SOLE Estrogen Substudy (SOLE-EST) - Investigating Changes in Estrogen Levels and Grip Strength for Patients Participating in the SOLE Trial
Conditions: Breast Cancer
Sponsor: ETOP IBCSG Partners Foundation

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 
 
 
 
 
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 
 
 
 
 
 
 
 
 
 
 
 
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.   
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. 

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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 
8.3. 
Data management........................................................................................................ 33 

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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-

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hydroxyprogesterone, ACTH 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 
tamoxifen were recently analyzed [16]. At a median follow-up of 51 months, 352 DFS events 

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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 
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 

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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 

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conservation, 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. 
Suspicious: 
skeletal symptoms or positive scan showing only one new lesion (until 
confirmed by other imaging study). 

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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 
 
1
A 
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 
• requires significant medical intervention 

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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 

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• Normal laboratory values 
• 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 
Central Pathology Review Office.  Please ensure that the blocks and slides are carefully 

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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 
explained to the individual by the physician.  The potential patient should also be informed of 

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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 

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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 

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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   
24. Lewis JS, Cheng D, Jordan VC: Targeting oestrogen to kill the cancer but not the patient. 
Br J Cancer 90: 822–32, 2004 

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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. 
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34. O’Brien PC, Fleming TR: A multiple testing procedure for clinical trials.  Biometrics 
35:549-556, 1979 

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Appendix III 
Patient Reported Symptoms and Quality of Life Substudy 
INTERNATIONAL BREAST CANCER 
STUDY GROUP 
IBCSG 35-07 
BIG 1–07 
        S    LE 
Study of Letrozole Extension 

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Table of Contents 
 
1.   Introduction ............................................................................................................................ 3 
2.   Objectives ............................................................................................................................... 3 
2.1  Primary Hypothesis ........................................................................................................... 3 
2.2  Secondary Hypotheses ...................................................................................................... 4 
3.   Patient selection ...................................................................................................................... 4 
4.   Study design ........................................................................................................................... 4 
5.   Measures ................................................................................................................................. 5 
5.1   Patient characteristics and Co-morbidity ......................................................................... 5 
6.   Timing requirements, Data Collection and Local Data Management .................................... 6 
6.1   Timing requirements ........................................................................................................ 6 
6.2   Data Collection and Local Data Management ................................................................. 6 
6.3   Central Data Management ................................................................................................ 6 
7.   Statistical Considerations ....................................................................................................... 7 
7.1  Sample Size Determination ............................................................................................... 7 
7.2   Statistical Analysis ........................................................................................................... 8 
8.   References .............................................................................................................................. 9 

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1.   Introduction 
Information about concomitant and late symptoms of adjuvant endocrine therapies for breast 
cancer is crucial to prepare women for physical and psychological consequences of treatment 
and for making informed decisions. Several randomized trials in the adjuvant setting assessed 
self-reported symptoms related to endocrine therapy in postmenopausal women with breast 
cancer [1-4]. In the ATAC trial, patients of all three treatment arms reported a worsening of 
symptoms related to endocrine therapy (overall endocrine symptom score) during the first 3 
months after study entry, which subsequently stabilized or slightly improved at 2- and 5-year 
follow-up. However, specific side-effects were significantly more frequent with anastrozole 
compared to tamoxifen (i.e., diarrhea, vaginal dryness, diminished libido, and dyspareunia), 
whereas dizziness and vaginal discharge were less frequent with anastrozole compared to 
tamoxifen [1, 2]. Postmenopausal women participating in the Intergroup Exemestane Study 
(IES) reported a high severity of vasomotor symptoms and sexual problems. The switch from 
tamoxifen to exemestane neither increased nor decreased endocrine symptoms after 2 to 3 years 
of tamoxifen [3]. In the MA.17 extended-adjuvant trial, only a minority of patients receiving 
either letrozole or placebo after five years of tamoxifen indicated symptoms to be bothersome 
[4]. Small but statistically significant differences of mean change scores from baseline to month 
6, 12 and 24 showing a worsening for the letrozole group were seen for vasomotor symptoms 
(i.e., hot flushes/flashes and night sweats) and a number of quality of life (QL) domains 
including physical function, bodily pain, vitality and sexuality.  
 
Although these studies revealed no major effect on overall QL by the different endocrine agents 
[1-4], differences in some QL domains were observed. An extension of treatment implies a 
continuation of symptoms, which may be a burden to the patient. Patient-reported symptoms 
(PRS) will therefore be evaluated in a subsample of patients participating in the IBCSG Trial 
35-07 by comparing the occurrence and severity of symptoms between the two different 
administration schedules, and their relative impact on global QL indicators. 
 
2.   Objectives 
The objective of this QL substudy is to compare differences in patient-reported symptoms and 
quality of life between continuous letrozole for 5 years and intermittent letrozole over a 5-year 
period among postmenopausal women who are disease-free following 4 to 6 years of prior 
adjuvant endocrine therapy for endocrine-responsive node-positive operable breast cancer. We 
hypothesize that introducing 3-month treatment-free intervals during the course of 5 years of 
extended letrozole will reduce both the number and the bother of symptoms associated with 
letrozole in this patient population. 
 
Despite the potential decrease of symptoms in the intermittent arm, we hypothesize that starting 
and stopping treatment repeatedly over 5 years may be more burdensome on a global QL level 
than undergoing continuous treatment for 5 years.  
 
2.1  Primary Hypothesis 
Twelve months after randomization (i.e., before patients in the intermittent group start letrozole 
again) hot flushes/flashes will be worse in patients randomized to receive continuous letrozole 
compared with patients randomized to receive intermittent letrozole.  
 

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2.2  Secondary Hypotheses 
Twelve months after randomization, both musculoskeletal and vaginal problems will be worse 
in patients randomized to receive continuous letrozole compared with patients randomized to 
receive intermittent letrozole.  
 
Starting and stopping treatment repeatedly over the course of 5 years for patients randomized to 
receive intermittent letrozole is more burdensome on a global QL level compared with patients 
randomized to receive continuous letrozole for 5 years.  
 
3.   Patient selection 
The QL assessment will be conducted in selected centers participating in the IBCSG Trial 
35-07. It is strongly recommended that patients complete a baseline QL and PRS Form prior to 
randomization, and the baseline forms must be completed prior to start of treatment. If the 
patient is randomized beforehand, the patient should be informed of the randomization result 
only after completion of the baseline forms. The only exceptions are physical impairment that 
interferes with any assessment, or inability to read any of the languages available on the 
QL/PRS Forms. 
 
4.   Study design 
In order to evaluate intermediate and long-term effects, a longitudinal design is used, including 
a baseline assessment and assessments at 6, 12, 18 and 24 months after randomization (Figure 
1). To eliminate any differential anticipatory effects on baseline scores and to help insure 
compliance with the protocol requirements, the baseline QL/PRS Forms should be completed 
prior to randomization. 
 
 
Figure 1: 
QL assessment time points 
 
 
 
 
0 
6 
12 
18 
24 
30 
36 
42 
48 
54 
60 
 
 
 
 
Continuous letrozole for 5 years (Arm A)
Intermittent letrozole over 5 years (Arm B) 
QL assessment time points 

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5.   Measures 
Patient-reported endocrine symptoms will be assessed by the Breast Cancer Prevention Trial 
(BCPT) Symptom Scales [5]. These scales represent a refinement of the 42-item BCPT 
symptom checklist reducing the original scale to meaningful symptom dimensions. Both 
exploratory and confirmatory factor analysis revealed eight scales corresponding to the 
physical symptom dimensions associated with cancer treatment, chemoprevention, menopause 
or normal aging: 1) hot flushes/flashes (2 items), 2) nausea (2 items), 3) bladder control (2 
items), 4) vaginal problems (2 items), 5) musculoskeletal pain (3 items), 6) cognitive problems 
(3 items), 7) weight problems (2 items), 8) arm problems (2 items). Patients are asked to 
indicate how much they were bothered by each symptom during the past 4 weeks on a 5-point 
severity scale (0= not at all; 1= slightly; 2= moderately; 3= quite a bit; 4= extremely). In 
addition to the eight scale scores, a total score will be computed.  
The psychometric properties of the scales are satisfying, but limited to data provided by 
patients who were previously diagnosed with breast cancer (i.e., breast cancer survivors) or 
women at risk for breast cancer, but not by patients currently undergoing chemotherapy or 
endocrine treatment [5]. 
 
Several global QL indicators will be assessed using selected items from the IBCSG QL Core 
Form, which was developed in 1986 and was subsequently revised for IBCSG Trials 10-93 
through 14-93 (starting on May 1, 1993) [6, 7] and the IBCSG QL Module Form developed for 
IBCSG Trial 24-02. The IBCSG Trial 35-07 QL Form includes global linear analogue self-
assessment (LASA) indicators for physical well-being, mood [8], and coping (PACIS [9]). The 
indicators for physical well-being, mood and coping were confirmed to be responsive to mental 
distress and psychosocial dysfunction in patients with early breast cancer [10]. They are 
suitable to describe patients’ adaptation over time. Validation studies are summarized 
elsewhere [7]. In addition, one global indicator is included for overall treatment burden 
(“Overall, how much are you bothered by any treatment related difficulties?”). This indicator 
has been shown to be responsive to side-effects of anti-emetic and cytotoxic therapies [11] and 
to endocrine symptoms [12]. These global indicators are complemented with LASA indicators 
specific to symptoms which are not covered by the BCPT Checklist: Tiredness and sleep 
disturbance, as well as two indicators referring to sexuality (i.e., loss of sexual interest and 
difficulties becoming aroused). The latter question has to be answered only if a patient 
indicates that she has been sexually active during the past 6 months. As a reference measure we 
include the symptom specific LASA indicator for hot flushes/flashes. In IBCSG Trial VIII [13], 
scores of this measure were analyzed in relation to amenorrhea, providing further information 
for interpretation. In addition, the responsiveness of the LASA indicator for hot flushes/flashes 
will be compared with the corresponding item and subscale of the BCPT Symptom Scales. 
 
5.1   Patient characteristics and Co-morbidity 
Patient characteristics and co-morbidity are part of the standard study documentation.  Thus, 
this information will not be collected as part of this QL study; however, the information will be 
used in the PRS/QL analyses. 

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6.   Timing requirements, Data Collection and Local Data Management 
6.1   Timing requirements 
Assessment time points are determined by the interval from date of randomization, and 
coincide with the required clinical follow-up time points. The QL assessment time points are 
illustrated in Figure 1. 
 
The schedule for submitting the QL/PRS Forms must be followed as closely as possible. If 
exact timing is not possible, assessment should be done as close as possible to the required 
date, but before restart of treatment at the 12 and 24 month time points for patients randomized 
to the intermittent letrozole arm. The QLC/PRS Forms must always be completed prior to any 
communication about the patient’s medical information. 
 
For methodological reasons, the required schedule has to be followed exactly, with neither 
more nor fewer assessments. Shortly after randomization, the IBCSG sends the local 
investigator a schedule of the dates of required QL/PRS Forms. This list should be put into 
each patient's chart to aid in the correct timing for completing the QL/PRS Forms. 
 
6.2   Data Collection and Local Data Management 
Within the first 2 years, every patient participating in the QL substudy is to complete the 
QL/PRS Forms at each scheduled assessment time point, as described in Figure 1. 
 
If the patient does not complete the required QL/PRS Forms, then the reason why the 
assessment was not completed must be provided. This can be done by completing the 
Assessment Form (Form 35-AC) 
 
The QL/PRS Forms are to be filled in at the clinic. If the patient is being followed elsewhere, 
arrangements are to be made with the clinic or physician to have the patient fill in the forms as 
required.  If, for administrative reasons, the forms have not been presented to the patient, they 
may be filled in at home and mailed. 
 
For the first assessment, the QL/PRS Forms have to be explained to the patient, with particular 
emphasis on making sure the patient understands both the categorical response format and the 
LASA format. For later assessments, the patient should be instructed to seek help only if she 
has problems in understanding any of the items in the form. 
 
All questions on the QL/PRS Forms should be answered. The forms should be checked after 
completion and, if necessary, the patients should be asked to fill in missing answers. Patients 
may wish to leave some questions unanswered if they make them feel very uncomfortable. 
They should be encouraged to answer all items, however, especially those concerning 
symptoms, as they represent a primary objective of the ancillary study. 
 
6.3   Central Data Management 
Computerized data quality control measures will be used to monitor the submission rates of the 
QL forms and the timing of assessment as required by the study protocol.  Institutions will 
receive feedback on their performance and specific problems on a regular basis. 

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7.   Statistical Considerations 
The QL substudy of this phase III randomized clinical trial is designed to compare differences 
in patient reported symptoms and quality of life between continuous letrozole for 5 years and 
intermittent letrozole over a 5-year period among postmenopausal women who are disease-free 
following 4 to 6 years of prior adjuvant endocrine therapy for endocrine-responsive node-
positive operable breast cancer.  We hypothesize that introducing 3-month treatment-free 
intervals during the course of 5 years of extended letrozole will reduce both the number of 
symptoms and the bother of symptoms associated with letrozole in this patient population.  We 
will test this hypothesis by comparing the two treatment arms using patient reported symptoms 
at 5 time points over the first 24 months of treatment.  In addition, despite the hypothesized 
decrease in symptoms associated with intermittent letrozole, we hypothesize that repeatedly 
starting and stopping treatment over 5 years may be more of a burden on patients’ global QL 
than undergoing continuous treatment with letrozole for 5 years.  We will test this secondary 
hypothesis by comparing the longitudinal pattern of patient reported overall treatment burden 
between the two treatment arms over the first 24 months of treatment.  
 
7.1  Sample Size Determination 
The hot flushes/flashes symptom scale captured on the BCPT Symptom Scales [5] is selected 
as the primary endpoint.  This scale consists of 2 items of patient reported hot flushes/flashes 
and night sweats which have been shown to be a measurable side-effect of letrozole.  
Secondary endpoints include the musculoskeletal pain and vaginal problems scales, both 
anticipated symptoms induced by letrozole.  Musculoskeletal pain consists of 3 items on the 
BCPT Symptom Scales, namely, general aches and pains, joint pains, and muscle stiffness 
while vaginal problems is captured by pain with intercourse and vaginal dryness.        
 
The BCPT Symptom Scales asks the patient to indicate how much they were bothered by each 
symptom during the past 4 weeks on a 5-point severity scale (0= not at all; 1= slightly; 2= 
moderately; 3= quite a bit; 4= extremely). Scales are formed by averaging the scores on items 
forming each scale. 
 
The sample size for this QL substudy will be based on the between-group comparison of the 
change from baseline to 12 months in the hot flushes/flashes scale.  The sample size will be 
selected to achieve 90% statistical power to detect an effect size of 0.25 between the two 
groups using a two-sided 0.05 level t-test.  Three hundred and thirty eight patients in each 
randomized treatment arm (676 total) will be sufficient to achieve the stated objective.  To 
allow for a 10% non-compliance rate, the sample size is inflated to 744 patients. 
 
The between-group comparison of the change from baseline to 12 months for the two 
secondary endpoints, musculoskeletal pain and vaginal problems scales, will also be performed.  
In order to control the inflated Type I error rate, evaluation of each of these two other important 
comparisons will be conducted using a two-sided alpha level of 0.025.  The power to detect an 
effect size of 0.25 for each secondary endpoint is 84%. 
 
The QL substudy will be conducted in selected centers and the centers will be compensated for 
participating.  This approach is intended to result in at least a 90% completion rate for each 
patient at each of the 5 time points (baseline, and at months 6, 12, 18, and 24 post-
randomization). 

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7.2   Statistical Analysis 
The statistical analysis plan will involve five separate steps aimed at minimizing bias and 
emphasizing the clinical meaningfulness of the data:  a comparison of the completion rates for 
the BCPT Symptom Scales and QL measures between groups; a comparison of baseline scores 
between groups; a comparison of mean change of the symptom scales and QL measures from 
baseline; a comparison between groups of the longitudinal pattern of symptoms and QL 
measures during the first 24 months; and a comparison of the proportion of patients with 
improved, stable, or worsened symptoms between groups.  The latter is called a response 
analysis and identifies the proportion of patients demonstrating a minimally important 
improvement or worsening of symptoms at any time during follow-up. 
 
The primary analyses will be based on treatment differences (continuous letrozole for 5 years 
vs. intermittent letrozole over a 5-year period) of the change in each symptom scale from 
baseline to 12 months post-randomization.  In addition, we will analyze treatment differences 
of the change from baseline to month 24 as well as at each assessment time point for both the 
BCPT Symptom Scales and QL measures.  The two-sample t-test will be the basis of 
comparisons between the groups.    
 
Demographic factors will be collected from each patient and incorporated in the data analysis.  
We will use linear regression to analyze treatment differences at each time point and of the 
change in the bother of symptoms and QL measures from baseline adjusting for patient’s 
culture, type of prior adjuvant endocrine therapy, and other demographic factors as necessary.  
In particular, in the event that we detect any baseline imbalances we will adjust for these 
factors.  A linear mixed-effects model will also be used as a longitudinal analysis to estimate 
and describe treatment effects on symptoms and QL measures, in particular overall treatment 
burden, over time and at specific time points.  This model uses all available PRS/QL 
information obtained on the patient while allowing for the repeated measurements to exhibit 
within-subject correlation of observations over time.  A compound symmetry covariance matrix 
will be assumed and used to estimate and describe treatment effects, but other covariance 
structures will be explored. 
 
The response analysis will be based on the proportion of patients observed to have an improved 
(important reduction in the bother of the symptom from baseline), stable (did not experience an 
important change in the bother of the symptom from baseline), or worsened score (important 
increase in the bother of the symptom from baseline) during the course of the study. A 
minimally important change in the bother of the symptom will be calculated by using a half 
standard deviation of the scale [14]. As additional analyses, we will perform a logistic 
regression to evaluate baseline characteristics that predicts a minimally important worsening in 
symptoms at any time point.   
 
To gain a better understanding of what specific symptoms might be affected by letrozole, we 
will also look at each individual item on the BCPT Symptom Scales.  We will compare 
between groups the proportion of patients after random assignment who report being very 
bothered by a symptom with a score of 3 or 4 on a scale ranging from 0 (not at all bothered) to 
4 (extremely bothered) and for each item.  The χ2 test will be used to test for statistical 
significance between the groups. 
 
Further exploratory analyses will address the relationships between patient reported symptoms 
captured on the BCPT Symptom Scales and the corresponding LASA indicator (i.e. hot 

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flushes/flashes) as well as the global QL indicators (physical well-being, mood, coping, overall 
treatment burden). 
 
We will be collecting information on reasons why the patient did not fill out the QL/PRS Forms 
form.  As an additional analysis, this information will be used to impute patients’ missing QL 
scores.  A sensitivity analysis will be done in parallel with various imputation techniques to 
validate the effect that imputing values has on the parameter estimates. 
8.   References 
1. Fallowfield L., Cella D., Cuzick J., Francis S., Locker G.,Howell A., Quality of life of 
postmenopausal women in the Arimidex, Tamoxifen, Alone or in Combination (ATAC) 
Adjuvant Breast Cancer Trial. J Clin Oncol, 2004. 22(21): p. 4261-71. 
2. Cella D., Fallowfield L., Barker P., Cuzick J., Locker G.,Howell A., Quality of Life of 
Postmenopausal Women in the ATAC ("Arimidex", Tamoxifen, Alone or in Combination) 
Trial after Completion of 5 years' Adjuvant Treatment for Early Breast Cancer. Breast 
Cancer Res Treat, 2006. 100(3): p. 273-84. 
3. Fallowfield L.J., Bliss J.M., Porter L.S., Price M.H., Snowdon C.F., Jones S.E., et al., 
Quality of life in the intergroup exemestane study: a randomized trial of exemestane versus 
continued tamoxifen after 2 to 3 years of tamoxifen in postmenopausal women with 
primary breast cancer. J Clin Oncol, 2006. 24(6): p. 910-7. 
4. Whelan T.J., Goss P.E., Ingle J.N., Pater J.L., Tu D., Pritchard K., et al., Assessment of 
quality of life in MA.17: a randomized, placebo-controlled trial of letrozole after 5 years of 
tamoxifen in postmenopausal women. J Clin Oncol, 2005. 23(28): p. 6931-40. 
5. Stanton A.L., Bernaards C.A.,Ganz P.A., The BCPT symptom scales: a measure of physical 
symptoms for women diagnosed with or at risk for breast cancer. J Natl Cancer Inst, 2005. 
97(6): p. 448-56. 
6. Hürny C., Bernhard J., Gelber R.D., Coates A., Castiglione M., Isley M., et al., Quality of 
life measures for patients receiving adjuvant therapy for breast cancer: an international trial. 
The International Breast Cancer Study Group. Eur J Cancer, 1992. 28(1): p. 118-124. 
7. Bernhard J., Hürny C., Coates A.S., Peterson H.F., Castiglione Gertsch M., Gelber R.D., et 
al., Quality of life assessment in patients receiving adjuvant therapy for breast cancer: the 
IBCSG approach. The International Breast Cancer Study Group. Ann Oncol, 1997. 8(9): p. 
825-835. 
8. Hurny C., Bernhard J., Coates A., Peterson H.F., Castiglione-Gertsch M., Gelber R.D., et 
al., Responsiveness of a single-item indicator versus a multi-item scale: assessment of 
emotional well-being in an international adjuvant breast cancer trial. Med Care, 1996. 
34(3): p. 234-48. 
9. Hürny C., Bernhard J., Bacchi M., van Wegberg B., Tomamichel M., Spek U., et al., The 
Perceived Adjustment to Chronic Illness Scale (PACIS): a global indicator of coping for 
operable breast cancer patients in clinical trials. Swiss Group for Clinical Cancer Research 
(SAKK) and the International Breast Cancer Study Group (IBCSG). Support Care Cancer, 
1993. 1(4): p. 200-208. 
10. Bernhard J., Sullivan M., Huerny C., Coates A.S.,Rudenstam C.M., Clinical relevance of 
single item quality of life indicators in cancer clinical trials. Br. J. Cancer, 2001. 84(9): p. 
1156-1165. 
11. Bernhard J., Maibach R., Thurlimann B., Sessa C.,Aapro M.S., Patients' estimation of 
overall treatment burden: why not ask the obvious? J Clin Oncol, 2002. 20(1): p. 65-72. 

IBCSG 35-07/BIG 1-07 SOLE Appendix III: Quality of Life Substudy 
III-10 
 
V1.2  06Jul07 
 
 Coordinating Center Effingerstrasse 40 CH -3008 Bern Switzerland www.ibcsg.org 
12. Ribi K., Bernhard J., Rufibach K., Thürlimann B., R. v.M., T. R., et al., Endocrine 
symptom assessment in women with breast cancer: what a simple "yes" for the patients 
mean. submitted. 
13. Bernhard J., Zahrieh D., Castiglione-Gertsch M., Hurny C., Gelber R.D., Forbes J.F., et al., 
Adjuvant chemotherapy followed by goserelin compared with either modality alone: the 
impact on amenorrhea, hot flashes, and quality of life in premenopausal patients--the 
International Breast Cancer Study Group Trial VIII. J Clin Oncol, 2007. 25(3): p. 263-70. 
14. Sloan J.A., Frost M.H., Berzon R., Dueck A., Guyatt G., Moinpour C., et al., The clinical 
significance of quality of life assessments in oncology: a summary for clinicians. Support 
Care Cancer, 2006. 14(10): p. 988-98. 
 
 

SOLE-EST: SOLE Estrogen Substudy 
 
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SOLE-EST 
SOLE Estrogen Substudy 
 
 Investigating changes in estrogen levels and grip strength for 
patients participating in the SOLE Trial 
 
 
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 
      
INTERNATIONAL BREAST CANCER 
STUDY GROUP 
IBCSG 35-07 
BIG 1–07 
S    LE 
Study of Letrozole Extension 
 

SOLE-EST: SOLE Estrogen Substudy 
 
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V1.0 26Oct10 
 
 
Substudy Chairs 
 
Substudy Co-Chair 
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 
 
 
 
Substudy Co-Chair 
Prof. Guy Jérusalem 
CHU Sart Tilman 
Medical Oncology 
Domaine Universitaire B35 
4000 Liège, Belgium 
Email: g.jerusalem@chu.ulg.ac.be 
Tel: +32 43 667 664 
Fax: +32 43 667 448 
 
 
Central Laboratory 
 
Central Laboratories 
 
 
 
 
Dr. Frank Z. Stanczyk, PhD. 
Reproductive Endocrine Research  
Laboratory 
Keck School of Medicine, USC 
Livingston Research Building 
1321 N. Mission Road 
Annex – Room 124 
Los Angeles, CA 90033 
Email: fstanczyk@socal.rr.com 
Tel: +1 323 226 3220 
Fax: +1 323 226 2850 
 
 
 
 
 
 
 
Prof. Patrick Neven 
Vesalius Research Center 
K.U. Leuven and VIB  
Herestraat 49 
3000 Leuven, Belgium 
 
Email: 
patrick.neven@uz.kuleuven.ac.be  
Tel: +32 16 34 46 34 
Fax: +32 16 34 68 34 
 
 
Endocrinology Advisor 
 
Prof. Susan R. Davis 
Department of Medicine 
Monash University Alfred Hospital 
Commercial Rd 
Prahran 3181 Vic, Australia 
 
Email: 
Susan.Davis@med.monash.edu.au 
Tel: 61 (0) 3 9903 0684/ 0827 
Fax: 61 (0) 3 99030828 
 
 
 
IBCSG Offices and Contacts 
 
Safety & Regulatory Office 
Medical Affairs 
Quality of Life Office 
European Contact 
Dr. Barbara Ruepp 
Dr. Manuela Rabaglio 
Dr. Karin Ribi 
MSc. Susanne Roux 
IBCSG Coordinating Center 
Effingerstrasse 40 
Email: safetyoffice@ibcsg.org   
Email: manuela.rabaglio@ibcsg.org  
Email: karin.ribi@ibcsg.org 
Email: susanne.roux@ibcsg.org 
 
Tel: +41 31 389 9391 
 
CH-3008 Bern, Switzerland 
Fax: +41 31 389 9392 
 
 
 
Data Management Center 
Karolyn Scott, DataFax Data Management 
Section Head 
Cynthia Westby, Data Manager 
Holly Shaw, Lead Trial Coordinator 
Email: ibcsg35_sole@fstrf.org  
Tel: +1 716 898 7500 (general) 
Fax: +1 716 836 6097 
 
FSTRF, 4033 Maple Rd. 
 
 
Amherst, NY  14226  USA 
 
 
 
 
Statistical Center 
Meredith M. Regan, ScD 
Karen Price 
Julie Aldridge, MS 
Email : mregan@jimmy.harvard.edu 
Email: price@jimmy.harvard.edu   
Email: julie@jimmy.harvard.edu 

SOLE-EST: SOLE Estrogen Substudy 
 
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Dept. of Biostatistics & Computational 
Biology 
Tel: +1 617 632 3603 
 
Dana-Farber Cancer Institute 
Fax: +1 617 632 2444 
 
44 Binney St. 
 
 
Boston, MA 02115  USA 
 
 
 
 
IBCSG Tissue Bank 
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 
 
 
 
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 
Via Ripamonti 435 
I-20141 Milan, Italy 
Fax: +39 02 57489212 
 
 
Prof. Alan Coates 
 
Tel: +61 29331 3521 
 
40 Cook Road 
Fax: +61 28324 6466 
 
Centennial Park 
Email: alan.coates@ibcsg.org  
 
Sydney NSW 2021, Australia 
 
 
 
 
 
GROUP SPECIFIC CONTACT INFORMATION 
Please refer to Section 1 of Appendix V of the SOLE protocol for group-specific contact 
information to direct your inquiries about participation/eligibility/treatment for the SOLE 
parent trial. 
 

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Protocol Signature Page  
 
 
IBCSG 35-07/ BIG 1-07 
 
Study of Letrozole Extension – SOLE 
 
SOLE Estrogen Substudy – SOLE-EST 
 
 
 
Approved by:  
Anita Hiltbrunner  
Director, International Breast Cancer Study Group 
 
 
(Signature on file) 
 
 
 
 
26Oct10 
 
Signature 
 
 
 
 
 
Date  
 
 
Approved by:  
Dr. Meredith M. Regan 
Group Statistician, International Breast Cancer Study Group  
 
 
(Signature on file) 
 
 
 
 
26Oct10 
 
Signature 
 
 
 
 
 
Date  

SOLE-EST: SOLE Estrogen Substudy 
 
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Principal Investigator Protocol Signature Page  
 
SOLE Estrogen Substudy (SOLE-EST) of IBCSG 35-07 / BIG 1-07 / SOLE 
Version 1.0 26Oct10 
 
I have read the protocol and agree that it contains all necessary details for conducting this 
substudy. I will conduct the substudy as outlined in the following protocol and in compliance with 
GCP. I will provide copies of the protocol to all physicians responsible to me who participate 
in this substudy. I will discuss this material with them to assure that they are fully informed 
regarding the conduct of the substudy. I agree to keep records on all patient information (Case 
Report Forms and patient's Informed Consent statement), and all other information collected 
during the substudy for a minimum period of 15 years.  
 
Name of Principal Investigator: 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature 
 
 
 
 
 
 
 
Date  

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Substudy Summary and Schema 
 
SOLE Estrogen Substudy (SOLE-EST) 
 
A substudy of the SOLE Trial to investigate estrogen levels for patients participating in 
the SOLE Trial 
 
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, who have been randomized into the SOLE Trial and participate in the Quality of Life 
substudy. 
Entry:  Patients should be enrolled to SOLE-EST at the time of entry into the main study and 
the Quality of Life substudy. The first serum sample must be obtained after randomization but 
prior to starting letrozole on study according to the guidelines in the SOLE-EST Manual for 
Blood Sample Logistics and Vigorimeter Use. 
Sample size:  100 patients, 25 from arm A (continuous letrozole) and 75 from arm B 
(intermittent letrozole). 
 
 
SOLE-EST schema and blood sampling timepoints 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomize 
to SOLE 
(arm A or 
arm B) 
Register to 
SOLE-EST 
SOLE-EST serum sampling 
timepoints 
 0                                 6                                  12 
SOLE Protocol Visits at Month (1st year) 
SOLE-EST whole blood 
sampling timepoint 
0
SOLE-EST grip strength 
measurement 
9 
12 
0 
9 
12 
0 
10.5 

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Table of Contents 
1. 
Introduction and Rationale ........................................................................................................ 8 
1.1. Estrogen levels ................................................................................................................. 8 
1.2. Measuring estrogen levels ................................................................................................ 8 
1.3. Rationale for present study (SOLE-EST) ......................................................................... 9 
2. 
Objectives and endpoints ........................................................................................................ 11 
2.1. Primary objective ........................................................................................................... 11 
2.2. Secondary objectives: ..................................................................................................... 11 
2.3. Primary endpoints ........................................................................................................... 11 
2.4. Secondary endpoints ....................................................................................................... 11 
3. 
Study design ............................................................................................................................ 12 
4. 
Patient Selection ...................................................................................................................... 12 
4.1. SOLE-EST Participating Centers ................................................................................... 12 
4.2. Inclusion criteria ............................................................................................................. 12 
5. 
Patient Registration ................................................................................................................. 12 
6. 
Study Parameters and Data Submission .................................................................................. 13 
6.1. Assessments .................................................................................................................... 13 
6.2. Timing of assessments .................................................................................................... 13 
6.3. Required Samples ........................................................................................................... 13 
6.4. Forms submission ........................................................................................................... 14 
6.5. Sample collection logistics ............................................................................................. 14 
6.6. Grip strength measurement ............................................................................................ 14 
6.7. Blood banking ................................................................................................................ 14 
6.8. Determination of estrogen levels and SHBG ................................................................. 15 
6.9. SNP analysis ................................................................................................................... 15 
7. 
Measurement of toxicity and quality of life ............................................................................ 15 
8. 
Statistical Considerations ........................................................................................................ 16 
8.1. Study design and objectives ........................................................................................... 16 
8.2. Sample size considerations ............................................................................................. 16 
8.3. Data analyses .................................................................................................................. 17 
9. 
References ............................................................................................................................... 17 
 
Appendix I.  Sample patient information and informed consent 
 

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1. 
Introduction and Rationale 
Third generation aromatase inhibitors such as letrozole profoundly suppress estrogen levels in 
postmenopausal women, which is the mechanism of their action against hormone receptor 
positive breast cancer. The hypothesis under investigation in the SOLE Trial is that removing 
this suppression for a period of time will allow re-sensitization of breast cancer cells to 
estrogen deprivation resulting in a delay or prevention of the development of resistance to the 
anti-cancer effect of letrozole.  
 
The estrogen substudy will investigate the changes in estrogen levels that occur on letrozole 
and during the three month gap phase without letrozole. Estrogen suppression and recovery 
may also be linked with clinical outcomes including toxicity and disease free survival. In 
addition, the substudy will address the relationships between changes in patient reported 
musculoskeletal symptoms, grip strength, and QoL and related changes on letrozole and 
during the gap phase. As genes important for the metabolism and activity of letrozole may 
influence estrogen levels, single nucleotide polymorphisms (SNPs) related to these will be 
assessed and analyzed. 
1.1. 
Estrogen levels 
There are three biologically important circulating estrogens present in postmenopausal 
women:  
 
17 
Estradiol (E2) is a product of both estrone and testosterone and the most 
abundant circulating estrogen in premenopausal women  
 
Estrone (E1) is the major product of aromatase enzyme activity in postmenopausal 
women 
 
Estrone sulphate (E1S) is the most stable estrogen fraction measured and provides a 
robust surrogate-parameter for suppression of estrogen biosynthesis in vivo. 
 
Mean plasma levels of estradiol (E2), estrone (E1) and estrone sulphate (E1S) in 
postmenopausal women are reported to be 20, 80 and 4-500 pmol/L1,2,3 respectively.  
Suppression of estrogen production by letrozole reduces levels close to or below the level of 
detection in many assays.  
1.2. 
Measuring estrogen levels 
Gas chromatography/tandem mass spectrometry (GC-MS/MS) is considered the reference 
standard for measuring both male and female sex steroids. However, GC-MS/MS is not 
presently practical for the analysis of large sample sets and as with all assays, many variables 
factor into the accuracy of mass spectrometry methods including standardizing reagents, 
procedures, and hardware4. In postmenopausal women with low E2, indirect E2 assays 
correlate best with GC-MS/MS1,5, the extraction step in indirect assays removing potentially 
interfering substances, particularly cross-reacting water-soluble steroid conjugates. It is 
critical to note that direct assay measurements systematically overestimate E2 levels and as E2 
levels increase, the overestimation increases5,6. It is also important to measure sex hormone 
binding globulin (SHBG) as it is the major determinant of bioavailability of E1 and E2 in 
serum. Serum estrogen levels in postmenopausal women will also vary substantially by years 
since menopause, body mass index (BMI) and level of physical activity6,7. 
 
Data regarding estrogen levels using GC-MS/MS come from three main studies. In a large 
study5 including 374 postmenopausal women, the mean E2 level was 5.6 pg/ml (x 3.67=20.5 
pmol/L). In a second study9, 147 postmenopausal patients with early breast cancer were 

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randomized to receive placebo or exemestane. Mean baseline values for E2, E1 and E1S were 
4.0 and 4.8 pg/ml, 21 and 24.9 pg/ml and 179 and 212 pg/ml in placebo and exemestane 
groups, respectively. After 12 months of treatment with exemestane, mean values for E2, E1 
and E1S were reduced by 83, 93 and 93%, respectively. No individual values or estrogen 
levels were reported at 12 months. In a third report10, 55 postmenopausal women were treated 
either with atamestane/toremifene or letrozole/placebo. After a maximum of 12 weeks of 
aromatase inhibitor treatment estradiol levels fell from a mean value of 5.9 to <0.63 pg/ml. 
 
In the NSABP P-1 study, the median plasma E2 concentration using a validated indirect assay 
among untreated case subjects was 21 pmol/L (25th–75th percentile, 12 to 33 pmol/L) and the 
median SHBG plasma concentration among case subjects was 33 nmol/L (25th–75th 
percentile,  25 to 49 nmol/L)11. In a study of 54 patients receiving adjuvant AIs (anastrazole 
and letrozole), mean estrone sulphate levels were in the order of 1,054 pmol/L untreated (95% 
CI ,854 to 1,302) and with letrozole therapy fell to a mean of 20.7 pmol/L (95% CI,16.5 to 
25.9)12 In this study, baseline E2 levels ranged from 3 pmol/L to 91 pmol/L with a mean of 
25.7pmol/L and with letrozole were suppressed to a mean of 1.560 (95%CI,1.37 to 1.780). 
Other studies have shown similar suppression of estrogen levels by letrozole.1 
  
In conclusion, estrogen levels on letrozole are very low1,2,3,10,11,12,13. Measurement by 
extraction-based indirect assay appears to correlate well with the gold standard GC-MS/MS 
and is the most practical for this study. The laboratory of Frank Stanczyk will perform these 
assays; the lab sensitivity for E2 is 2pg/ml (7.34 pmol/L) for E1 is 3pg/ml (11.01 pmol/L) and 
for E1S RIA is 9 pg/ml (24.57 pmol/L).  
1.3. 
Rationale for present study (SOLE-EST) 
In the SOLE Trial, regular repeated episodes of low level estrogen exposure will occur during 
the break from letrozole due to renewed peripheral and potentially intra-tumoral aromatization 
of androgens. It is hypothesized that this may help to prevent development of resistance 
thereby increasing the efficacy of the extended adjuvant letrozole when given intermittently 
rather than continuously. There are a number of preclinical and clinical observations that 
support this hypothesis. 
 
After a time of very low estrogen levels breast cancer cells may develop estrogen independent 
growth and progress despite ongoing estrogen deprivation 14,15. It has also been shown that in 
cancer cell lines that are resistant to estrogen deprivation, estrogen can produce apoptosis and 
tumor regression 16 and there is also evidence that re-exposure to estrogen after a period of 
estrogen deprivation can re-sensitize breast cancer cells to estrogen deprivation, thereby 
overcoming resistance. Further animal studies (Long Term Letrozole Treated MCF-7Ca 
xenografts) have also demonstrated that stopping treatment with letrozole can reverse 
acquired resistance – in this study the break from letrozole was 4 months17. In addition, in a 
clinical study of estrogen deprived breast cancer there was also some evidence that estradiol 
(E2) may produce a treatment response17. 
 
The above hypothesis is however dependent on the renewed estrogen production following 
cessation of letrozole. The size and timing of this renewed estrogen production may vary 
between patients and may therefore potentially influence the value of this intervention. There 
is no clinical data on the effect of letrozole cessation on estradiol (E2) and other estrogen 
levels.  
 

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1.4 
Toxicity and Quality of Life 
 
Toxicity from letrozole is well documented19 and includes hot flushes, arthralgia, anxiety and 
depression, diarrhea and fatigue. A reduction in bone density and increased risk of fracture is 
also associated with its use. Several randomized trials in the adjuvant setting assessed self-
reported symptoms related to endocrine therapy in postmenopausal women with breast 
cancer20,21,22,23. Although these studies revealed no major effect on overall quality of life 
(QoL) by the different endocrine agents, difference in some QoL domains were observed. In 
the MA 17 extended-adjuvant trial comparing letrozole to placebo after 4.5-6 years of 
adjuvant tamoxifen, small but statistically significant differences of mean change scores from 
baseline to month 6, 12 and 24 showing a worsening for the letrozole group were seen for 
vasomotor symptoms (i.e., hot flushes and night sweats) and a number of QoL domains 
including physical function, bodily pain, vitality and sexuality23. Regarding the proportion of 
patients who demonstrated an important change in QoL, a significant difference was seen 
between groups with a higher percentage of patients in the letrozole group reporting a 
worsening in bodily pain and the vasomotor domains. Musculoskeletal side effects are 
amongst the most common and most troublesome side effects associated with aromatase 
inhibitors24,25,26and have been assessed in a number of ways. A simple and validated measure 
is grip strength using a modified sphygmomanometer19. The side effects and their impact on 
QoL due to treatment with an aromatase inhibitor for a duration longer than 5 years is as yet 
unknown. In addition, the effect of a three month break is not known. It is hypothesized that 
the increase in estrogen levels during the three month gap will reduce side effects, especially 
musculoskeletal side effects and patient-reported symptoms and that this will correlate with 
the absolute estrogen levels. It is also hypothesized that the increase in estrogen levels will 
improve QoL overall.  
 
The SOLE-EST Substudy will test these hypotheses by using the toxicity data collected in the 
main study and the QoL data collected in the QoL substudy and by measuring the grip 
strength of the patients. 
 
 
1.5  
Single Nucleotide Polymorphisms (SNPs) and relationship to estrogen levels 
 
Changes in the metabolisation of letrozole may translate into altered estrogen levels, and may 
therefore affect efficacy. 
 
Letrozole is metabolized by cytochrome P450 (CYP) isoenzymes including CYP2A6 and 
CYP3A4. Genetic variations in the genes encoding for those enzymes can alter the 
metabolism and therefore plasma levels of letrozole. This can have an impact on the efficacy 
of letrozole. Desta et al found significant differences in letrozole concentrations between 
slow, intermediate and normal CYP2A6 genotypes27. Therefore, SNPs on alleles CYP2A6*2, 
CYP2A6*9, CYP2A6*12 and CYP2A6*35 will be analyzed. In the CYP3A4 gene, only the 
CYP3A4*1B and CYP3A4*7 SNP have a known effect on the enzymatic activity and a 
frequency of more than 1% in the Caucasian population. Therefore, for the CYP3A4 gene, 
only those two SNPs will be genotyped. 
 
The gene encoding CYP19 (the aromatase enzyme that produces estrogen from testosterone) 
is a highly polymorphic gene that may influence the efficacy of letrozole through an altered 
(increased or decreased) activity. For this reason, the SNPs with a frequency of >10% in the 
Caucasian population and with a known effect on the enzymatic activity will be analyzed, 
namely rs4646, rs10046, rs727479, rs10459592, rs4775936, rs6493497 and rs717600528,29,32. 

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Rs4646, rs10459592 and rs4775936 have already been associated with an improved efficacy 
of letrozole28,29.  
 
There is also some evidence that genetic variation may explain the variation of the degree of 
side effects amongst women on letrozole. Ingle et al found 4 SNPs (rs7158782, rs7159713, 
rs2369049 and rs6637820) that were associated with the degree of musculoskeletal symptoms 
using a genome-wide association case-control study30. These SNPs will also be analyzed. The 
SNPs will be analyzed using the Sequenom MassARRAY® technology and the presence of 
the SNPs will be correlated with estrogen levels.  
 
In addition, further SNPs will be analyzed based on scientific evidence available at the time of 
evaluation. 
 
2. 
Objectives and endpoints 
2.1. 
Primary objective 
2.1.1. 
To determine the serum level of estrogens Estradiol (E2), Estrone (E1) and Estrone 
Sulphate (E1S) and Sex Hormone Binding Globulin (SHBG) during letrozole 
treatment.  
2.1.2. 
To determine the degree of recovery of Estradiol (E2), Estrone (E1) and Estrone 
Sulphate (E1S) during the 3 month gap.  
2.2. 
Secondary objectives: 
2.2.1. 
To link the estrogen level changes with the clinical outcomes of toxicity and QoL. 
2.2.2. 
To determine the effect of the following factors on estrogen levels: 
 prior adjuvant endocrine therapy 
 age 
 BMI 
 type of menopause  
2.2.3. 
To explore variability of estrogen level changes and link these with germline SNPs. 
2.3. 
Primary endpoints 
2.3.1 
Levels of Estradiol (E2), Estrone (E1) and Estrone Sulphate (E1S)  at 0, 9, 10.5 and 12 
months from randomization to the core protocol. 
 
2.3.2 
% change (suppression or recovery) of E2, E1 and E1S from baseline at 9 months, 
10.5 months and at 12 months from randomization to the core protocol. 
2.4. 
Secondary endpoints 
2.4.1. 
Toxicity grade changes (for arthralgia, hot flushes and insomnia) between 6 months 
(on letrozole) and 12 months (off letrozole for 3 months) and correlation with % 
recovery of estrogen levels. 

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2.4.2. 
Quality of life score change between 6 months (on letrozole) and 12 months (off 
letrozole for 3 months) and correlation with % recovery of estrogen levels. 
2.4.3. 
Changes in grip strength score at 9 months and 12 months. 
 
3. 
Study design  
Collection of blood for SNPs will be at baseline. 
 
Time points of serum collection for measurement of estrogen levels are 0 (pre-treatment), 9, 
10.5 and 12 months. 
 
Time points for measurement of grip strength are 0 (pre-treatment), 9 and 12 months. 
 
The substudy will include 75 patients from the intermittent arm and 25 from the continuous 
arm of the SOLE parent trial. The first 50 patients will be included from both arms (25 
patients from each arm), and the last 50 patients will be included from arm B (intermittent 
arm) alone.  
 
4. 
Patient Selection 
4.1. 
SOLE-EST Participating Centers 
SOLE-EST will be conducted in selected countries and Centers. These Centers will also be 
participating in the QoL substudy. All eligible patients randomized to SOLE from these 
Centers should be offered participation in SOLE-EST, but inclusion is not mandatory. 
4.2. 
Inclusion criteria 
4.2.1. 
Patient must be randomized to the parent SOLE Trial. 
4.2.2. 
Patient must participate in QoL substudy. 
4.2.3. 
Written informed consent for the SOLE-EST Substudy must be obtained. 
5. 
Patient Registration 
Registration to SOLE-EST should immediately follow randomization to the parent SOLE 
Trial, using the IBCSG Registration/Randomization System. The Confirmation of 
Registration Form (35-SE-A) should be completed prior to registration to confirm eligibility. 
Patients must be entered in the substudy immediately after their randomized allocation in the 
main SOLE Trial is known and prior to starting allocated treatment in order to obtain 
pretreatment baseline estrogen levels. A separate consent form applies to the substudy. 
 
During the recruitment period of the substudy, participating Centers are encouraged to 
approach all patients who enroll in SOLE for SOLE-EST participation. It is recommended 
that informed consent for SOLE-EST be obtained at the same time as for the parent trial. The 
baseline sample must be obtained prior to receiving protocol treatment. 

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6. 
Study Parameters and Data Submission 
6.1. 
Assessments 
A complete “estrogen profile” will be performed centrally: estradiol (E2), estrone (E1), and 
estrone sulphate (E1S). SHBG will also be performed centrally. The results of these 
assessments will not be available to make treatment decisions during the protocol treatment 
period. Blood will also be drawn at baseline for SNP analysis. 
6.2. 
Timing of assessments 
Assessment timepoints are determined by the interval from date of randomization to the core 
protocol and some do not coincide with the required clinical follow-up timepoints of the 
SOLE Trial. 
 
Substudy Parameters 
 
 
 
 
 
Regular SOLE visit number 
1 
2 
 
 
3 
Year 
1 
1 
1 
1 
2 
Trial Month 
0 
6 
9 
10.5 
12 
Visit only for SOLE-EST Substudy 
 
 
x 
x 
 
   Whole blood sample 
x 
 
 
 
 
   Serum sample 
x 
 
x 
x 
x 
   Grip strength 
x 
 
x 
 
x  
   Form 35-SE-SC 
x 
 
x 
x 
x 
x = mandatory 
Note: Serum and Form 35-SE-SC must also be submitted at discontinuation (see below) 
 
Blood samples can be taken at any time of day and do not need to be fasting. 
6.3. 
Required Samples 
Baseline sample (Month 0): After randomization to the SOLE Trial but prior to 
commencement of SOLE protocol therapy, a whole blood sample and a serum sample have to 
be drawn. 
 
Months 9 and 10.5 samples: Special visits only for the substudy. Only serum sample is 
needed. 
 
Month 12 sample: At the required clinical follow-up visit. For patients in arm B, it is 
mandatory that the blood is drawn prior to restart of letrozole. Only serum sample is needed. 
 
The Sample Collection Form (35-SE-SC) should be completed and submitted via DataFax at 
each collection timepoint listed above. This Case Report Form (CRF) confirms that the 
required samples were obtained, and can be submitted with the other CRFs for the SOLE 
Trial. Grip strength will also be reported on this form. 
 
For patients who come off study drug in Year 1 of trial treatment, a final blood sample will be 
collected. If a patient discontinues the SOLE-EST Substudy prior to the 12-month sample, for 
any reason (e.g., relapse or drug intolerance), then an Early Discontinuation (35-SE-ED) 
Form should be completed and submitted via DataFax.   
 

SOLE-EST: SOLE Estrogen Substudy 
 
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6.4. 
Forms submission 
The Data Management Manual for this substudy contains instructions for submitting forms 
using the DataFax system. 
 
 
6.5. 
Sample collection logistics  
Blood collection kits containing cryovials, labels and cryoboxes will be supplied to the 
participating Centers. These kits must be used for collection, storage and shipment of serum 
samples. At baseline a volume of 10 mL of blood has to be drawn in an EDTA treated tube 
and be stored at -20°C until shipment for SNP analysis to Vesalius Research Center, K.U. 
Leuven and VIB , Leuven, Belgium. At Months 0, 9, 10.5 and 12, a volume of 7.5-10 mL of 
blood should be drawn and processed to obtain two aliquots of serum, according to the SOLE-
EST Manual for Blood Sample Logistics and Vigorimeter Use. Every aliquot should be 
labeled as instructed in the SMM and stored at -20 ºC until delivery to the central laboratory,  
Reproductive Endocrine Research Lab Los Angeles, USA, for estrogen assays. All samples 
must be labeled with pre-printed self-adhesive labels, contained in the blood collection kits. 
The Sample Collection Form (Form 35-SE-SC) should be faxed into DataFax or entered into 
iDataFax at the time of the blood draw to inform IBCSG that the collection has been made.  
Samples have to be stored and shipped at -20°C. All assay results will be assessed centrally 
and results submitted to the IBCSG Data Management Center. The SOLE-EST Manual for 
Blood Sample Logistics and Vigorimeter Use contains the details for sample collection, 
storage, and shipping, as well as measuring grip strength.  
 
Samples will be anonymized and confidentiality will be maintained during the entire process. 
The costs of blood collection will be covered by the additional patient fee and shipping will be 
free of charge. 
6.6. 
Grip strength measurement 
Grip strength will be measured using the Martin Vigorimeter and recorded on Form 35-SE-
SC. The Vigorimeter will be provided or reimbursed by IBCSG.  Grip Strength will be 
measured at Baseline and Months 9 and 12. 
6.7. 
Blood banking 
Surplus DNA isolated from the whole blood as well as surplus serum will be transferred to the 
IBCSG Tissue Bank located at the IBCSG Central Pathology Office, Milan, Italy, for use in 
not yet specified future research. As part of the informed consent process, patients are asked 
IC Form 
Informed Consent Form 
Obtain before registration for SOLE-EST and keep 
with patient records. 
Form 35-SE-A 
Confirmation of Registration Form 
Complete before contacting your Randomization 
Center or entering the IBCSG 
Registration/Randomization system to register.  
DataFax the completed form for all patients registered 
or enter it into iDataFax. 
Form 35-SE-
BMC 
Biological Material Consent Form 
DataFax after registration with Form 35-SE-A or enter 
into iDataFax. 
Form 35-SE-
SC 
SOLE-EST Sample (and grip 
strength) Collection Form 
DataFax (via fax or iDataFax) at baseline (after 
randomization to SOLE but prior to commencement of 
protocol therapy), Months 9, 10.5 and 12 (grip strength 
not tested at Month 10.5) 
Form 35-SE-
ED 
SOLE-EST Early Discontinuation 
Form 
Submit to DataFax (via fax or iDataFax) once upon 
early discontinuation of the substudy. 

SOLE-EST: SOLE Estrogen Substudy 
 
15 
V1.0 26Oct10 
 
 
to indicate whether they agree that their sample is used for such research. The use of the DNA 
and serum for unspecified future research will be under the auspices of the IBCSG Biological 
Protocols Working Group and any project has to be approved by the IBCSG Ethics 
Committee.  
6.8. 
Determination of estrogen levels and SHBG 
Estrogen levels must be measured using a highly sensitive assay. Direct radioimmunoassay 
(RIA) does not provide adequate sensitivity at low levels. RIA specificity can be increased by 
an organic solvent extraction step, which if combined with chromatographic separation of 
estrogen from interfering steroids, will enable reliable measurement of the steroid. 
 
A central laboratory (Reproductive Endocrine Research Lab,  Los Angeles, USA) will do the 
assays, and the sensitivity they quote for their RIA using a 1.0 ml aliquot of serum is as 
follows: 
 
for estradiol (E2) is 2 pg/ml  (7.34pmol/L)  
 
for estrone(E1) is 3 pg/ml (11.01pmol/L) 
 
for estrone sulphate (E1S) is 9 pg/ml (33.03pmol/L) 
 
It is considered that a 50% increase in estradiol (E2) levels or a level of >12pmol/L (for those 
whose levels were below the lower limit of sensitivity for the assay) after cessation of 
letrozole would be clinically significant. 
 
6.9. 
SNP analysis 
The Sequenom MassARRAY® technology, which is an innovative technology platform for 
high-throughput genotyping of gene polymorphisms, will be used for the SNP analysis. It 
efficiently multiplexes up to 40 different genotypes into one reaction, and thereby provides 
very flexible, effective, rapid and accurate genotypes at an affordable price. The Sequenom 
platform is fully operational at the Vesalius Research Center, K.U. Leuven and VIB, Belgium. 
 
7. 
Measurement of toxicity and quality of life 
Collection of toxicity information: 
Adverse event information will be collected at baseline and at 6 and 12 months as per the 
main study on Form 35-AE.  
 
Measurement of musculoskeletal toxicity: 
An additional assessment of musculoskeletal toxicity will be undertaken with the use of a grip 
strength measure at baseline, 9 and 12 months using a modified sphygmomanometer (Martin 
Vigorimeter). To perform the hand grip test, the patient is asked to squeeze the balloon of a 
modified sphygmomanometer three times with maximal force and the maximal value of three 
trials of each hand will be used for evaluation. This assessment has high inter-rater reliability 
and takes a minimal amount of time. 
 
Quality of life assessment: 
Patient-reported symptoms will be assessed by the Breast Cancer Prevention Trial (BCPT) 
Symptom Scales31 on Form 35-PRS. In addition, several global QoL indicators will be 
assessed using the IBCSG Trial 35-07 QL Form. For detailed descriptions of the measures 

SOLE-EST: SOLE Estrogen Substudy 
 
16 
V1.0 26Oct10 
 
 
please refer to Appendix III of the IBCSG 35-07/BIG 1-07 Protocol: Patient Reported 
Symptoms and Quality of Life Substudy. 
8. 
Statistical Considerations 
8.1. 
Study design and objectives  
The study will use a longitudinal design with samples drawn over a 12-month period (0, 9, 
10.5 and 12 months after randomization to the core protocol). Only patients enrolled in the 
parent trial are eligible. The target accrual to the substudy is 100 patients. The main objectives 
are: 
8.1.1. 
To describe estrogen levels (E2, E1 and E1S) at different timepoints during the first 12 
months of protocol treatment, including:  
 
The degree of recovery of E2, E1 and E1S during the 3 month break from letrozole. 
 
Levels and degree of suppression from baseline of E2, E1 and E1S during 12 months 
of treatment with letrozole taken either continuously or intermittently. 
 
The within-patient variability of E2, E1 and E1S across time among patients 
continuously taking letrozole. 
 
Whether levels or degree of suppression of estrogens vary according to:  
o prior adjuvant endocrine therapy (type, duration, duration without therapy prior 
to study entry)  
o current age  
o type of menopause  
o BMI 
8.1.2. 
To assess the correlation of estrogen levels and of changes in estrogen levels from 
baseline with clinical outcomes of toxicity (musculoskeletal toxicity [as assessed by 
grip strength], arthralgia, hot flushes and insomnia) and quality of life measures and 
with germline SNPs.  
8.2. 
Sample size considerations  
The target accrual to the substudy is 100 patients, 25 in arm A (continuous letrozole) and 75 
in arm B (intermittent letrozole). Taking into account the actual accrual of participating 
Centers, enrollment is expected to be completed at the time the parent trial closes to accrual. 
 
Sample size was determined based on a conservative approach to the primary analysis in 
which patients are classified as to whether or not the change in E2 between 9 and 12 months 
exceeds a certain threshold indicative of clinically significant recovery of E2. Clinically 
significant recovery is defined as a 50% increase in estradiol (E2) levels or a level of 
>12pmol/L (for those whose levels were below the lower limit of sensitivity for the assay). 
With a sample size of 100 patients, 25 in arm A (continuous letrozole) and 75 in arm B 
(intermittent letrozole), and assuming conservatively that only 80% of patients have paired 
samples at 9 and 12 months, then there is over 90% power to detect a difference between 10% 
vs. 50% of patients having recovery of E2 during the 3-month interval (Fisher’s exact test; 
two-sided α=0.05).  
 
Further, the sample size will allow exploration of the relation of other factors – specified 
patient characteristics, clinical measures and germline SNPs – with E2 changes measured on 
the continuum. Again focusing on the change in E2 between 9 and 12 months among patients 
in arm B, and considering a range of the frequency of a binary factor in the population from 

SOLE-EST: SOLE Estrogen Substudy 
 
17 
V1.0 26Oct10 
 
 
50-50% to 10-90% , the detectable effect size between two groups ranges from about 0.75 to 
1.25 SD (80% power, two-sided α=0.05, two-sample t-test). For a continuous factor a 
Pearson’s correlation coefficient of 0.36 vs. null value of 0 would be detectable.   
8.3. 
Data analyses  
Estrogen levels (E2, E1, E1S) will be summarized over time among all patients and by 
treatment arm using descriptive statistics (mean, SD, median, quartiles) and graphically. It is 
anticipated based on the literature that log-transformation of estrogen levels may be required, 
in which case the geometric mean would be reported. Values will also be summarized as 
percent change from baseline levels.  
 
Using linear mixed modeling of all available data over the 4 timepoints (or of 3 timepoints 
relative to baseline), each estrogen level will be modeled as a function of time and treatment 
arm and the interaction of the two factors to investigate the time pattern of estrogen levels and 
differences in levels between treatment arms. Of primary interest is whether the change from 
9 to 10.5 and 12 months differs among patients assigned to intermittent vs. continuous 
letrozole. It may be the case that estrogen levels while on treatment are below the assay lower 
limit of detection, in which case the analysis method would be changed to account for this sort 
of “floor effect” or “left censoring” of data. Relationships of specified patient characteristics 
(prior endocrine therapy, age at and/or type of menopause, BMI) with the estrogen levels and 
changes in levels will also be investigated, as well as specific toxicities and quality of life 
measures and germline SNPs. 
 
9. 
References 
 
1. Geisler J, Haynes B, Anker G, Dowsett M, Lonning PE  Influence of letrozole and 
anastrazole on total body aromatization and plasma estrogen levels in postmenopausal 
breast cancer patients evaluated in a randomized cross-over study.   J.Clin.Oncol. 2002 
Jul1; 20(3):751-7 
2. Geisler J, Ekse D, Helle H, Duong NK, Lonning PE. An optimised, highly sensitive 
radioimmunoassay for the simultaneous measurement of estrone, estradiol and estrone 
sulfate in the ultra low range in human plasma samples. J Steroid Biochem Mol Biol. 2008 
Mar;109(1-2):90-95 
3. Lonning PE, Geisler J, Johannessen DC et al. Plasma estrogen suppression with aromatase 
inhibitors evaluated by a novel, sensitive assay for estrone sulphate. J Steroid Biochem. 
Mol Biol. 61:225-260,1997 
4. Stanczyk FZ, Clarke NJ. Advantages and challenges of mass spectrometry assays for 
steroid hormones. J Steroid Biochem Mol Biol. 2010 Aug;121(3-5):491-5. Epub 2010 
May 12. 
5. Lee JS, Ettinger B, Stanczyk FZ et al Comparison of methods to measure low serum 
estradiol levels in postmenopausal women. J Clin Endocrinol Metab 2006; 91(10): 3791-
3797  
6. Stanczyk FZ, Jurow J, Hsing AW. Limitations of direct immunoassays for measuring 
circulating estradiol levels in postmenopausal women and men in epidemiologic studies. 
Cancer Epidemiol Biomarkers Prev. 2010 Apr;19(4):903-6. Epub 2010 Mar 23. 
7. Lamar CA, Dorgan JF, Longcope C, Stanczyk FZ, Falk RT, Stephenson HE Jr   Serum 
sex hormones and breast cancer risk factors in postmenopausal women. Cancer Epidemiol 
Biomarkers  Prev Apr 2003 ;12 (4): 380-383, April 2003   

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8. Van Gils CH, Peeters PH, Schoenmakers MC, Nijmeijer RM, Onland-Moret,NC, van der 
Schow YT, Monninkhof EM . Physical activity and sex hormone level in postmenopausal 
women: a cross-sectional study in the Prospect-EPIC Cohort. Cancer Epidemiol 
Biomarkers Prev. 2009 Feb;18(2):377-83 
9. Lonning PE, Geisler J, Krag LE et al. Effects of exemestane administered for 2 years 
versus placebo on bone mineral density, bone biomarkers, and plasma lipids in patients 
with surgically resected early breast cancer. J Clin Oncol 23.5126-5137,2005 
10. Santen RJ, Demers L, Ohorodnik S, Settlage J, Langecker P, Blanchett D, Goss PE, Wang 
S. Superiority of gas chromatography/tandem mass spectometry assay (GC/MS/MS) for 
estradiol for monitoring of aromatase inhibitor therapy. Steroids. 2007 Jul;72(8):666-71 
11. Beattie MS, Constantino JP, Cummings SR, Wickerham DL, Vogel VG, Dowsett M, 
Folkerd EJ, Willett WC, Wolmark N, Hankinson SE. 2006.J Natl Cancer Inst.  2006 Jan 
18;98(2):110-115 Endogenous sex hormones, breast cancer risk and tamoxifen response: 
an ancillary study in the NSABP Breast Cancer Prevention Trial (P1). 
12. Dixon JM, Renshaw L, Young O, Murray J, Macaskill EJ, McHugh M, Folkerd E, 
Cameron DA, A’Hern RP, Dowsett M    Letrozole suppresses plasma oestradiol and 
oestrone sulphate more completely than anastrazole in postmenopausal women with breast 
cancer.  J.Clin.Oncol. 2008 Apr1; 26(10):1671-6 
13. Geisler J, Helle H, Ekse D, Duong NK, Evans DB, Nordbo Y, Aas T, Lonning PE. 
Letrozole is superior to anastrazole in suppressing breast cancer tissue and plasma 
estrogen levels. Clin Cancer Res 2008 Oct 1;14(19):6330-5 
14. Brodie A, Jelovac D, Macedo L, Sabnis G, Tilghman S, Goloubeva O   Therapeutic 
observations in MCF-7 aromatase xenografts  Clin. Cancer Res. 2005 Jan 15;11(2 pt 
2):884s-8s 
15. Brodie A, Jelovec D, Sabnis G, Long B, Macedo L, Galoubeva O   Model systems: 
mechanisms involved in the loss of sensitivity to letrozole   J. Steroid Biochem. Mol. Biol. 
2005 May; 95(1-5): 41-8 
16. Lewis at al   Estrogen induces apoptosis and tumour regression in a breast cancer cell line 
resistant to estrogen deprivation.  J. Natl. Cancer Inst 2005; 97:1746-59 
17. Sabnis GJ, Macedo LF, Goloubeva O, Shayowitz A, Brodie AM  Stopping treatment can 
reverse acquired resisitance to letrozole   Cancer res 2008 Jun 15;68(12):4518-24 
18. Ellis MJ, Dehdahti F, Kommareddy A, Jamalabadi-Majidi S, Crowder R, Jeffe DB, Gao F, 
Fleming G, Silverman P, Dickler M, Carey L, Marcom PK      A randomized phase 2 trial 
of low dose (6 mg daily) versus high dose (30 mg daily) estradiol for patients with 
estrogen receptor positive aromatase inhibitor resistant advanced breast cancer.  Abstract 
16, San Antonio Breast Cancer Symposium  2008 
19. Morales L, Pans S, Verschueren K, et al: Prospective study to assess short-term intra-
articular and tenosynovial changes in the aromatase inhibitor–associated arthralgia 
syndrome. J Clin Oncol 2008; 26: 3147-52. 
20. Fallowfield L., Cella D., Cuzick J., Francis S., Locker G.,Howell A., Quality of life of 
postmenopausal women in the Arimidex, Tamoxifen, Alone or in Combination (ATAC) 
Adjuvant Breast Cancer Trial. J Clin Oncol, 2004. 22(21): p. 4261-71. 
21. Cella D., Fallowfield L., Barker P., Cuzick J., Locker G.,Howell A., Quality of Life of 
Postmenopausal Women in the ATAC ("Arimidex", Tamoxifen, Alone or in 
Combination) Trial after Completion of 5 years' Adjuvant Treatment for Early Breast 
Cancer. Breast Cancer Res Treat, 2006. 100(3): p. 273-84. 
22. Fallowfield L.J., Bliss J.M., Porter L.S., Price M.H., Snowdon C.F., Jones S.E., et al., 
Quality of life in the intergroup exemestane study: a randomized trial of exemestane 
versus continued tamoxifen after 2 to 3 years of tamoxifen in postmenopausal women 
with primary breast cancer. J Clin Oncol, 2006. 24(6): p. 910-7. 

SOLE-EST: SOLE Estrogen Substudy 
 
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23. Whelan T.J., Goss P.E., Ingle J.N., Pater J.L., Tu D., Pritchard K., et al., Assessment of 
quality of life in MA.17: a randomized, placebo-controlled trial of letrozole after 5 years 
of tamoxifen in postmenopausal women. J Clin Oncol, 2005. 23(28): p. 6931-40. 
24. The ATAC Trialists’ Group. Results of the ATAC (Arimidex, Tamoxifen Alone or in 
Combination) trial after completion of 5 years’ adjuvant treatment for breast cancer. 
Lancet 2005; 365:60-62. 
25. 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 2004; 350:1081-1092.  
26. Goss P, Ingle J, Martino S, et al. A randomized trial of letrozole in postmenopausal 
women after 5 years of  tamoxifen therapy for early-stage breast cancer. N Eng J Med 
2003, 349:1-10. 
27. Desta Z, Tyndale R, Hoffmann E, Kreutz Y, Nguyen AT et al. Cytochrome P450 (CYP) 
2A6 Genetic Variation Predicts Letrozole Plasma Concentrations in Postmenopausal 
Women with Breast Cancer. San Antonio Breast Cancer Symposium 2009; Abstract 5160. 
28. Colomer R, Monzo M, Tusquets I, Rifa J, Baena JM et al. A single-nucleotide 
polymorphism in the aromatase gene is associated with the efficacy of the aromatase 
inhibitor letrozole in advanced breast carcinoma. Clin Cancer Res. 2008;14(3):811-6. 
29. Park IH, Ro J, Lee KS, Kim S-Y, Lee Y-S. Single Nucleotide Polymorphisms of 
CYP19A1, rs10459592 and rs4775936 Predict Clinical Benefit of Letrozole in Patients 
with Metastatic Breast Cancer. San Antonio Breast Cancer Symposium 2009; Abstract 
2117. 
30. Ingle J, Schaid D, Goss P, Mushiroda T, Chapman J-A et al. A Genome-Wide Association 
Study in Patients Experiencing Musculoskeletal Adverse Events on Aromatase Inhibitors 
as Adjuvant Therapy in Early Breast Cancer Entered on NCIC CTG Trial MA.27. A 
Pharmacogenetics Research Network-RIKEN Collaboration. San Antonio Breast Cancer 
Symposium 2009; Oral Presentation 15. 
31. Stanton A.L., Bernaards C.A., Ganz P.A., The BCPT symptom scales: a measure of 
physical symptoms for women diagnosed with or at risk for breast cancer. J Natl Cancer 
Inst, 2005. 97(6): p. 448-56. 
32. Wang L, Ellsworth KA, Moon I, Pelleymounter LL, Eckloff BW et al. Functional genetic 
polymorphisms in the Aromatase gene CYP19 Vary the Response of Breast Cancer 
Patients to Neoadjuvant Therapy with Aromatase Inhibitors. Cancer Res 2010; 70 (1):319-
28. 
 

 
 
 
 
 
 
 
 
International Breast Cancer Study Group Statistical Center 
 
 
SOLE (Trial 35-07/BIG 1-07) 
 
Statistical Analysis Plan 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Version 
Author 
Date
Status
1 
Weixiu Luo 
Jan 2017
For primary trial report 
2 
Meredith Regan, ScD 
May 2019 
For 
final, 
updated 
report 
[updates/changes to SAP from 2017 
report tracked, marked as edited or 
marked as new]  
 
 
 
 
 

SOLE SAP: May 2019 
 
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 
Last Visit: 
31 December 2018 
 
 
 
 
 

SOLE SAP: May 2019 
 
Trial 35-07 -- 3 
 
 
Trial Schema: 
 
 
 
 
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 5 
years of extended letrozole will improve disease-free survival. 
 
The randomization was stratified according to participating center and prior SERM/AI endocrine 
therapy (SERM(s) alone, AI(s) alone, both SERM(s) and AI(s)). Patients were randomized 1:1 to 
one of two extended adjuvant endocrine therapy groups: 
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, with 
treatment-free intervals for the last 3 months of years 1 through 4, followed by 12 months of 
letrozole 2.5 mg daily in year 5 
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. All patients will be followed 
every 6 months for years 1 to 5, and yearly thereafter for assessment of disease status and for 
survival data collection. 
 
1.3 
SAMPLE SIZE CONSIDERATIONS 
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 detect the treatment difference 647 DFS events are required, assuming 4800 patients are 
accrued (1600 patients per year for 3 years), 5% non-assessability at 4 years, and approximately 

SOLE SAP: May 2019 
 
Trial 35-07 -- 4 
 
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. 
 
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. The final DSMC review was undertaken on 
13 November 2017 after all patients had completed the 5-year protocol therapy period, and 
determined that follow-up should continue as planned. 
 
1.6 
PRIMARY RESULTS 
After a median follow-up of 5 years  (data cut-off, 31 October 2016), DFS events were reported 
for 665 of 4851 patients in the intention-to-treat population. Patients assigned intermittent 
letrozole did not have a significantly reduced hazard of a DFS event vs. patients assigned 
continuous letrozole (HR=1.08; 95% CI, 0.93 to 1.26; P=0.31). The estimated 5-year DFS was 
85.8% among patients assigned intermittent letrozole versus 87.5% for patients assigned 
continuous letrozole. Similar results were observed for secondary endpoints of breast cancer-free 
interval (431 events, HR=0.98; 95% CI, 0.81 to 1.18; P=0.84), distant recurrence-free interval 
(338 events, HR=0.88; 95% CI, 0.71 to 1.09; P=0.25), and overall survival (316 deaths, 
HR=0.85; 95% CI, 0.68 to 1.06; P=0.16). At 60 months median follow-up, 27% of patients 
continued on protocol treatment. 36.2% and 34.5% of patients assigned to intermittent versus 
continuous letrozole had grade 3-5 targeted AEs reported, of which grade 3-4 hypertension was 
most frequently reported. 
 
The results were presented at the 2017 ASCO Annul Meeting in June 2017 [1] and subsequently 
published in The Lancet Oncology [2]. In postmenopausal women with hormone receptor-
positive breast cancer, extended use of intermittent letrozole did not improve disease-free 
survival compared with continuous use of letrozole. 

SOLE SAP: May 2019 
 
Trial 35-07 -- 5 
 
 
1.7 
FINAL, UPDATED ANALYSIS 
A decision was made following publication of the primary results to cease follow-up as of 31 
December 2018 (last patient, last FU visit), at which point the median follow-up would be 
extended from 5 to approximately 7 years (range 6 to 11 years). A SOLE Flash newsletter was 
distributed to investigators, providing information regarding closure of data collection at the end 
of 2018. 
 
In addition to an update of the primary and secondary endpoints, adverse events and final 
treatment status (the 5 years of protocol treatment was reached as of October 2017) , it was 
decided that this final analysis would include also the SOLE-EST substudy and further 
investigate whether there is heterogeneity of treatment efficacy according to type and duration of 
prior endocrine therapies, .  
 
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. The final, updated analysis will 
continue to use an ITT approach and the ITT population as originally reported will be used, even 
if information has changed since the primary report; the only exception would be for a case in 
inadequately documented informed consent or withdrawal of consent to use any data. 
 
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 

SOLE SAP: May 2019 
 
Trial 35-07 -- 6 
 
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 (i.e., DFS events): Hierarchy of failures from least to worst, following 
standard IBCSG definition: 
o 
Local 
o 
Contralateral Breast ± above 
o 
Regional ± above 
o 
Soft tissues/distant nodes ± above 
o 
Bone ± above 
o 
Viscera (including ‘other’) ± above 
as well as, 
o 
second (non-breast) malignancy,  
o 
death without prior cancer event (aka death without subsequent cancer event) 
o 
death with breast cancer recurrence suspected 
o 
death with no information about recurrence. 
 
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: May 2019 
 
Trial 35-07 -- 7 
 
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 reported 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. Since the first report, the 35-RC form SOP was clarified that in cases 
with multiple proven sites of first recurrence (within 2 months of each other), that the date first 
suspected should be the earliest of suspected dates from among those proven sites (which may 
not necessarily correspond to the site with the earlies proven date). 
 
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).  
 
The final, Uupdated results will be presented every approximately two to three years thereafter 
the primary report. 
 
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. 
 

SOLE SAP: May 2019 
 
Trial 35-07 -- 8 
 
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 
between RA and A forms to compare the information obtained at randomization versus that on 
the A forms. [done, no longer needed] 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 [EDITED] 
2.6.1 Enrollment, Follow-up Compliance 
2.6.1.1 Overview of enrollment 
Figures: 
• Enrollment over time; x-axis time in 6-montly intervals; y-axis number enrolled 
2.6.1.2 Follow-up submission 
Tables: 
• Institutional follow-up compliance by group/country (rows) 
2.6.1.3 CONSORT 
In the manner of the CONSORT diagram, the following will be summarized, with changes from the 
primary report highlighted. 
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 
[not expected to change since primary analysis] 
o Number in analysis population who never started protocol treatment [note any 
changes since primary analysis] 
o Number in analysis population who WC/LFU [update] 
o Number of patients analyzed in analysis population [same as number included; 
not expected to change since primary analysis] 
 
2.6.1.3 Stratification 
Tables 
• Distribution of stratification factors, overall and according to treatment assignment 
• Listing of any new information about actual (from A-form) values of stratification factors 

SOLE SAP: May 2019 
 
Trial 35-07 -- 9 
 
2.6.1.4 Withdrawn consent/loss to follow-up status 
Summary should mention any centers that were lost to follow-up since the primary report. 
Tables: 
• Withdrawn consent and lost to follow-up status, overall and according to treatment 
assignment 
 
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). The 
same tables will be re-run, and may differ slightly from the primary report as the data will reflect 
any updates to the database since the primary database lock. 
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 [this was an error; not collected] 
o BMI at randomization 
o Menopausal status at primary cancer diagnosis 
o Symptoms (from baseline AE form) [n.b., slight redefinition] 
• 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 [not reported; not useful] 
o Prior endocrine therapy [stratification factor; actual] and years of prior endocrine 
therapy [<4.5; 4.5-5.5; >5.5]; more detail will be added, see section 2.6.5 below  
o Duration from end of prior adjuvant therapy to randomization [≤1 vs >1 month] 
• Disease:  
o ER/PgR and HER2 status (H form) 
o Nodal involvement (number of positive lymph nodes 0, 1-3, 4-9, 10+, unknown)  
o Tumor size (<1, 1-2, >2-5, >5 cm) and grade (1, 2, 3), primary histology (ductal 
vs lobular vs other; and other details from H form) 
o Disease laterality and location 
 

SOLE SAP: May 2019 
 
Trial 35-07 -- 10 
 
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 (and IQR and 
range; overall and by treatment assignment) will be reported. Numbers of outcome events at 
primary analysis and at final, updated analysis will be tabulated, for ease of reference. 
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), overweight (25 - <30), normal (<25), unknown) 
• 
Tumor size (≤2 vs >2 cm; unknown) 
• 
Tumor Grade (1,2,3,unknown) 
• 
ER/PgR subgroup (+/+; +/-; -/+; unknown and other)   [too few not +/+ to be meaningful] 
• 
HER2 status (positive, negative, unknown) [too few positive to be meaningful] 
• 
No. of positive lymph nodes (0, 1-3, 4+, unknown) 
• 
Type of prior endocrine therapy (AI, SERM, AI and SERM) & more details? 
• 
Duration of prior endocrine therapy (<4.5, 4.5-5.5, >5.5 years) & more details? 
• 
Interval of time since the cessation of prior endocrine therapy till randomization (≤1, >1 mo) 
2.6.3.2 
Models 
Stratified Cox PH regression models will be used to: estimate HRs (95% CI) for treatment effect, 
unadjusted and 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 and 7yr DFS, SE and 95% CI 
• Treatment effects within subgroups: N events and patients and 7yr rates within each 
subgroup, treatment HR, 95% CI, p-value for test of treatment-by-variable interaction 
Figures: 

SOLE SAP: May 2019 
 
Trial 35-07 -- 11 
 
• KM plot of DFS, by treatment group, for entire analysis population (y-axis: Percent Alive 
and Disease-Free; x-axis: Time since Randomization (1-year intervals); x-axis limited to 
6 8 years (median follow-up plus 1 year) and numbers at risk at each yearly 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 assignment.  
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 & 7yr DFS, SE and 95% CI 
• Sites of first failure, overall and by treatment assignment 
• Types of second non-breast malignancies, as site of first failure, overall and by treatment 
assignment.  
• Second non-breast malignancies and Death without prior cancer event (list of patients 
with type of malignancy or cause of death, respectively) 
Figures: 
• KM plots of BCFI, by treatment group, for entire analysis population (y-axis: Percent 
Free from Breast Cancer; x-axis: Time since Randomization (1-yr intervals); x-axis 
limited to 68 years (median survival plus 1 year) and numbers at risk at each yearly 
interval) 
• KM plots of DRFI, by treatment group, for entire analysis population (y-axis: Percent 
Free from Distant Recurrence; x-axis: Time since Randomization (1-yr intervals); x-axis 
limited to 6 8 years (median survival plus 1 year) and numbers at risk at each yearly 
interval) 
• KM plot of OS, by treatment group, for entire analysis population (y-axis: Percent Alive; 
x-axis: Time since Randomization (1-yr intervals); x-axis limited to 6 8 years (median 
survival plus 1 year) and numbers at risk at each yearly interval) 
 
2.6.5 Treatment Efficacy in Relation to Prior Endocrine Therapy Type & Duration (new) 
Motivation: Investigate whether duration of prior AI is associated with treatment responsiveness; 
hypothesize that different duration of prior AI may be differentially sensitive to AI interruption 

SOLE SAP: May 2019 
 
Trial 35-07 -- 12 
 
on basis of heterogeneity of extended AI trial results depending on prior therapy of enrolled 
population. 
 
Endpoints: BCFI, DRFI, DFS; OS to be analyzed only if other results of interest, to ensure 
consistency of message. 
 
1) Define prior ET type and duration in more detail: 
• number of months of prior AI, number of months of prior SERM;  
• first drug taken, most recent drug taken;  
• number of weeks of prior AI within the 1 yr before randomization.  
Re-tabulate categories of AI duration, in particular looking more closely at those with both prior 
AI and SERM exposure to better differentiate those with sequential tam>AI (approx. 2>3 yrs) as 
separate from those that had a short duration of AI and mostly tamoxifen (i.e., more like SERM-
only), or had at least 4 yrs of AI (i.e., more like AI-only).  [0-<6m; 6m -<2y; 2-<3y; 3-<4y; ≥4y] 
 
2) Assess relation of prior AI use with other covariates, especially age and menopausal status at 
diagnosis, and disease characteristics.  
• Tabulate patient, disease and treatment characteristics reported at randomization, overall 
and according to AI duration categories above (without regard to treatment assignment). 
 
3) Assess relation of prior AI use (AI duration categories above) with time to protocol therapy 
cessation (with DFS event as competing risk); with and without regard to treatment assignment. 
• There is particular interest in a group of patients who had very short AI exposure (>0 but 
<6m to 1yr) early in adjuvant treatment and presumably stopped because of tolerability 
(i.e., do not include pts whose short AI exposure was just prior to randomization); the 
clinical question would be whether such patients should re-try AI for extended adjuvant 
or also very likely to cease early.  
 
4) Assess relation prior AI duration with treatment comparison; 
• STEPP analysis, on HR and 7-yr event rate, with continuous prior AI duration as x-axis; 
note this doesn’t adjust for covariates. 
• Using unstratified Cox model, test prior AI categories (as above) vs treatment assignment 
interaction, adjusted for selected patient and disease characteristics [age or menopausal 
status, BMI; nodes, tumor size, tumor grade, HER2 status; prior chemo? prior local-
therapy?]  (n.b., 3-category prior ET already done in forest plot, unadjusted; may want to 
repeat this in adjusted Cox model) 
• If useful as part of unadjusted analyses, KM plots of subgroups defined by prior AI 
duration categories (as above) and treatment assignment, with 7-yr estimates.  
 

SOLE SAP: May 2019 
 
Trial 35-07 -- 13 
 
2.6.6 Adverse Events / Safety 
2.6.6.1 
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 (noting any difference from primary 
report). 
2.6.6.2 
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. 95% 
exact CIs will be calculated for each targeted AE, according to treatment group. 
 
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.  
 
Late adverse events (LAEs: cardiac ischemia/infarction, thrombosis/thrombus/embolism, CNS 
cerebrovascular ischemia, and fractures) were requested on CRFs, but very little was reported, 
thus we will not automatically summarize these data, as we’re concerned that this would 
underrepresent the prevalence of such events.  
 
2.6.6.3 
Tables and Figures 
Tables: 
• 
Numbers of patients in the safety population, overall and by stratum and treatment 
assignment; listing of any changes since primary analysis and listing of any patients who started 
treatment but do not have AE CRFs submitted 
• 
Targeted AEs by grade, reported according to treatment assignment; N, % 
• 
Targeted AEs, % grade 1-5 AE with 95% CI; % grade 3-5 AE with 95% CI, reported 
according to treatment assignment 
• 
Targeted AEs by grade, reported according to prior endocrine therapy and treatment 
assignment; N, frequency 
• 
Other non-targeted grade 3-5 AEs, deemed possibly, probably or definitely related to study 
treatment(s) according to treatment assignment, N 
 

SOLE SAP: May 2019 
 
Trial 35-07 -- 14 
 
2.6.7 Treatment 
Final 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 permanent 
treatment discontinuation will be summarized using KM curves according to treatment 
assignment; this will be done without regard to reason to summarize the exposure period, and 
secondarily with disease events as competing risks as a measure of adherence with 5-yr treatment 
period. 
Details of scheduled (and unscheduled) interruptions were analyzed and reported in the primary 
Clinical Trial Report. These analyses below will not be repeated: 
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. 
 
 

SOLE SAP: May 2019 
 
Trial 35-07 -- 15 
 
Tables 
• Final status of protocol-assigned treatment, overall and according to treatment 
assignment (same as CTR table 8.1.1) 
• Number (%) patients with per-protocol interruptions and resumptions for patients 
assigned intermittent letrozole (CTR table 8.3.1) 
• Number (%) patients who took not-per-protocol interruptions over the 5 years, according 
to treatment assignment (CTR table 8.3.2) 
• Number (%) patients on treatment by month, according to treatment assignment 
(denominator is pts who have not perm. d/c at beginning of month; numerator is pts on 
treatment at beginning of month; %) 
Figures 
• Time from randomization to permanent treatment discontinuation, according to treatment 
assignment, with yearly estimates: all reasons (CTR Fig 8.2.1), and then with disease 
event as competing risk (x-axis: months 0-72 since randomization; y-axis: percent on 
treatment 0-100) 
• Percentage of patients on treatment by month, according to treatment assignment (x-axis: 
month 1 to 60, y-axis: percentage; CTR Fig 8.3.1) 
• Percentage of patients on treatment by 3-month intervals, according to treatment group 
(x-axis: interval 1 to 20 quarters, y-axis: percentage; CTR Fig 8.3.2) 
• Mean percentage of days on treatment during 3-month intervals, according to treatment 
group (x-axis: interval 1 to 20 quarters, y-axis: mean percentage; CTR Fig 8.3.3) 
 
3 
SOLE-EST SUBSTUDY 
3.1 
SUMMARY 
Third generation aromatase inhibitors such as letrozole profoundly suppress estrogen levels in 
postmenopausal women, which is the mechanism of their action against hormone receptor 
positive breast cancer. The hypothesis under investigation in the SOLE trial is that removing this 
suppression for a period of time will allow re-sensitization of breast cancer cells to estrogen 
deprivation resulting in a delay or prevention of the development of resistance to the anti-cancer 
effect of letrozole.  
 
The estrogen suppression substudy enrolled patients at randomization and aims to describe the 
changes in serum levels of estrogen levels that occur on letrozole and during the three-month 
treatment gap without letrozole. The blood sampling time points were over the first year since 
randomization (see schema). Estrogen suppression and recovery may also be linked with clinical 
outcomes including toxicity and disease free survival. SOLE-EST will also examine the 
relationship between estrogen level changes and changes in toxicity, patient-reported 
musculoskeletal symptoms and QL, and grip strength. As genes important for the metabolism 
and activity of letrozole may influence estrogen levels,  single nucleotide polymorphisms (SNPs) 
related to these will be assessed and analyzed in relation to the variability of estrogen level 
changes.  

SOLE SAP: May 2019 
 
Trial 35-07 -- 16 
 
 
SOLE-EST was activated in IBCSG Participating Centers located in Belgium, Australia, and 
Milan on 19 November 2010 and the first patient enrolled on 31 January 2011. Enrollment was 
closed 12 July 2012, with a final accrual of 104 patients (25 from the continuous arm and 79 
from the intermittent arm) enrolled at 14 Participating Centers.  
 
All eligible patients randomized to SOLE from these Centers were to be offered participation in 
SOLE-EST, but inclusion was not mandatory. 
 
 
SOLE-EST OVERVIEW 
Title: 
SOLE-EST: SOLE Estrogen Substudy: Investigating changes in estrogen levels 
and grip strength for patients participating in the SOLE Trial. 
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, who: have been randomized into the SOLE trial; participate in the Quality of 
Life substudy; provide written informed consent. 
Entry: 
Patients should be enrolled to SOLE-EST at the time of entry into the main study and 
the Quality of Life substudy. The first serum sample must be obtained after 
randomization but prior to starting letrozole on study according to the guidelines in 
the SOLE-EST Manual for Blood Sample Logistics and Vigorimeter Use. 
Activation Date: 
19 November 2010 (First patient enrolled on 31 January 2011) 
Target Accrual:  
100 patients: 25 from the continuous arm and 75 from the intermittent arm. 
Closure Date: 
12 July 2012 (Arm A closed 29 Sept 2011) 
Final Accrual: 
104 patients 
 
 
 

SOLE SAP: May 2019 
 
Trial 35-07 -- 17 
 
3.2 
BACKGROUND 
There are three biologically important circulating estrogens present in postmenopausal women:  
17 β-Estradiol (E2) is a product of both estrone and testosterone and the most abundant 
circulating estrogen in premenopausal women; estrone (E1) is the major product of aromatase 
enzyme activity in postmenopausal women; estrone sulphate (E1S) is the most stable estrogen 
fraction measured and provides a robust surrogate-parameter for suppression of estrogen 
biosynthesis in vivo. Mean plasma levels of E2, E1 and E1S in postmenopausal women are 
reported to be 20, 80 and 4-500 pmol/L respectively. Suppression of estrogen production by 
letrozole reduces levels close to or below the level of detection in many assays. 
 
Musculoskeletal side effects are amongst the most common and most troublesome side effects 
associated with aromatase inhibitors and have been assessed in a number of ways. A simple and 
validated measure is grip strength using a modified sphygmomanometer. The effect of a three 
month break on QL was reported for the overall trial population. It was hypothesized that the 
increase in estrogen levels during the three month gap would reduce side effects, especially 
musculoskeletal side effects and patient-reported symptoms; and it is hypothesized that this will 
correlate with the absolute estrogen levels. It is also hypothesized that the increase in estrogen 
levels will improve QoL overall. The SOLE-EST substudy will test these hypotheses by using 
the toxicity data collected in the main study and the QoL data collected in the QoL substudy and 
by measuring the grip strength of the patients. 
 
Letrozole is metabolized by cytochrome P450 (CYP) isoenzymes including CYP2A6 and 
CYP3A4. Genetic variations in the genes encoding for those enzymes can alter the metabolism 
and therefore plasma levels of letrozole. The gene encoding CYP19 (the aromatase enzyme that 
produces estrogen from testosterone) is a highly polymorphic gene that may influence the 
efficacy of letrozole through an altered (increased or decreased) activity. There is also some 
evidence that genetic variation may explain the variation of the degree of side effects amongst 
women on letrozole. Ingle et al. found 4 SNPs that were associated with the degree of 
musculoskeletal symptoms using a genome-wide association case-control study.  
 
3.3 
OBJECTIVES AND ENDPOINTS 
Primary objective:  
• To determine the serum level of estrogens E2, E1 and E1S and Sex Hormone Binding 
Globulin (SHBG) during letrozole treatment  
• To determine the degree of recovery of E2, E1 and E1S during the 3 month gap.  
Also noted, describe the within-patient variability of E2, E1 and E1S across time among patients 
continuously taking letrozole. 
Secondary objectives:  
• To link the estrogen level changes with the clinical outcomes of toxicity (musculoskeletal 
toxicity [as assessed by grip strength], arthralgia, hot flushes and insomnia) and QoL.  

SOLE SAP: May 2019 
 
Trial 35-07 -- 18 
 
• To determine the effect of the following factors on estrogen levels: prior adjuvant endocrine 
therapy (type, duration, duration without ET prior to study entry); age; BMI; type of 
menopause. 
• To explore variability of estrogen level changes and link these with germline SNPs.  
 
Primary endpoints  
• Levels of E2, E1 and E1S at 0, 9, 10.5 and 12 months from randomization to the core 
protocol.  
• % change (suppression or recovery) of E2, E1 and E1S from baseline at 9 months, 10.5 
months and at 12 months from randomization to the core protocol.  
Secondary endpoints  
• Toxicity grade changes (for arthralgia, hot flushes and insomnia) between 6 months (on 
letrozole) and 12 months (off letrozole for 3 months) and correlation with % recovery of 
estrogen levels. 
• Quality of life score change between 6 months (on letrozole) and 12 months (off letrozole 
for 3 months) and correlation with % recovery of estrogen levels.  
• Changes in grip strength score at 9 months and 12 months. 
 
3.4 
SUBSTUDY DESIGN AND PROCEDURES 
3.4.1 Blood Samples and Assays 
A whole blood sample was obtained at baseline. Serum samples were obtained at 4 time points 
(0, 9, 10.5 and 12 months); they were taken at any time of day and were not fasting. Samples 
were taken using provided blood collection kits and stored locally at -20°C. Assays were 
performed centrally.  
 
To be checked. Estrogen levels must be measured using a highly sensitive assay. A central 
laboratory (Reproductive Endocrine Research Lab of Frank Stanczyk, Los Angeles, USA) will 
do the assays, and the sensitivity they quote for their RIA using a 1.0 mL aliquot of serum is as 
follows:  
• for estradiol (E2) is 2 pg/ml (7.34pmol/L)  
• for estrone(E1) is 3 pg/ml (11.01pmol/L)  
• for estrone sulphate (E1S) is 9 pg/ml (33.03pmol/L) 
• for SHBG .  
 
It is considered that a 50% increase in estradiol (E2) levels or a level of >12pmol/L (for those 
whose levels were below the lower limit of sensitivity for the assay) after cessation of letrozole 
would be clinically significant. 
 

SOLE SAP: May 2019 
 
Trial 35-07 -- 19 
 
The protocol stated the SNPs were to be analyzed using the Sequenom MassARRAY® 
technology in the laboratory of Vesalius Research Center, K.U. Leuven and VIB, Belgium:  
• SNPs on alleles CYP2A6*2, CYP2A6*9, CYP2A6*12 and CYP2A6*35  
• In the CYP3A4 gene, only the CYP3A4*1B and CYP3A4*7 SNP have a known effect on 
the enzymatic activity and a frequency of more than 1% in the Caucasian population. 
Therefore, for the CYP3A4 gene, only those two SNPs will be genotyped. 
• The CYP19 SNPs with a frequency of >10% in the Caucasian population and with a 
known effect on the enzymatic activity will be analyzed, namely rs4646, rs10046, 
rs727479, rs10459592, rs4775936, rs6493497 and rs7176005. 
• SNPs previously associated with musculoskeletal symptoms: rs7158782, rs7159713, 
rs2369049 and rs6637820. 
 
3.4.2 Measurement of toxicity and quality of life 
Adverse event information will be collected at baseline and at 6 and 12 months as per the main 
study. Primary AEs are arthralgia, hot flushes and insomnia. 
 
Patient-reported symptoms will be assessed by the Breast Cancer Prevention Trial (BCPT) 
Symptom Scales on Form 35-PRS. In addition, several global QoL indicators will be assessed 
using the IBCSG Trial 35-07 QL Form.  
 
Grip strength will be measured using the Martin Vigorimeter (a modified sphygmomanometer , 
provided or reimbursed by IBCSG) at 0, 9, 12 months. To perform the hand grip test, the patient 
is asked to squeeze the balloon of a modified sphygmomanometer three times with maximal 
force and the maximal value of three trials of each hand will be used for evaluation. This 
assessment has high inter-rater reliability and takes a minimal amount of time. 
 
3.4.3 Sample size considerations 
Sample size was determined based on a conservative approach to the primary analysis in which 
patients are classified as to whether or not the change in E2 between 9 and 12 months exceeds a 
certain threshold indicative of clinically significant recovery of E2. Clinically significant 
recovery is defined as a 50% increase in estradiol (E2) levels or a level of >12pmol/L (for those 
whose levels were below the lower limit of sensitivity for the assay). With a sample size of 100 
patients, 25 in arm A (continuous letrozole) and 75 in arm B (intermittent letrozole), and 
assuming conservatively that only 80% of patients have paired samples at 9 and 12 months, then 
there is over 90% power to detect a difference between 10% vs. 50% of patients having recovery 
of E2 during the 3-month interval (Fisher’s exact test; two-sided α=0.05).  
 
Further, the sample size will allow exploration of the relation of other factors – specified patient 
characteristics, clinical measures and germline SNPs – with E2 changes measured on the 
continuum. Again focusing on the change in E2 between 9 and 12 months among patients in arm 

SOLE SAP: May 2019 
 
Trial 35-07 -- 20 
 
B, and considering a range of the frequency of a binary factor in the population from 50-50% to 
10-90% , the detectable effect size between two groups ranges from about 0.75 to 1.25 SD (80% 
power, two-sided α=0.05, two-sample t-test). For a continuous factor a Pearson’s correlation 
coefficient of 0.36 vs. null value of 0 would be detectable. 
 
3.4.4 Analysis plan (from protocol) 
Estrogen levels (E2, E1, E1S) will be summarized over time among all patients and by treatment 
arm using descriptive statistics (mean, SD, median, quartiles) and graphically. It is anticipated 
based on the literature that log-transformation of estrogen levels may be required, in which case 
the geometric mean would be reported. Values will also be summarized as percent change from 
baseline levels.  
 
Using linear mixed modeling of all available data over the 4 timepoints (or of 3 timepoints 
relative to baseline), each estrogen level will be modeled as a function of time and treatment arm 
and the interaction of the two factors to investigate the time pattern of estrogen levels and 
differences in levels between treatment arms. Of primary interest is whether the change from 9 to 
10.5 and 12 months differs among patients assigned to intermittent vs. continuous letrozole. It 
may be the case that estrogen levels while on treatment are below the assay lower limit of 
detection, in which case the analysis method would be changed to account for this sort of “floor 
effect” or “left censoring” of data. Relationships of specified patient characteristics (prior 
endocrine therapy, age at and/or type of menopause, BMI) with the estrogen levels and changes 
in levels will also be investigated, as well as specific toxicities and quality of life measures and 
germline SNPs. 
 
3.4.5 Analysis plan for trial reporting 
We plan as part of the report of the parent trial to include the analysis of the SOLE-EST primary 
objective. The secondary objectives will be analyzed separately, with separate SAP. 
 
3.4.5.1 
Population and Available Samples 
Accrual: 
Tabulate by country, site: numbers of patients, first/last enrollment dates 
 
Accounting: 
* Patients: Pt participation over the 12 months, incl. protocol treatment status at 9 (arms A & B) 
and 12 (arm A) months 
* Samples: Sample assay results availability, by timepoint; timing relative to planned collection 
timepoints  
* Flow diagram 
 

SOLE SAP: May 2019 
 
Trial 35-07 -- 21 
 
Characteristics, same tabs as parent trial: 
* tabulate SE pts vs all ITT patients  
* tabulate SE pts vs all ITT patients at the participating sites 
* tabulate SE pts vs all ITT patients at the participating sites during SE enroll period 
 
Additional Characteristics: 
In addition to characteristics from the main trial, collected for SOLE-EST are: 
• Dominant hand 
• Type of menopausal will be derived from additional data collected on SE-A form:  
o menopause 
information 
(bilateral 
oophorectomy, 
RT 
ovarian 
ablation, 
chemotherapy-induced amenorrhea, natural menopause before BC diagnosis, 
natural menopause since BC diagnosis) 
o potential for residual ovarian function (whether age<55, ovarian function 
recovered following chemotherapy, receipt of GnRH/LHRH in past 2 yrs; last 
menstruation within past 2 yrs, other potential for residual ovarian function 
specify) 
 
 
Hormone levels at baseline: 
* descriptive statistics in relation to: prior ET; most recent prior ET; duration from end of prior 
ET to randomization; duration prior AI category, age, type menopause  
 
Hormone levels over time: 
* note, may need to look at variability in planned vs actual timing of samples and whether that 
influences levels; 
* descriptive statistics, boxplots, spaghetti plots according to timepoint and treatment assignment 
[absolute levels] 
* descriptive statistics of percent change and fold-change from baseline, according to timepoint 
and treatment assignment 
* descriptive statistics, graphical summaries of percent change and fold-change from 9m to 10.5 
and 12m, according to timepoint and treatment assignment 
 
* according to other characteristics? 
 

 
 
 
 
 
 
 
 
International Breast Cancer Study Group Statistical Center 
 
 
SOLE-EST (Trial 35-07/BIG 1-07) 
 
Statistical Analysis Plan 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Version 
Author 
Date
Status
1 
Subrina Farah 
March 2020 
Analysis of primary and secondary 
objectives
 
 
 

SOLE-EST SAP: March 2020 
 
Trial 35-07 -- 2 
 
1 
INTRODUCTION 
1.1 
SUMMARY 
Third generation aromatase inhibitors such as letrozole profoundly suppress estrogen levels in 
postmenopausal women, which is the mechanism of their action against hormone receptor positive 
breast cancer. The hypothesis under investigation in the SOLE trial is that removing this 
suppression for a period of time will allow re-sensitization of breast cancer cells to estrogen 
deprivation resulting in a delay or prevention of the development of resistance to the anti-cancer 
effect of letrozole.  
 
The estrogen suppression substudy enrolled patients at randomization and aims to describe the 
changes in serum levels of estrogen levels that occur on letrozole and during the three-month 
treatment gap without letrozole. The blood sampling time points were over the first year since 
randomization (see schema). Estrogen suppression and recovery may also be linked with clinical 
outcomes including toxicity and disease-free survival. SOLE-EST will also examine the 
relationship between estrogen level changes and changes in toxicity, patient-reported 
musculoskeletal symptoms and QL, and grip strength. As genes important for the metabolism and 
activity of letrozole may influence estrogen levels, single nucleotide polymorphisms (SNPs) 
related to these will be assessed and analyzed in relation to the variability of estrogen level 
changes.  
 
SOLE-EST was activated in IBCSG Participating Centers located in Belgium, Australia, and 
Milan on 19 November 2010 and the first patient enrolled on 31 January 2011. Enrollment was 
closed 12 July 2012, with a final accrual of 104 patients (25 from the continuous arm and 79 from 
the intermittent arm) enrolled at 14 Participating Centers.  
 
All eligible patients randomized to SOLE from these Centers were to be offered participation in 
SOLE-EST, but inclusion was not mandatory. 
 
 
 
 

SOLE-EST SAP: March 2020 
 
Trial 35-07 -- 3 
 
SOLE-EST OVERVIEW 
Title: 
SOLE-EST: SOLE Estrogen Substudy: Investigating changes in estrogen levels and 
grip strength for patients participating in the SOLE Trial. 
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, who: have been randomized into the SOLE trial; participate in the Quality of 
Life substudy; provide written informed consent. 
Entry: 
Patients should be enrolled to SOLE-EST at the time of entry into the main study and 
the Quality of Life substudy. The first serum sample must be obtained after 
randomization but prior to starting letrozole on study according to the guidelines in the 
SOLE-EST Manual for Blood Sample Logistics and Vigorimeter Use. 
Activation Date: 
19 November 2010 (First patient enrolled on 31 January 2011) 
Target Accrual:  
100 patients: 25 from the continuous arm and 75 from the intermittent arm. 
Closure Date: 
12 July 2012 
Final Accrual: 
104 patients 
 
 
 
1.2 
BACKGROUND 
There are three biologically important circulating estrogens present in postmenopausal women:  
17 β-Estradiol (E2) is a product of both estrone and testosterone and the most abundant circulating 
estrogen in premenopausal women; estrone (E1) is the major product of aromatase enzyme activity 
in postmenopausal women; estrone sulphate (E1S) is the most stable estrogen fraction measured 
and provides a robust surrogate-parameter for suppression of estrogen biosynthesis in vivo. Mean 
plasma levels of E2, E1 and E1S in postmenopausal women are reported to be 20, 80 and 4-500 
pmol/L respectively. Suppression of estrogen production by letrozole reduces levels close to or 
below the level of detection in many assays. 
 

SOLE-EST SAP: March 2020 
 
Trial 35-07 -- 4 
 
Musculoskeletal side effects are amongst the most common and most troublesome side effects 
associated with aromatase inhibitors and have been assessed in a number of ways. A simple and 
validated measure is grip strength using a modified sphygmomanometer. The effect of a three-
month break on QL was reported for the overall trial population. It was hypothesized that the 
increase in estrogen levels during the three-month gap would reduce side effects, especially 
musculoskeletal side effects and patient-reported symptoms; and it is hypothesized that this will 
correlate with the absolute estrogen levels. It is also hypothesized that the increase in estrogen 
levels will improve QoL overall. The SOLE-EST substudy will test these hypotheses by using the 
toxicity data collected in the main study and the QoL data collected in the QoL substudy and by 
measuring the grip strength of the patients. 
 
Letrozole is metabolized by cytochrome P450 (CYP) isoenzymes including CYP2A6 and 
CYP3A4. Genetic variations in the genes encoding for those enzymes can alter the metabolism 
and therefore plasma levels of letrozole. The gene encoding CYP19 (the aromatase enzyme that 
produces estrogen from testosterone) is a highly polymorphic gene that may influence the efficacy 
of letrozole through an altered (increased or decreased) activity. There is also some evidence that 
genetic variation may explain the variation of the degree of side effects amongst women on 
letrozole. Ingle et al. found 4 SNPs that were associated with the degree of musculoskeletal 
symptoms using a genome-wide association case-control study.  
 
2 
OBJECTIVES AND ENDPOINTS 
Primary objective:  
• To determine the serum level of estrogens E2, E1 and E1S and Sex Hormone Binding 
Globulin (SHBG) during letrozole treatment  
• To determine the degree of recovery of E2, E1 and E1S during the 3-month gap.  
Also noted, describe the within-patient variability of E2, E1 and E1S across time among patients 
continuously taking letrozole. 
Secondary objectives:  
• To link the estrogen level changes with the clinical outcomes of toxicity (musculoskeletal 
toxicity [as assessed by grip strength], arthralgia, hot flushes and insomnia) and QoL. 
• To determine the effect of the following factors on estrogen levels: prior adjuvant endocrine 
therapy (type, duration, duration without ET prior to study entry); age; BMI; type of 
menopause. 
• To explore variability of estrogen level changes and link these with germline SNPs.  
 
Primary endpoints  
• Levels of E2, E1 and E1S at 0, 9, 10.5 and 12 months from randomization to the core protocol.  
• % change (suppression or recovery) of E2, E1 and E1S from baseline at 9 months, 10.5 
months and at 12 months from randomization to the core protocol.  

SOLE-EST SAP: March 2020 
 
Trial 35-07 -- 5 
 
o Calculated as timepoint minus baseline, so that positive are increases from baseline 
and negative are decreases from baseline 
• Addition: % change (suppression or recovery) of E2, E1 and E1S from 9 months at 10.5 
months and at 12 months 
o Calculated as timepoint minus 9mo, so that positive are increases from 9mo and 
negative are decreases from 9mo  
Secondary endpoints  
• Toxicity grade changes (for arthralgia, hot flushes and insomnia) between 6 months (on 
letrozole) and 12 months (off letrozole for 3 months) and correlation with % recovery of 
estrogen levels. 
o Calculated as 12mo minus 6mo, so that positive is increase in grade and negative 
is decrease in grade 
• Quality of life score change between 6 months (on letrozole) and 12 months (off letrozole for 
3 months) and correlation with % recovery of estrogen levels.  
o LASA scores higher value is better condition, thus change is calculated as 12mo 
minus 6 mo so that positive is improved condition and negative is declined 
condition. 
• Changes in grip strength score [from baseline] at 9 months and 12 months. 
o Higher value is greater strength, thus change is calculated as 12mo minus 9 mos so 
that positive is improved condition and negative is declined condition. 
 
3 
SUBSTUDY DESIGN AND PROCEDURES 
3.1.1 Blood Samples and Assays 
A whole blood sample was obtained at baseline. Serum samples were obtained at 4 time points (0, 
9, 10.5 and 12 months); they were taken at any time of day and were not fasting. Samples were 
taken using provided blood collection kits and stored locally at -20°C. Assays were performed 
centrally.  
 
Estrogen levels must be measured using a highly sensitive assay. A central laboratory 
(Reproductive Endocrine Research Lab of Frank Stanczyk, Los Angeles, USA) will do the assays, 
and the sensitivity they quote for their RIA using a 1.0 mL aliquot of serum is as follows [to be 
confirmed with lab after assays]:  
• for estradiol (E2) is 2 pg/ml (7.34pmol/L)  
• for estrone(E1) is 3 pg/ml (11.01pmol/L)  
• for estrone sulphate (E1S) is 9 pg/ml (33.03pmol/L).  
 
It is considered that a 50% increase in estradiol (E2) levels or a level of >12pmol/L (for those 
whose levels were below the lower limit of sensitivity for the assay) after cessation of letrozole 
would be clinically significant. 

SOLE-EST SAP: March 2020 
 
Trial 35-07 -- 6 
 
 
The SNPs were to be analyzed using the Sequenom MassARRAY® technology in the laboratory 
of Vesalius Research Center, K.U. Leuven and VIB, Belgium [methodology to be re-confirmed]. 
The protocol noted the following. 
• SNPs on alleles CYP2A6*2, CYP2A6*9, CYP2A6*12 and CYP2A6*35  
• In the CYP3A4 gene, only the CYP3A4*1B and CYP3A4*7 SNP have a known effect on 
the enzymatic activity and a frequency of more than 1% in the Caucasian population. 
Therefore, for the CYP3A4 gene, only those two SNPs will be genotyped. 
• The CYP19 SNPs with a frequency of >10% in the Caucasian population and with a known 
effect on the enzymatic activity will be analyzed, namely, rs10046, rs727479, rs10459592, 
rs4775936, rs6493497 and rs7176005. 
• SNPs previously associated with musculoskeletal symptoms: rs7158782, rs7159713, 
rs2369049 and rs6637820. 
The listing at the end of this document includes the notes from 2013 when SNP selection was 
planned; SNPs run are highlighted, and the few additional SNPs run (3 CYP19, 4 CYP17A1, 1 
SLCO1B1) are added. 
 
3.1.2 Measurement of toxicity and quality of life 
Adverse event information will be collected at baseline and at 6 and 12 months as per the main 
study. Primary AEs are arthralgia, hot flushes and insomnia. 
 
Patient-reported symptoms will be assessed by the Breast Cancer Prevention Trial (BCPT) 
Symptom Scales on Form 35-PRS. In addition, several global QoL indicators will be assessed 
using the IBCSG Trial 35-07 QL Form. QL measures were taken every 6 months until 24 months. 
 
Grip strength will be measured using the Martin Vigorimeter (a modified sphygmomanometer , 
provided or reimbursed by IBCSG) at 0, 9, 12 months. To perform the hand grip test, the patient 
is asked to squeeze the balloon of a modified sphygmomanometer three times with maximal force 
and the maximal value of three trials of each hand will be used for evaluation. This assessment has 
high inter-rater reliability and takes a minimal amount of time. 
 
3.1.3 Additional Characteristics 
In addition to characteristics from the main trial, collected for SOLE-EST are: 
• Dominant hand 
• Type of menopausal will be derived from additional data collected on SE-A form:  
o menopause 
information 
(bilateral 
oophorectomy, 
RT 
ovarian 
ablation, 
chemotherapy-induced amenorrhea, natural menopause before BC diagnosis, 
natural menopause since BC diagnosis) 

SOLE-EST SAP: March 2020 
 
Trial 35-07 -- 7 
 
o potential for residual ovarian function (whether age<55, ovarian function recovered 
following chemotherapy, receipt of GnRH/LHRH in past 2 yrs; last menstruation 
within past 2 yrs, other potential for residual ovarian function specify) 
 
3.1.4 Sample size considerations (from protocol) 
Sample size was determined based on a conservative approach to the primary analysis in which 
patients are classified as to whether or not the change in E2 between 9 and 12 months exceeds a 
certain threshold indicative of clinically significant recovery of E2. Clinically significant recovery 
is defined as a 50% increase in estradiol (E2) levels or a level of >12pmol/L (for those whose 
levels were below the lower limit of sensitivity for the assay). With a sample size of 100 patients, 
25 in arm A (continuous letrozole) and 75 in arm B (intermittent letrozole), and assuming 
conservatively that only 80% of patients have paired samples at 9 and 12 months, then there is 
over 90% power to detect a difference between 10% vs. 50% of patients having recovery of E2 
during the 3-month interval (Fisher’s exact test; two-sided α=0.05).  
 
Further, the sample size will allow exploration of the relation of other factors – specified patient 
characteristics, clinical measures and germline SNPs – with E2 changes measured on the 
continuum. Again focusing on the change in E2 between 9 and 12 months among patients in arm 
B, and considering a range of the frequency of a binary factor in the population from 50-50% to 
10-90% , the detectable effect size between two groups ranges from about 0.75 to 1.25 SD (80% 
power, two-sided α=0.05, two-sample t-test). For a continuous factor a Pearson’s correlation 
coefficient of 0.36 vs. null value of 0 would be detectable. 
 
3.1.5 Analysis plan (from protocol) 
Estrogen levels (E2, E1, E1S) will be summarized over time among all patients and by treatment 
arm using descriptive statistics (mean, SD, median, quartiles) and graphically. It is anticipated 
based on the literature that log-transformation of estrogen levels may be required, in which case 
the geometric mean would be reported. Values will also be summarized as percent change from 
baseline levels.  
 
Using linear mixed modeling of all available data over the 4 timepoints (or of 3 timepoints relative 
to baseline), each estrogen level will be modeled as a function of time and treatment arm and the 
interaction of the two factors to investigate the time pattern of estrogen levels and differences in 
levels between treatment arms. Of primary interest is whether the change from 9 to 10.5 and 12 
months differs among patients assigned to intermittent vs. continuous letrozole. It may be the case 
that estrogen levels while on treatment are below the assay lower limit of detection, in which case 
the analysis method would be changed to account for this sort of “floor effect” or “left censoring” 
of data. Relationships of specified patient characteristics (prior endocrine therapy, age at and/or 
type of menopause, BMI) with the estrogen levels and changes in levels will also be investigated, 
as well as specific toxicities and quality of life measures and germline SNPs. 

SOLE-EST SAP: March 2020 
 
Trial 35-07 -- 8 
 
 
4 
ANALYSIS PLAN 
4.1.1 Primary objectives: To determine the serum levels during letrozole treatment: 
• Descriptive statistics tabulation of E2, E1, E1s and SHBG values with respect to most 
recent ET taken prior to randomization. 
• Descriptive statistics tabulation of E2, E1, E1s and SHBG values over time by treatment 
arms. 
• Descriptive statistics tabulation of the percent change in values of E2, E1, E1s and SHBG 
from baseline to timepoint by treatment arms. 
• Descriptive statistics tabulation of the fold change in values of E2, E1, E1s and SHBG from 
baseline to timepoint by treatment arms. 
• Scatter box plots to depict level of E2, E1, E1s and SHBG over time by treatment arms. 
• Spaghetti plots of E2 levels over time for each treatment arm separately.  
 
4.1.2 Primary objectives: To determine the degree of recovery during the 3-month gap: 
• Descriptive statistics tabulation of the percent change in values of E2, E1, E1s from month 
9 to timepoint by treatment arms. 
• Descriptive statistics tabulation of the fold change in values of E2, E1, E1s from month 9 
to timepoint by treatment arms. 
• Statistical testing of E2 recovery for intermittent group from 9 to 12 months and 
secondarily from 9 to 10.5 months (i.e., is recovery already evident by 10.5 mos). 
(Wilcoxon Signed Rank Test)  
• E2 recovery comparison test for intermittent vs. continuous group from 9 to 12 months and 
9 to 10.5 months. (Wilcoxon Rank sum Test), to confirm that recovery is greater than 
variability of E2 while continuing treatment. 
 
4.1.3 Secondary Objective: To link the estrogen level changes with the clinical outcomes 
of toxicity, QoL and grip strength 
• Scatter plot E2 % change 9-12 mos. vs change of QoL LASA measures 6-12 mos. (except 
coping effort and treatment burden) and calculate corresponding Spearman correlation 
coefficients.  
• Scatter plot E2 % change 9-12 mos. vs change 9-12 mos of grip strength dominant and 
non-dominant hand and Spearman correlation coefficients. 
• Scatter and box plots of AE toxicity grade changes (no grade, positive and negative) 6-12 
mos. with respect to E2 % change 9-12 mos. by treatment assignment. 
 
 

SOLE-EST SAP: March 2020 
 
Trial 35-07 -- 9 
 
 
4.1.4 Secondary Objective: Effect of factors on estrogen levels 
• Tabulation of baseline E2, E1, E1s and SHBG by characteristics (categorized where 
needed): most recent ET, duration of prior AI, duration of prior ET to rando, age, BMI, 
types of menopause; and scatterplots baseline E2 with continuous characteristics. 
Transpose table, Spearman correlation coeff matrix with all cont. variables by treatment 
arms. 
• Tabulation of E2 % change (9-12 mos and 9-10.5m) by characteristics: most recent ET, 
duration of prior ET, duration of prior AI, duration of prior ET to rando, age, BMI, types 
of menopause; transpose table and scatterplot E2 % change 9-12 mos with continuous 
characteristics. One correlation coeff matrix.  
• Statistical modeling of natural log transformation of fold change from 9-12 months (linear 
regression multivariate analysis) with respect to characteristics. 
o Investigate relations between the characteristics, tabulations and scatterplots and 
correlation coefficient matrix depending on what’s helpful 
o Effect on E2 over 9m of AI (all patients without regard to treatment assignment) 
lnE2(9)=lnE2(0)+age (without treatment assignment). (series of mixed model with 
one covariate at a time and final model with all covariates) 
o Effect on E2 recovery (intermittent only) from 9 to 10.5 and 12 months 
Mixed modelling: lnE2(10.5,12)=ln E2(9) + timepoint as covariate + age (series of 
mixed model with one covariate at a time and final model with all covariates) 
 
 
4.1.5 Secondary Objective: Link of estrogen level changes with germline SNPs 
To be added in the future