Conditions: Breast Cancer
Keywords: stage IA breast cancer stage IB breast cancer stage II breast cancer stage IIIA breast cancer
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 4884
Healthy volunteers: no

Brief summary:
RATIONALE: Estrogen can cause the growth of breast cancer cells. Letrozole may fight breast cancer by lowering the amount of estrogen the body makes. It is not yet known which regimen of letrozole is more effective in postmenopausal women who have received hormone therapy for early-stage breast cancer.

PURPOSE: This randomized phase III trial is comparing two different regimens of letrozole in preventing cancer in postmenopausal women who have received 4-6 years of hormone therapy for hormone receptor-positive, lymph node-positive, early-stage breast cancer.

Detailed description:
OBJECTIVES:

Primary

* Compare the disease-free survival (DFS) of postmenopausal women treated with continuous letrozole for 5 years vs intermittent letrozole over a 5-year period.

Secondary

* Compare overall survival of patients treated with these two regimens.
* Compare distant DFS of these patients.
* Compare breast cancer-free interval of these patients.
* Compare sites of first DFS failure in these patients.
* Compare second (nonbreast) malignancies in these patients.
* Compare deaths without prior cancer events in these patients.
* Compare adverse events resulting from these two regimens.

OUTLINE: This is a multicenter study. Patients are stratified according to treatment center and type of prior endocrine therapy (selective estrogen receptor modulators \[SERMs\] alone vs aromatase inhibitors \[AIs\] alone vs both SERMs and AIs each for at least 1 month). Patients are randomized to 1 of 2 treatment arms.

* Arm I: Patients receive oral letrozole daily for 5 years.
* Arm II: Patients receive oral letrozole daily for the first 9 months of years 1 through 4, followed by 12 months in year 5.

After completion of study therapy, patients are followed annually.

Arms:
arm 1: Continuous letrozole: 5 years continuously (2.5 mg Letrozole daily) arm 2: Intermittent letrozole: 48 months over 5 yrs: 4 x 9 months (9 mo followed by 3 mo treatment-free interval in yrs 1-4, -\> 36 mo) plus 1 x 12 mo in yr 5 -\> 48 months

Interventions: intervention 1: Letrozole intervention 2: Letrozole
Intervention descriptions: intervention 1: Film-coated tablet, oral use, 2.5 mg Letrozole daily for 5 years continuously intervention 2: Film-coated tablet, oral use, 2.5 mg daily, 48 months over 5 yrs: 4 x 9 months (9 mo followed by 3 mo treatment-free interval in yrs 1-4, -\> 36 mo) plus 1 x 12 mo in yr 5 -\> 48 months

Protocol document:
Prot_000.pdf: 
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A phase III trial evaluating the role of continuous letrozole versus 
intermittent letrozole following 4 to 6 years of prior adjuvant endocrine 
therapy for postmenopausal women with hormone-receptor positive, node 
positive early stage breast cancer 
 
 
 
 
Coordinating Group:   
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 
 
 
 
NCT Number: 
NCT00553410 
 
 
 
 
 
 
 
 
 
 
 
INTERNATIONAL BREAST 
CANCER STUDY GROUP 
IBCSG 35-07 
BIG 1–07 
        S    LE 
 Study of Letrozole Extension 


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Trial Specific Contacts 
 
Study Chair 
Dr. Marco Colleoni  
European Institute of Oncology 
Via Ripamonti 435 
20141 Milan, Italy 
Email: marco.colleoni@ieo.it 
Tel: +39 02 574 89 439 
Fax: +39 02 574 89 581 
 
 
 
Study Co-Chairs 
Assoc. Prof. Per Karlsson 
Sahlgrenska University Hospital 
S - 41345 Göteborg, Sweden 
Email: per.karlsson@oncology.gu.se 
Tel: +46 31 342 1000 
Fax: +46 31 820 114 
 
 
 
 
Prof. Stefan Aebi 
Inselspital PT2C 
3010 Bern, Switzerland 
Email: Stefan.Aebi@insel.ch 
Tel: +41 31 632 41 14 
Fax: +41 31 382 12 37 
 
 
 
 
Dr. Jacquie Chirgwin 
Box Hill Hospital 
Nelson Road (PO Box 94) 
BOX HILL VIC 3128, Australia 
Email: chirgwin@tpg.com.au 
Tel: +61 3 9897 4688 
Fax: +61 3 9897 3800 
 
 
 
Trial Statistician 
Dr. Meredith Regan 
IBCSG Statistical Center 
Email: mregan@jimmy.harvard.edu 
Tel: +1 617-632-3012 
Fax: +1 617-632-5444 
 
 
 
Trial Data Managers 
Mary Caporale 
Jennifer Meshulam 
IBCSG Data Management Center 
 
Email: soledmc@fstrf.org 
 
Trial Coordinators 
Melanie Schärlig-Strausak 
Daniela Bärtschi 
IBCSG Coordinating Center 
Email: SOLE@ibcsg.org 
Tel: +41 31 389 93 91 
Fax: +41 31 389 93 92 
 
 
 
Novartis Contact 
Dr. David Emanuel 
Business Unit Oncology  
Novartis 
One Health Plaza 
East Hanover, NJ  07936 
Email: david.emanuel@novartis.com 
Tel: +1 862 778 3883      
Fax: +1 973 781 3813 
 
 
 
IBCSG Contacts 
 
Coordinating Center 
 
 
Prof. Monica Castiglione 
Ms. Anita Hiltbrunner 
Dr. Barbara Ruepp 
Dr. Manuela Rabaglio 
Ms. Regula Studer 
Dr. Rudolf Maibach 
IBCSG Coordinating Center 
Email: monica.castiglione@ibcsg.org 
Email: anita.hiltbrunner@ibcsg.org  
Email: barbara.ruepp@ibcsg.org   
Email: manuela.rabaglio@ibcsg.org  
Email: regula.studer@ibcsg.org  
Email: rudolf.maibach@ibcsg.org  
Tel: +41 31 389 9391 
 
Effingerstrasse 40 
Fax: +41 31 389 9392 
 
CH-3008  Bern, Switzerland 
 


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Data Management Center 
Ms. Lynette Blacher 
Email: blacher.lynette@fstrf.org 
 
FSTRF, 4033 Maple Rd. 
Tel: +1 716 834 0900 
 
Amherst, NY  14226  USA 
Fax: +1 716 834 8675 
 
 
 
 
Statistical Center 
Prof. Richard D. Gelber 
Ms. Karen Price 
Email: gelber@jimmy.harvard.edu 
Email: price@jimmy.harvard.edu 
 
Dept. of Biostatistics and 
Computational Biology 
Tel: +1 617-632-3012 
Fax: +1 617-632-5444 
 
Dana-Farber Cancer Institute 
 
 
44 Binney St. 
 
 
Boston, MA 02115  USA 
 
 
 
 
Central Pathology Office 
Prof. Giuseppe Viale 
University of Milan & European 
Institute of Oncology 
Via Ripamonti 435 
20141 Milan, Italy 
 
Tel: +39 02 5748 9419 
Fax: +39 02 5748 9417 
E-mail: giuseppe.viale@ieo.it 
QL Office 
Dr. Karin Ribi 
Ms. Daniela Gerber 
IBCSG Coordinating Center 
 
Mr. David Zahrieh 
IBCSG Statistical Center 
E-mail: karin.ribi@ibcsg.org  
E-mail: daniela.gerber@ibcsg.org  
 
 
E-mail: zahrieh@jimmy.harvard.edu  
 
 
 
 
Scientific Committee Chairs 
Prof. Aron Goldhirsch 
Tel: +41 91 811 79 23 
 
Oncology Institute of Southern 
Switzerland, Ospedale Italiano 
Fax: +41 91 811 79 25 
 
 
Via Capelli 
Email: aron.goldhirsch@ibcsg.org 
 
CH-6962 Viganello-Lugano and 
 
 
European Institute of Oncology 
Fax: +39 02 57489212 
 
Via Ripamonti 435 
20141 Milan, Italy 
 
 
 
Prof. Alan Coates 
 
Tel: +61 2 9331 3521 
 
40 Cook Road 
Fax: +61 2 9380 8233 
 
Centennial Park NSW 2021 
Email: alan.coates@ibcsg.org 
 
Australia 
 
 
Central Pathology Offices 
Prof. Giuseppe Viale 
University of Milan & European 
Institute of Oncology 
Via Ripamonti 435 
20141 Milan, Italy 
 
Tel: +39 02 5748 9419 
Fax: +39 02 5748 9417 
E-mail: giuseppe.viale@ieo.it 
 
 
 
 


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Protocol Signature Page 
 
IBCSG 35-07/ BIG 1-07 
 
Study of Letrozole Extension - SOLE 
 
 
Approved by: 
CEO, International Breast Cancer Study Group 
Prof. Dr. med. M. Castiglione 
 
 
 
 
___________________________________________________ 
______________ 
 
 
 
Date 
 
 
Approved by: 
Novartis representative(s) 
 
 
 
 
___________________________________________________ 
______________ 
 
 
 
Date 
 
 
Approved by: 
Group Statistician, International Breast Cancer Study Group 
Prof. R.D. Gelber 
 
 
 
 
 
___________________________________________________ 
______________ 
 
 
 
Date 
 


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Principal Investigator Protocol Signature Page 
 
IBCSG 35-07/ BIG 1-07 
Study of Letrozole Extension - SOLE  
 
I have read the protocol and agree that it contains all necessary details for conducting this study. 
I will conduct the study as outlined in the following protocol and in compliance with GCP. I 
will provide copies of the protocol and all drug information relating to pre-clinical and prior 
clinical experience furnished to me by IBCSG, to all physicians responsible to me who 
participate in this study. I will discuss this material with them to assure that they are fully 
informed regarding the drug and the conduct of the study. I agree to keep records on all patient 
information (Case Report Forms and patient's informed consent statement), drug shipment and 
return forms, and all other information collected during the study for a minimum period of 15 
years. 
 
Name of Principal Investigator:___________________________________________ 
 
 
_____________________________________________________ ______________ 
 
 
Signature 
Date 
 


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Protocol Summary and Schema 
SOLE 
Study of Letrozole Extension 
A phase III trial evaluating the role of continuous letrozole versus intermittent letrozole 
following 4 to 6 years of prior adjuvant endocrine therapy for postmenopausal women 
with hormone-receptor positive, node positive early stage breast cancer 
Patient population 
Postmenopausal women who are disease-free following 4-6 years of prior adjuvant endocrine 
therapy with selective estrogen receptor modulator(s) (SERM) and/or aromatase inhibitor(s) 
(AI) for endocrine-responsive, node-positive operable breast cancer.   
Rationale 
In 2006, the standard duration of adjuvant endocrine therapy for breast cancer (either SERMs or 
AIs) is five years.  Patients who receive extended adjuvant letrozole for five years following 
approximately five years of tamoxifen obtain further benefit compared with the five years of 
tamoxifen alone.  Similarly, benefit has been demonstrated for switching from tamoxifen to an 
AI after 2 to 3 years of tamoxifen to complete five years of endocrine therapy, as well as 
initiating therapy with AI following surgery and administering the AI for five years.   
Questions remain about the optimal duration and best schedule of AIs in the extended adjuvant 
setting.  This trial tests the hypothesis that introducing 3-month treatment-free intervals during 
the course of five years of extended adjuvant letrozole will improve disease-free survival.  This 
hypothesis is based on the theoretical principle that letrozole withdrawal for 3 months will 
permit some estrogenic stimulation which makes residual resistant disease susceptible to 
letrozole reintroduction.  
Objective 
To compare continuous letrozole for five years with intermittent letrozole over a five year 
period for postmenopausal women who are disease-free following 4-6 years of prior adjuvant 
endocrine therapy with SERM(s) and/or AI(s) for endocrine-responsive, node-positive, operable 
breast cancer. 
Trial end points 
 
Primary end point: Disease-free survival (DFS): time from randomization to local (including 
invasive recurrence restricted to the breast after breast conserving treatment), regional or distant 
relapse, contralateral breast cancer, appearance of a second (non-breast) malignancy, or death 
from any cause, whichever occurs first.   


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Secondary end points: overall survival (OS), distant disease-free survival (DDFS), breast cancer 
free interval (BCFI), sites of first failure, second (non-breast) malignancies, deaths without prior 
cancer events, and adverse events. 
Statistical analysis 
The randomization will be stratified according to participating center and prior SERM/AI 
endocrine therapy (SERM(s) alone, AI(s) alone, both SERM(s) and AI(s). 
The primary analysis will be undertaken with the intention-to-treat population of all randomized 
patients. The primary endpoint is disease-free survival (DFS) and will be compared between 
treatment arms using a two-sided stratified logrank test with an overall experiment-wise alpha 
level equal to at most 0.05. Kaplan-Meier estimates of the DFS distributions will be calculated 
for each of the two treatment arms. Cox proportional hazards regression models will be used to 
investigate whether the treatment comparison is modified by adjustments for various covariates. 
Sample size and anticipated trial duration 
The sample size was determined to provide 80% power to detect a 20% reduction in the risk of 
an event defining DFS associated with intermittent letrozole compared with continuous 
letrozole (hazard ratio = 0.80; 25% increase in 4-year DFS from 90% to 91.917%) using a two-
sided 0.05 level test of significance.  
To achieve this goal requires 647 events defining DFS, assuming 4800 patients are accrued 
(1600 patients per year for 3 years), 5% non-assessability at 4 years,  and approximately 5 years 
of additional follow-up. One year of start-up time, as participating centers obtain ethics 
committee approval and complete regulatory processes, is anticipated. 
Procedures 
All patients will be followed every 6 months for years 1 to 5, and thereafter yearly for 
assessment of disease status and for survival data collection. 
Risks and benefits 
Adjuvant treatment with letrozole has been shown to have a favorable effect on time without 
recurrence of breast cancer. The adjuvant treatment with letrozole is generally well tolerated. 


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Trial Design 
At completion of 4 to 6 years of prior adjuvant SERM/AI endocrine therapy, patients will be 
randomized to one of two treatment groups: 
Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
Extended Adjuvant Endocrine Therapy 
Letrozole: 
A: Continuous letrozole 2.5 mg daily for 5 years 
B: Intermittent letrozole 2.5 mg daily for the first 9 months of years 1 
through 4, followed by 12 months in year 5 
Randomization Timing 
In principle, patients should start trial treatment as soon as possible after randomization. Trial 
treatment should begin no later than 6 weeks from the date of randomization.   
 
Stratify: 
 Institution 
 Prior adjuvant 
endocrine therapy 
(AI(s), SERM(s)): 
AI alone, SERM 
alone, both SERM 
and AI 
R 
A 
N 
D 
O 
M 
I 
Z 
E 
Continuous letrozole for 5 years 
 
 
Intermittent letrozole over 5 years    
 9 mos 
9 mos 
9 mos 
9 mos 
12 mos 
 
 
 
0 
6 
12 
18 
24 
30 
36 
42 
48 
54 
60 
 
A 
 
 
 
B 


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TABLE OF CONTENTS  
 
Section 
Page 
 
1. 
Introduction ......................................................................................................................... 11 
1.1. 
Adjuvant treatment in breast cancer ............................................................................ 11 
1.2. 
Letrozole ..................................................................................................................... 11 
1.3. 
Aromatase inhibitors in the adjuvant setting .............................................................. 12 
1.4. 
Extended treatment with letrozole after 5 years of tamoxifen .................................... 14 
1.5. 
Optimal sequence of endocrine therapy in a low estrogen environment .................... 14 
1.6. 
Cost-effectiveness of intermittent delayed letrozole ................................................... 15 
2. 
Trial objectives .................................................................................................................... 15 
2.1. 
Primary endpoint ......................................................................................................... 15 
2.2. 
Secondary endpoints ................................................................................................... 15 
3. 
Patient selection: criteria for patient eligibility/ineligibility ............................................... 16 
3.1. 
Patient characteristics .................................................................................................. 16 
3.2. 
Disease characteristics ................................................................................................ 16 
3.3. 
Prior surgery and radiotherapy .................................................................................... 17 
3.4. 
Prior/concurrent disease and conditions ..................................................................... 17 
3.5. 
Prior treatment ............................................................................................................ 17 
3.6. 
Concurrent treatment .................................................................................................. 17 
3.7. 
Protocol requirements before randomization .............................................................. 18 
4. 
Randomization and stratification ........................................................................................ 18 
4.1. 
Randomization timing ................................................................................................. 18 
4.2. 
Registration procedures............................................................................................... 18 
4.3. 
Randomization help desk ............................................................................................ 19 
4.4. 
Randomized groups .................................................................................................... 19 
4.5. 
Stratification ................................................................................................................ 20 
5. 
Treatment details ................................................................................................................. 20 
5.1. 
Trial treatments ........................................................................................................... 20 
5.2. 
Side effects of letrozole .............................................................................................. 20 
5.3. 
Concomitant treatments .............................................................................................. 22 
5.4. 
Study drug supply ....................................................................................................... 22 
6. 
End points and definitions of treatment failure ................................................................... 22 
6.1. 
Trial end points ........................................................................................................... 22 
6.2. 
Diagnosis of Events .................................................................................................... 23 
6.3. 
Other Events ................................................................................................................ 25 
7. 
Study parameters ................................................................................................................. 27 
7.1. 
Table of study parameters ........................................................................................... 27 
7.2. 
Adverse event reporting .............................................................................................. 29 
7.3. 
Serious Adverse Event (SAE) reporting ..................................................................... 29 
8. 
Data submission .................................................................................................................. 32 
8.1. 
Case report forms schedule ......................................................................................... 32 
8.2. 
Signing and submitting forms ..................................................................................... 33 


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8.3. 
Data management ........................................................................................................ 33 
8.4. 
Investigators’ file ........................................................................................................ 33 
8.5. 
Authorization log ........................................................................................................ 34 
8.6. 
Patient identification log ............................................................................................. 34 
9. 
Statistical considerations ..................................................................................................... 34 
9.1. 
Study design, objectives, and stratification ................................................................. 34 
9.2. 
Data analyses ............................................................................................................... 35 
9.3. 
Sample size considerations ......................................................................................... 35 
9.4. 
Interim monitoring ...................................................................................................... 36 
9.5. 
Data and Safety Monitoring Committee (DSMC) ...................................................... 36 
10. 
Additional protocol-specific evaluations ........................................................................ 36 
10.1. 
Pathology and pathology material banking ............................................................. 36 
10.2. 
Patient Reported Symptoms and Quality of Life Substudy .................................... 37 
11. 
Regulatory approval procedures and Patient Informed Consent ..................................... 38 
11.1. 
Ethical Review Board/Ethics Committee ............................................................... 38 
11.2. 
Regulatory approval procedures ............................................................................. 38 
11.3. 
Protection of human subjects .................................................................................. 38 
11.4. 
Informed consent ..................................................................................................... 38 
11.5. 
Quality Assurance ................................................................................................... 39 
12. 
Administrative Considerations........................................................................................ 39 
12.1. 
Insurance ................................................................................................................. 39 
12.2. 
Steering Committee ................................................................................................ 39 
13. 
References ....................................................................................................................... 40 
 
 
 
 
 
Appendices  
 
I. 
Requirements for Informed Consent  
II. 
NCI Common Terminology Criteria for Adverse Events v3.0 [available from the internet 
at:  http://ctep.cancer.gov/reporting/ctc.html 
III. 
Patient Reported Symptoms and Quality of Life Substudy 
IV. 
Authorization Log 
V. 
Participating Group Specific Logistical Information  
VI. 
IBCSG Publication and Presentations Guideline 
 


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1. 
Introduction 
1.1. 
Adjuvant treatment in breast cancer  
Breast cancer is the most common malignant disease in women; and the most common form of 
cancer death in women in Europe with an estimated 370,100 new cases diagnosed and 129,900 
deaths [1].  At diagnosis, 90% of the patients appear to have an operable breast cancer, that is, 
disease confined to the breast and to the ipsilateral axilla.  More than 50% of these patients, 
however, die of metastatic disease.  In fact, once metastases become overt, the disease is 
considered, with very few exceptions, incurable.  Since the late nineteen-forties randomized 
trials of adjuvant systemic therapy (either endocrine or cytotoxic) have been conducted in an 
effort to reduce the number of relapses and to prolong the survival of patients with operable 
disease.  The Oxford Overview summarizing the available results of all such trials indicated that 
adjuvant systemic treatments with chemotherapy, endocrine therapy, and combinations of both 
improved prognosis of patients with breast cancer [2]. 
1.2. 
Letrozole 
There are two classes of third generation AI(s). Agents such as anastrozole and letrozole act by 
reversibly binding to the aromatase enzyme, which is responsible for the production of 
estrogens in post menopausal women. Exemestane is an oral irreversible inactivator of 
aromatase that depletes plasma estrogen by more than 90% and whole body aromatization by 
98%. Unlike reversible AI(s), it cannot be displaced from the aromatase enzyme. At clinically 
administered doses, the plasma half-lives of anastrozole (1 mg once daily), letrozole (2.5 mg 
once daily), and exemestane (25 mg once daily) were 41-48 hours, 2-4 days, and 27 hours, 
respectively. The time to steady-state plasma levels was 7 days for both anastrozole and 
exemestane and 60 days for letrozole. Androgenic side effects have been reported only with 
exemestane [3]. There is evidence in postmenopausal women with metastatic disease that AI(s) 
produce response rates and survival equivalent to or superior to those seen with tamoxifen [4, 
5]. Letrozole is up to 150-250 times more potent than the first generation aromatase inhibitor 
aminoglutethimide (AG), in vitro and more than 10,000 times as potent as AG in inhibiting 
aromatase in vivo [6].  
The high potency of letrozole is not accompanied by any significant effect on adrenal 
steroidogenesis in vitro or in vivo over its maximally effective dose range [7, 8]. Inhibition of 
adrenal steroidogenesis resulting in adrenal hypertrophy does occur with therapeutic doses of 
AG. The high potency and selectivity of letrozole explains its pharmacological profile and high 
therapeutic index. In postmenopausal patients with advanced breast cancer, daily doses of 0.1 
mg to 5 mg letrozole suppressed plasma levels of estradiol, estrone and estrone sulfate to 75-
95% from baseline [9]. Estrogen suppression was maintained throughout the treatment period of 
28 days in all patients.  
Letrozole is a highly selective inhibitor of the aromatase enzyme. No clinically relevant changes 
in the plasma levels of cortisol, aldosterone, 11-deoxycortisol, 17-hydroxyprogesterone, ACTH 


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or plasma renin activity were found in postmenopausal patients treated with a daily dose of 
letrozole ranging from 0.1 to 5 mg [10, 11].  
For postmenopausal women with endocrine responsive disease, the use of letrozole has been 
shown to yield some advantage in terms of treatment outcome as compared to tamoxifen in  
advanced disease [3] and preoperative setting where a double-blinded, randomized phase III trial of 
primary endocrine therapy was recently reported [12]. Letrozole 2.5 mg or tamoxifen 20 mg were 
given daily for 4 months to postmenopausal women with hormone receptor–positive breast 
cancer who were ineligible for breast-conserving surgery [12]. Among the 250 patients who 
received letrozole, 60% responded and 48% underwent successful breast-conserving surgery. 
The response to tamoxifen was significantly lower in terms of response rate (41%), and 
proportion of patients eligible for breast saving surgery. Differences in response rates between 
letrozole and tamoxifen were most striking for tumors that overexpressed ErbB-1 and/or ErbB-2 
and were ER positive (88% vs 21%, p= .0004). In this study, the incidence of adverse events 
(AEs) was the same (57%) for the letrozole and tamoxifen groups. The most commonly 
reported AEs in both groups were hot flushes, headache, and nausea. The frequency of AEs 
suspected to be related to the study drugs was comparable for both groups (38% and 34% in the 
letrozole and tamoxifen groups, respectively). No other treatment-related effects with either of 
the study drugs were seen. Four patients discontinued study medication because of AEs (one 
patient in the letrozole group for a pulmonary embolism and 3 patients in the tamoxifen group 
for hepatitis C, erythema multiforme or cholestasis) [12].  
1.3. 
Aromatase inhibitors in the adjuvant setting 
Trials comparing AIs to tamoxifen for postmenopausal women in the adjuvant setting are 
mature.  AIs have been studied in the adjuvant setting either as alternatives to tamoxifen or as 
sequential therapy after tamoxifen among postmenopausal women. The Arimidex, Tamoxifen 
Alone or in Combination (ATAC) trial compared primary use of an aromatase inhibitor, 
anastrozole, with either tamoxifen alone or the combination of the two as adjuvant therapy for 
early-stage breast cancer. The ATAC trial demonstrated improvements in disease-free survival 
(hazard ratio = 0.82) with use of anastrozole as monotherapy [13-15]. There was no benefit to 
combining the estrogen-deprivation effects of anastrozole with the antiestrogen effects of 
tamoxifen. Patients who were treated with anastrozole had significantly lower incidences of the 
following predefined adverse events compared with those treated with tamoxifen: hot flushes, 
vaginal bleeding, vaginal discharge, endometrial cancer, ischemic cerebrovascular events, 
venous thromboembolic events, and deep venous thromboembolic events.  Women who were 
treated with anastrozole had significantly higher incidences of arthralgia and fractures than 
those treated with the bone-sparing agent tamoxifen; however, the risk ratio for fractures 
relative to tamoxifen has been shown to stabilize with treatment duration beyond two years. 
The Breast International Group (BIG) 1-98 trial has recently reported on the use of the 
aromatase inhibitor letrozole compared with tamoxifen as primary therapy for early-stage breast 
cancer [16, 17]. 8028 women were randomized between March 1998 and May 2003 to receive 
five years of adjuvant endocrine therapy with letrozole, tamoxifen, or a sequence of these 
agents. Of these, the 4922 patients allocated continuous therapy with either letrozole or 


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tamoxifen were recently analyzed [16]. At a median follow-up of 51 months, 352 DFS events 
among 2463 patients allocated letrozole and 418 events among 2459 patients allocated 
tamoxifen were observed. This reflected an 18% reduction in the risk of an event (hazard ratio 
0.82; 95 percent confidence interval 0.71 to 0.95; P= 0.007). Hazard ratios for the other defined 
endpoints were similar, though those for overall survival and systemic disease-free survival 
were not statistically significant. No subgroups showed significantly different relative efficacy; 
in particular, no significant heterogeneity was observed by nodal involvement status or 
progesterone receptor status. 
Compared to patients receiving tamoxifen, more patients receiving letrozole reported at least 
one adverse event (AE) of any grade (2292 patients vs 2165 patients). Patients on tamoxifen 
experienced significantly more thromboembolic events, endometrial pathology, hot flushes, 
night sweats and vaginal bleeding. Patients on letrozole experienced significantly more bone 
fractures, arthralgia, low-grade cholesterol elevation, and cardiovascular events other than 
ischemic heart disease and cardiac failure. The relatively higher recording of low-grade 
cholesterol elevation on letrozole may be largely an artifact reflecting a cholesterol-lowering 
effect of tamoxifen. The overall incidence of cardiac failure did not differ significantly between 
the two arms. 
Different trials have reported that the use of tamoxifen followed by aromatase inhibitor therapy 
may be clinically advantageous. The Intergroup Exemestane Study (IES) compared sequential 
treatment strategies. Patients in the IES trial had received 2 to 3 years of tamoxifen without 
evidence of tumor recurrence before random assignment to either ongoing tamoxifen treatment 
or to the aromatase inhibitor exemestane. Cross over from tamoxifen to exemestane yielded 
improved disease-free survival. Switching to exemestane was associated with a significantly 
lower incidence of gynecological symptoms, vaginal bleeding, muscle cramps and 
thromboembolic events compared with continued tamoxifen. However, switching to 
exemestane was associated with a significantly higher incidence of arthralgia, diarrhea and 
visual disturbances compared with continued tamoxifen. There was a suggestion towards 
increased osteoporosis (7.4% vs 5.7%; P=0.02) and higher fracture rates in the exemestane 
group than in the tamoxifen group (3.1% vs 2.3%; P=0.08) [18]. The updated safety data 
confirmed that patients switching to exemestane experienced fewer gynecological symptoms, 
vaginal bleeding, muscle cramps and thromboembolic events compared with continued 
tamoxifen. Switching to exemestane continued to be associated with a significantly higher 
incidence of diarrhea and arthralgia compared with continued tamoxifen. In addition, other 
musculoskeletal adverse events were more common with exemestane (with the exception of 
muscle cramps). Importantly, exemestane was associated with a higher incidence of myocardial 
infarction compared with tamoxifen, although it remains a possibility that this is attributable to 
the protective effects of tamoxifen, reducing the atherogenic risk profile. The Austrian Breast 
and Colorectal Cancer Study Group (ABCSG) Trial 8/Arimidex-Nolvadex (ARNO) 95 trial also 
examined sequential therapy, either switching patients from tamoxifen to anastrozole after 2 
years or leaving patients on tamoxifen for a total of 5 years. The cross-over improvement 
resulting from sequential switching of treatment at 2 years in the ABCSG/ARNO trial was 
slightly more favorable than the improvement seen in the IES trial (hazard ratio, 0.60 vs 0.67, 
respectively) [19]. In the related but much smaller Italian Tamoxifen Anastrozole (ITA) trial 


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among women with lymph node–positive breast cancer who were free of recurrence after 2 to 3 
years of tamoxifen treatment, patients were randomly assigned to either ongoing tamoxifen or 
cross over to anastrozole resulting in significantly improved disease free survival with the 
introduction of anastrozole [20].  
1.4. 
Extended treatment with letrozole after 5 years of tamoxifen  
The MA.17 trial, led by the National Cancer Institute of Canada, was open to women who had 
completed 5 years of tamoxifen as primary adjuvant therapy for early-stage breast cancer and 
who were without clinical evidence of recurrence. These patients were randomly assigned to 
either extended adjuvant therapy with the aromatase inhibitor, letrozole, or placebo. After 2 to 3 
years of follow-up, extended treatment with letrozole after 5 years of tamoxifen demonstrated a 
reduction in the risk of both locoregional and distant breast cancer recurrence compared with 
placebo. For the sequential strategy of 5 years of tamoxifen followed by an aromatase inhibitor, 
the recurrence rate associated with cross over to an aromatase inhibitor was 43% lower than the 
recurrence rate of tamoxifen alone (hazard ratio = 0.57) [21]. Letrozole was associated with a 
significantly higher incidence of hot flushes, arthritis, arthralgia and myalgia, but a significantly 
lower incidence of vaginal bleeding compared with placebo. There were no significant 
differences between letrozole and placebo in the incidence of osteoporosis (5.8% vs 4.5%; 
P=0.07) or fracture rates (3.6% vs 2.9%; P=0.24). Efficacy and safety data from an update of 
the MA.17 trial (median follow-up of 2.5 years) were consistent with the initial analysis. In 
addition, newly diagnosed osteoporosis was higher in the letrozole group compared with 
placebo (P=0.003), although the incidence of bone fractures was similar for both groups 
(P=0.25) [22]. 
1.5. 
Optimal sequence of endocrine therapy in a low estrogen environment 
Recent evidence suggests that estradiol is capable of inducing programmed cell death (i.e., 
apoptosis) in breast cancer cells that have developed resistance following extensive 
antihormonal therapy. In particular, cells that are maintained estrogen-free for years initially 
start to grow spontaneously; in this case, even minimal concentrations of estrogen produce a 
cytocidal effect on cells that are exhaustively deprived of estrogen [23-25]. An antitumor action 
was observed also for physiological levels of estradiol on breast tumors grown in athymic mice 
[26]. 
Clinical observations also indicate an antitumor activity of estradiol, supporting a role for 
intermittent treatment with antiaromatase therapy. In fact, a small study of high-dose estrogen 
therapy following exhaustive antihormonal therapy was recently reported. Evaluation of 
response was performed after 3 months on therapy. On 26 evaluable patients, 4 patients 
obtained complete response and 6 patients partial response. In addition, two patients had stable 
disease for ≥6 months duration. [27].  
These new data suggest a rational approach for the treatment of patients with ER-positive breast 
cancer during extensive antihormonal therapy. Low-dose estrogen levels (achievable through 
interruptions of treatment with AIs) could be used to induce apoptosis in breast cancer cells that 
might have developed resistance following extensive antihormonal therapy. 


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The 3 months interruption after 9 months of letrozole is based on the prolonged estradiol and 
estrone suppression observed after a single administration of letrozole in healthy 
postmenopausal women. In these subjects estradiol was maintained suppressed 2 weeks after a 
single dose of letrozole [28]. Moreover, the maximal response to estradiol of breast tumors 
transplanted into athymic mice was observed after 4 weeks of treatment [29]. Finally, as 
mentioned above, a clinical effect of high-dose estrogen therapy following exhaustive 
antihormonal therapy was observed after 3 months of treatment. 
1.6. 
Cost-effectiveness of intermittent delayed letrozole 
Modelled analyses from the UK and the US suggest that, in postmenopausal women with 
hormone-receptor-positive early-stage breast cancer, letrozole as extended adjuvant therapy 
after tamoxifen, rather than no further treatment, is a cost-effective treatment strategy. 
Sensitivity analyses have shown these results to be robust [30]. However, a recent study 
compared the efficiency of adjuvant therapy with AIs or with tamoxifen in postmenopausal 
women with operable breast cancer and positive estrogen receptors. The follow-up of a 
hypothetical cohort of women starting treatment at 63 years of age was simulated during 10 and 
20 years. The probabilities and costs of transition between health states and quality adjusted life 
years (QALYs) were evaluated. The cost of gaining one QALY was lower with the introduction 
of exemestane after tamoxifen than with letrozole after 5 years of tamoxifen, indicating that the 
latter option might be less cost-effective [31]. The introduction of a regimen that decreases to 
75% the yearly amount of letrozole may improve the cost-effectiveness of extended letrozole 
administration. 
2. 
Trial objectives 
This trial will compare continuous letrozole for five years with intermittent letrozole over a five 
year period for postmenopausal women who are disease-free following 4-6 years of prior 
adjuvant endocrine therapy with SERM(s) and/or AI(s) for endocrine-responsive node-positive 
operable breast cancer.  
2.1. 
Primary endpoint 
Disease-free survival (includes second (non-breast) malignancies and deaths) 
2.2. 
Secondary endpoints 
2.2.1. 
Overall survival 
2.2.2. 
Distant disease-free survival  
2.2.3. 
Breast cancer free interval (events are reappearance of invasive breast cancer at any site 
including contralateral disease) 
2.2.4. 
Sites of first DFS failure 


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2.2.5. 
Second (non-breast) malignancies  
2.2.6. 
Deaths without prior cancer event 
2.2.7. 
Adverse events 
3. 
Patient selection: criteria for patient eligibility/ineligibility 
3.1. 
Patient characteristics 
3.1.1. 
Patients must be postmenopausal using any one of the following criteria.  Because 
letrozole is not effective in pre- or perimenopausal patients, and may stimulate ovarian 
function, definitive confirmation of postmenopausal status is required.  
 Patients of any age who have had a bilateral oophorectomy (including radiation 
castration AND amenorrheic for > 3 months) 
 Patients 56 years old or older.  If the patient has any evidence of ovarian function, 
biochemical evidence of definite postmenopausal status (defined as estradiol, LH, 
and FSH in the postmenopausal range) is required.    
 Patients 55 years old or younger must have biochemical evidence of definite 
postmenopausal status (defined as estradiol, LH, and FSH in the postmenopausal 
range. Patients who have received prior LHRH analogue within the last year are 
eligible if they have definite evidence of postmenopausal status as defined above.  
3.1.2. 
Patients must be accessible for follow-up. 
3.2. 
Disease characteristics 
3.2.1. 
At diagnosis, patients must have had operable, non-inflammatory breast cancer.  
3.2.2. 
Patients must be clinically disease-free at randomization.  (Note: It is recommended 
but not required that disease-free status be verified by abdominal ultrasound, chest x-
ray, and bone scan (if symptomatic). A mammogram within one year prior to 
randomization is recommended.) 
3.2.3. 
Patients must have had steroid hormone receptor positive tumors (ER and/or PgR), 
determined 
by 
immunohistochemistry, 
after 
primary 
surgery 
and 
before 
commencement of prior endocrine therapy.  
3.2.4. 
Following primary surgery, eligible patients must have had evidence of lymph node 
involvement either in the axillary or internal mammary nodes, but not supraclavicular 
nodes.   


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3.2.5. 
There must have been no evidence of recurrent disease or distant metastatic disease at 
any time prior to randomization.  
3.2.6. 
Not eligible:  Patients who have had bilateral breast cancer. 
3.3. 
Prior surgery and radiotherapy 
3.3.1. 
Patients must have had proper local treatment including surgery with or without 
radiotherapy for primary breast cancer with no known clinical residual loco-regional 
disease.   
3.4. 
Prior/concurrent disease and conditions 
3.4.1. 
Patients must have clinically adequate hepatic function. 
3.4.2. 
Not eligible: Patients who have had a bone fracture due to osteoporosis at any time 
during the 4-6 years of prior endocrine SERM/AI therapy. 
3.4.3. 
Not Eligible: Patients who have had any previous or concomitant malignancy EXCEPT 
adequately treated: basal or squamous cell carcinoma of the skin, in situ carcinoma of 
the cervix or bladder, contra- or ipsilateral in situ breast carcinoma. 
3.4.4. 
Not eligible: Patients who have had any other non-malignant systemic diseases 
(cardiovascular, renal, lung, etc.) that would prevent prolonged follow-up.   
3.4.5. 
Not eligible: Patients with psychiatric, addictive, or any disorder which compromises 
compliance with protocol requirements. 
3.5. 
Prior treatment  
3.5.1. 
Patients must have completed 4 to 6 years of prior adjuvant endocrine therapy with 
SERM(s), aromatase inhibitor(s), or a sequential combination of both.  When 
calculating 4-6 years, neoadjuvant endocrine therapy should not be included. 
3.5.2. 
Patients must have stopped prior endocrine SERM/AI therapy, and must be 
randomized within 12 months (1 year) of the last dose of prior endocrine SERM/AI 
therapy. 
3.5.3. 
Patients may have received any type of prior adjuvant therapy, including but not 
limited to neoadjuvant chemotherapy, neoadjuvant endocrine therapy, adjuvant 
chemotherapy, trastuzumab, ovarian ablation, GnRH analogues, lapatinib. 
3.6. 
Concurrent treatment 
3.6.1. 
Patients must have stopped hormone replacement therapy (HRT), bisphosphonates 


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(except for treatment of bone loss), or any investigational agent at randomization.  
(Note: These agents are also not permitted during trial treatment.) 
3.7. 
Protocol requirements before randomization 
3.7.1. 
Pathology material from the primary tumor must be available for submission for 
central review as part of the quality control measures for this protocol.  
3.7.2. 
Written Informed Consent (IC) must be signed and dated by the patient and the 
investigator prior to randomization.  
3.7.3. 
Written consent to pathology material submission, indicating the patient has been 
informed of and agrees to tissue material use, transfer and handling, must be signed 
and dated by the patient and the investigator prior to randomization. 
4. 
Randomization and stratification 
This trial will use a web-based randomization system.  Each Participating Group will determine 
how its Participating Centers will access the randomization system, either through a Group 
Randomization Center, or directly from the Participating Center.  The following procedures 
should be used in either case.  Specific details for randomizing are in the “IBCSG 
Registration/Randomization Procedures Manual,” which is available on the IBCSG website 
(www.ibcsg.org). 
4.1. 
Randomization timing 
In principle, patients should start trial treatment as soon as possible after randomization.  Trial 
treatment should begin no later than 6 weeks from the date of randomization.   
4.2. 
Registration procedures 
 
Complete the following steps to randomize a patient on this trial. 
4.2.1. 
Verify eligibility. 
4.2.2. 
Obtain written informed consent both for the clinical trial and the pathology material 
submission, signed and dated by the patient and physician 
4.2.3. 
Complete Confirmation of Registration Form (A). The date the Informed Consent 
Form and the consent to pathology material submission section of the Informed 
Consent Form were signed by the patient and the date signed by the investigator are 
both required to complete randomization. 
4.2.4. 
Depending on your Group’s choice, either  


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 Telephone or fax your Randomization Center to review the eligibility and 
randomization information.  Your Randomization Center will access the IBCSG 
Registration/Randomization System. 
 Directly access the IBCSG Registration/Randomization System. 
 
In the former case, the Randomization Center will provide the Participating Center 
with the following information.  In the latter case the Randomization System will 
provide this information via e-mail. 
 Randomization number (patient ID) 
 Treatment assignment 
 Date of randomization 
4.2.5. 
When randomization is complete, fill in Confirmation of Registration Form (A) with 
the information above and fax Confirmation of Registration Form (A) and Pathology 
Material Consent Form (PMC) to an IBCSG DataFax number. These forms are 
considered the essential documents for regulatory purposes. They should be filed at 
your institution.  
4.2.6. 
File original of all forms.  
4.3. 
Randomization help desk  
 
The IBCSG Data Management Center (located at FSTRF) is responsible for developing and 
maintaining the IBCSG Registration/Randomization System.   The Randomization Help Desk 
includes technical personnel and administrators of the randomization programs at the Data 
Management Center in Amherst, NY, USA. 
Business Hours:  7:30-18:00 US Eastern Time 
FSTRF Randomization Help Desk 
Frontier Science & Technology Research Foundation (FSTRF) 
4033 Maple Rd, Amherst, NY 14226 USA 
Phone: +1 716 834 0900 ext. 301 
Fax: +1 716 834 8432  
Email: bc.helpdesk@fstrf.org 
 
4.4. 
Randomized groups 
Randomization (1:1) to 2 groups: 
Arm A: Continuous letrozole for 5 years 
Arm B: Intermittent letrozole over a 5 year period 


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4.5. 
Stratification 
4.5.1. 
Institution 
4.5.2. 
Prior endocrine SERM/AI therapy (SERM(s) and aromatase inhibitor(s) only) 
 SERM(s) alone (without AI(s)) 
 AI(s) alone (without SERM(s)) 
 Both SERM(s) and AI(s), each for at least 1 month 
5. 
Treatment details 
5.1. 
Trial treatments 
Arm A: Continuous letrozole 2.5 mg daily for 5 years 
Arm B: Intermittent letrozole 2.5 mg daily for the first 9 months of years 1 through 4, followed 
by 12 months in year 5 
Compliance: At each visit, patients should return the last dispensed drug container. The 
investigator or designee will count the remaining pills and record the information on the CRF. 
5.2. 
Side effects of letrozole 
5.2.1. 
Adverse effects [6] 
Safety data of letrozole are available from a wide range of clinical trials in first-line and second-
line advanced breast cancer, with adjuvant and extended adjuvant treatment as well as from 
post-marketing experience. 
Approximately one third of the patients with metastatic breast cancer treated with 2.5 mg 
letrozole, 40% of the patients under adjuvant letrozole and 70-75% of the patients under 
letrozole following standard adjuvant tamoxifen (extended adjuvant therapy) experienced 
adverse events. 
The most frequent adverse experiences reported during the course of clinical trials irrespective 
of causality were hot flushes, musculoskeletal disorders (bone pain, back pain, arthralgia), 
nausea, dyspnea, and fatigue.  
The following adverse reactions were observed during clinical trials and in the postmarketing 
phase:  
Very common (≥ 10%): Arthralgia, hot flushes. 
Common (1 – 10%): Myalgia, bone pain, osteoporosis, bone fractures, fatigue, peripheral 
edema, elevated serum cholesterol, increased appetite, weight gain, anorexia, depression, 


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headache, dizziness, nausea, vomiting, dyspepsia, constipation, diarrhea, alopecia, increased 
sweating, rash. 
Uncommon (0.1 – 1%): Arthritis, thrombophlebitis (including superficial and deep vein 
thrombosis), hypertension, ischemic cardiac events (including angina pectoris, myocardial 
infarction, cardiac failure), palpitations, tachycardia, cerebrovascular accident, somnolence, 
insomnia, memory impairment, dysesthesia, taste disturbance, general edema, cataract, eye 
irritation, blurred vision, anxiety, dyspnea, increased hepatic enzymes, weight loss, abdominal 
pain, stomatitis, dry mouth, vaginal bleeding, vaginal discharge, vaginal dryness, breast pain, 
pruritus, dry skin, urticaria. 
Rare (0.01 – 0.1%): Pulmonary embolism, arterial thrombosis, transient ischemic attack 
(cerebrovascular infarction). 
For the extended adjuvant therapy after standard adjuvant tamoxifen no significant qualitative 
differences with respect to the general safety profile were found. The most frequently observed 
adverse events were hot flushes (49.7%), fatigue (33.6%), arthralgia/arthritis (28.7%) night 
sweats (24.2%), edema (18.4%), headache (20.1%) hypercholesterolemia (15.5%), dizziness 
(14.2%), constipation (11.3%), nausea (8.6%), and myalgia (6.7%). Of these common adverse 
events, hot flashes (49.7 % vs. 43.3%), arthralgia/arthritis (27.7 % vs. 22.2 %) and myalgia 
(9.5% vs. 6.7 %) occurred at a significantly higher incidence under letrozole than placebo. 
In the adjuvant setting, hot flashes (33.7%), arthralgia/arthritis (21.2%), night sweating (13.9%), 
weight increase (10.7%), nausea (8.8%), bone fractures (5.7%) and fatigue (5.3%) were the 
most common reported adverse events. Compared to tamoxifen, bone fractures (5.7% vs 4%), 
arthralgia (21.2% vs 13.5%) and – although a rare event – osteoporosis (2.0% vs 1.1%) were 
significantly more frequent under letrozole. Conversely, the incidence of hot flashes, night 
sweats, thromboembolic events (1.2% vs 2.8%), endometrial cancer (0.2% vs 0.4%) and 
endometrial proliferative disorders (0.3% vs 1.8%) was higher for tamoxifen. Myocardial 
infarctions were seen at similar rates (0.6% vs 0.4%). 
Patients receiving letrozole had less secondary malignancies reported at any time after 
randomization (1.9% vs 2.4%)  with endometrial cancer being the most common (0.4 vs 0.2%).  
Of the non-breast cancer related deaths, deaths related to other second (non-breast) malignancy 
and cardiovascular cause were most frequently reported. 
5.2.2. 
Drug Interactions 
Letrozole inhibits in vitro the cytochrome P450-isoenzymes 2A6 and moderately 2C19, 
however, CYP2A6 does not play a major role in drug metabolism. In in vitro experiments 
letrozole did not substantially inhibit the metabolism of diazepam (a substrate of CYP2C19) at 
concentrations approximately 100-fold higher than those observed in plasma at steady-state. 
Thus, clinically relevant interactions with CYP2C19 are unlikely to occur. Nevertheless, caution 
should be used in the concomitant administration of drugs whose disposition is mainly 
dependent on these isoenzymes and whose therapeutic index is narrow. 


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There was no evidence of other clinically relevant interaction in patients receiving other 
commonly prescribed drugs (e.g. benzodiazepines; barbiturates; NSAIDs such as diclofenac 
sodium, ibuprofen; paracetamol; furosemide; omeprazole). 
Clinical interaction studies with cimetidine and warfarin indicated that the coadministration of 
letrozole with these drugs does not result in clinically significant drug interactions, even though 
cimetidine is a known inhibitor of one of the cytochrome P450 isoenzymes capable of 
metabolising letrozole in vitro. 
There is no clinical experience to date on the use of letrozole in combination with other anti-
cancer agents. 
5.3. 
Concomitant treatments 
5.3.1. 
Patients may not receive HRT, bisphosphonates (except for the treatment of bone loss) 
or any other investigational agent during trial treatment. 
5.3.2. 
Patients may not receive any SERMs or AIs except for protocol-specified letrozole 
during trial treatment.  
5.4. 
Study drug supply  
Study drug will be supplied by Novartis. Details of drug supply, drug accountability and 
compliance are described in Appendix V. 
6. 
End points and definitions of treatment failure 
6.1. 
Trial end points 
6.1.1. 
Primary Endpoint:  
Disease-free survival (DFS) is defined as the time from randomization to local (including 
invasive recurrence restricted to the breast after breast conserving treatment), regional or distant 
relapse, contralateral breast cancer, appearance of a second (non-breast) malignancy, or death 
from any cause, whichever occurs first. Appearance of DCIS or LCIS either in the ipsilateral or 
in the contralateral breast will not be considered as an event for DFS (but must be reported on 
the Follow-Up Form (E)). See Section 6.3 for other exceptions. 
6.1.2. 
Secondary end points: 
 Overall survival (OS) is defined as the time from randomization to death from any 
cause. 
 Distant disease-free survival (DDFS) is defined as the time from randomization to 
any recurrent or metastatic disease in distant sites (i.e., other than the local 
mastectomy scar/chest wall/skin, the ipsilateral breast in case of breast conservation, 


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or the ipsilateral axilla and internal mammary lymph nodes), second (non-breast) 
malignancy, or death from any cause, whichever occurs first.   
 Breast cancer free interval (BCFI) is defined as the time from randomization to local 
(including recurrence restricted to the breast after breast conserving treatment), 
regional, or distant relapse, or contralateral breast cancer. In calculating BCFI, 
second (non breast) malignancies are ignored and deaths without cancer event are 
censored at the time of death as a competing event. Appearance of DCIS or LCIS 
either in the ipsilateral or in the contralateral breast is not considered a BCFI event, 
but should be recorded on the Follow-up Form (E).   
 Sites of first DFS failure. 
 Second (non-breast) malignancies 
 Deaths without prior cancer event 
 Adverse events 
6.2. 
Diagnosis of Events 
The diagnosis of failure event depends on evidence of recurrent disease which can be classified 
as either suspicious or acceptable.  In either case, this should be specified and reported.  
Acceptable evidence of failure according to site is defined below. Any events not included in 
this section are considered unacceptable as evidence of recurrent disease. Failures include: 
local, regional, contralateral breast, and distant failures, second (non-breast) primaries, and 
deaths without recurrence. Histological confirmation of cytological evidence of recurrence is 
recommended in easily accessible lesions. 
The date of failure event is the time of first appearance of a suspicious lesion, later proven to be 
a definitive recurrence or metastasis.  All events described below should be recorded on the 
Follow-up Form (E). 
6.2.1. 
Local failure 
Local failure is defined as a tumor recurrence in any soft tissues of the ipsilateral, conserved 
breast or the chest wall, mastectomy scar, and/or skin. 
Acceptable for recurrence in conserved breast: positive cytology or histology. 
Acceptable for recurrence in chest wall, mastectomy scar, and/or skin: positive cytology or 
histology or evidence of new lesions (by CT or MRI) without any obvious benign etiology. 
Suspicious: a visible or palpable lesion. 
Appearance of DCIS or LCIS either in the ipsilateral or in the contralateral breast is not 
considered a BCFI event, but should be recorded on the Follow-up Form (E). 


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6.2.2. 
Regional Failure 
Regional failure is defined as a tumor recurrence in the ipsilateral axillary lymph nodes, 
extranodal soft tissue of the ipsilateral axilla, ipsilateral internal mammary lymph nodes, and/or 
ipsilateral supraclavicular lymph nodes.  
Acceptable: 
positive cytology or histology or evidence of new lesions by CT or MRI without 
a benign etiology. 
Suspicious: 
a visible or palpable lesion. 
6.2.3. 
Contralateral breast failure 
Acceptable: 
positive cytology or histology. 
Suspicious: 
a visible or palpable lesion, suspicious mammogram, ultrasound, or MRI. 
Appearance of DCIS or LCIS in the contralateral breast is not considered an event for DFS.   
6.2.4. 
Distant failure 
Tumors in all areas other than those defined above are considered distant metastases. The 
following criteria apply: 
6.2.4.1. Bone marrow 
 
Acceptable: 
positive cytology, aspiration, or biopsy. 
Suspicious: 
unexplained depression of peripheral blood counts and/or a leucoerythroblastic 
blood picture. 
6.2.4.2. Lung 
Acceptable: 
positive cytology or histology or a positive CT or MRI without obvious benign 
etiology or evidence of progressive disease. (Progressive disease is confirmed by 
two consecutive X-rays with the second showing worsening disease.) 
Suspicious: 
new radiological lesion(s). 
6.2.4.3. Pleura 
 
Acceptable: 
positive cytology or histology. 
Suspicious: 
new pleural effusion. 
6.2.4.4. Bone 
Acceptable: 
positive cytology or histology or a positive X-ray, MRI, or CT, one bone scan 
with new multiple lesions and no obvious benign etiology. 


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Suspicious: 
skeletal symptoms or positive scan showing only one new lesion (until 
confirmed by other imaging study). 
6.2.4.5. Liver 
Acceptable: 
positive cytology or histology, or positive CT or MRI without an obvious benign 
etiology, or evidence of progressive disease by ultrasound. (Progressive disease 
in this case is confirmed by two ultrasounds with the second showing worsening 
disease). 
Suspicious: 
any two of the following: hepatomegaly on physical examination, equivocal 
ultrasound and abnormal liver function test. 
6.2.4.6. Central nervous system 
Acceptable: 
positive cytology or histology. Positive MRI or CT when the clinical picture is 
suspicious. 
Suspicious: 
any other clinical findings suggestive of this diagnosis. 
6.2.4.7. Distant lymph nodes 
Acceptable: 
positive cytology or histology, or enlarged lymph nodes in CT or MRI, or 
progressive disease by physical exam without an obvious benign etiology. 
Suspicious: 
evidence of enlarged lymph nodes by physical exam. 
6.2.4.8. Other sites 
Acceptable: 
positive cytology or histology or evidence of progressive disease if only indirect 
means of diagnosis were used (e.g., X-ray). 
Suspicious: 
clinical and radiological evidence of a tumor. 
6.3. 
Other Events 
6.3.1. 
Second (non-breast) malignancy 
Any positive diagnosis of a second (non-breast) malignancy other than basal cell or squamous 
cell carcinoma of the skin, cervical carcinoma in situ, or bladder cancer in situ is considered an 
DFS event and should be reported on the Follow-up Form (E) and on the Serious Adverse Event 
Forms (SAE-A and SAE-B).  
6.3.2. 
Death without prior cancer event 
Any death without a prior cancer event described in 6.2.1 through 6.2.4 above is considered a 
DFS event.  The death, date, and the cause should be reported on the Follow-up Form (E) 
regardless of whether it occurs during or after trial treatment, and on the Serious Adverse Event 
Forms (SAE-A and SAE-B) if occurring during trial treatment.   


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6.3.3. 
Other noteworthy events 
These events are NOT considered endpoints in this trial, but must be recorded on the Follow-up 
Form (E). 
 Ipsilateral and contralateral breast cancer in situ 
 Cervical carcinoma in situ, bladder cancer in situ 
 Basal or squamous cell carcinoma of the skin 


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7. 
Study parameters 
7.1. 
Table of study parameters  
Visit 
 
1A 
2 
3 
4 
5 
6 
7 
8 
9 10 11 
Yearly until death 
Year 
0 
1 
1 
2 
2 
3 
3 
4 
4 
5 
5 
 
Trial month 
0 
6 12 18 24 30 36 42 48 54 60 
 
Informed consent and 
pathology material 
consent 
x 
 
 
 
 
 
 
 
 
 
 
 
Check of inclusion & 
exclusion criteria 
x 
 
 
 
 
 
 
 
 
 
 
 
History 
x 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
including weight 
x 
 
x 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Estradiol, FSH, LHB  
m 
 
 
 
 
 
 
 
 
 
 
 
Adverse Events (AE)C 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Late AEsD 
 
 
 
 
 
 
 
 
 
 
 
x 
Laboratory tests 
 
 
 
 
 
 
 
 
 
 
 
 
  HematologyE 
r 
m 
m 
m 
m 
m 
m 
m 
m 
m 
m 
 
  Blood chemistryF  
r 
m 
m 
m 
m 
m  m  m  m  m  m 
 
Investigations 
 
 
 
 
 
 
 
 
 
 
 
 
MammogramG 
r 
 
r 
 
r 
 
r 
 
r 
 
r 
 
  Chest-X-rayH 
  (PA and lateral views) 
r 
m 
m 
m 
m 
m 
m 
m 
m 
m 
m 
 
  Bone scanI 
m 
m 
m 
m 
m 
m 
m 
m 
m 
m 
m 
 
  Abdominal US, CT or 
  liver scanJ 
r 
m 
m 
m 
m 
m 
m 
m 
m 
m 
m 
 
 Gynecological examK 
m 
 
m 
 
m 
 
m 
 
m 
 
m 
 
Bone mineral 
densitometryL 
m 
 
m 
 
m 
 
m 
 
m 
 
m 
 
x 
= mandatory 
r 
= recommended 
m = if medically indicated 
 
Legend to Table 7.1  
A. The day of randomization is considered Day 0 for the purpose of follow-up. 
B. Biochemical evidence of definite postmenopausal status, defined as estradiol, FSH, and LH in the 
postmenopausal range, is required at study entry for some patients as defined in section 3.1.1. 
C. Adverse events should be graded using the NCI CTCAE V.3 (Appendix II).  The following targeted 
adverse events should be recorded on the CRF during the reporting period in which they occur: 
 
Hot flashes/flushes 
 
Osteoporosis 


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 
Bone fracture  
 
Musculoskeletal symptoms (myalgia, arthralgia (joint pain), stiffness not including bone 
fractures)  
 
Mood alteration / depression 
 
Hypertension 
 
Cardiac ischemia/infarction 
 
Thrombosis / thrombus / embolism 
 
CNS cerebrovascular ischemia 
 
Hemorrhage, CNS 
 
Insomnia  
 
Fatigue 
 
Bone pain 
 
Other Grade 3 or higher adverse events 
 
D. Late adverse events (adverse events occurring after trial treatment is completed) should be recorded 
on Follow-up Form (E). 
E. Hematology is recommended within 2 months prior to randomization and should be done whenever 
medically indicated.   
F. Blood chemistry (includes liver function tests with alkaline phosphatase) is recommended within 2 
months prior to randomization and should be done whenever medically indicated.   
Radiological assessments 
G. A bilateral mammography is recommended within one year prior to randomization.  A 
mammography of the conserved and contralateral breast is recommended at yearly intervals or 
should be done according to national standards or hospital specific requirements. 
H. A chest X-ray is recommended prior to randomization.  A chest X-ray should be performed any 
time it is medically indicated or according to specific local requirements.  Both PA view and lateral 
view should be done. 
I. 
A bone scan should be done at baseline if clinically indicated.  A bone scan should be performed 
during treatment with trial drug if alkaline phosphatase is significantly elevated (e.g. > 3 x ULN) or 
if medically indicated otherwise (e.g. bone pain).  If the bone scan showed areas suspicious for 
tumor then these areas should be confirmed by X-ray or CT or MRI. 
J. Abdominal ultrasound or liver scan or abdominal CT is recommended prior to randomization or 
during treatment if liver function tests are significantly abnormal or if medically indicated or 
according to specific local requirements. 
Other procedures 
K. In the event of a pelvic complaint (i.e., abnormal vaginal bleeding) patients should have a 
gynecological examination.   
L. Bone densitometry by DEXA should be done at baseline and then yearly for 5 years if medically 
indicated.   


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7.2. 
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 3.0. The CTCAE 
is available for downloading on the internet at (http://ctep.cancer.gov/reporting/ctc.html). 
An adverse event is defined as any untoward medical occurrence that occurs from the first dose 
of study medication until 30 days after the final dose, regardless of whether it is considered 
related to a medication. 
In addition, any known untoward event that occurs subsequent to the adverse event reporting 
period that the investigator assesses as possibly related to the protocol treatment should be 
considered an adverse event. 
Symptoms of the targeted cancer (if applicable) should not be reported as adverse events. 
The 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: 
 
1 = Grade 1 
Mild 
2 = Grade 2 
Moderate 
3 = Grade 3 
Severe 
4 = Grade 4 
Life-threatening 
5 = Grade 5 
Fatal 
 
7.3. 
Serious Adverse Event (SAE) reporting 
7.3.1. 
Definition 
An SAE is defined in general as any undesirable medical occurrence/adverse drug experience 
that occurs during or within 30 days after stopping study treatment that, at any dose, results in 
any of the following:  
 is fatal (any cause) 
 life-threatening, 
 requires or prolongs inpatient hospitalization, 
 results in persistent or significant disability/incapacity 
 is an unexpected grade 4 toxicity 
 is a congenital anomaly or birth defect 
 is a secondary (non-breast) malignancy 


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 requires significant medical intervention 
Second (non-breast) malignancies are always considered SAEs, no matter when they are 
diagnosed.  These events should be reported on the Serious Adverse Event Forms (SAE-A and 
SAE-B) and on the Follow-Up Form (E). 
Other significant/important medical events which may jeopardize the patient are also considered 
serious adverse events. 
Serious 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. 
A related adverse event is one for which the investigator assesses that there is a reasonable 
possibility that the event is related to the investigational drug. All adverse events judged as 
having a reasonable suspected causal relationship to the trial medication qualify as adverse 
reactions. 
7.3.2. 
Exceptions to the definition 
Any death or serious adverse event that occurs more than 30 days after stopping study treatment 
but is considered to be at least possibly related to previous trial treatment is also considered an 
SAE. 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.  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.  
Events not considered to be serious adverse events are hospitalizations occurring under the 
following circumstances:  
 elective surgery;  
 occur on an outpatient basis and do not result in admission (hospitalization < 24 h);  
 are part of the normal treatment or monitoring of the studied treatment; 
 progression of disease. 
7.3.3. 
Reporting SAEs 
Any serious adverse event occurring in a patient after providing informed consent must be 
reported. Information about all serious adverse events will be collected and recorded on the 
IBCSG Serious Adverse Event Report Forms (SAE–A and SAE-B). 


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To ensure patient safety, the IBCSG must learn of each SAE using the procedures described 
below: 
 The investigator/MD responsible for the patient must FAX a signed Serious 
Adverse Event Form (SAE-A) in English within 24 hours to the DataFax data 
submission fax number for the Participating Center.  A copy is automatically 
forwarded to the IBCSG Coordinating Center for medical review. 
 Follow-up information should be completed on the Serious Adverse Event Form 
(SAE-B) within 15 days of the initial report and must be faxed to the DataFax data 
submission fax number for the Participating Center. A copy is automatically 
forwarded to the IBCSG Coordinating Center.  If the event is not resolved within 15 
days, submit an additional Serious Adverse Event Form (SAE-B) to report the final 
resolution. 
 If a non-serious adverse event becomes serious, this and other relevant follow-up 
information must also be provided within 24 hours. 
The original Serious Adverse Event Forms (SAE-A and SAE-B) and the fax confirmation 
sheet(s) must be kept with the CRFs at the Participating Center. 
The IBCSG Coordinating Center will inform Novartis Corporation 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 Coordinating Center. 
The IBCSG Coordinating Center will record the SAE and prepare a summary report of all SAEs 
received at the end of each month. Principal Investigators will receive the summary report on a 
monthly basis, and these reports can be found on the IBCSG web site (www.ibcsg.org). 


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8. 
Data submission 
We will conduct the trial according to the ICH Good Clinical Practice (GCP) guidelines.  
Keeping accurate and consistent records is essential to a cooperative study.  The following 
forms are to be submitted at the indicated times by the participating institutions for each patient: 
8.1. 
Case report forms schedule 
RANDOMIZATION FORMS 
Informed 
Consent Form 
Consent to participation in clinical 
trial 
Obtain before randomization and keep with patient records. 
Pathology 
material consent  
Consent to submission of 
pathology material 
Obtain before randomization and keep with patient records. 
Form PMC 
Pathology Material Consent Form 
DataFax after randomization with Form 35-A. 
Form 35-A 
Confirmation of Registration Form Fill in before contacting your Randomization Center or entering 
the IBCSG Registration/Randomization system to randomize.  
DataFax completed form for all patients randomized. 
BASELINE FORMS 
Form 35-H 
History Form  
DataFax within 1 month of randomization. 
Pathology 
Report 
Pathology Report of original 
diagnosis 
DataFax within 1 month of randomization. See Section 10 for 
pathology material requirements. 
Form 35-AE 
Adverse Event Form 
Complete prior to starting protocol treatment (letrozole) and 
DataFax within 1 month of randomization.  This form is also 
required at follow-up (see instructions below).   
Form 35-CCM 
Concomitant Medications Form 
Complete prior to starting protocol treatment (letrozole) and 
DataFax within 1 month of randomization.  This form is also 
required at follow-up (see instructions below).   
FOLLOW-UP FORMS 
Form 35-E 
Follow-Up Form 
DataFax every 6 months during Years 1-5, and yearly until death. 
Form 35-L 
 
Letrozole Form 
DataFax at each follow-up period until the completion of 
letrozole.   
Form 35-AE 
Adverse Event Form 
DataFax at each follow-up period during protocol therapy 
(letrozole).  This form is also required at baseline. 
Form 35-CCM 
Concomitant Medications Form 
DataFax at each follow-up period during protocol therapy 
(letrozole).  This form is also required at baseline. 
EVENT-DRIVEN FORMS 
Form 35-SAE-
A 
Serious Adverse Event Form (A) 
DataFax within 24 hours when SAE occurs, see Section 7.3. 
Form 35-SAE-
B 
Serious Adverse Event Form (B) 
DataFax within 15 days of the initial report and/or at the definitive 
SAE outcome, see Section 7.3. 
 
The Data Managers’ Manual for this trial contains instructions for submitting forms using the 
DataFax system. 


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8.2. 
Signing and submitting forms 
All forms should be signed by the Principal Investigator or designee.  An authorization log (see 
Appendix IV) should be completed at each participating center. 
CRFs should be faxed to an IBCSG DataFax number. SAE Forms should also be faxed to an 
IBCSG DataFax number for automatic transmission to the IBCSG Coordinating Center.  Full 
instructions on submitting forms will be distributed to each Participating Center and are 
available on the IBCSG website (www.ibcsg.org).  Also available on the website is a list of fax 
numbers that are available for faxing CRFs. 
For Centers participating through a Group: Please consult your Participating Group Specific 
Logistical Information (Appendix VI) for special instructions about how to submit data. 
8.3. 
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. 
8.4. 
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 
 Randomization Manual 
 Patient information and Informed Consent templates approved by Ethics Committee 
 Investigator's Brochure and updates 
 Ethics Committee approval of protocol, Patient Information Sheet and IC, 
amendments 
 Ethics Committee review of SAE, investigators' alert, and other documents 
 Correspondence with Ethics Committee 
 Malpractice insurance information 
 Agreement with IBCSG 
 Correspondence with IBCSG Coordinating Center, Data Management Center 
 SAE reports from IBCSG Coordinating Center 
 Accrual reports from IBCSG 
 Normal laboratory values 


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 Laboratory Certifications 
 CV of Principal Investigator and co-investigators 
 Authorization log 
 Patient identification log 
 Drug accountability log (incl certificates of destruction if applicable)   
 ICH GCP guidelines/Declaration of Helsinki and updates 
 Audits/monitoring reports 
8.5. 
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 CRFs, queries, etc. (See 
template in Appendix IV.) 
8.6. 
Patient identification log 
As per GCP, patients have the right to confidentiality.  Therefore, no patients’ names should be 
used in CRFs or any other documentation transmitted to IBCSG central offices.  Items that are 
used to identify a patient include initials of patient's name, date of birth, randomization number. 
When no names are used, at least 2 of the above are usually required to identify the patients’ 
records.  It is therefore imperative that the local data manager keeps an identification log for all 
patients entered in this trial including: 
 Patient's name 
 Patient's initials 
 Randomization number 
 Date of birth 
Other items that could be included are date of randomization and treatment arm. 
9. 
Statistical considerations  
9.1. 
Study design, objectives, and stratification 
The SOLE trial is a multinational Phase III randomized clinical trial designed to compare 
continuous letrozole for 5 years with intermittent letrozole over a 5-year period among 
postmenopausal women who are disease-free following 4 to 6 years of prior adjuvant endocrine 
therapy with SERM(s) and/or AI(s) for endocrine-responsive node-positive operable breast 
cancer. The hypothesis is that introducing 3 month treatment-free intervals during the course of 
five years of extended letrozole will improve disease-free survival. 
Randomization will be stratified according to participating center and prior SERM/AI endocrine 
therapy use (SERM(s) alone, AI(s) alone, both SERM(s) and AI(s)). 


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9.2. 
Data analyses 
The primary analysis will be undertaken with the intention-to-treat population of all randomized 
patients. The primary endpoint is disease-free survival (DFS: Section 6.1.1) and will be 
compared between treatment arms using a two-sided stratified logrank test with an overall 
experiment-wise alpha level equal to at most 0.05. Kaplan-Meier estimates of the DFS 
distributions will be calculated for each of the two treatment arms. Cox proportional hazards 
regression models will be used to investigate whether the treatment comparison is modified by 
adjustments for various covariates. 
Other factors will be used to characterize the patients enrolled in the study and to provide 
descriptive statistics of outcomes according to subgroups of the population. These factors 
include age at randomization, body mass index, tumor size, tumor grade, number of positive 
lymph nodes, ER/PgR and HER2 status of the primary tumor, type of prior endocrine therapy, 
interval of time since the cessation of prior endocrine therapy. These analyses will be 
considered as secondary and descriptive. 
The following secondary endpoints will be assessed: overall survival, distant disease-free 
survival, breast cancer-free interval, sites of first DFS failure, incidence of second (non-breast) 
malignancies, deaths without prior cancer event, incidence of targeted adverse events. 
9.3. 
Sample size considerations 
Postmenopausal women with hormone receptor positive early breast cancer continue to be at 
risk for disease recurrence following completion of 4 to 6 years of adjuvant endocrine therapy. 
The MA.17 trial provides an estimate for the baseline risk of an event defining DFS for patients 
enrolled in the continuous letrozole group. Overall, the 4-year DFS in the update of MA.17 was 
94.4% [22]. Among the subgroup of patients with node-positive disease, the 4-year DFS was 
91.8% [32]. DFS in the MA.17 trial considered only breast cancer recurrence and contralateral 
breast cancer as events; specifically it did not consider deaths prior to recurrence or second 
(non-breast) malignancies as events. Therefore, in the eligible population of patients with node-
positive disease at initial diagnosis, the baseline risk following randomization used for sample 
size determination is assumed to be 90% at 4 years.   
The sample size was determined to provide 80% power to detect a 20% reduction in the risk of 
an event defining DFS (Section 6) associated with intermittent letrozole compared with 
continuous letrozole (hazard ratio = 0.80; 25% increase in 4-year DFS from 90% to 91.917%) 
using a two-sided 0.05 level test of significance.  
To achieve this goal requires 647 events defining DFS, assuming 4800 patients are accrued 
(1600 patients per year for 3 years), 5% non-assessability at 4 years, and approximately 5 years 
of additional follow-up [33]. One year of start-up time, as Participating Centers obtain Ethics 
Committee approval and complete regulatory processes, is anticipated. 


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9.4. 
Interim monitoring 
A group sequential design with two interim analyses and one final analysis is used [33]. The 
target number of events for the final analysis is 647, and interim analyses are planned after 40% 
and 70% information (259 and 453 events observed respectively). At each interim analysis and 
at the final analysis, testing will be performed using O’Brien-Fleming boundaries [34]. 
9.5. 
Data and Safety Monitoring Committee (DSMC) 
The study will be presented for review by the IBCSG Data and Safety Monitoring Committee 
(DSMC) at each of their semi-annual meetings. Accrual, safety, events, and deaths will be 
monitored. Analyses of efficacy according to randomization group will be presented only at the 
time points specified for formal interim analysis. The DSMC will also make recommendations 
concerning potential modifications to the design criteria for this study if the assumptions used in 
the design are found to be inaccurate. A formal review of the accrual rate will be performed two 
years after study activation to assess whether modifications are required. 
10. 
Additional protocol-specific evaluations 
10.1. 
Pathology and pathology material banking 
10.1.1. Pathology requirements 
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 biopsy and/or mastectomy specimen, 
including precise documentation of tumor size, margins of the primary, the total number of 
lymph nodes examined, and the number of nodes involved.  All lymph nodes must be examined 
from each patient.  If the patient has received a sentinel node biopsy, each sentinel node must be 
evaluated.  The central review pathologist will review the submitted specimens and complete 
the central pathology review. 
The following items are required for all patients: 
1. Pathology Reports (including steroid hormone receptor determination) 
2. Tumor block for banking (Ideally the block should contain at least some invasive tumor 
taken from the periphery of the tumor.) 
3. Normal tissue block for banking 
4. 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 reports, slides, and blocks must be marked with the randomization number.  If materials are 
not properly marked, we cannot guarantee that the slides and blocks will be forwarded to the 


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Central Pathology Review Office.  Please ensure that the blocks and slides are carefully 
packaged as otherwise they could easily get damaged during transport. The slides should be sent 
in customized slide boxes and should be wrapped with tissue paper to prevent any movement. 
The slides and blocks have not been packed securely enough if they move around when the box 
is shaken. 
10.1.2. Pathology material banking 
The IBCSG has established a central repository for tissue blocks and slides from every patient 
enrolled in IBCSG clinical trials.  The required pathological material (described in the previous 
section) is submitted to, catalogued, and maintained in the IBCSG Coordinating Center Office 
in Bern (IBCSG Coordinating Center, Pathology Coordinating Office, Effingerstrasse 40, 
CH- 3008 Bern).  The primary tumor H&E section and block are sent for central pathology 
review to the European Institute of Oncology in Milan, Italy, and then  returned to the IBCSG 
Tissue Bank in Bern for storage.  Central pathology review reports will be available to 
institution pathologists who wish to see them.  Central pathology review will include 
histopathological parameters (tumor type and grade, occurrence of peritumoral vascular 
invasion), hormone receptors (estrogen and progesterone receptors), HER2 status and the tumor 
proliferative fractions (Ki-67 immunolabelling).  Testing for genes which may be inherited is 
not a part of the central pathology review of this study. The blocks will be available for 
prospective and retrospective studies approved by the IBCSG Biological Protocols Working 
Group and by the IBCSG Ethics Committee. 
The IBCSG requires a suitable tissue bank for application of the newer assays which are likely 
to become available in the very near future. In particular, IBCSG expects that novel predictive 
parameters will be identified by gene expression profiling. This will open at least one of the 
following possibilities: 
1. The application of gene expression profiling to paraffin embedded material 
2. The identification of specific mRNAs which could be detectable by molecular biology 
assays (RT-PCR, in situ hybridization, etc) in paraffin-embedded tissue 
3. The identification of protein molecules detectable by immunohistochemistry. 
These assays will most likely require a comparison between neoplastic and normal tissue, and 
this is why IBCSG is banking two sets of samples per patient. In many cases (but not all) 
normal tissue may be found around the invasive tumors. Separate blocks are necessary for 
extractive techniques in order to avoid neoplastic cells contaminating the normal sample.  
10.2. 
Patient Reported Symptoms and Quality of Life Substudy  
Some of the Participating Centers will participate in the ancillary study of Patient Reported 
Symptoms and Quality of Life. Details of the rationale, logistics, and statistical considerations 
are in Appendix III. 


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11. 
Regulatory approval procedures and Patient Informed Consent 
11.1. 
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 must be sent to the IBCSG Coordinating Center 
prior to enrollment of the first patient. The IBCSG Ethics Committee also approves the protocol 
and reviews it annually. 
11.2. 
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 Coordinating Center prior to Participating Center activation. 
11.3. 
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 11.4. Additional 
institution-specific sections should be added to Appendix I as described in Section 11.4. 
The medical record must be available for review by the IBCSG audit team as described in 
Section 11.5. 
Serious adverse event (SAE) reports are distributed monthly. In addition they are available on 
the IBCSG website (www.ibcsg.org) for IBCSG member institutions. 
11.4. 
Informed consent  
Informed consent for each patient will be obtained prior to initiating any trial procedures in 
accordance with the “IBCSG Patient Information 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" (http://www.wma.net/e/policy/b3.htm ) 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 


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Coordinating Center Effingerstrasse 40 CH-3008 Bern Switzerland www.ibcsg.org 
 
explained to the individual by the physician.  The potential patient should also be informed of 
her right to not participate or to withdraw from the trial at any time.  The patient should be told 
that material from her tumor will be stored and potentially used for additional studies not 
described in this protocol.  
If the patient is in a dependent relationship to the physician or gives consent under duress, the 
informed consent should be obtained by an independent physician.  If the patient is 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) for IBCSG 
members. 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. 
11.5. 
Quality Assurance 
The IBCSG conducts trials according to the ICH Good Clinical Practice (GCP) guidelines.  The 
Study Data Manager reviews each CRF as it is received. 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. 
12. 
Administrative Considerations 
12.1. 
Insurance 
The 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 
group/institution should report all alleged claims immediately to the IBCSG Coordinating 
Center. 
The IBCSG insurance does NOT cover patients from the United States of America or from 
Canada.  Each group will be responsible for obtaining proper insurance coverage. 
12.2. 
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 


IBCSG 35-07/BIG 1-07  Study of Letrozole Extension (SOLE) 
40 
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light of emerging clinical or scientific data from other trials. Second, the Steering Committee is 
responsible for translation of recommendations of the IBCSG Data and Safety Monitoring 
Committee into decisions (see section 9.5.). Membership will include IBCSG officials, study 
chair and co-chairs, trial statisticians, representatives from some participating institutions and 
groups, and representatives from Novartis. 
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 
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 of the trial. 
13. 
References  
1. Boyle P, Ferlay J:  Cancer incidence and mortality in Europe 2004. Ann Oncol 16:481-8, 
2005.  
2. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG): Effects of chemotherapy 
and hormone replacement therapy for early breast cancer on recurrence and 15-year 
survivial: an overview of the randomised trials. Lancet 365:1687-717, 2005 
3. Buzdar AU, Robertson JF, Eiermann W, et al: Overview of the pharmacology and 
pharmacokinetics of the newer generation aromatase inhibitors anastrozole, letrozole, and 
exemestane. Cancer 95:2006-16, 2002 
4. Dombernowsky P, Smith I, Falkson G, et al: Letrozole, a new oral aromataseinhibitor for 
advanced breast cancer: double-blind randomized trial showing a dose effectand improving 
efficacy and tolerability compared with megestrol acetate. J Clin Oncol 16: 453 – 61, 1998 
5. Mouridsen H, Gershanovich M, Sun Y, et al: Superior efficacy of letrozole versus 
tamoxifen as first-line therapy for postmenopausal women with advanced breast cancer: 
results of a phase III study of the International Letrozole Breast Cancer Group. J Clin Oncol 
19:2596-606, 2001 
6. Investigator's Brochure, FEM345, Letrozole Edition 11, release date 23-Sep-2006 Novartis 
Ltd., Basel, Switzerland 
7. Bhatnagar AS, Häusler A, Schieweck, K, et al: Highly selective inhibition of estrogen 
biosynthesis by CGS 20267, a new non-steroidal aromatase inhibitor. J. Steroid Biochem 
Molec Biol 37:1021-27, 1990 
8. Bhatnagar AS, Batzl C, Häusler A, et al: The role of estrogen in the feedback regulation of 
follicle-stimulating hormone secretion in the female rat. J Steroid Biochem Molec Biol 
47:161-166, 1993 
9. Iveson TJ, Smith EE, Ahern J, Smithers DA, et al: Phase I study of the oral nonsteroidal 
aromatase inihbitor CGS 20 267 in postmenopausal patients with advanced breast cancer. 
Cancer Res 53:266-270, 1993 


IBCSG 35-07/BIG 1-07  Study of Letrozole Extension (SOLE) 
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Coordinating Center Effingerstrasse 40 CH-3008 Bern Switzerland www.ibcsg.org 
 
10.  CGS 20267: (Non-steroidal aromatase inhibitor): Open, Phase I trial in post Menopausal 
patients with advanced breast cancer. Trial protocol No. ARJBC 1. CIBA-GEIGY Ltd., 
Basle, Switzerland. October 22,1993   
11. CGS 20267: (Non-steroidal aromatase inhibitor): Open, Phase I trial in post menopausal 
patients with advanced breast cancer. (Extension Phase). Report AR/BC.CIBA 
Pharmaceuticals Ltd., Horsham, UK. July 31, 1994 
12. 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 
19:3808-16, 2001 
13. The ATAC Trialists' Group: Arimidex, tamoxifen alone or in combination Anastrozole 
alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of 
postmenopausal women with early breast cancer: first results of the ATAC randomised 
trial. Lancet 359:2131-9, 2002 
14. The ATAC Trialists' Group: Anastrozole alone or in combination with tamoxifen versus 
tamoxifen alone for adjuvant treatment of postmenopausal women with early-stage breast 
cancer: Results of the ATAC (Arimidex, Tamoxifen Alone or in Combination) trial 
efficacy and safety update analyses. Cancer 98:1802-10, 2003 
15.  ATAC Trialists' Group: Results of the ATAC (Arimidex, Tamoxifen, Alone or in 
Combination) trial after completion of 5 years' adjuvant treatment for breast cancer, Lancet 
365:60–2, 2005 
16. Coates AS, Keshaviah A, Thürlimann B, et al:  Five years of Letrozole compared with 
tamoxifen as initial adjuvant therapy for postmenopausal women with endocrine-
responsive early breast cancer: update of study BIG 1-98. J Clin Oncol, in press 
17.  BIG 1-98 Collaborative Group: A comparison of letrozole and tamoxifen in 
postmenopausal women with early breast cancer.  N Engl J Med 353:2747-57, 2005 
18. Coombes RC, Hall E, Gibson LJ, et al: A randomized trial of exemestane after two to three 
years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J 
Med 350:1081-92, 2004 
19. Jakesz R, Jonat W, Gnant M, et al: Switching of postmenopausal women with endocrine-
responsive early breast cancer to anastrozole after 2 years' adjuvant tamoxifen: combined 
results of ABCSG trial 8 and ARNO 95 trial, Lancet 366:455–62, 2005  
20.  Boccardo F, Rubagotti A, Puntoni M, et al: Switching to anastrozole versus continued 
tamoxifen treatment of early breast cancer: preliminary results of the Italian Tamoxifen 
Anastrozole trial, J Clin Oncol 23:5138–47, 2005 
21. Goss PE, Ingle JN, Martino S, et al: A randomized trial of letrozole in postmenopausal 
women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med 
349:1793-1802, 2003  
22. Goss PE, Ingle JN, Martino S, et al: Randomized trial of letrozole following tamoxifen as 
extended adjuvant therapy in receptor-positive breast cancer: updated findings from NCIC 
CTG MA.17. J Natl Cancer Inst 97:1262-71, 2005 
23. Song RX, Mor G, Naftolin F, McPherson RA, et al: Effect of long-term estrogen 
deprivation on apoptotic responses of breast cancer cells to 17beta-estradiol. J Natl Cancer 
Inst 93:1714–23, 2001   


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24. Lewis JS, Cheng D, Jordan VC: Targeting oestrogen to kill the cancer but not the patient. 
Br J Cancer 90: 822–32, 2004 
25. Lewis JS, Osipo C, Meeke K, et al: Estrogen-induced apoptosis in breast cancer model 
resistant to long-term estrogen withdrawal. J Steroid Biochem Mol Biol 94: 131–41, 2005 
26. Yao K, Lee ES, Bentrem DJ, et al: Antitumor action of physiological estradiol on 
tamoxifen-stimulated breast tumors grown in athymic mice. Clin Cancer Res 6:2028–36, 
2000 
27. Lonning PE, Taylor PD, Anker G, et al: High-dose estrogen treatment in postmenopausal 
breast cancer patients heavily exposed to endocrine therapy. Breast Cancer Res Treat 
67:111–6, 2001 
28. Iveson TJ, Smith IE, Ahern J, et al: Phase I study of the oral nonsteroidal aromatase 
inhibitor CGS 20267 in healthy postmenopausal women.  J Clin Endocrinol Metab 77:324-
31, 1993 
29. Osipo C, Liu H, Meeke K, et al: The consequences of exhaustive antiestrogen therapy in 
breast cancer: estrogen-induced tumor cell death. Exp Biol Med 229:722–31, 2004 
30. Dunn C, Keam SJ: Letrozole: a pharmacoeconomic review of its use in postmenopausal 
women with breast cancer. Pharmacoeconomics 24:495-517, 2006 
31. Gil JM, Rubio-Terres C, Del Castillo A, et al: Pharmacoeconomic analysis of adjuvant 
therapy with exemestane, anastrozole, letrozole or tamoxifen in postmenopausal women 
with operable and estrogen receptor-positive breast cancer. Clin Transl Oncol 8:339-48, 
2006 
32. Tu D and Goss P, personal communication, 2006. 
33. East 4 (version 4.0.1) statistical software package. Cytel Software Corporation, Cambridge, 
MA, USA, 2005 
34. O’Brien PC, Fleming TR: A multiple testing procedure for clinical trials.  Biometrics 
35:549-556, 1979 

SAP_001.pdf: 
 
 
 
 
 
 
 
 
International Breast Cancer Study Group Statistical Center 
 
 
SOLE (Trial 35-07/BIG 1-07) 
 
Statistical Analysis Plan 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Version 
Author 
Date 
Status 
1 
Weixiu Luo 
 25 Jan 2017 
Approved by … 
 
 
 
Updated reason … 
 
 
 
 
 
 
 


SOLE SAP: 25 Jan 2017 
 
Trial 35-07 -- 2 
 
1 
INTRODUCTION 
1.1 
BACKGROUND 
In 2006, the standard duration of adjuvant endocrine therapy for breast cancer (either SERMs or 
AIs) is five years. Patients who receive extended adjuvant letrozole for five years following 
approximately five years of tamoxifen obtain further benefit compared with the five years of 
tamoxifen alone.  Similarly, benefit has been demonstrated for switching from tamoxifen to an 
AI after 2 to 3 years of tamoxifen to complete five years of endocrine therapy, as well as 
initiating therapy with AI following surgery and administering the AI for five years. 
 
Questions remain about the optimal duration and best schedule of AIs in the extended adjuvant 
setting. This trial tests the hypothesis that introducing 3-month treatment-free intervals during 
the course of five years of extended adjuvant letrozole will improve disease-free survival. This 
hypothesis is based on the theoretical principle that letrozole withdrawal for 3 months will permit 
some estrogenic stimulation which makes residual resistant disease susceptible to letrozole 
reintroduction. 
 
1.2 
TRIAL DESIGN 
 
SOLE (IBCSG 35-07 / BIG 1-07) OVERVIEW 
Title: 
Study Of Letrozole Extension (SOLE): A phase III trial evaluating the role of 
continuous letrozole versus intermittent letrozole following 4 to 6 years of prior 
adjuvant endocrine therapy for postmenopausal women with hormone receptor 
positive, node-positive early stage breast cancer. 
Patient 
Population: 
Postmenopausal women who are disease-free following 4-6 years of prior  adjuvant 
endocrine therapy with selective estrogen receptor modulator(s) (SERM) and/or 
aromatase inhibitor(s) (AI) for endocrine-responsive, node-positive early breast 
cancer. 
Entry: 
Patients must have stopped prior endocrine SERM/AI therapy, and must be 
randomized within 12 months (1 year) of the last dose of prior endocrine SERM/AI 
therapy. 
Activation Date: 
8 November 2007 (First patient randomized on 5 December 2007) 
Target Accrual:  
4800 patients 
Closure Date: 
12 July 2012 (Last patient randomized on 8 October 2012) 
Final Accrual: 
4884 patients 
 
 
 
 
 
 


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SOLE SAP: 25 Jan 2017 
 
Trial 35-07 -- 4 
 
1.4 
INTERIM MONITORING PLAN (FROM PROTOCOL) 
 
A group sequential design with two interim analyses and one final analysis is used. The target 
number of events for the final analysis is 647, and interim analyses are planned after 40% and 
70% information (259 and 453 events observed respectively). At each interim analysis and at the 
final analysis, testing will be performed using O’Brien-Fleming boundaries.   
 
1.5 
DATA AND SAFETY MONITORING COMMITTEE REVIEWS 
 
The Data and Safety Monitoring Committee (DSMC) reviews the safety information, including 
adverse events, second (non-breast) malignancies, and deaths without prior cancer event, every 
six months and has recommended the trial continue as planned. The first interim efficacy 
analysis was performed for spring 2014 DSMC report when 324 DFS events (50% information) 
were observed. At that time the O’Brien-Fleming boundary was not crossed and there was not 
enough evidence to support early stopping of the trial due to efficacy. The DSMC recommended 
that SOLE treatment administration and follow-up continue as planned. The same results held for 
the second interim efficacy analysis which was performed for spring 2015 DSMC report when 
454 DFS events (70% information) were observed. 
 
 
2 
EFFICACY ANALYSIS PLANS 
2.1 
OBJECTIVES 
The primary objective is to compare continuous letrozole for five years with intermittent 
letrozole over a five year period for postmenopausal women who are disease-free following 4-6 
years of prior adjuvant endocrine therapy with SERM(s) and/or AI(s) for endocrine-responsive, 
node-positive, operable breast cancer. 
 
2.2 
ANALYSIS POPULATIONS 
The primary analysis will use an intention-to-treat (ITT) approach. The ITT population will 
include all randomized patients, regardless of eligibility status; the possible exceptions are 
patients who immediately withdrew consent prior to treatment initiation and declined all 
participation, patients determined (e.g., via audit) to be without documented informed consent, 
and/or patients at a participating center determined not to be compliant with protocol procedures. 
Any exclusion from the ITT population will be determined prior to the analysis and will be 
summarized in listing and CONSORT in the trial report. 
 


SOLE SAP: 25 Jan 2017 
 
Trial 35-07 -- 5 
 
2.3 
ENDPOINT DEFINITIONS 
2.3.1 Primary Endpoint 
• 
Disease-free survival (DFS) is defined as the duration of time from randomization to the 
first indication of the following events: invasive recurrence at local (including recurrence 
restricted to the breast after breast conserving treatment), regional or distant sites; a new invasive 
cancer in the contralateral breast; any secondary (non-breast) malignancy; or a death without 
prior cancer event.  Appearance of DCIS or LCIS either in the ipsilateral or in the contralateral 
breast will not be considered as an event for DFS. In the absence of an event, DFS is censored at 
the date of last follow-up. 
 
2.3.2 Secondary Endpoints 
• 
Overall survival (OS) is defined as the duration of time from randomization to death from 
any cause, or is censored at the date last known alive.  (Note, for patients who withdrew consent 
or were lost to follow-up but follow-up for survival was possible through hospital or registry 
records, OS is censored at the date last known alive rather than date of last follow-up/withdrawn 
consent). 
• 
Distant disease-free survival (DDFS) was a secondary endpoint in protocol. It will be 
replaced by a more modern definition -- distant recurrence-free interval (DRFI) defined as the 
duration of time from randomization to the first indication of invasive breast recurrence at a 
distant site. In the absence of an event, DRFI is censored at the date of last follow-up or date of 
death without distant recurrence. 
• 
Breast cancer-free interval (BCFI) is defined as the duration of time from randomization to 
the first indication of the following events: invasive breast recurrence at local, regional or distant 
sites; a new invasive cancer in the contralateral breast. In the absence of an event, BCFI is 
censored at the date of last follow-up or date of death without prior breast cancer event.  (Second 
non-breast malignancies are ignored) 
• 
Site of First Failure: Hierarchy of failures from least to worst, following standard IBCSG 
definition: 
o 
Local 
o 
Contralateral Breast 
o 
Regional ± above 
o 
Soft Tissues/Distant Nodes ± above 
o 
Bone ± above 
o 
Viscera (including ‘other’) ± above 
 
as well as incidence of 2nd (non-breast) malignancy, death without prior cancer event, and 
adverse events. 
 
For “site of first failure,” if there are 2 or more failure sites within 2 months of each other, then 
the “worst” site is considered as the site of first failure. For example if there is a regional 
recurrence and a bone recurrence within 2 months of each other, then the bone would be 


SOLE SAP: 25 Jan 2017 
 
Trial 35-07 -- 6 
 
considered the “worst” site of failure and considered as “site of first failure.” If second 
malignancy is coincident with breast cancer recurrence then site of first failure is considered as 
the breast cancer recurrence. 
 
Per IBCSG standard, the date of DFS event is the date a proven recurrence was first suspected. 
In rare cases that the date suspected is prior to randomization, date of randomization is 
considered as date of event. 
 
2.4 
FOLLOW-UP 
 
Number of DFS events per person-year of follow-up is calculated at each DSMC review time to 
guide the timing for the database lock. The data cut-off is planned for prior to November 1, 2016 
when we expect the number of DFS events will reach the target of 647 for the analysis with 
database lock in Q1 2017. Data as of the database cut-off will be used for analysis. 
 
Median follow-up is calculated from the Kaplan-Meier estimate of overall survival, with the 
event/censoring indicator inverted (i.e. alive as event and dead as censored).  
 
Updated results will be presented every two to three years thereafter. 
 
2.5 
TESTS AND ESTIMATES 
The primary endpoint, DFS, will be compared between treatment arms using a two-sided 
stratified logrank test with an overall experiment-wise alpha-level equal to at most 0.05. The test 
statistic and p-value will be taken from the stratified Cox PH model score test. Hazard ratios will 
be estimated from a stratified Cox PH model, with 95% CIs. Kaplan-Meier estimates of the DFS 
distributions will be calculated for each of the treatment arms, with reporting of the 5yr DFS. We 
will check the proportional hazards assumption by visually assessing the plot of log(-
log(survival)) versus log of survival time for parallelism. This will be done overall, and 
according to strata. 
 
2.5.1 Stratification 
The stratification factor during randomization is prior SERM/AI endocrine therapy (SERM(s) 
alone, AI(s) alone, both SERM(s) and AI(s)) as reported on randomization (RA) form. 
Institutions were balanced using dynamic balancing. Logrank test and Cox PH model will be 
stratified by prior SERM/AI endocrine therapy. 
 
Note about values of strata as provided at randomization vs. actual values: The randomization 
form (RA form) collects the values entered into the IBCSG randomization system and used for 
stratification of the randomization assignment. If these values are incorrect then they are 
amended on the Registration form (A-form). We will cross-tabulate the stratification variables 


SOLE SAP: 25 Jan 2017 
 
Trial 35-07 -- 7 
 
between RA and A forms to compare the information obtained at randomization versus that on 
the A forms. For primary and secondary overall analyses we will use the stratification factor 
entered on randomization form. For subgroup analyses, we will use the actual values entered in 
the A form when available. 
 
2.6 
ANALYSIS COMPONENTS 
2.6.1 Enrollment, Eligibility, Follow-up Compliance 
This section summarizes accrual, eligibility, exclusions from ITT population, institutional CRF 
and follow-up compliance. 
 
2.6.1.1 All randomized patients 
Tables: 
 Enrollment by group/country (rows), according to year and prior endocrine therapy strata 
(columns) 
 Patient randomization treatment assignment and prior endocrine therapy strata 
 Institutional follow-up compliance by group/country (rows) 
 Case report form submission status (baseline forms) 
 
Figures: 
 Enrollment over time; x-axis time in 6-montly intervals; y-axis number enrolled 
2.6.1.2 CONSORT 
In the manner of the CONSORT diagram, the following will be summarized. 
Tables: 
 CONSORT diagram content numbers by treatment assignment 
o Number of patients randomized 
o Number of patients included vs excluded from analysis population, with reasons 
 Listing of patients excluded from analysis population (patid, randomizing 
institution, randomization date, reason excluded, treatment assignment) 
o Number in analysis population who never started protocol treatment 
o Number in analysis population who WC/LFU 
o Number of patients analyzed in analysis population [same/as number included] 
 
2.6.1.3 Analysis population 
Tables: 
 Enrollment by group/country (rows)  
 Patient randomization assignment and prior endocrine therapy strata 


SOLE SAP: 25 Jan 2017 
 
Trial 35-07 -- 8 
 
 Eligibility status and reasons ineligible, overall and by treatment assignment 
 Listing of ineligible patients (patid, randomizing institution, randomization date, reason 
ineligible, treatment assignment) 
 Withdrawn consent and lost to follow-up status 
 
2.6.2 Patient, Disease and Prior Treatment Characteristics 
Characteristics of the analysis population will be summarized overall and by treatment group. 
Continuous variables are summarized as mean, SD, min/max, and quartiles. Categorical 
variables are summarized as N(%); for variables with unavailable (missing, unknown, not done) 
values, the default approach is to include an unknown category that is included in the 
denominator for percentages (rather than just listing the number of unknowns as a category).  
Tables (overall and by treatment group, unless otherwise specified): 
 Patient:  
o Age at randomization (continuous; categorized in 5-year intervals) 
o Race/ethnicity 
o Performance status at randomization 
o BMI at randomization 
o Menstruation status at primary cancer diagnosis 
o Symptoms (from baseline AE form) 
 Treatment:  
o Local therapy (combining surgery [Mx/BCS] and radiotherapy [yes/no]  
o Chemotherapy (whether used; regimen [anthracycline-based; taxane-based; both; 
other] 
o Biologic therapy 
o Prior endocrine therapy and years of prior endocrine therapy 
o Duration from end of prior adjuvant therapy to randomization 
 Disease:  
o ER/PgR status and details (H form) 
o HER2 status (H form) 
o Nodal involvement (number of positive lymph nodes 0-1, 2-3, 4-9, and 10+)  
o Tumor size (<1, 1-2, >2-5, >5 cm) and grade (1, 2, 3), primary histology (and 
other details from H form) 
o Disease laterality and location 
 
2.6.3 Primary Efficacy Analysis 
The primary efficacy analysis will proceed as summarized in Section 2.5 above. The data cut-off 
and database lock dates used for the analyses and the median follow-up duration will be reported. 


SOLE SAP: 25 Jan 2017 
 
Trial 35-07 -- 9 
 
2.6.3.1 Subgroup Analyses 
The protocol pre-specified factors that will be used to characterize the patients enrolled in the 
study and to provide descriptive statistics of outcomes according to subgroups of the population. 
These factors include: age at randomization, body mass index, tumor size, tumor grade, number 
of positive lymph nodes, ER/PgR, HER2 status, type of prior endocrine therapy, duration of prior 
endocrine therapy by type, interval of time since the cessation of prior endocrine therapy till 
randomization. These analyses will be considered as secondary and descriptive.  
The plans for these variables are summarized below: 
• 
Age (5-year age groups (<55,55-59,60-64,65-69,≥70)) 
• 
BMI (obese (>=30), normal or overweight (25 - <30), normal (<25), unknown) 
• 
Chemotherapy (anthracycline-based, taxane-based, both, other, none)  
• 
Surgery/RT (Mx+RT; Mx alone; BCS+RT; BCS alone; unknown) 
• 
Tumor size (≤2 vs >2 cm; unknown) 
• 
Tumor Grade (1,2,3,unknown) 
• 
ER/PgR subgroup (+/+; +/-; -/+; unknown and other):  
• 
HER2 status (positive, negative, unknown) 
• 
No. of positive lymph nodes (0, 1-3, 4+) 
• 
type of prior endocrine therapy (AI, SERM, AI and SERM) 
• 
duration of prior endocrine therapy (<4.5, 4.5-5.5, >5.5 years) 
• 
Interval of time since the cessation of prior endocrine therapy till randomization (<= 1 
month, >1 month) 
 
2.6.3.2 Models 
Stratified Cox PH regression models will be used to: estimate HRs (95% CI) for treatment effect, 
adjusted for these covariates in Section 2.6.3.1; and estimate HRs (95% CI) for treatment effect 
within subgroups by including treatment-by-covariate interaction in the model (but not other 
covariates) and using contrasts. 
 
2.6.3.3 Tables and Figures 
Tables: 
 Primary treatment comparison: N events and patients, HR, 95% CI, log-rank test statistic 
and p-value, 5yr DFS, SE and 95% CI 


SOLE SAP: 25 Jan 2017 
 
Trial 35-07 -- 10 
 
 Treatment effects within subgroups: N events and patients within each subgroup, 
treatment HR, 95% CI, p-value for test of treatment-by-variable interaction 
Figures: 
 KM plot of DFS, by treatment group, for entire analysis population (y-axis: Percent Alive 
and Disease-Free; x-axis: Time since Randomization (12-month intervals); x-axis limited 
to 6 years (median follow-up plus 1 year) and numbers at risk at each 12-monthly 
interval) 
 Forest plot of DFS, overall and for subgroups 
 
2.6.4 Secondary Efficacy Endpoints 
Breast cancer-free interval, distant recurrence-free interval and overall survival will be 
summarized as described for DFS. Sites of first treatment failure will be summarized overall and 
by treatment group as N (%). Second (non-breast) malignancies as site of first failure, and deaths 
without prior cancer event will be summarized overall and by treatment group.  
 
2.6.4.1 Tables and Figures 
Tables: 
 Primary treatment comparison for each of the 3 secondary endpoints: N events and 
patients, HR, 95% CI, log-rank test statistic and p-value, 5yr DFS, SE and 95% CI 
 Sites of first failure, overall and by treatment group 
 Types of second non-breast malignancies, as site of first failure, overall and by treatment 
group.  
 Death without recurrence (list of patients with cause of death) 
 
Figures: 
 KM plots of BCFI, by treatment group, for entire analysis population (y-axis: Percent 
Free from Breast Cancer; x-axis: Time since Randomization (12-month intervals); x-axis 
limited to 6 years (median survival plus 1 year) and numbers at risk at each 12-monthly 
interval) 
 KM plots of DRFI, by treatment group, for entire analysis population (y-axis: Percent 
Free from Distant Recurrence; x-axis: Time since Randomization (12-month intervals); 
x-axis limited to 6 years (median survival plus 1 year) and numbers at risk at each 12-
monthly interval) 
 KM plot of OS, by treatment group, for entire analysis population (y-axis: Percent Alive; 
x-axis: Time since Randomization (12-month intervals); x-axis limited to 6 years (median 
survival plus 1 year) and numbers at risk at each 12-monthly interval) 


SOLE SAP: 25 Jan 2017 
 
Trial 35-07 -- 11 
 
 
2.6.5 Adverse Events / Safety 
2.6.5.1 Population 
The toxicity population is the subset of patients in the ITT analysis population who started 
protocol treatment.  Any patients without at least 1 post-baseline AE form submitted will not be 
able to contribute; note any such patients in trial report. 
 
2.6.5.2 Analysis 
Targeted AEs, and other grade 3-5 AEs, are collected on CRFs. The grade and causality 
attribution are recorded according to the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 3.0. 
The targeted AEs will be summarized by AE type and maximum grade over time, regardless of 
causality attribution. The maximum grade consolidates the reports of a given type of AE for a 
patient over time since randomization (i.e., baseline reports are excluded) by taking the 
maximum across time (i.e., a patient appears only once for a given type of AE). Patients with 
reports of multiple AEs of different types are reported multiple times under the relevant AE 
categories. Maximum grade 0 indicates that the AE type has not been reported.  
 
2.6.5.3 Tables and Figures 
Tables: 
• 
Targeted AEs reported according to treatment group 
• 
Targeted AEs reported according to prior endocrine therapy and treatment assignment 
• 
Tables above repeated for the subset of events deemed possibly, probably or definitely 
related to study treatment(s) 
Other grade 3 or higher AEs are also requested on CRFs, by write-in text. All will be tabulated, 
similarly according to max grade, but the intention is to focus on those deemed possibly, 
probably or definitely related to study treatment(s), which will also be tabulated.  
95% exact CIs will be calculated for each targeted AE, according to treatment group. 
The following late adverse events (LAEs) will be summarized descriptively in a table according 
to treatment group: cardiac ischemia/infarction, thrombosis/thrombus/embolism, CNS 
cerebrovascular ischemia, and fractures. 
 
2.6.6 Treatment 
Protocol treatment status as of the clinical data cut-off will be summarized. In this report, status 
will be summarized by treatment assignment. Time from randomization to treatment termination 
will be summarized using KM curves according to treatment assignment. 


SOLE SAP: 25 Jan 2017 
 
Trial 35-07 -- 12 
 
Per SOLE Data Manager’s Hand Book v3.0 (dated 21Mar13), for Arm B patients, interruptions 
should be every 9 months and should last for 3 months in years 1-4. Any interruption up to 4 
months is considered a “protocol-specified interruption” and the reason for interruption is 
defined as “protocol-defined interval” on L forms; any interruption of 4 months +1 day (121 
days or more) is considered a “non-protocol interruption”. 
The Idealized Scheduler contains a link to an Excel file on the IBCSG web site. This file 
calculates the letrozole dispensation and interruptions (Arm B) based off of the Randomization 
Date. 
Treatment variation scenarios: 
• 
Patient on Arm B stops letrozole early (e.g., at Month 6 instead of Month 9). The patient 
should stop for three months. Patient should re-start letrozole and continue until the pre-defined 
date of the next interruption. This will get the patient back on schedule. 
• 
Patient on Arm B took medication during the protocol-specified interruption. Patient should 
continue until Month 9 of the next year and then start the interruption. This will get the patient 
back on schedule. 
• 
Patient forgot to take some pills and therefore has some left at the date the interruption 
should start. The patient should not finish the medication. The patient should interrupt on the 
pre-defined date to stay on schedule. 
For Arm A patients, not-per-protocol interruptions are those of over a month in duration. 
Reasons for treatment interruptions will be summarized by treatment assignment. Note that there 
could be more than one reason for an interruption spanning more than one L Form: for example, 
a patient start interruption per protocol on one L form, but due to adverse event, the interruption 
continues to the next L form without restarting after 4 months. The first reason would be 
“protocol-defined interval” and then the second reason would be “Adverse Event”. 
Based on information on Data Manager’s Handbook, to describe adherence with protocol-
assigned treatment, the following tables and figures are proposed. 
Table 2.6.6.1. Patients’ Treatment Compliance by treatment assignment 
 
Arm A 
Arm B 
Overall 
  
N 
% 
N 
% 
N 
% 
Did not start protocol treatment  
 
 
 
 
 
 
Receiving protocol treatment 
 
 
 
 
 
 
Stopped all study treatment 
 
 
 
 
 
 
      Completed treatment per protocol               
 
 
 
 
 
      Stopped all study treatment early 
 
 
 
 
 
 


SOLE SAP: 25 Jan 2017 
 
Trial 35-07 -- 13 
 
           Adverse event                                         
 
 
 
 
 
           Disease related                                        
 
 
 
 
 
           Patient decision                                       
 
 
 
 
 
           Other 
 
 
 
 
 
 
           Patient Lost to Follow-up 
 
 
 
 
 
 
Treatment status unknown due to missing 
information on forms 
 
 
 
 
 
 
Total number of patients w. treatment data 
available 
  
  
  
  
  
  
 
Table 2.6.6.2. Days of Treatment on by treatment assignment during year one to five 
 
Arm A 
Arm B 
Year 
N 
Median  
IQR 
N 
Median  
IQR 
1 
 
 
 
 
 
 
2 
 
 
 
 
 
 
3 
 
 
 
 
 
 
4 
 
 
 
 
 
 
5 
  
  
  
  
  
  
Note: N is total number of patients on treatment during that treatment year 
 
Table 2.6.6.3 Number of patients with per-protocol interruptions and resumes for patients on 
Arm B only 
 
Per-protocol Interruption 
Per-protocol Resume 
Year 
n 
N 
% (n/N) 
n 
N 
% (n/N) 
1 
 
 
 
 
 
 
2 
 
 
 
 
 
 
3 
 
 
 
 
 
 
4 
 
 
 
 
 
 
Overall  
 
 
 
 
 
Note: N is total number of patients on treatment any time during the treatment year 


SOLE SAP: 25 Jan 2017 
 
Trial 35-07 -- 14 
 
 
Table 2.6.6.4 Not-per-protocol interruptions for patients on Arm A and Arm B 
 
Arm A 
Arm B 
Year 
n 
N 
% 
n 
N 
% 
1 
 
 
 
 
 
 
2 
 
 
 
 
 
 
3 
 
 
 
 
 
 
4 
 
 
 
 
 
 
5 
  
  
  
  
  
  
Note: N is total number of patients on treatment any time during the treatment year 
 
Table 2.6.6.5 Reasons for treatment interruptions by treatment assignment 
 
Arm A 
Arm B 
Reasons 
N 
% 
N 
% 
Protocol-defined interval (Arm B only) 
 
 
 
 
Patient decision 
 
 
 
 
Medical decision 
 
 
 
 
adverse event 
 
 
 
 
Other 
  
  
  
  
Note: there could be more than one reason for an interruption spanning more than one L Form 
 
Figure 2.6.6.1 Percentage of patients on treatment by month, according to treatment group (x-
axis: month 1 to 60, y-axis: percentage) 
Figure 2.6.6.2 Percentage of patients on treatment by 3-month intervals, according to treatment 
group (x-axis: interval 1 to 20, y-axis: percentage) 
Figure 2.6.6.3 Mean percentage of days on treatment during 3-month intervals, according to 
treatment group (x-axis: interval 1 to 20, y-axis: mean percentage)