measured by breast tumor 
imaging will be used and the WHO criteria will be followed. 
No confirmatory assessment will be required. 
10.2.1. Complete response (CR) 
The disappearance of all known disease. 
10.2.2. Partial response (PR) 
A 50% or more decrease in total tumor size, i.e., the sum of the products of the maximal 
diameter (MD) and the corresponding largest perpendicular diameter (LPD) of the lesions 
which have been measured to determine the effect of therapy. In addition, there can be no 
appearance of new lesions or progression of any lesion. 
10.2.3.  Stable disease (SD)  
Neither a 50% decrease in total tumor size (i.e., the sum of the products MD*LPD of 
lesions), nor a 25% increase in the size of one or more measurable lesions has been 
determined. 
10.2.4. Progressive disease (PD) 
An increase of least 25% in total tumor size relative to the smallest size measured during the 
trial (i.e. the sum of the products MD*LPD of lesions), and/or the appearance of one or 
more new lesions. 
10.3. 
Best overall response 
Best overall response is defined as best response recorded from the start of treatment across 
all time points until disease progression. Confirmation of partial or complete response by an 
additional scan is not requested in this trial. Best overall response will be determined by a 
team consisting of the Study Chair, Co-chair and IBCSG Head of Medical Affairs. 
 
 


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10.4. 
Treatment in case of progression 
Patients with evidence of complete response, partial response, or no change will remain on 
treatment for the full 6 cycles of endocrine treatment. 
Patients with progressive disease confirmed by imaging will undergo surgery. 
11. 
Clinical and laboratory evaluations 
11.1. 
Before randomization 
11.1.1. Breast palpation with tumor measurement and nodal status – caliper or ruler 
measurements preferred 
11.1.2. Bilateral mammography and breast ultrasound (mandatory) 
11.1.3. Chest X-ray; not required in patients who have undergone a PET scan 
11.1.4. Abdominal ultrasound or CT scan is required if alkaline phosphatase or AST is 
>2.5 x ULN; not required in patients who have undergone a PET scan  
11.1.5. Bone scan is required if alkaline phosphatase is >2.5 x ULN or if the patient has 
unexplained bone pain; not required in patients who have undergone a PET scan 
11.1.6. Tumor measurements according to WHO criteria for determination of response (see 
section 10) by mammography and breast ultrasound 
11.1.7. Physical examination, ECOG Performance Status, and body weight 
11.1.8. Hematology: Hemoglobin, platelet count, white blood cell count including 
differential (absolute neutrophil count) 
11.1.9. Blood chemistry: blood urea nitrogen, creatinine, alkaline phosphatase, AST and 
ALT, total bilirubin, calcium, urea, total cholesterol, LDL and HDL cholesterol, 
triglycerides 
11.1.10. CEA and CA 15.3 
11.1.11. Menopausal status 
11.1.12. Serum pregnancy test; has to be repeated before treatment start, if treatment does 
not start within 15 days of the previous test 
11.1.13. Medical history including details of malignancy: date of diagnosis, primary tumor 
type characteristics (histology, grade, stage) 
11.1.14. The determination of the estradiol level is mandatory within 4 days prior to 
randomization in order to check eligibility,  
11.1.15. Patient must complete baseline PRS questionnaire. 


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11.2. 
During first cycle of trial treatment 
11.2.1. For estradiol level determination by central laboratory (for primary trial endpoint): 
Take a blood sample on day 1 of treatment before the administration of the first 
dose, thereafter at 24 and 72 hours, 7 days and 14 days after first injection; extract 
serum and store at -80°C. Please consult the Manual for Blood Sample Logistics 
for details.  
11.3. 
Day 1 of every treatment cycle 
11.3.1. Physical examination, ECOG Performance Status, and body weight 
11.3.2. Collection of any adverse event and assignment of appropriate adverse events 
grade according to the NCI CTCAE Version 4 
11.3.3. Record all concomitant medication 
11.3.4. Breast palpation with tumor measurement and nodal status (caliper or ruler 
measurements preferred) 
11.3.5. For estradiol level determination by central laboratory (for primary trial endpoint): 
Take a blood sample before the administration of the next dose of the GnRH 
agonist or antagonist; extract serum and store at -80°C. 
11.3.6. Local determination of estradiol level 
11.3.7. The patient must complete a PRS questionnaire on day 1 of cycles 2 and 4 
11.4. 
After three cycles of trial treatment 
11.4.1. Hematology: Hemoglobin, platelet count, white blood cell count including 
differential (absolute neutrophil count) 
11.4.2. Blood chemistry: blood urea nitrogen, creatinine, alkaline phosphatase, AST and 
ALT, total bilirubin, calcium, urea, total cholesterol, LDL and HDL cholesterol, 
triglycerides 
11.4.3. CEA and CA 15.3 
11.4.4. Breast palpation with tumor measurement and nodal status (caliper or ruler 
measurements preferred) 
11.4.5. Bilateral mammography and breast ultrasound (mandatory) 
11.4.6. Tumor measurements according to WHO criteria for determination of response (see 
section 10) by mammography and breast ultrasound 
11.5. 
At visit prior to surgery 
11.5.1. Physical examination, ECOG Performance Status and body weight 
11.5.2. Hematology: Hemoglobin, platelet count, white blood cell count including 


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differential (absolute neutrophil count) 
11.5.3. Blood chemistry: blood urea nitrogen, creatinine, alkaline phosphatase, AST and 
ALT, total bilirubin, calcium, urea, total cholesterol, LDL and HDL cholesterol, 
triglycerides 
11.5.4. CEA and CA 15.3 
11.5.5. Local determination of estradiol level 
11.5.6. Collection of any AE and assignment of appropriate adverse events grade 
according to the NCI CTCAE Version 4 
11.5.7. Record all concomitant medication 
11.5.8. Breast palpation with tumor measurement and nodal status (caliper or ruler 
measurements preferred) 
11.5.9. Bilateral mammography and breast ultrasound (mandatory) 
11.5.10. Tumor measurements according to WHO criteria for determination of response (see 
section 10) by mammography and breast ultrasound 
11.5.11. Patient has to complete PRS questionnaire 
11.6. 
At visit 30 days after surgery 
11.6.1. Collection of any AE and SAE and assignment of appropriate adverse events grade 
according to the NCI CTCAE Version 4 
11.6.2. Record all concomitant medication 
12. 
Safety 
12.1. 
Adverse effects of degarelix 
The following adverse reactions have been reported in clinical trials in male patients: 
(NOTE: Only partly categorized according to CTCAE version 4.) 
Very common (≥ 10%):  
Vascular disorders: hot flushes 
General disorders and administration site conditions: injection site adverse events 
Common (1 – 10%): 
Blood and lymphatic system disorders: anemia 
Metabolism and nutrition disorders: weight increase 
Psychiatric disorders: insomnia 
Nervous system disorders: dizziness, headache 


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Gastrointestinal disorders: diarrhea, nausea 
Hepatobiliary disorders: liver transaminases increased 
Skin and subcutaneous tissue disorders: hyperhidrosis (including night sweats), rash 
Musculoskeletal, connective tissue and bone disorders: musculoskeletal pain and discomfort 
Reproductive system and breast disorders: gynecomastia 
General disorders and administration site conditions: chills, pyrexia, fatigue, influenza-like 
illness. 
Uncommon (0.1 – 1%):  
Immune system disorders: hypersensitivity 
Metabolism and nutrition disorders: hyperglycemia/diabetes mellitus, cholesterol increased, 
weight decreased, appetite decreased, changes in blood calcium 
Psychiatric disorders: depression, libido decreased 
Nervous system disorders: mental impairment, hypoesthesia 
Eye disorders: vision blurred 
Cardiac disorders: cardiac arrhythmia (incl. atrial fibrillation), palpitations  
Vascular disorders: hypertension, vasovagal reaction (incl. hypotension) 
Respiratory, thoracic and mediastinal disorders: dyspnea 
Gastrointestinal disorders: constipation, vomiting, abdominal pain, abdominal discomfort, 
dry mouth 
Hepatobiliary disorders: bilirubin increased, alkaline phosphatase increased 
Skin and subcutaneous tissue disorders: urticaria, skin nodule, alopecia, pruritus, erythema 
Musculoskeletal, connective tissue and bone disorders: osteoporosis/osteopenia, arthralgia, 
muscular weakness, muscle spasms, joint swelling/stiffness 
Renal and urinary disorders: pollakiuria, micturition urgency, dysuria, nocturia, renal 
impairment, incontinence 
Reproductive system and breast disorders: breast pain, pelvic pain, genital irritation 
General disorders and administration site conditions: malaise, peripheral edema 
Changes in laboratory parameters: 
Changes in laboratory values seen during one year of treatment in the confirmatory phase III 
study (N=409) were in the same range for degarelix and a GnRH-agonist (leuprorelin) used 
for comparison. Markedly abnormal (>3×ULN) liver transaminase values (ALT, AST and 
GGT) were seen in 2%-6% of patients with normal values prior to treatment, following 
treatment with both medicinal products. Marked decrease in haematological values, 
hematocrit (≤0.37) and hemoglobin (≤115 g/l) were seen in 40% and 13%-15%, respectively 
among those patients with normal values prior to treatment, following treatment with both 
medicinal products. It is unknown to what extent this decrease in haematological values was 
caused by the underlying prostate cancer and to what extent it was a consequence of 
androgen deprivation therapy. Markedly abnormal values of potassium (≥5.8 mmol/l), 
creatinine (≥177 μmol/l) and BUN (≥10.7 mmol/l) in patients with normal values prior to 


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treatment, were seen in 6%, 2% and 15% of degarelix treated patients and 3%, 2% and 14% 
of leuprorelin treated patients, respectively.  
Changes in ECG measurements: 
Changes in ECG measurements seen during one year of treatment in the confirmatory phase 
III study (N=409) were in the same range for degarelix and a GnRH-agonist (leuprorelin) 
used as comparator. Three (<1%) out of 409 patients in the degarelix group and four (2%) 
out of 201 patients in the leuprorelin 7.5 mg group, had a QTcF 
500 msec. From baseline 
to end of study the median change in QTcF for degarelix was 12.0 msec and for leuprorelin 
was 16.7 msec. 
12.2. 
Drug interactions with degarelix 
No drug-drug interaction studies were conducted.  
Since androgen deprivation treatment may prolong the QTc interval, the concomitant use of 
degarelix with medicinal products known to prolong the QTc interval or medicinal products 
able to induce torsades de pointes such as class IA (e.g., quinidine, disopyramide) or class 
III (e.g., amiodarone, sotalol, dofetilide, ibutilide) antiarrhythmic medicinal products, 
methadone, cisapride, moxifloxacine, antipsychotics, etc., should be carefully evaluated. 
Degarelix is not a substrate for the human CYP450 system. Degarelix is not an inducer or 
inhibitor of the CYP450 system in vitro. Therefore, clinically significant CYP450 
pharmacokinetic drug-drug interactions are unlikely. 
12.3. 
Adverse effects of triptorelin 
The following adverse reactions have been reported in clinical trials and from post-
marketing surveillance (gonapeptyl depot 3.75mg, Ferring): 
(NOTE: Only partly categorized according to CTCAE version 4.) 
Common (1 – 10%): 
Endocrine: depressive mood, irritation 
Gastrointestinal: nausea 
Musculoskeletal system: myalgia, arthralgia 
Body as a whole – general: tiredness, sleep disturbances, hypersensitivity reactions (itching, 
skin rash, fever) 
Application site disorders: temporary pain at injection site 
Uncommon (0.1 – 1%):  
Metabolic and nutritional: elevated enzyme levels (LDH, yGT, SGOT, SGPT); slight rise in 
serum cholesterol 
Central and peripheral nervous system: visual disturbances, paresthesia 
General: aching of back 
Body as a whole – general: anaphylaxis 
Application site disorders: foreign body reaction at injection site 


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12.4. 
Adverse effects of letrozole 
The following adverse reactions have been reported in clinical trials and from post-
marketing surveillance: 
(NOTE: Only partly categorized according to CTCAE version 4.) 
Very common (≥ 10%):  
Musculoskeletal and connective tissue disorders: arthralgia  
General disorders and administration site conditions: hot flushes 
Common (1 – 10%): 
Metabolism and nutrition disorders: general edema 
Psychiatric disorders: depression 
Nervous system disorders: headache, dizziness 
Gastrointestinal disorders: nausea, vomiting, dyspepsia, constipation, diarrhea  
Skin and subcutaneous disorders: alopecia, increased sweating, rash 
Musculoskeletal and connective tissue disorders: myalgia, bone pain, osteoporosis, bone 
fractures 
General disorders and administration site conditions: fatigue, peripheral edema 
Investigations: weight increase 
Uncommon (0.1 – 1%):  
Infections and infestations: urinary tract infection 
Neoplasms, benign, malignant and unspecified (including cysts and polyps): tumor pain 
Blood and lymphatic system disorders: leucopenia 
Metabolism and nutrition disorders: general edema 
Psychiatric disorders: anxiety  
Nervous system disorders: somnolence, insomnia, memory impairment, dysesthesia, taste 
disturbance, cerebrovascular accident, carpal tunnel syndrome 
Eye disorders: cataract, eye irritation, blurred vision 
Cardiac disorders: palpitations, tachycardia 
Vascular disorders: thrombophlebitis, hypertension, ischemic cardiac events 
Rare (0.01 – 0.1%): 
Vascular disorders: pulmonary embolism, arterial thrombosis, cerebrovascular infarction 
Respiratory, thoracic and mediastinal disorders: dyspnea, cough 
Gastrointestinal disorders: abdominal pain, stomatitis, dry mouth 
Hepatobiliary disorders: increased hepatic enzymes 
Skin and subcutaneous disorders: toxic epidermal necrolysis, erythema mutiforme 
Musculoskeletal and connective tissue disorders: arthritis 


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Renal and urinary disorders: increased urinary frequency 
Reproductive system and breast disorders: vaginal bleeding, vaginal discharge, vaginal 
dryness, breast pain 
General disorders and administration site conditions: pyrexia, mucosal dryness, thirst 
Investigations: weight loss 
13. 
Adverse event and serious adverse event reporting 
13.1. 
Adverse event reporting 
The main criterion for tolerability is the occurrence of toxicities and adverse events.  The 
severity and causality will be classified according to the NCI CTCAE Version 4. The 
CTCAE 
is 
available 
for 
downloading 
on 
the 
internet 
at 
http://evs.nci.nih.gov/ftp1/CTCAE/About.html. An interactive version can be found at 
http://safetyprofiler-ctep.nci.nih.gov/CTC/CTC.aspx. 
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. 
Symptoms of the targeted cancer (if applicable) should not be reported as adverse events. 
An overdose, accidental or intentional, whether or not it is associated with an AE, of an 
investigational product should be reported as an SAE. 
13.1.1. Severity / intensity 
The adverse event 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: 
 Grade 1 = Mild – transient or mild discomfort; no limitation in activity; no medical 
intervention/therapy required 
 Grade 2 = Moderate – mild to moderate limitation in activity, some assistance may 
be needed; no or minimal medical intervention/therapy required 
 Grade 3 = Severe – marked limitation in activity, some assistance usually required; 
medical intervention/therapy required, hospitalization is possible 
 Grade 4 = Life threatening – extreme limitation in activity, significant assistance 
required; significant medical intervention/therapy required, hospitalization 
or hospice care probable 
 Grade 5 = Death – the event results in death 
The term “severe” is often used to describe the intensity of a specific event (as in mild, 
moderate or severe myocardial infarction); the event itself, however, may be of relatively 
minor medical significance (such as severe headache).  This criterion is not the same as 


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“serious” which is based on subject/event outcome or action criteria associated with events 
that pose a threat to a subject’s life or functioning.   
Seriousness, not severity, serves as a guide for defining regulatory obligations. 
13.1.2. Causality 
The Investigator must determine the relationship between the administration of trial drug(s) 
and the occurrence of an AE/SAE as Not Suspected or Suspected as defined below: 
Not suspected: 
The temporal relationship of the adverse event to trial drug(s) 
administration makes a causal relationship unlikely or remote, 
or other medications, therapeutic interventions, or underlying 
conditions provide a sufficient explanation for the observed 
event. 
Suspected: 
The temporal relationship of the adverse event to trial drug(s) 
administration makes a causal relationship possible, and other 
medications, therapeutic interventions, or underlying conditions 
do not provide a sufficient explanation for the observed event. 
13.1.3. Duration 
For both AEs and SAEs, the Investigator will provide a record of the start and stop dates of 
the event. 
13.1.4. Action taken 
The Investigator will report the action taken with trial drug(s) as a result of an AE or SAE, 
as applicable (e.g., discontinuation of trial drug(s)) and in case of an SAE report if 
concomitant and/or additional treatments were given for the event. 
13.2. 
Targeted adverse events 
The presence or absence of any of the following adverse events will have to be indicated on 
each occasion that an Adverse Event Form (Form 41-AE) is completed.  
Adverse events should be graded using the NCI CTCAE version 4.0. The following list 
provides targeted adverse events (ordered by System Organ Class) that should be recorded 
on the eCRF at any time. Treatments to alleviate these should be recorded on the 41-CCM 
Form:  
Reproductive system and breast disorders: 
Vaginal dryness  
Dyspareunia 
Psychiatric disorders: 
Libido decreased  
Depression  
Anxiety 
Insomnia  
Renal and urinary disorders: 
Urinary incontinence  


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Vascular disorders: 
Hot flashes  
Hypertension  
Thromboembolic event 
Musculoskeletal and connective tissue disorders: 
Osteoporosis  
Myalgia 
Arthralgia 
Injury, poisoning and procedural complications: 
Fracture  
Nervous system disorders: 
Stroke 
Transient ischemic attacks 
Intracranial hemorrhage  
Cardiac disorders: 
Acute coronary syndrome 
Myocardial infarction 
Ventricular arrhythmia 
Ventricular fibrillation 
Gastrointestinal disorders: 
Nausea  
General disorders and administration site conditions: 
Fatigue  
Injection site reaction  
Immune system disorders: 
Allergic reaction  
Metabolism and nutrition disorders: 
Glucose Intolerance 
Hyperglycemia  
Investigations: 
Aspartate aminotransferase (AST) increased 
Alanine aminotransferase (ALT) increased 
Blood bilirubin increased 
Electrocardiogram QT corrected interval prolonged 


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13.3. 
Abnormal Laboratory Values 
An abnormal laboratory value grade 3 or higher is considered to be an AE if the 
abnormality: 
 results in discontinuation from the study; 
 requires treatment, modification/ interruption of trial drug(s) dose, or any other 
therapeutic intervention; or 
 is judged to be of significant clinical importance. 
Regardless of severity grade, only laboratory abnormalities that fulfill a seriousness criterion 
need to be documented as a serious adverse event. 
If a laboratory abnormality is one component of a diagnosis or syndrome, then only the 
diagnosis or syndrome should be recorded on the AE page/screen of the eCRF.  If the 
abnormality was not a part of a diagnosis or syndrome, then the laboratory abnormality 
should be recorded as the AE. 
13.4. 
Serious adverse event (SAE) reporting 
13.4.1. Definition 
An SAE is defined in general as any undesirable medical occurrence/adverse drug 
experience that occurs during or within 30 days after stopping trial treatment that, at any 
dose, results in any of the following:  
 fatal (any cause) 
 life-threatening 
 requires or prolongs inpatient hospitalization 
 persistent or significant disability/incapacity 
 congenital anomaly or birth defect 
 secondary (non-breast) malignancy 
 constitutes an important medical event 
 neonatal deaths within 28 days of birth 
Important medical events are defined as those occurrences that may not be immediately life 
threatening or result in death, hospitalization, or disability, but may jeopardize the subject or 
require medical or surgical intervention to prevent one of the other outcomes listed above.  
Medical and scientific judgment should be exercised in deciding whether such an AE should 
be considered serious. 
All serious adverse events must also be reported for the period in which the trial protocol 
interferes with the standard medical treatment given to the patient.  After completion of trial 
treatments, report all SAEs that are considered at least possibly related to previous trial 
treatment. Cases of second (non-breast) malignancies and congenital abnormalities are to be 
regarded as SAEs, regardless of whether they occur during or after study treatment. These 
events should be reported on the Serious Adverse Event eCRFs (SAE-A and SAE-B). 
SAE also includes any other event that the Investigator or the IBCSG Safety Office 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 summary of product characteristics. 


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A related adverse event is one for which the Investigator assesses that there is at least a 
reasonable possibility that the event is related to the investigational drug. All adverse events 
judged as having a reasonable suspected causal relationship to the trial medication qualify as 
adverse reactions. 
13.4.2. Exceptions to the definition 
Hospitalizations occurring under the following circumstances are not considered to be 
serious adverse events:  
 elective surgery 
 occur on an outpatient basis and do not result in admission (hospitalization 
<24h) 
 are part of the normal treatment or monitoring of the studied treatment 
 progression of disease 
13.4.3. 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 eCRFs (SAE–A and SAE-B). 
To ensure patient safety, the IBCSG must be informed of each SAE using the procedures 
described below: 
 The Investigator/MD responsible for the patient must complete a Serious Adverse 
Event (SAE-A) eCRF in English within 24 hours via iDataFax. A copy is 
automatically forwarded to the IBCSG Safety Office for medical review. 
 Follow-up information should be completed, via iDataFax, on the Serious Adverse 
Event (SAE-B) eCRF within 15 days of the initial report, even if the event reported 
in the SAE-A eCRF is not yet resolved.  If the event is not resolved within 15 days, 
revise the original Serious Adverse Event (SAE-B) eCRF in iDataFax to report the 
final resolution. 
 All SAEs that have not resolved upon discontinuation of the subject’s participation 
in the trial must be followed until recovered, recovered with sequelae, not recovered 
(death due to another cause) or death (due to the SAE). 
 If a non-serious adverse event becomes serious, this and other relevant follow-up 
information must also be provided within 24 hours. 
 Photocopies of all examinations carried out with the dates on which they were 
performed should be sent by fax into the DataFax system. Care should be taken to 
ensure that the patient's identity is protected and the patient’s Randomization ID 
Number is properly included on ALL pages of any reports. For laboratory results, 
include the laboratory normal ranges. 
 In the event the eCRF system is not working, the SAE Forms can be sent via fax into 
the DataFax system. 
If a Serious Adverse Event (SAE-A and SAE-B) was submitted by fax, the original forms 
and the fax confirmation sheet(s) must be kept at the Participating Center. 
The IBCSG will inform Ferring and other appropriate persons about all SAEs related to trial 
medication (per either Investigator or IBCSG medical review) within 24 hours of receipt at 
the IBCSG. 


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The IBCSG will record the SAE and prepare a monthly SAE report. Principal Investigators 
will receive the summary report on a monthly basis, and these reports can be found on the 
IBCSG web site (www.ibcsg.org). 
13.5. 
Pregnancy 
Pregnancies and suspected pregnancies of a patient occurring during trial treatment, or 
within 30 days of the last dose of trial drug(s), are considered immediately reportable 
events. Trial drug(s) are to be discontinued immediately and the patient instructed to return 
any unused portion of the trial drug(s) to the Investigator.  The pregnancy, suspected 
pregnancy, or positive pregnancy test must be reported within 24 hours of the Investigator’s 
knowledge using the Pregnancy Form (Form 41-PREG) to the IBCSG who will inform 
Ferring immediately. 
The patient should be referred to an obstetrician-gynecologist, preferably one experienced in 
reproductive toxicity for further evaluation and counseling.   
The Investigator will follow the patient until completion of the pregnancy, and must notify 
IBCSG immediately about the outcome of the pregnancy by completing the corresponding 
section on the Pregnancy Form (41-PREG). 
All neonatal deaths that occur within 28 days of birth should be reported, without regard to 
causality, as SAEs.  In addition, any infant death after 28 days that the Investigator suspects 
is related to the in utero exposure to trial drug(s) should also be reported within 24 hours of 
the Investigator’s knowledge of the event using the SAE Forms. 
13.6. 
Safety review of degarelix 
Every six months the adverse events observed during trial treatment will be summarized in a 
safety report. Investigators should document treatment and adverse events immediately at 
the end of each cycle by completing the appropriate eCRFs.  
The safety reports will be reviewed by the Data and Safety Monitoring Committee (see 
section 19.3). 
14. 
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: 


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14.1. 
Case report forms schedule 
Registration/Randomization  
ALL data should be submitted in iDataFax (iDF) 
(unless otherwise specified) 
Informed 
Consent 
Form 
Consent to participation in clinical 
trial including consent for 
biomaterial submission 
Obtain before randomization and keep with patient 
records as documentation (hard copy only). 
41-A 
Confirmation of Registration Form 
Complete in iDF after you or your Randomization Center 
has randomized the patient in the IBCSG Reg./Rand. 
System.  
41-PRS 
Patient-Reported Symptoms 
Patient to complete prior to randomization and fax into 
DataFax after randomization. 
Baseline  
41-H 
History Form 
Complete in iDF within 1 week of randomization. 
Pathology 
Report 
Pathology Report on diagnostic 
biopsy 
Fax Report to DataFax System within 1 week of 
randomization. 
41-PBx 
Pathology Form for diagnostic core 
biopsy 
Complete in iDF within 1 week of randomization. 
41-BS 
Baseline Symptoms Form 
Complete in iDF within 1 week of randomization.   
41-CCM 
Concomitant Medications Form  
Complete in iDF each time a medication is started, 
amended, or ended, including within 14 days of starting 
treatment, during treatment, and during follow-up. 
41-TEV-B 
Baseline Tumor Evaluation Form 
Complete in iDF within 1 week of randomization.  
During trial treatment 
41-AE 
Adverse Events Form 
Complete in iDF at the end of each 28 day  cycle. 
41-TEV 
Tumor Evaluation Form 
Complete in iDF at the end of cycle 3 and prior to 
surgery. 
41-PRS 
Patient-Reported Symptoms 
Complete at day 1 of cycle 2 and 4 (i.e. after 4 and 12 
weeks), and prior to surgery. 
41-CCM 
Concomitant Medications Form 
Review the original CCM Form at the end of each cycle.  
Update in iDF any current medications if needed and add 
new medications taken. 
41-PT 
(Cycle 1) 
Protocol Therapy Form 
(including lab values) 
Complete in iDF at the end of cycle 1. 
41-PT 
(Cycles 2-6) 
Protocol Therapy Form 
(including lab values) 
Complete in iDF at the end of cycles 2-6. 
Surgery 
41-C 
Surgery Form 
Complete in iDF 30 days after surgery. 
41-P 
Pathology Form 
Complete in iDF 30 days after surgery. 
Pathology 
Report 
Pathology Report for definitive 
surgery 
Fax report to DataFax System within 30 days after 
surgery. 
End of treatment, after surgery 
41-AE 
Adverse Events Form 
Complete in iDF 30 days after surgery. 
41-CCM 
Concomitant Medications Form 
Update in iDF any current medications if needed and add 
new medications taken. 
Event Driven  
41-SAE-A 
Serious Adverse Event initial report 
Complete within 24 hours of the SAE in iDF. If iDF is 
not available, fax the form within 24 hours to DataFax. 
41-SAE-B 
Serious Adverse Event B follow-up 
report 
Complete in iDF within 15 days of initial report (42-
SAE-A). If event is not resolved in 15 days, complete 
42-SAE-B again at time of resolution. 
41-PREG 
Pregnancy Form 
Complete in iDF if a patient becomes pregnant on trial 
treatment.  Complete the second section of the form at 
the end of pregnancy. 
42-SM 
Second Malignancy Form 
Complete in iDF if a patient has a second (non-breast) 
malignancy while on trial treatment. 
42-Death 
Death Form 
Complete in iDF if a patient dies while on trial treatment. 
42-COC 
Change of Consent Form 
Complete in iDF if a patient  withdraws consent for 
further trial participation. 


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The Data Managers’ Manual for this trial contains instructions for submitting forms using 
the DataFax system. 
14.2. 
Signing and submitting forms 
An Authorization Log (see section 14.5) should be completed at each Participating Center to 
identify the persons who are authorized to complete eCRFs. 
eCRFs should be completed on-line in iDataFax. PRS Forms, reports (lab, pathology, etc.) 
and any other non-eCRF data will need to be faxed to the DataFax system.  Full instructions 
on submitting forms will be available on the IBCSG website (www.ibcsg.org).  Also 
available on the website is a list of fax numbers that are available for faxing CRFs. 
14.3. 
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. 
14.4. 
Investigators’ file 
Each Participating Center should keep documentation about this trial in an Investigators' 
File, which should include the following documents: 
 Protocol and appendices 
 Amendments 
 Signed Protocol Signature Pages 
 Sample CRFs including blank SAE Forms 
 Data Managers’ Manual 
 Obvious Corrections Document and Signature Page 
 Randomization Manual 
 iDataFax (iDF) Manual 
 Drug Supply Manual 
 Manual for Blood Sample Logistics 
 Patient information and Informed Consent templates approved by Ethics 
Committee 
 Investigator's Brochure and updates 
 Ethics Committee (and Health Authority, if applicable) approval of protocol, 
Patient Information Sheet and IC, amendments 
 Ethics Committee review of SAE, Investigators' alert, and other documents 
 Correspondence with Ethics Committee and Health Authority (if applicable) 
 Certificate of clinical trial insurance 
 Agreement with IBCSG 
 Center Activation e-mail from DMC 
 Correspondence with IBCSG Coordinating Center, Data Management Center 
 SAE Reports sent from IBCSG Data Management Center 
 Normal laboratory values/reference ranges 
 Laboratory Certifications 
 CV of Principal Investigator and Co-Investigators, GCP certificates  


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 Trial Training Certificates issued by IBCSG 
 Authorization Log 
 Patient identification log (see section 14.6) 
 Drug accountability log (including certificates of destruction if applicable)   
 Temperature logs 
 ICH GCP guidelines/Declaration of Helsinki and updates 
 Audit certificates / monitoring reports 
14.5. 
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 eCRFs, queries, etc. 
Instructions for completing the Authorization Log can be found in the Authorization Log 
Manual, posted on the IBCSG website.   
14.6. 
Patient identification log 
No patients’ names should be used in CRFs or any other documentation transmitted to 
IBCSG central offices.  The only item used to identify a patient is the randomization 
number. It is therefore imperative that the local data manager keep an identification log for 
all patients entered in this trial including: 
 Patient's name 
 Patient ID (Randomization number) 
 Date of birth 
Other items that could be included are date of randomization and treatment arm. 
15. 
Statistical considerations 
The primary objective of this randomized phase II trial is to compare the endocrine activity 
of neoadjuvant degarelix and triptorelin in premenopausal patients receiving letrozole. The 
endocrine activity is measured by time to optimal ovarian function suppression with the 
hypothesis that degarelix will achieve faster ovarian suppression than triptorelin. Patients 
will be randomized equally (1:1 ratio) between the two treatment arms with stratification 
based on age (≤39 vs. ≥40 years). 
15.1. 
Primary endpoint 
The primary endpoint of time to optimal ovarian function suppression will be assessed in the 
two treatment arms and is defined as time from the first injection of degarelix or triptorelin 
to the first assessment of E2 ≤2.72 pg/mL or ≤10 pmol/L during the 6 cycles of neoadjuvant 
treatment. E2 levels will be determined centrally from samples taken at day 1 of the first 
treatment cycle before the administration of the first dose of degarelix or triptorelin 
(baseline), and thereafter at 24 and 72 hours, 7 days and 14 days after the first injection, and 
on day 1 of cycles 2 to 6 before the administration of degarelix or triptorelin. 
The primary endpoint will be compared between the two treatment arms using a stratified 
log-rank test.  The type I error will be controlled at a two-sided 0.05.   


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15.1.1. Sample size justification 
The following table provides the assumption on the cumulative percent of patients who are 
anticipated to reach optimal ovarian function suppression (E2 level ≤2.72 pg/mL or ≤10 
pmol/L) during the 6 cycles of neoadjuvant treatment.   
 
Percent (%) of  patients  with  E2 ≤2.72 pg/mL or ≤10 pmol/L 
Treatment arms 
2 weeks 
4 weeks 
8 weeks 
12 weeks 
16 weeks 
Triptorelin+Letrozole 
(control) 
30 
60 
75 
90 
100 
Degarelix+Letrozole 
(experiment) 
60 
95 
100 
100 
100 
With 23 patients in each treatment arm and based on the assumption in the table above, the 
study has 90% power to detect a difference in time to optimal ovarian function suppression 
(E2 ≤2.72 pg/mL or ≤10 pmol/L) between the two treatment arms, using a two-sample log-
rank test at a two-sided significance level of 0.05. Calculations were performed using 
nQuery Advisor® (logrank test of survival in two groups, simulation with percentages 
specified in above table).  
To allow for missing data, the study plans to enroll 25 patients to each treatment arm for a 
total of 50 patients. The accrual is expected to be 2 patients per month with an accrual 
period of approximately 24 months and additional 7 months of follow up after the last 
patient is enrolled. 
15.1.2. Analysis of the primary endpoint 
Primary analysis will use the modified intent to treat principle.  Randomized patients who 
receive at least one injection of triptorelin or degarelix will be included in the primary 
analysis. The primary endpoint will be compared between the two treatment arms using a 
stratified two-sample log-rank test, with age as stratification factor. The distribution of the 
primary endpoint will be summarized using the method of Kaplan-Meier and the two-sided 
95% confidence interval (CI) for the difference in proportion of patients who achieve 
optimal ovarian function suppression (defined as E2 level ≤2.72 pg/mL or ≤10 pmol/L) 
between the two treatment arms at the end of the 1st, 2nd and 4th cycle will also be provided.  
Cox proportional hazards model will also be used to assess the difference in time to optimal 
ovarian function suppression between the treatment arms adjusting for selected covariates 
including baseline E2 level, body mass index (BMI), smoking history, and recent oral 
contraceptive usage.  
15.2. 
Secondary objectives 
Secondary objectives include evaluation with respect to several secondary endpoints as 
defined in section 4.2. Analyses of the secondary endpoints will be descriptive. Tests of 
significance, whenever applicable, will not be controlled for multiple comparisons. Due to 
the limited sample size, the tests will largely be underpowered except in cases where 
differences between treatment groups are substantial. Randomized patients who received at 
least one dose of study treatment are included in the analysis unless otherwise indicated. 
15.2.1. Tolerability (Safety of combined neoadjuvant therapy): 
Tolerability will be evaluated in each treatment arm separately. Randomized patients who 
received at least one dose of the trial treatment will be included in the tolerability analyses. 


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The frequencies of adverse events (AE) according to CTCAE 4 by type and worst grade 
experienced while on the neoadjuvant treatments will be summarized and tabulated by 
treatment arms. Two-sided 90% confidence interval (CI) for the difference in proportion of 
patients with each type of grade 3 or higher targeted adverse event (see section 13.2) 
between the treatment arms will be assessed.  
15.2.2. Changes in Ki67 expression levels 
Patients who received at least one dose of study treatment and who have biospecimen 
available will be included in the analysis. 
 The percentage change in Ki67 expression (geometric means*) from pre-
treatment to surgery will be summarized for each treatment arm and two-sided 
90% CI for the change will be calculated. 
 The percentage changes in Ki67 expression (geometric means*) between the 
treatment arms at baseline and surgery are assessed using a two-sided 90% CI  
and  explored using  a two-sample Wilcoxon Rank Sum test. 
 Other descriptive summary such as boxplots for the marker data will be 
provided. 
* Due to the approximate lognormal distribution of the data 
In cases with no residual invasive tumor detected at surgery, the percentage change in Ki67 
will be recorded as 100%. 
15.2.3. The Preoperative Endocrine Prognostic Index (PEPI) score at the time of surgery 
Patients with available central pathology review results will be included in the assessment. 
See section 3.2 for the calculation of the PEPI score. 
Descriptive statistics will be used to summarize the PEPI score by treatment arm. Two-sided 
90% CI for the difference in the PEPI scores between the two arms will also be assessed. 
For example, a patient with pathologically node-negative T1 or T2 disease, Ki67 level 
≤2.7% (or ≤1% on a natural log scale) and persistent ER expression after completion of 
neoadjuvant therapy is assigned a PEPI score of 0 (best prognostic group). Logistic 
regression modeling will be used to explore whether the PEPI score of 0 differs from PEPI 
score >0 with respect to disease characteristics at baseline. 
15.2.4. Best overall (disease) response (defined in Section 4.2) 
Descriptive summaries of the best overall response rate by the treatment arms and two sided 
90% CI for the difference in best overall response rate will be provided. Tumor assessment 
is scheduled at the end of 3rd and 6th cycle of treatment. Clinical responses including 
complete response (CR), partial response (PR), stable disease (SD) and progressive disease 
(PD) as defined in Section 10.2 will also be descriptively summarized by treatment arms. 
15.2.5. Node negative disease at surgery 
The percentage of patients with node-negative disease at surgery will be descriptively 
summarized by treatment arm. Two sided 90% CI for the difference in percentage of 
patients with node-negative disease between treatment arms will be assessed. 
15.2.6. Breast-conserving surgery (BCS) rate 
The proportion of patients undergoing BCS is evaluated in two analyses. First, considering 
all patients enrolled, the percent of patients in each treatment arm who had a breast-


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conserving surgery will be presented, and the difference between the treatment arms 
assessed using a two-sided 90%CI. Second (i.e., rate of conversion), considering only 
patients who are reported at baseline not to be candidates for BCS, the percent in each 
treatment arm who had a BCS after neoadjuvant therapy will be presented, and the 
difference between the arms assessed using a two-sided 90% CI. 
15.2.7. Patient-reported symptoms (PRS) outcomes (menopausal symptoms) 
The PRS Study is described in section 16. 
15.3. 
Stopping Rules and Data Monitoring 
No formal stopping rule regarding the primary efficacy endpoints is planned.  
Adverse events and safety monitoring are important for this study, as there are currently no 
safety data for degarelix used in high dose and in combination with letrozole for 
premenopausal women with invasive breast cancer. This study will implement detailed 
toxicity monitoring as described in section 13. 
Adverse event reports are to be submitted within 28 days of each clinic visit. All relevant 
adverse events will be reviewed by the DSMC every 6 months (twice a year). The DSMC 
will make recommendation to the study management team if it notes any concerns regarding 
patient safety or if further action needs to be taken based on the safety monitoring review 
results. Formal assessment of targeted adverse events will also be included in statistical 
analysis for secondary objectives as detailed in section 15.2.1. 
15.4. 
Accrual 
The overall accrual goal of this trial is 50 patients. We anticipate that the accrual rate will be 
approximately 2 patients per month and the accrual will be completed within approximately 
24 months, with additional 7 months of follow up after the last patient is enrolled. 
16. 
Patient-reported symptoms (PRS) 
16.1. 
Introduction 
In clinical trials, toxicities and tolerability profiles are usually derived from a physician-
recorded grading of adverse events (e.g. CTCAE). However, there is some evidence that 
these proxy ratings do not adequately reflect the burden of symptoms experienced by 
patients. Rates of symptoms related to endocrine therapy are suggested to be higher when 
self-reported compared to physician-recorded as shown in two studies, each comparing rates 
of patient-reported symptoms in their own sample to the prevalence rates published in 
pivotal trials (33,34). Several randomized trials in the adjuvant setting evaluated patient-
reported symptoms related to endocrine therapy in postmenopausal women with breast 
cancer (35,36,37). These studies revealed no major effect on overall quality of life by the 
different endocrine agents, yet different profiles with regard to specific symptoms. To date, 
the ZIPP trial (Zoladex in Premenopausal Patients trial;38) is the only trial with published 
results on patient-reported side-effects of adjuvant endocrine treatment in premenopausal 
breast cancer patients. In this trial patient-reported side-effects were compared between 
women receiving goserelin (a GnRH agonist), goserelin plus tamoxifen, or tamoxifen alone. 
The treatment with goserelin was the most burdensome with similar symptom levels 
reported during previous chemotherapy, while side effects of tamoxifen alone were milder, 


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except for vaginal discharge. Two studies compared chemotherapy (i.e. cyclophosphamide, 
methotrexate, fluorouracil (CMF)) to goserelin treatment in pre- and perimenopausal women 
with lymph node-negative (39) or lymph node-positive (40) breast cancer. Both studies 
showed that patients receiving goserelin reported worse endocrine symptoms during the 
goserelin treatment period. This difference was reversed after cessation of goserelin 
treatment (after 3 years), then endocrine symptom scores were worse in those patients who 
had received chemotherapy. 
With respect to degarelix one study assessed self-reported symptoms in patients with 
prostate cancer (41). A more rapid onset of self-reported hot flushes was seen in patients 
receiving degarelix compared to those receiving leuprolide, with a higher median hot flushes 
score during the first 3 months, but no differences in overall median hot flush scores over 
the entire 12 months of treatment. 
16.2. 
PRS Objectives 
The primary objective is to assess the differences in patient-reported symptoms (PRS) 
measurements between the two treatment arms over time. The PRS scores are measured at 
baseline, day 1 of cycle 2 and cycle 4 of triptorelin or degarelix administration and prior to 
surgery. 
Secondary objectives are: 
 To correlate estradiol levels with the total PRS score measured on day 1 of cycle 2 
and day 1 of cycle 4 of triptorelin or degarelix administration. 
 To summarize each of the 18 individual (endocrine symptom) items of the FACT-ES 
descriptively over time as the proportion of patients with “clinically significant” 
symptoms (those scoring 3 or 4). 
16.3. 
PRS Patient selection 
All patients randomized into this trial are required to complete Patient-Reported Symptoms 
Form 41-PRS. Patients must complete a baseline PRS Form prior to randomization. There 
will be no patient selection within Participating Centers. The only exceptions are physical 
impairment that interferes with any assessment. 
16.4. 
PRS design 
A longitudinal assessment is used to evaluate the differential effects of the randomized 
treatments on patients’ PRS. Patients are asked to complete a PRS Form at baseline (prior to 
randomization), day 1 of cycle 2 and cycle 4 of triptorelin or degarelix administration and 
prior to surgery. 
16.5. 
PRS assessment 
Patient-reported symptoms will be assessed using the Functional Assessment of Cancer 
Therapy Endocrine Subscale (FACT-ES). The FACT-ES (42) comprises 18 items, with a 
maximum possible sum score of 72.  Each item or question has response choices ranging 
from 0 (‘‘not at all’’) to 4 (‘‘very much a problem’’). FACIT guidelines (www.facit.org) 
will be used for scoring and interpretation of the FACT-ES total score. To provide clinically 
useful information regarding treatment side effects, patient responses to each ES question 
can be labeled as ‘‘clinically significant’’ if they scored 3 or 4 (corresponding to ‘‘quite a 
bit’’ or ‘‘very much’’ a problem, respectively, on the questionnaire) and as ‘‘not clinically 


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significant’’ for scores of 0, 1, or 2 (‘‘not at all’’, ‘‘a little bit’’, or ‘‘somewhat’’ a problem, 
respectively) (34). The questionnaire is completed before any subsequent procedures or 
treatment and refers to the past 7 days. 
16.6. 
PRS statistical considerations 
16.6.1. Primary analysis 
The differences in PRS measurements between the two treatment arms over time will be 
assessed.  We hypothesize that the PRS may change over time and that women receiving 
degarelix will experience a more rapid onset of PRS symptoms related to endocrine therapy 
than those receiving triptorelin. Repeated measures analysis based on generalized estimating 
equation (GEE) model will be used to investigate the differences in PRS between treatment 
arms, controlling for the stratification factor of age. All patients who receive at least one 
dose of study treatment and with at least one PRS assessment will be included in the 
analysis. This model will describe the effects of two neoadjuvant treatments (letrozole plus 
either degarelix or triptorelin) on PRS for the observation period. The analysis will be 
exploratory, given the limited sample size (maximum 25 patients per treatment arm). The 
power of the repeated measure test is likely to be low except if treatment differences are 
substantial. 
16.6.2. Analysis for secondary objectives 
 Correlation between the E2 levels and total PRS score measured on day 1 of cycle 2 
and cycle 4 of triptorelin or degarelix administration will be assessed by treatment 
arms using Spearman’ rank correlation coefficient. 
 Each of the 18 (endocrine symptom) items of the FACT-ES will also be summarized 
descriptively over time by treatment arms as the proportion of patients with 
“clinically significant” symptoms (those scoring 3 or 4). Two sided 90% CI for the 
difference in the proportion will also be assessed. 
Missing assessments may be due to stopping treatment, not completing the PRS 
assessments, and other reasons. Information on reasons why the patient did not complete the 
PRS Form will be collected.  
16.7. 
PRS Timing requirements 
All PRS Forms are to be completed during the patients’ visits in the clinic. The schedule of 
PRS assessment time points must be followed as closely as possible. Timing effects have an 
impact on patients’ self-estimation of PRS (43). It is important that the questionnaire is 
completed before any diagnostic procedures or communication of diagnostic information to 
the patient (exception: baseline assessment) and before any administration of treatment. If, 
for administrative reasons, the form has not been presented to the patient, it may be filled in 
at home and mailed. 
16.8. 
PRS data collection and local data management 
For the first assessment, the PRS Form has to be explained to the patient, with particular 
emphasis on making sure the patient understands the categorical response format. All 
questions must be answered. The completed questionnaire is to be checked while the patient 
is still present. If necessary, the patient should be asked to fill in missing answers. If the 
patient does not complete a scheduled PRS assessment, an empty PRS Form should be 


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faxed with the Patient ID number, the date the questionnaire was meant to be filled in, and 
the reason for not completing the questionnaire. 
Questions regarding PRS assessment should be addressed to ibcsg41_TREND@fstrf.org. 
17. 
Additional protocol-specific evaluations 
17.1. 
Pathology and pathology material banking 
The work of the pathologist is basic to the success of all studies.  Each Participating 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 diagnostic biopsy and definitive 
surgery 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. 
NOTE: Central pathology review on the primary tumor is mandatory for this trial, but 
patients will be evaluated for eligibility by tumor characteristics as determined by the local 
pathologist. 
Both the breast diagnostic biopsy specimen and a final breast surgery specimen have to be 
submitted for Central Pathology Review.  
17.2. 
Submitting pathology material to IBCSG 
The following items are required for all patients: 
1. Pathology Report (including steroid hormone receptor, HER2 and Ki67) of the 
diagnostic core biopsy 
2. Pathology Report (including steroid hormone receptor, HER2 and Ki67) of the 
definitive surgery  
3. Tumor block for banking from diagnostic core biopsy 
4. Tumor block for banking from definitive surgery. This should include at least 5mm 
invasive tumor and a minor component of normal breast tissue (whenever it is 
available). Please notify the pathologist of this requirement in advance. 
5. Representative H & E sections of the above blocks 
The tissue blocks may be returned to the Participating Center upon request after 4, 1mm 
cores have been taken for preparing tissue micro-arrays (TMAs). 
All Pathology Reports, and FFPE blocks must be marked with the IBCSG Patient ID 
number. Please erase or black out any other identifiers like name or date of birth. Refer to 
the IBCSG website for additional FFPE specimen shipping recommendations. 
Mailing address for the FFPE blocks, H&E slides and Pathology Reports: 
IBCSG Central Pathology Office 
European Institute of Oncology, EIO  
Division of Pathology  
Via Ripamonti 435  
20141 Milano, Italy  
E-mail: pathology.ibcsg@ieo.it 
Both Pathology Reports should also be submitted by Fax to DataFax. 


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17.3. 
Banking biological material 
All FFPE blocks will be banked in the IBCSG Tissue Bank, to have available for 
Translational Research.  If the return of the block is requested, cores (2-4 cores, 1mm thick) 
for tissue microarray (TMA) construction and cores (2-3 cores, 1mm thick) for banking for 
future translational research will be taken.  DNA will be extracted. 
All biological material will be logged in the IBCSG Pathology Material Tracking System 
/Translational Research System and banked in the IBCSG Tissue Bank.   
The use of the biological material for unspecified future research will be under the auspices 
of the IBCSG Biological Protocols Working Group and any project has to be approved by 
the IBCSG Ethics Committee.  As part of the Informed Consent process, patients are asked 
to indicate whether they agree to donate their sample for unspecified future research. The 
patient’s decision is recorded on the IBCSG Confirmation of Registration (41-A) Form. 
17.4. 
Blood samples 
For determination of FSH, LH, E2 by the central laboratory, serum samples have to be taken 
and stored at -80°C at day 1 of treatment before the administration of the first dose, 
thereafter at 24 and 72 hours, 7 days and 14 days after first injection, and on day 1 of cycles 
2 to 6, before the administration of the next dose. Serum has to be extracted and stored at 
-80°C locally at the Participating Center. At the end of the trial, samples will be collected by 
courier and sent to: 
Harriet Johansson 
Lab Senior Assistant 
Division of Cancer Prevention and Genetics 
European Institute of Oncology 
Via Ripamonti 435, 20141 Milan, Italy, 
Samples will be analyzed for FSH and LH. Then they will be batch shipped to the laboratory 
of Prof. Frank Stanczyk for the determination of E2 levels (primary endpoint of the trial): 
Prof. Frank Stanczyk 
Reproductive Endocrine Research Laboratory 
USC Keck School of Medicine 
Women’s & Children’s Hospital 
1240 N. Mission Rd., Room 1M2 
Los Angeles, CA 90033, USA 
Please consult the Blood Sample Logistics Manual for details. 
18. 
Ethical aspects, regulatory approval, and patient informed consent 
The Investigator will ensure that this study is conducted in full conformance with the 
principles of the “Declaration of Helsinki” or with the laws and regulations of the country in 
which the research is conducted, whichever affords the greater protection to the individual. 
The study must fully adhere to the principles outlined in “Guideline for Good Clinical 
Practice” ICH Tripartite Guideline (January 1997) or with local law if it affords greater 
protection to the patient. For studies conducted in the EU/EEA countries, the Investigator 
will ensure compliance with the EU Clinical Trial Directive (2001/20/EC). 


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18.1. 
Ethical Review Board/Ethics Committee 
All protocols and the patient Informed Consent Forms must have the approval of a properly 
constituted committee or committees responsible for approving clinical trials. The ERB/IRB 
written, signed approval letter/form must contain approval of the designated Investigator, 
the protocol (identifying protocol title and version number), and of the patient Informed 
Consent. Documentation of Ethics Committee approval(s) must be sent to the IBCSG Data 
Management Center prior to enrollment of the first patient. The IBCSG Ethics Committee 
also approves the protocol and reviews it annually. 
Any modifications made to the protocol will be reviewed by the IBCSG Ethics Committee 
and must also be submitted to the appropriate ERB/IRB for information or approval in 
accordance with local procedures and regulatory requirements and to Health Authorities if 
required.  
Once approved or acknowledged by the appropriate ERB/IRB and by the Health Authorities 
(if required), the Investigator shall implement the protocol modifications. Protocol 
modifications for urgent safety matters may be directly implemented following the 
instructions of IBCSG. 
18.2. 
Regulatory approval procedures 
If applicable, in addition to the approval of the Ethics Committee according to national 
legislation, the protocol, other protocol-related documents including patient information and 
Informed Consent and other documents as required locally must be submitted to and be 
approved by the health authority. Documentation of health authority approval must be sent 
to the IBCSG Data Management Center prior to Participating Center activation. 
18.3. 
Protection of human subjects 
The IBCSG has an Office for Human Research Protection (OHRP) Federal Wide Assurance 
(FWA00009439) and follows all of the policies and procedures that are part of that 
assurance.  All potential subjects for this trial will receive a full explanation of the trial, its 
purpose, treatments, risks, benefits, and all of the other items listed in Section 18.4. 
Additional institution-specific sections should be added to Appendix I as described in 
section 18.4. 
The medical record must be available for review by the IBCSG audit team and regulatory 
authorities as described in section 19.5. 
Serious Adverse Event (SAE) Reports are distributed monthly. In addition they are available 
on the IBCSG website (www.ibcsg.org) for participating Centers. 
18.4. 
Informed Consent 
Informed Consent for each patient will be obtained prior to initiating any trial procedures in 
accordance with the “IBCSG Patient Information Sheet and 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. Verification of signed 
Informed Consent and the date signed are required for randomization to this trial.   
The "Declaration of Helsinki"  recommends that consent be obtained from each potential 
patient in biomedical research trials after the aims, methods, anticipated benefits, and 
potential hazards of the trial, and discomfort it may entail, are explained to the individual by 


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the physician (http://www.wma.net/en/30publications/10policies/b3/index.html).  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 
legally incompetent (i.e., a minor, or mentally incompetent), 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 (Appendix I), which can be downloaded and 
edited to incorporate information specific to your institution (see www.ibcsg.org). 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”. The final version should receive 
the Institutional Review Board/ Local Ethics Committee approval in advance of its use. 
Centers should send their locally modified PIS/IC to the IBCSG Data Management Center 
for review and approval before submitting to their Ethics Committee.  
18.5. 
Premature withdrawal 
18.5.1. Withdrawal from trial treatment 
Patients have the right to refuse further trial treatment at any time during the trial. Patients 
may also be withdrawn at any time from trial treatment at the discretion of the Investigator 
due to an adverse event, or based on any other relevant medical condition. Such patients will 
remain in the trial and will proceed to surgery. The patient will continue to be documented 
according to protocol. 
18.5.2. Change of consent 
Patients have the right to withdraw consent for further trial participation at any time without 
having to specify the reason. The data recorded up to the time point of withdrawal will 
continue to be evaluated in the trial. The Investigator should ask the patient for her consent 
to continue to be documented according to protocol. 
It should be documented in both the medical records and in the eCRF (Form 41-COC) 
whether it is acceptable for the patient to be documented according to protocol despite her 
withdrawal of study consent. 
19. 
Governance and Administrative Considerations 
19.1. 
Insurance 
IBCSG will contract the appropriate liability insurance for this trial. Patients who suffer 
injuries due to the trial should report them immediately to their physician. The local Center 
should report all alleged claims immediately to the IBCSG. 


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19.2. 
Steering Committee 
A Steering Committee will be constituted for this trial. The primary responsibilities of the 
Steering Committee are twofold. First, the Steering Committee is responsible for 
maintaining the scientific integrity of the trial, for example, by recommending changes to 
the protocol in light of emerging clinical or scientific data from other trials. Second, the 
Steering Committee is responsible for the translation of recommendations of the IBCSG 
Data and Safety Monitoring Committee into decisions. Membership will include IBCSG 
officials, study chair and co-chairs, trial statisticians, representatives from some 
Participating Centers, and representatives from Ferring Pharmaceuticals. 
General partition of responsibilities: 
The Steering Committee has the authority to make and implement any final decisions, such 
as substudies of the trial or amendments to the trial protocol, and may recommend the 
termination/early termination of the trial. 
The IBCSG Executive Committee is responsible for the implementation of all final 
decisions taken by the Steering Committee. 
The IBCSG Foundation Council decides on the termination/early termination of the trial. 
19.3. 
Data and Safety Monitoring Committee (DSMC) 
The trial will be presented for review to the IBCSG Data and Safety Monitoring Committee 
(DSMC) at each of their semi-annual meetings. Accrual and safety will be monitored.  
19.4. 
Premature discontinuation of the trial 
The trial may be discontinued early in parts or completely if the information on the trial 
treatment leads to doubt as to the benefit/risk ratio. 
19.5. 
Quality Assurance 
The IBCSG conducts trials according to the ICH Good Clinical Practice (GCP) guidelines.  
The Trial IBCSG Data Manager reviews each eCRF. In addition, the 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. 
The Investigator should ensure that source documents are made available to appropriately 
qualified personnel from IBCSG or its designees, or to health authority inspectors after 
appropriate notification. 
Ferring-designated staff and quality assurance auditors may audit the conduct of any site and 
shall be granted reasonable access to facilities during normal business hours. Such auditors 
shall not be entitled to access, make copies of the source documents and/or to take them 
away. 
At regular intervals during the clinical trial, the Center will be contacted, through 
monitoring visits, letters or telephone calls, by a representative of the Monitoring Team to 
review study progress, Investigator and patient compliance with clinical trial protocol 
requirements and any emergent problems. These monitoring visits will include but not be 
limited to review of the following aspects: patient Informed Consent, patient recruitment 
and follow-up, SAE documentation and reporting, AEs with pre-specified monitoring 
documentation and reporting, AE documentation, trial treatment administration, patient 


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compliance with the regimens, drug accountability, concomitant therapy use and quality of 
data. 
19.6. 
Data protection 
A unique Patient Identification Number (ID) will be assigned by the IBCSG Registration/ 
Randomization System to each patient randomized into the trial. The names of the patients 
will not be disclosed to the IBCSG.  
Only the Patient ID will be used to identify a patient on the eCRF. Identification of patients 
must be guaranteed at the Participating Center. In order to avoid identification errors, 
Centers should keep a Patient Identification Log containing the patients’ name, year of birth, 
hospital number and the Patient ID allocated by IBCSG. 
Regulatory authorities and the pertinent Ethics Committee (ERB/IRB) may have access to 
patient data on-site. IBCSG audit or monitoring personnel will also have access to such data 
on-site. 
19.7. 
Record Retention 
The Center must retain all essential documents according to ICH GCP. This includes copies 
of the patient trial records, which are considered as source data, patient Informed Consent 
statement, laboratory printouts, drug inventory and destruction logs, and all other 
information collected during the trial. These documents are to be stored until at least 15 
years after the termination of the trial. IBCSG guarantees access and availability of the data 
entered into iDataFax for at least 15 years after the termination of the trial. 
Longer retention may be required for Participating Centers according to national 
regulations. 
In the event that the Principal Investigator retires or changes employment, custody of the 
records may be transferred to another competent person who will accept responsibility for 
those records. Written notice of such transfer has to be given to IBCSG and the local Ethics 
Committee at least one month in advance. 
20. 
Confidentiality 
The protocol, eCRFs and other protocol-related documents are confidential and are the 
property of the IBCSG. 
21. 
References 
1. Kaufmann M, von Minckwitz G, Mamounas EP. et al. Recommendations from an 
International Consensus Conference on the Current Status and Future of Neoadjuvant 
Systemic Therapy in Primary Breast Cancer. Ann Surg Oncol. 2011 Dec 23. [Epub 
ahead of print] 
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5. Kaufmann M, Hortobagyi GN, Goldhirsch A. Recommendation from International 
Expert panel on the use of neoadjuvant (primary) systemic treatment of operable breast 
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6. Colleoni M, Viale G,  Zahrieh D,  et al. Chemotherapy is more effective in patients with 
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7. Gianni L, Baselga J, Eiermann  W, et al. Feasibility and tolerability of sequential 
doxorubicin/paclitaxel followed by cyclophosphamide, methotrexate, and fluorouracil 
and its effects on tumor response as preoperative therapy. Clin Cancer Res 2005; 11: 
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8. Abrial C, Mouret-Reynier M-A, Curé H, et al Neoadjuvant endocrine therapy in breast 
cancer. The Breast 2006; 15: 9-19. 
9. 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 2001; 19: 2596-2606. 
10. Eiermann W, Paepke S, Appfelstaedt J, et al Preoperative treatment of postmenopausal 
breast cancer patients with letrozole: A randomized double-blind multicenter study. 
Ann Oncol 2001; 12: 1527-1532. 
11. Ellis MJ, Coop A, Singh B, Mauriac L, et al. Letrozole is more effective neoadjuvant 
endocrine therapy than tamoxifen for ErbB-1- and/or ErbB-2-positive, estrogen 
receptor-positive primary breast cancer: evidence from a phase III randomized trial. J 
Clin Oncol. 2001; 19: 3808-16. 
12. Smith IE, Dowsett M, Ebbs SR, et al: Neoadjuvant treatment of postmenopausal breast 
cancer with anastrozole, tamoxifen, or both in combination: the Immediate Preoperative 
Anastrozole, Tamoxifen, or Combined with Tamoxifen (IMPACT) multicenter double-
blind randomized trial. J Clin Oncol 2005; 23:5108-16. 
13. Cataliotti L, Buzdar AU, Noguchi S, et al. Comparison of anastrozole versus tamoxifen 
as preoperative therapy in postmenopausal women with hormone receptor-positive 
breast cancer: the Pre-Operative "Arimidex" Compared to Tamoxifen (PROACT) trial. 
Cancer 2006; 106:2095-103. 
14. Semiglazov V, Kletsel A, Semiglazov V et al. Exemestane versus tamoxifene as 
neoadjuvant endocrine therapy for postmenopausal women with ER+ breast cancer 
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15. Semiglazov VF, Semiglazov VV, Dashyan GA, et al.: Phase 2 randomized trial of 
primary endocrine therapy versus chemotherapy in postmenopausal patients with 
estrogen-receptor positive breast cancer. Cancer 2007; 110:244-254. 
16. Jones RL, Salter J, A'Hern R, et al. The prognostic significance of Ki67 before and after 
neoadjuvant chemotherapy in breast cancer. Breast Cancer Res Treat. 2009; 116:53-68. 


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17. Colleoni M, Bagnardi V, Rotmensz N. et al. A risk score to predict disease-free survival 
in patients not achieving a pathological complete remission after preoperative 
chemotherapy for breast cancer. Ann Oncol. 2009; 20:1178-1184. 
18. Ellis MJ, Tao Y, Luo J, et al. Outcome prediction for estrogen receptor-positive breast 
cancer based on post neoadjuvant endocrine therapy tumor characteristics. J Natl 
Cancer Inst 2008; 100:1380-1388. 
19. Chia YH, Ellis MJ, Ma CX. Neoadjuvant endocrine therapy in primary breast cancer: 
indications and use as a research tool. Br J Cancer 2010;103:759-764 
20. Dixon JM, Jackson J, Renshaw L, Miller WR. Neoadjuvant tamoxifene and aromatase 
inhibitors: comparisons and clinical outcomes. J Steroid Biochem Mol Biol 2003; 86: 
295-299. 
21. Gazet JC, Ford HT, Gray R, et al. Estrogen-receptor-directed neoadjuvant therapy for 
breast cancer: results of a randomised trial using formestane and methotrexate, 
mitozantrone and mitomycin C (MMM) chemotherapy. Ann Oncol 2001; 12:685-691 
22. Torrisi R, Bagnardi V, Pruneri G, et al: Antitumor and biological effects of letrozole 
and GnRH analogue as primary therapy in premenopausal women with ER and PgR 
positive locally advanced operable breast cancer. Br J Cancer 2007; 97: 802-808. 
23. Masuda N., Sagara Y, Kinoshita T, et al.  Neoadjuvant anastrozole versus tamoxifen in 
patients receiving goserelin for premenopausal breast cancer (STAGE): a double-blind, 
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24. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology – 
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25. Van Poppel H, Tombal B, de la Rosette JJ, et al:  Degarelix: a novel gonadotrophin-
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phase 2 dosage-finding study in the treatment of prostate cancer. Eur Urol 2008; 54: 
805-815. 
26. Gittelman M, Pommerville PJ, Persson BE, et al: A 1-year,open-label, randomized 
phase II dose finding study of degarelix, a novel gonadotropin-releasing hormone 
(GnRH) receptor blocker, in the treatment of prostate cancer in North America. J Urol 
2008; 180:1986-1992.  
27. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
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28. Klotz L, Boccon-Gibod L, Shore ND, Andreou C, Persson BE, Cantor P, Jensen JK, 
Olesen TK, Schröder FH. The efficacy and safety of degarelix: a 12-month, 
comparative, randomized, open-label, parallel-group phase III study in patients with 
prostate cancer. BJU Int. 2008;102:1531-1538. 
29. Heyns CF, Simonin MP, Grosgurin P, et al. South African Triptorelin Study Group. 
Comparative efficacy of triptorelin pamoate and leuprolide acetate in men with 
advanced prostate cancer. BJU Int. 2003;92:226-31. 
30. Celio L, Martinetti A, Ferrari L, Buzzoni R, Mariani L, Miceli R, Seregni E, Procopio 
G, Cassata A, Bombardieri E, Bajetta E. Premenopausal breast cancer patients treated 
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31. Rossi E, Morabito A, De Maio E, Di Rella F, Esposito G, Gravina A, Labonia V, Landi 
G, Nuzzo F, Pacilio C, Piccirillo MC, D'Aiuto G, D'Aiuto M, Rinaldo M, Botti G, Gallo 
C, Perrone F, de Matteis A. Endocrine effects of adjuvant letrozole + triptorelin 
compared with tamoxifen + triptorelin in premenopausal patients with early breast 
cancer. J Clin Oncol. 2008; 26:264-270. 
32. Smith IE, Dowsett M, Yap Y et al. Adjuvant aromatase inhibitors for early breast 
cancer after chemotherapy-induced amenorrhea: caution and suggested guidelines. J 
Clin Oncol 2006; 24:2444-2447. 
33. Ruhstaller T,  Moos R, Rufibach K, Ribi K, Glaus A,  Spaeti B Koeberle D, Mueller U, 
Hoefliger M, Hess D, Boehme C, Thuerlimann B Breast Cancer Patients on Endocrine 
Therapy Reveal More Symptoms when Self-Reporting than in Pivotal Trials: An 
Outcome Research Study. Oncology 2009; 76:142-148. 
34. Oberguggenberger A, Hubalek M, Sztankay M, Meraner V, Beer B, Oberacher 
H,Giesinger J, Kemmler G, Egle D, Gamper EM, Sperner-Unterweger B, Holzner B. Is 
the toxicity of adjuvant aromatase inhibitor therapy underestimated? Complementary 
information from patient-reported outcomes (PROs). Breast Cancer Res Treat 2011; 
128:553-561. 
35. Cella D., Fallowfield L., Barker P., Cuzick J., Locker G.,Howell A., Quality of Life 
ofPostmenopausal Women in the ATAC ("Arimidex", Tamoxifen, Alone or in 
Combination)Trial after Completion of 5 years' Adjuvant Treatment for Early Breast 
Cancer. Breast Cancer Res Treat 2006; 100:273-284. 
36. Fallowfield L.J., Bliss J.M., Porter L.S., Price M.H., Snowdon C.F., Jones S.E., et 
al.,Quality of life in the intergroup exemestane study: a randomized trial of exemestane 
versuscontinued tamoxifen after 2 to 3 years of tamoxifen in postmenopausal women 
withprimary breast cancer. J Clin Oncol 2006; 24:910-917. 
37. Whelan T.J., Goss P.E., Ingle J.N., Pater J.L., Tu D., Pritchard K., et al., Assessment 
ofquality of life in MA.17: a randomized, placebo-controlled trial of letrozole after 5 
years oftamoxifen in postmenopausal women. J Clin Oncol 2005; 23:6931-6940. 
38. Nystedt M, Berglund G, Bolund C, Fornander T, Rutqvist LE: Side effects of adjuvant 
endocrine treatment in premenopausal breast cancer patients: a prospective randomized 
study. J Clin Oncol 2003;21:1836-1844. 
39. Bernhard J, Zahrieh D, Castiglione-Gertsch, M Hürny C, Gelber R, Forbes JF, Murray 
E, Collins J, Aebi S, Thürlimann B, Price KN, Goldhirsch A, and Coates AS. Adjuvant 
Chemotherapy Followed By Goserelin Compared With Either Modality Alone: The 
Impact on Amenorrhea, Hot Flashes, and Quality of Life in Premenopausal Patients—
The International Breast Cancer Study Group Trial VIII. J Clin Oncol 2007; 25:263-
270. 
40. De Haes H, Olschewski M, Kaufmann M, Schumacher M, Jonat W, Sauerbrei W. 
Quality of Life in Goserelin-Treated Versus Cyclophosphamide Methotrexate _ 
Fluorouracil–Treated Premenopausal and Perimenopausal Patients With Node-Positive, 
Early Breast Cancer: The Zoladex Early Breast Cancer Research Association Trialists 
Group. J Clin Oncol 2003 (24):4510-4516. 
41. Iversen P., Karup C., van der Meulen E., Tanko´ LB., Huhtaniemi I . Hot flushes in 
prostatic cancer patients during androgen-deprivation therapy with monthly dose of 
degarelix or leuprolide. Prostate Cancer and Prostatic Diseases 2011; 14:184-190. 


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42. Fallowfield LJ, Leaity SK, Howell A, Benson S, Cella D. Assessment of quality of life 
in women undergoing hormonal therapy for breast cancer: validation of an endocrine 
symptom subscale for the FACT-B. Breast Cancer Res Treat 1999; 55:189-199. 
43. Hürny C, Bernhard J, Coates A, et al. Timing of baseline quality of life assessment in 
an international adjuvant breast cancer trial: its effect on patient self-estimation. The 
International Breast Cancer Study Group. Ann Oncol 1994; 5:65-74. 
 
22. 
List of abbreviations 
 
AE 
Adverse event 
CI 
Confidence interval 
CR 
Complete response 
CRF 
Case report form 
NCI CTCAE National Cancer Institute common toxicity criteria for adverse events 
DMC 
Data Management Center (IBCSG) 
DSMC 
Data and Safety Monitoring Committee 
ECOG PS Eastern Cooperative Oncology Group Performance Status 
E2 
17--estradiol 
eCRF 
Electronic case report form 
ER 
Estrogen receptor 
FFPE 
Formalin fixed paraffin embedded 
FSH 
follicle-stimulating hormone 
FSTRF 
Frontier Science and Technology Research Foundation 
GCP 
Good clinical practice 
GnRH 
Gonadotropin-releasing hormone 
H&E 
Hematoxylin and eosin 
HER2 
Human epidermal growth factor 2 
HR 
Hazard ratio 
i.m. 
intramuscular 
IBCSG 
International Breast Cancer Study Group 
IC 
Informed Consent 
ICH 
International conference on harmonization 
iDF 
iDataFax 
INN 
International Non-proprietary Name 
IUN 
Intra-Uterine Device 
LH 
luteinizing hormone 


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LHRH 
luteinizing hormone-releasing hormone 
OS 
Overall survival 
PFS 
Progression-free survival 
PgR 
Progesterone receptor 
PD 
Progressive disease 
PEPI 
Preoperative Endocrine Prognostic Index 
PR 
Partial response 
PRS 
Patient-reported symptoms 
s.c. 
subcutaneous 
SAE 
Serious adverse event 
SD 
Stable disease 
SERM 
selective estrogen receptor modulator 
SPC 
Summary of product characteristics 
ULN 
Upper limit of normal 
USAN 
United States Adopted Name 
WHO 
World Health Organization 

SAP_000.pdf: 
 
 
 
 
 
 
 
 
INTERNATIONAL BREAST CANCER STUDY GROUP 
 
TREND (TRIAL 41-13) 
TRial on the Endocrine activity of Neoadjuvant Degarelix:  
Statistical Analysis Plan (SAP) 
 
October 2017 
 
 
 
 
 
 
Version 
Author 
Date 
Status 
1.0 
Kathryn P Gray, PhD 
10/2017 
Final 
 
 
 


TREND (IBCSG 41-13) SAP October 2017 
Trial 41-13 – Page 2 
 
1 
STUDY OVERVIEW 
1.1 
SYNOPSIS 
The TREND randomized phase II trial evaluates neoadjuvant endocrine therapy (degarelix 
[GnRH antagonist] versus triptorelin [GnRH agonist]) in combination with letrozole as treatment 
for premenopausal women diagnosed with endocrine-responsive cancer. A 1:1 randomization 
allocation (degarelix+ letozole vs triptorelin +letozole) is used. The primary objective is to 
compare the endocrine activity of neoadjuvant degarelix and triptorelin in premenopausal 
patients receiving letrozole for primary endocrine-responsive breast cancer. The endocrine 
activity is measured by time to optimal ovarian function suppression, with the hypothesis that 
degarelix will achieve faster ovarian suppression than triptorelin. 
The study was activated on 28 March 2013 and the first patient was enrolled on 24 February 
2014, with the delay due to changes in trial activation rules in Italy during that time.   
The trial activated in seven participating centers in Italy: Bologna, Genoa, Milan, Pavia, Prato, 
Rimini, and Varese.   
 
1.2 
TRIAL DESIGN 
TREND (TRIAL 41-13) OVERVIEW  
 
Title 
TRial on the Endocrine activity of Neoadjuvant Degarelix (TREND): A 
randomized phase II trial evaluating the endocrine activity and efficacy of 
neoadjuvant degarelix versus triptorelin in premenopausal patients receiving 
letrozole for primary endocrine responsive breast cancer 
Patient 
Population 
Premenopausal patients with histologically confirmed primary breast cancer and 
with primary tumor which is ER+ and PgR+ (>50%) and HER2-negative or not 
amplified 
Entry 
Patients must be entered before initiating any treatment for primary invasive breast 
cancer. Patients cannot have received GnRH analogue, SERM or AI within 12 
months prior to randomization, and cannot have used hormonal treatment in the two 
months prior to randomization. 
Premenopausal status must be determined by estradiol (E2) above 54 pg/mL (or 
above 198 pmol/L), measured in a local laboratory within 14 days prior to 
randomization. 
Activation Date 
28 March 2013 (first patient entered  24 February 2014) 
Target Accrual 
50 
Closure Date 
12 January 2017 (Last patient enrolled 10 January 2017) 
Final Accrual  
51 


TREND (IBCSG 41-13) SAP October 2017 
Trial 41-13 – Page 3 
 
Schema:  
 
 
 
Stratification Factors: 
Age:  ≤39 versus 40+ (years). 
Treatment Schedules: 
Arm A: Triptorelin 3.75 mg administered intramuscularly (i.m.) on day 1 of every cycle* + 
letrozole 2.5 mg/day orally for 6 cycles 
Arm B: Degarelix 240 mg given as two subcutaneous injections (s.c.) of 120 mg on day 1 of 
cycle* 1, followed by 80 mg sc on day 1 of cycles 2 to 6 + letrozole 2.5 mg/day orally 
for 6 cycles 
*one cycle is 28 days 
 
Blood Sampling Schedule: 
Blood will be sampled at the following times to determine estradiol (E2) levels in a central 
laboratory: 
 Baseline: day 1 of the first treatment cycle before the administration of the first dose of 
degarelix or triptorelin 
 24 and 72 hours thereafter 
 7 days and 14 days after the first injection 
 Day 1 of cycles 2 to 6 before the administration of degarelix or triptorelin. 
 


TREND (IBCSG 41-13) SAP October 2017 
Trial 41-13 – Page 4 
 
1.3 
STATISTICAL DESIGN AND SAMPLE SIZE 
50 patients will be randomized using 1:1 allocation and stratified based on age (≤39 vs. ≥40 
years). to 
 25 patients to treatment with triptorelin plus letozole; and 
 25 patients to treatment with degarelix plus letozole.  
The sample size was determined in consideration of the trial primary objectives.  Specifically, 
the primary endpoint of time to optimal ovarian function suppression will be assessed in the two 
treatment arms and is defined as time from the first injection of degarelix or triptorelin to the first 
centrally assessed E2 ≤2.72 pg/mL or ≤10 pmol/L during the 6 cycles of neoadjuvant treatment. 
The blood samples are taken at day 1 of the first treatment cycle before the administration of the 
first dose of degarelix or triptorelin (baseline), and thereafter at 24 and 72 hours, 7 days and 14 
days after the first injection, and on day 1 of cycles 2 to 6 before the administration of degarelix 
or triptorelin. 
The following table provides the assumption on the cumulative percent of patients who are 
anticipated to reach optimal ovarian function suppression (E2 level ≤2.72 pg/mL or ≤10 pmol/L) 
during the 6 cycles of neoadjuvant treatment.   
 
Cumulative percent (%) of  patients  with 
E2 ≤2.72 pg/mL or ≤10 pmol/L 
Treatment arms 
2 weeks 
4 weeks 
8 weeks 
12 weeks 
16 weeks 
Triptorelin+Letrozole 
(control: arm A) 
30 
60 
75 
90 
100 
Degarelix+Letrozole 
(experiment: arm B) 
60 
95 
100 
100 
100 
With 23 patients in each treatment arm and based on the assumption in the table above, the study 
has 90% power to detect a difference in time to optimal ovarian function suppression (E2 ≤2.72 
pg/mL or ≤10 pmol/L) between the two treatment arms, using a two-sample log-rank test at a 
two-sided significance level of 0.05. Calculations were performed using nQuery Advisor® 
(logrank test of survival in two groups, simulation with percentages specified in above table).  
To allow for missing data, the study enrolls 25 patients to each treatment arm for a total of 50 
patients.  
 


TREND (IBCSG 41-13) SAP October 2017 
Trial 41-13 – Page 5 
 
1.4 
TRIAL CONDUCT 
1.4.1 Protocol Versions/Amendments 
The trial was activated with protocol version 1.0 on dated 28 March 2013, and first patient 
enrolled on 24 February 2014.  Final patient enrolled in January 2017 with final enrollment of 
N=51. 
There is no amendment. 
1.4.2  
IBCSG Data and Safety Monitoring Committee (DSMC) conducts regularly scheduled semi-
annual reviews of interim clinical and safety data for trial 41-13 (TREND) 
The DSMC conducted reviews on April 24, 2014 and subsequently around every 6 month, 
concluded the trial to continue as planned. 
 
2 
OVERVIEW OF ANALYSIS PLANS 
       Analysis Steps: 
 Identify patients who are enrolled into two arms and check the treatment status. 
 Define primary endpoint using data from the relevant CRFs and centrally assessed 
E2 values at timepoints. 
 Define (baseline clinical) covariates for model adjustment and calculate age 
stratification factor (at randomization) 
 Use the method described below for analyses. 
2.1 
ANALYSIS POPULATIONS 
ITT population: All randomized patients without regard to adherence with treatment assigned. 
The safety population:  All patients who received at least one dose of trial treatment were 
included in assessments of safety and tolerability 
Surgery population:  All patients who received surgery at the end of neoadjuvant therapies. 
PRS population: All patients who received at least one dose of trial treatment and had at least 
one FACT-ES assessment were included in the analysis. 
 
2.2 
ANALYSIS PLANS 
2.2.1 Primary Objective 
To compare the endocrine activity of neoadjuvant degarelix and triptorelin in premenopausal 
patients receiving letrozole. The endocrine activity is measured by time to optimal ovarian 
function suppression. 


TREND (IBCSG 41-13) SAP October 2017 
Trial 41-13 – Page 6 
 
2.2.2 Secondary Objectives 
To evaluate: 
 Node-negative disease at surgery 
 Breast-conserving surgery (BCS) rate 
 The Preoperative Endocrine Prognostic Index (PEPI) score determined after completion 
of neoadjuvant therapy or at the time of surgery 
 Ki67 proliferation marker changes 
 Best overall (disease) response 
 Safety and tolerability as documented according to NCI CTCAE version v4.0 
 Patient-reported symptoms (PRS) outcomes 
2.2.3 Primary Endpoint  
Time to optimal ovarian function suppression (TTOFS): time from the first injection of degarelix 
or triptorelin to the first assessment of centrally assessed 17--estradiol (E2) level in the range of 
optimal ovarian function suppression (E2≤2.72 pg/mL or ≤10 pmol/L) during the 6 cycles of 
neoadjuvant treatments. Time for patients who do not reach the targeted E2 level will be 
censored at the last E2 assessment date. 
2.2.4 Secondary Endpoints 
1. Node-negative disease at surgery: The number of lymph nodes assessed at surgery minus 
the number of positives nodes identified, equal to zero.  
2. Breast-conserving surgery (BCS): Whether or not patient undergoes BCS (per Surgery 
form). If patient does not undergo surgery within the trial then patient is to be excluded 
from the surgery outcome summary (analysis is based on surgery population)  
3. Change in Ki67 expression level: the percent change in Ki67 expression from pre-treatment 
diagnostic (baseline) biopsy to surgery, calculated as (surgery-baseline)/baseline*100.  
4. The Preoperative Endocrine Prognostic Index (PEPI, range 0-12) score at time of surgery: 
By integrating central pathology review (CPR) results of pathological features and 
biomarkers with risk points (table below), the PEPI is the sum of the risk points with a 0 
score representing the best prognostic feature, as previously determined to be associated 
with recurrence-free survival (RFS):  
 
RFS 
Pathology, biomarker status 
HR 
Adverse Points 
Tumor size: 
 
T1/2 
 
T3/4 
 
 
2.8 
 
0 
3 
Nodal status 
 
Negative 
 
Positive 
 
 
3.2 
 
0 
3 
Ki67 level 
 
0 – 2.7%  
(0 – 1 a) 
 
>2.7 – 7.3%  
(1 – 2 a) 
 
 
1.3 
 
0 
1 


TREND (IBCSG 41-13) SAP October 2017 
Trial 41-13 – Page 7 
 
 
>7.3 – 19.7%  
(2 – 3 a) 
 
>19.7 – 53.1% 
(3 – 4 a) 
 
>53.1% 
(>4 a) 
1.7 
2.2 
2.9 
1 
2 
3 
ER status, Allred score 
 
0 – 2 
 
3 – 8 
 
2.8 
 
3 
0 
 
           aThe natural logarithm interval corresponding to the per cent Ki67 values on the original percentage scale 
5. Best overall response: based on WHO tumor measurement and response criteria [1], 
measured from the start of treatment across all time points until disease progression or the 
end of 6 cycles of neoadjuvant therapies, whichever comes first. Response was determined 
by the IBCSG Head of Medical Affairs. An internal review (IR) form was created to record 
the final determination on best overall response. Confirmation of partial or complete 
response by an additional scan was not required in this trial.   
Best overall response was assessed based on changes in tumor size from baseline to the 
assessments after 3 and after 6 cycles (denoted as day 1 of cycle 4 and prior to surgery 
respectively) as measured physically by caliper or ruler and as measured by breast tumor 
imaging (i.e., bilateral mammography and breast ultrasound). 
 Complete Response (CR): The disappearance of all known disease; 
 Partial Response (PR): A 50% or more decrease in total tumor size (i.e. the product of 
the lesion’s maximal diameter (MD) and the corresponding largest perpendicular 
diameter (LPD) of lesion) which have been measured to determine the effect of the 
therapy. In addition, there can be no appearance of new lesions or progression of any 
lesion; 
 Stable Disease (SD): Neither a 50% decrease in total tumor size (i.e. the product of the 
lesion’s two diameters, MD*LPD of lesion) nor a 25% increase in the size of one or 
more measurable lesions has been determined; 
 Progressive Disease (PD): An increase of at least 25% in total tumor size relative to the 
smallest size measured during the trial and/or appearance of one or more new lesions. 
6. Safety and tolerability: Adverse events (AE) were collected using CTCAE v4.0.  
a. Each targeted AE will be classified according to the maximum grade of the event while 
on trial treatment (grade 0,1,2,3,4,5; where 0=no report). 
b. Other grade 3-5 AEs will be classified according to the maximum grade of any reported 
other AE. 
7. Patient-reported symptoms (PRS) outcomes (see Section 2.2.6) 
2.2.5 
Analysis of the primary endpoint 
The primary endpoint (TTOFS) was compared between the two treatment arms using a stratified 
two-sample log-rank test, with a α=0.05 type I error, using stratification factors of age <=39 vs. 
40+ as defined for randomization. The test statistic and p-value were taken from the stratified 
Cox proportional hazards (PH) model (reported as score test). Hazard ratios (degarelix+letrozole 
/triptorelin+letrozole, so that HR>1 indicates increased hazard of event with degarelix+letrozole 


TREND (IBCSG 41-13) SAP October 2017 
Trial 41-13 – Page 8 
 
and HR<1 indicates decreased hazard of an event with degarelix+letrozole) were estimated from 
a stratified Cox PH model, with two-sided Wald 95% confidence intervals (CIs). Recall, here an 
event is a good thing, so we expect HR>1.  
Cox proportional hazards model were also used to assess the difference in time to optimal 
ovarian function suppression between the treatment arms adjusting for selected covariates 
including baseline E2 level, body mass index (BMI), smoking history, and recent oral 
contraceptive usage. 
The distribution of the primary endpoint was summarized using the method of Kaplan-Meier 
with reporting of median TTOFS as well as cumulative probability of time to OFS (1- event-free 
probability). The standard errors used Greenwood’s formula and the pointwise 95% CIs were 
obtained using complementary log(-log(endpoint)) transformation methodology. 
Two-sided 95% confidence interval (CI) for the difference in proportion of patients who 
achieved optimal OFS (defined as E2 level ≤2.72 pg/mL or ≤10 pmol/L) between the two 
treatment arms at the end of the 1st, 2nd and 4th cycle were to be provided. (Not performed due to 
all (except one data-point at end of cycle2) were at OFS by the end of cycle 1, not meaningful). 
Spider plots displayed the E2 data over scheduled sampling time. Boxplots illustrated the 
distribution of E2, FSH and LH at the scheduled sampling times.   
2.2.6 
Analyses of secondary endpoints 
 Node negative disease at surgery: The percentage of patients with node-negative disease at 
surgery will be descriptively summarized by treatment arm. Two sided 90% CI for the 
difference in percentage of patients with node-negative disease between treatment arms 
will be reported. 
 Breast-conserving surgery (BCS):  
o Details of the surgical procedure performed overall and according to treatment arms. 
o The percent of patients in each treatment arm who had a breast-conserving surgery 
were presented, and the difference between the treatment arms were assessed using a 
two-sided exact 90% CI.  
o Rate of conversion (patient identified as candidates/planned for BCS or mastectomy 
per data on RA-form vs surgery performed on C-form):  Cross-tabulation of surgery 
status between “planned” vs ‘performed’ and the percent in conversion overall and 
according to treatment arms were presented.   
 Change in Ki67 (Surgery population, unless otherwise noted)  
o Ki67 expressions at baseline (pre-treatment, based on ITT population) and at surgery 
were descriptively summarized (median, IQR and mean) according to treatment 
arms.  
o The change in Ki67 expression from baseline (pre-treatment) to surgery was 
summarized for each treatment arm and two-sided 90% CI for the change were 
calculated and explored using a paired sample Wilcoxon signed-rank test. 


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o The percentage changes in Ki67 expression between the treatment arms from 
baseline to surgery were assessed using a two-sided 90% CI and explored using a 
two-sample Wilcoxon rank sum test. 
o Boxplots were used to illustrate the marker distribution at baseline and surgery 
timepoints. 
o Spider plots were used to show the individual paired Ki67 data from baseline to 
surgery. 
 The preoperative endocrine prognostic index (PEPI) score at time of surgery 
Patients in surgery population will be included in the assessment. Descriptive statistics 
are used to summarize the PEPI score by treatment arm. Two-sided 90% CI for the 
difference in the PEPI scores between the two arms maybe constructed. (NOT DONE, 
given only one pt had PEPI score of 0) 
 Objective response was defined as CR/PR vs. Others (SD/PD/NE), where NE stands for 
non-evaluable: 
o Best overall response, overall and by treatment arm, were provided with Ns and 
proportions.  
o Objective response (CR/PR as best overall response) rate was summarized as N 
(%) with 90% CI, overall and by treatment arm, as well as the absolute percent 
difference of objective responses between arms were reported with exact 
binominal 90%CI. 
o Clinical responses at the end of cycle 3 and 6, including complete response (CR), 
partial response (PR), stable disease (SD) and progressive disease (PD) were 
descriptively summarized by treatment arms. 
 
 Safety and tolerability 
Tolerability was evaluated in each treatment arm separately, using the safety population. 
For each patient, the targeted AEs recorded over time were summarized for each AE type 
as the maximum grade reported for that AE (without regard to reported relation to study 
treatments). The frequencies and percentages of patients experiencing each targeted AE 
were reported according to maximum grade, separately by treatment arm.. Two-sided 
90% exact confidence interval (CI) for the difference in proportion of patients with each 
type of grade 3 or higher targeted AE between the treatment arms were assessed.  
o The maximum grade of all targeted AEs are summarized by treatment arm, and 
the number and percentage of patients experiencing at least one grade 3 or higher 
targeted AE will be reported (with CI) according to treatment arm.   
o Targeted adverse events (AEs) and other (non-targeted) grade 3 or higher AEs 
occurring during study were collected using CTCAE v4.0 on the AE Form. The 
AE Forms were submitted at the end of every cycle (27 days) and 30 days after 
surgery. All patients submitted AE data during 6 cycles of treatment period when 
available. 
o AEs are reported as maximum grade. The maximum grade consolidates the 
reports of a given type of AE for a patient over time by taking the maximum 


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Trial 41-13 – Page 10 
 
(worst grade) 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 was been reported. 
 
 Patient-reported symptoms (PRS) analysis 
Longitudinal assessments collected PRS outcome at baseline (prior to randomization), at day 
1 of cycle 2 (day29), at day 1 of cycle 4 (day 85) of triptorelin or degarelix administration and 
prior to surgery.  
The PRS were assessed using the Functional Assessment of Cancer Therapy Endocrine 
Subscale (FACT-ES: for endocrine symptom) comprising 19 items (each has score range 
from 0 to 4) with a possible maximum total score (denoted as ESS) of 76. Functional 
Assessment of Chronic Illness Therapy (FACIT) guidelines will be used for scoring and 
interpretation of the FACT-ES total score. 
The primary endpoint was FACT-ES total score (or ESS). Note that the FACT-ES items are 
negatively framed, thus scores were reversed for analysis so that high scores equate to a good 
quality of life (QOL) [Lesley et al]  
In order to better describe the specific type of QOL measures, as exploratory analysis, four 
subscales/groups of FACT-ES were also summarized, namely, 
 Vasomotor symptoms (VS, score 0-12): hot flashes, cold sweats, night sweat (note: 
sleeping difficult was an item not collected in our dataset) 
  Neuropsychological symptoms (NS, score 0-16): light-headed/dizzy, headache, mood 
swings, feeling irritable (lack of energy, nervous were not collected in our study) 
  GI symptoms (GIS, score 0-16): Vomiting, Gained weight, Diarrhea, bloated feeling 
(nausea no data) 
 Gynecologic symptoms (GYNS. score 0-28): vaginal discharge, vaginal irritation,  
vaginal bleeding, vaginal dryness, discomfort intercourse, lost interest in sex, breast 
tenderness 
To provide clinically useful information regarding treatment side effects, patient responses 
to each ES question are labeled as ‘‘clinically significant’’ if they scored 3 or 4 
(corresponding to ‘‘quite a bit’’ or ‘‘very much’’ a problem, respectively, on the 
questionnaire) and as ‘‘not clinically significant’’ for scores of 0, 1, or 2 (‘‘not at all’’, ‘‘a 
little bit’’, or ‘‘somewhat’’ a problem, respectively). The questionnaire is completed before 
any subsequent procedures or treatment and refers to the past 7 days. 
All patients who received at least one dose of study treatment and with at least one FACT-
ES assessment were included in the analysis (PRS population=ITT population).  
The differences in FACT-ES scores (ESS) measurements between the two treatment arms 
over time were assessed using a mixed-effect model (SAS proc mixed, note a change from 
GEE model stated in the protocol, due to the small sample size and for simplicity). The ESS 


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scores as well as the 4 subscales and individual FACT-ES items were modeled as a function 
of time and treatment arm to investigate the time pattern of FACT-ES scores and differences 
controlling for the stratification factor of age (dichotomized ≤39 vs 40+ years). The 
covariance structure used autoregressive (type =AR(1) assuming between observations on 
the same patient are not equal but decrease toward zero with increasing lag). All available 
data were included in the model. 
This model described the effects of two neoadjuvant treatments (degarelix+letrozole or 
triptorelin+letrozole) on FACT-ES for the observation period. The analysis will be 
exploratory, given the limited sample size (maximum 25 patients per treatment arm). The 
power of the repeated measure test is likely to be low except if treatment differences are 
substantial. 
Means scores at each timepoint for each treatment arm, and for the difference between the 
treatment arms, were estimated from the models and reported with 90% CIs. 
2.3 
CORRELATIVE OBJECTIVES/ANALYSIS 
A tumor block from the diagnostic core biopsy and one from final surgery will be collected and 
banked for central review and future translational research at the IBCSG Tissue Bank hosted by 
the European Institute of Oncology in Milan, Italy (Prof. G. Viale). 
No specific correlative/translational analysis is planned. 
3 
ADDITIONAL ANALYSIS COMPONENTS AND PRESENTATION 
3.1 
FOLLOW-UP 
The database cutoff is September 5, 2017 
Stratification: patients are stratified by age at randomization ((≤39 vs. > 39 years) 
Dynamic institution balancing will be used in order to balance randomized assignments within 
institutions. 
3.2 
INTERIM ANALYSIS/DATA MONITORING 
Interim analyses for primary efficacy were not planned. 
Adverse event reports are to be submitted within 28 days of each clinic visit. All relevant adverse 
events will be reviewed by the DSMC every 6 months (twice a year). The DSMC will make 
recommendation to the study management team if it notes any concerns regarding patient safety 
or if further action needs to be taken based on the safety monitoring review results. Formal 
assessment of targeted adverse events will also be included in statistical analysis for secondary 
objectives as detailed in section 2.2.6. 


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3.3 
ENROLLMENT, ELIGIBILITY, FOLLOW-UP COMPLIANCE 
This section summarizes registration, enrollment, eligibility according to internal review, 
exclusions from the ITT population, CRF submission status and follow-up compliance. 
3.3.1 Enrollment overview will include: 
 Tables 
o Enrollment period 
o Numbers of patients registered and randomized, over time, by participating 
centers, by stratification factors 
 Figures 
o Numbers of patients registered and randomized (two lines; y-axis) over time (x-
axis) 
3.3.2 CONSORT diagram, the following data will be summarized: 
 Number of patients registered. 
o Reasons registered patients were not randomized 
 Number of patients randomized to each treatment group 
 Patients excluded from ITT population (do not initiate treatment and WC for all 
participation), according to treatment group 
 Treatment status: initiation vs. non-initiation of assigned trial treatment 
 Follow-up status: complete per protocol (or on treatment) vs. WC/LFU 
3.3.3 Stratification factors will be overviewed (for the randomized population): 
 Tables: 
o Distribution of stratification factor, overall and by treatment assignment 
o Cross-tabulation of stratification factor, as randomized vs as corrected 
3.3.4 Eligibility status will be summarized (for the randomized population): 
 Tables 
o Distribution of eligibility status, overall and by treatment assignment 
o Tabulation of reasons ineligible 
o Listing of ineligible patients (patid, center id, mo/yr randomized, strat factors, 
treatment assignment, reason); sorted by reason 
3.3.5 Follow-up compliance will be summarized 
 Tables 
o CRF submission status 
o Trial status (e.g., completed per protocol, WC/LFU, in follow-up per protocol, 
continuing treatment per protocol) 
o Blood sample status (expected vs actual) 
 


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3.4 
PATIENT DEMOGRAPHICS AND BASELINE DISEASE AND PRIOR TREATMENT  
Characteristics of the ITT population will be summarized overall and according to treatment 
assignment..Continuous variables are summarized descriptively (e.g., mean, SD, minimum, 
maximum, and interquartiles(IQR)). 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. 
 Stratification factors (as analyzed) 
 Patient: 
o Age at randomization 
o  BMI at randomization  
o ECOG Performance status at randomization 
o Smoking status/history 
o Oral contraceptive use 
o Centrally assessed baseline E2 levels ) 
o Baseline AE/symptoms, comorbidity history 
 Pre-treatment Disease characteristics: 
o Tumor size or tumor lesion (via WHO criteria): product of maximum diameter 
(MD) and largest perpendicular diameter (LPD) of target lesions at baseline), 
multiple assessments (clinical, mammography, ultrasound) 
o Grade (centrally assess via core biopsy) 
o Histologic type (ductal, lobular, not determinable) 
o ER, PgR status, Allred score, and Her2 status of core biopsy 
o Clinical Nodal status 
o Ki67 label index (%) 
o Baseline CEA, CA15-3: CEA (carcinoembryonic antigen) and CA15-3 (breast 
cancer associated antigen) 
 Prior Treatment (Hform): 
o Type of prior endocrine therapies: SERM, AI and GnRH/LHRH agonist 
(eligibility exclusions for any endocrine Rx taken within 12 months or oral 
contraceptive use within 2 months of rando), mainly to confirm not taken it. 
 Tables 
o Characteristics, overall ITT population and by treatment assignment 
 
3.5 
TREATMENT 
Trial treatments are to start within 14 days of randomization and can be started at any time 
during the menstrual cycle. The neoadjuvant trial treatments will be administered in 4-week (28-
day) cycles for a total of 6 cycles or be stopped in the following cases, and the patient should 
undergo surgical intervention: 


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Trial 41-13 – Page 14 
 
 If ovarian function suppression is not achieved within 56 days after start of treatment 
according to local laboratory limits 
 In the case of an adverse event grade ≥ 3, judged by the Investigator to be at least 
possibly related to study drugs. 
Definitive surgery should be performed within 2 to 3 weeks after the last administration of 
triptorelin or degarelix. 
3.5.1.1 Protocol-assigned treatment 
 Number of cycles of study therapy (letrozole, triptorelin or degarelix) 
 Reasons for stopping therapy  
 
 Specifically, 
Triptorelin or degarelix, the following information will be calculated for each patient: 
 number injections administered 
 Number of skipped doses 
 Duration of exposure, from first injection to last injection +28 days 
 Time from randomization to cessation (last injection +28 days);  
 Reason stopped triptorelin or degarelix 
Letrozole, the following information will be calculated for each patient: 
 Duration of exposure, from date first dose to date last dose + 1 day 
 Number of times dose interruption/delay or modification within that exposure period 
 Reason stopped letrozole 
Also to summarize: 
 Time(days) lapse between blood sample (for measuring E2 levels) and last triptorelin or 
degarelix injection  
Tables and Figures 
 Descriptive statistics (median, IQR, min, max) of triptorelin or degarelix cycles exposure 
duration  
 Descriptive statistics (median, IQR, min, max) of letrozole, dose interruption/delay, 
exposure duration 
3.6 
PRIMARY ANALYSIS  
 Analysis of TTOFS  as described in 2.2.5 
Description of E2 and FSH/LH levels over the 6 month period. 
Tables 
 Serum sample status (expected vs actual drawn) 
 List of patients with missing samples/results and reasons 
 Sampling (blood draw) time vs OFS injection time (off schedule) 


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 Descriptive summaries (median, geometric mean with 95%CI, % change (reduction)  of 
markers from baseline to timepoints for each marker 
Figures: 
 Scatting plots of E2, FSH, LH data over time 
 Distribution of E2, FSH, LH using Boxplot  
3.7 
POST-TREATMENT SURGERY & PATHOLOGY 
Centrally pathology assessment based on surgical specimens included histology type,  tumor 
size, Ki67 level, ER status, ER Allred score, PgR status, PgR Allred score, Her2 status as 
measured by IHC or FISH, vessel invastion, LN status, and PEPI score (defined as in section 
2.3.2) 
 
Table of CPR pathological characteristics, overall and according to treatment assignments. 
 
 Ki67 and ER Allred score data: baseline, post neoadjuvant/surgery data and percent 
change from baseline will be summarized, difference with 90%CI 
 Node negative disease at surgery:  percent of patients with node-negative disease is 
summarized overall, by treatment arms, difference between arms using exact binominal 
90% CI 
3.8 
BREAST CONSERVAING SURGERY (BCS) RATE 
 Table of surgery received by treatment arms, difference in BCS rate between arms, 
90%CI. 
 Table of BCS conversion from planned or (candidate) at baseline  to actual received 
3.9 
 PRS SUMMARIES (SEE SECTION 2.2.6) 
4 
SUBSTUDY / CORRELATIVE 
NA 
5 
DEFINITIONS / ACRONYMS / ABBREVIATIONS 
6 
REFERENCES 
World Health Organization (WHO) criteria: WHO Handbook for Reporting Results of Cancer 
Treatment. Offset Publication, Geneva, Switzerland, 1979  
Miller AB HB, Staquet M, Winkler A: Report- ing results of cancer treatment. Cancer 47:207-
214, 1981  
Lesley J. Fallowfield, Judith M. Bliss, Lucy S. Porter, Miranda H. Price, Claire F. Snowdon, 
Stephen E. Jones, R. Charles Coombes, and Emma Hall. Quality of Life in the Intergroup 
Exemestane Study: A Randomized Trial of Exemestane Versus Continued Tamoxifen After 2 to 
3 Years of Tamoxifen in Postmenopausal Women With Primary Breast Cancer,  J Clin Oncol, 
2016, 24(6) 911-917