A Cohort Study to Evaluate Genetic Predictors of Aromatase Inhibitor Musculoskeletal Symptoms (AIMSS)
Phase: NA
Conditions: Estrogen Receptor-positive Breast Cancer, Musculoskeletal Complications, Progesterone Receptor-positive Breast Cancer, Recurrent Breast Cancer, Stage IA Breast Cancer, Stage IB Breast Cancer, Stage II Breast Cancer, Stage IIIA Breast Cancer, Stage IIIB Breast Cancer, Stage IIIC Breast Cancer
Sponsor: ECOG-ACRIN Cancer Research Group

 
E1Z11 
1 
A Cohort Study to Evaluate Genetic Predictors of 
Aromatase Inhibitor Musculoskeletal Symptoms (AIMSS) 
STUDY CHAIR: Vered Stearns, MD 
STUDY CO-CHAIR: Victor T. Chang, MD 
PHARMACOGENOMIC CO-CHAIR: David Flockhart, MD, PhD 
STUDY STATISTICIAN: Judith Manola, MS 
BREAST COMMITTEE CHAIR:  
PATIENT OUTCOMES & SURVIVORSHIP CHAIR: 
Joseph Sparano, MD 
Lynne I. Wagner, PhD 
SYMPTOM MANAGEMENT COMMITTEE CHAIR: Michael J. Fisch, MD, MPH 
COMMUNITY CANCER COMMITTEE CHAIR: Patrick J. Flynn, MD 
ALLIANCE CO-CHAIR: Charles Loprinzi, MD 
SWOG CO-CHAIR: Norah Lynn Henry, MD, PhD 
Version Date:  April 13, 2023 
STUDY PARTICIPANTS 
 
ACTIVATION DATE 
NRG / NRG Oncology Foundation, Inc. 
 
May 8, 2013 
ALLIANCE / Alliance for Clinical Trials in Oncology  
Addendum #1 - Incorporated Prior to Activation 
SWOG / SWOG 
 
Addendum #2 – 11/13  
 
 
Addendum #3 – 4/14 
 
 
Addendum #4 - 12/14 
 
 
 
Addendum #5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Rev. 3/14, 
12/14 

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Table of Contents 
Schema ...................................................................................................................... 6 
1. Introduction ........................................................................................................ 7 
1.1 
Rationale for Proposed Study ................................................................... 7 
2. Objectives ......................................................................................................... 11 
2.1 
Primary Objectives .................................................................................. 11 
2.2 
Secondary Objectives .............................................................................. 11 
3. Selection of Patients ......................................................................................... 12 
3.1 
Eligibility Criteria ..................................................................................... 12 
4. Registration Procedures .................................................................................... 14 
4.1 
Protocol Number ..................................................................................... 16 
4.2 
Investigator Identification ....................................................................... 16 
4.3 
Patient Identification .............................................................................. 16 
4.4 
Eligibility Verification .............................................................................. 16 
4.5 
Additional Requirements ........................................................................ 16 
4.6 
Instructions For Patients Who Do Not Start Assigned Protocol Treatment17 
5. Treatment Plan ................................................................................................. 18 
5.1 
Administration Schedule ......................................................................... 18 
5.2 
Adverse Event Reporting Requirements ................................................. 19 
5.3 
Patient Reported Outcome Administration ............................................ 21 
5.4 
Dose Modifications ................................................................................. 23 
5.5 
Concomitant Treatment .......................................................................... 24 
5.6 
Supportive Care ....................................................................................... 24 
5.7 
Duration of Therapy ................................................................................ 24 
5.8 
Duration of Follow-up ............................................................................. 24 
6. Study Measures ................................................................................................ 26 
6.1 
Patient Reported Outcome Measures Used In This Study Will Include 
The Following: ......................................................................................... 26 
6.2 
Patient Reported Outcome Measures To Be Used In This Study ............ 26 
7. Study Parameters .............................................................................................. 29 
7.1 
Data Collection ........................................................................................ 29 
8. Drug Formulation and Procurement ................................................................. 32 
8.1 
Drug Name Anastrozole .......................................................................... 32 
9. Statistical Considerations .................................................................................. 33 
9.1 
Statistical considerations for primary objective of SNP validation ......... 33 
9.2 
Secondary Endpoint Analyses ................................................................. 34 
9.3 
Statistical Considerations For Patient-Reported Outcomes ................... 35 
9.4 
Safety Monitoring ................................................................................... 37 
9.5 
Gender and Ethnicity .............................................................................. 37 
9.6 
Accrual Rates ........................................................................................... 37 

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10. Correlative Studies ............................................................................................ 38 
10.1 DNA Polymorphisms Associated with AIMSS and Discontinuation of 
Aromatase Inhibitors .............................................................................. 38 
10.2 Pharmacogenomic Study Methods ......................................................... 40 
10.3 ECOG Sample Tracking System ............................................................... 41 
10.4 Banking .................................................................................................... 42 
10.5 Lab Data Transfer Guidelines .................................................................. 42 
10.6 Sample Inventory Submission Guidelines ............................................... 42 
11. Electronic Data Capture .................................................................................... 43 
12. Patient Consent and Peer Judgment ................................................................ 43 
13. References ........................................................................................................ 43 
 Appendix I  Informed Consent Template for Cancer Treatment Trials (English 
Language) [Deleted in Addendum #3] .............................................................. 47 
Appendix II  Patient Thank You Letter ..................................................................... 48 
Appendix III  Patient Pill Calendar ........................................................................... 49 
Appendix IV  ECOG Performance Status ................................................................. 51 
Appendix V  Specimen Shipment Requisition Form ................................................ 52 
Appendix VI  Shipping Kit Request Facsimile Form ................................................. 54 
 

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STUDY CHAIR 
Vered Stearns, MD 
Sidney Kimmel Comprehensive Cancer Center 
Johns Hopkins Oncology Center 
Bunting-Blaustein Cancer Research Building 
1650 Orleans St, , Rm 144 
Baltimore, MD 21231-1000 
Tel: 443-287-6489 
Fax: 410-614-8160 
E-mail: vstearn1@jhmi.edu 
STUDY CO-CHAIR 
Victor T. Chang, MD 
VA New Jersey Health Care System 
Section of Hematology/Oncology 
385 Tremont Avenue 
East Orange, NJ 07018 
Tel: 973-676-1000 (Ext. 1531) 
Fax: 973-395-7096 
E-mail: victor.chang@va.gov 
STUDY CHAIR LIAISON (SCL) 
Judy Murray, CCRC 
550 N. Broadway, Suite 412 
Baltimore, MD 21205 
Phone: 410-955-4044 
Fax: 410-614-7344 
Email: jmurra33@jhmi.edu  
 
ALLIANCE STUDY CO-CHAIR 
SWOG STUDY CO-CHAIR 
Charles Loprinzi, MD 
Regis Professor of Breast Cancer Research 
Division of Medical Oncology 
Mayo Clinic 
200 First St S.W. 
Rochester, MN 55905 
Tel: 507-284-4849 
Fax: 507-284-1803 
Email: cloprinzi@mayo.edu 
Norah Lynn Henry, MD, PhD 
Assistant Professor 
Division of Hematology/Oncology 
Univ. of Michigan Comp Cancer Center 
1500 East Medical Center Drive 
Medical Inn Building Room C450 
Ann Arbor, MI 48109-5843 
Tel: 734-936-4991 
Fax: 734-936-4940 
E-mail: norahh@med.umich.edu 
 
Rev. 4/14 

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CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
To submit site registration 
documents: 
For patient enrollments: 
Data collection will be performed 
in Medidata Rave and in 
Assessment CenterTM: 
CTSU Regulatory Office 
1818 Market Street, Suite 1100 
Philadelphia, PA 19103 
Phone – 1-866-651-CTSU 
Fax – 215-569-0206 
Please refer to the patient 
enrollment section for 
instructions on using the 
OPEN system. 
Please refer to the Forms 
Completion Guidelines for the Forms 
Submission Schedule.  
The study protocol and all related forms and documents must be downloaded from the protocol-
specific Web page of the CTSU Member Web site located at https://www.ctsu.org.  Sites must use the 
current form version and adhere to the instructions and submission schedule outlined in the protocol. 
CTSU sites should follow procedures outlined in the protocol for Site registration, Patient Enrollment, 
Adverse Event Reporting, Data Submission (including ancillary studies), and Drug Procurement. 
For patient eligibility or treatment-related questions Contact the Study PI of the Coordinating Group. 
For questions unrelated to patient eligibility, treatment, or data submission contact the CTSU 
Help Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com. All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
For detailed information on the regulatory and monitoring procedures for CTSU sites please 
review the CTSU Regulatory and Monitoring Procedures policy located on the CTSU members’ website  
https://www.ctsu.org 
The CTSU Web site is located at   https://www.ctsu.org 
 

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Schema 
a.
Anastrozole will be given 1mg, po daily for 12 months.
b.
AIMSS diagnosis will be determined clinically by oncology MD or Nurse when patient complains of joint symptoms. See Section 5.
c.
Decision whether to continue anastrozole or to start a treatment for AIMSS will be made by patient & MD discussion. See Section 5.
d.
Blood collection is mandatory for pharmacogenomics as outlined in Section 10. If unable to collect at baseline, please collect at any other time point.
R
E
G
I
S
T
E
R
 AIMSS
 Symptoms
Accrual = 1,000 patients
Baseline:
· 
Physical Exam
· 
PRO
· 
Blood
A
N
A
S
T
R
O
Z
O
L
E
 No AIMSS
 Symptoms
 
MD Visit
· 
Physical Exam
· 
PRO
Follow up as scheduled q 3 
months, with PRO, up to 1 year
Continue AI
Holiday
Discontinue;
PRO
Follow up 1 
month, PRO
 
 

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1. 
Introduction 
1.1 
Rationale for Proposed Study 
1.1.1 
Significance of the Condition 
Breast cancer is one of the most prevalent cancers with 207,090 new 
cases of breast cancer and 39,840 deaths in women predicted for 
2010 in the United States(1).  Aromatase inhibitors (AIs) are used as 
first-line adjuvant therapy for postmenopausal women with early stage 
breast cancer(2).  The effectiveness of current therapy is widely 
recognized to be compromised by poor compliance because of 
aromatase inhibitor-associated musculoskeletal symptoms (AIMSS), a 
syndrome that affects up to 40-50% of women who take these 
medications. The syndrome that was not recognized during the 
registration trials for this class of drugs(3), it can lead to discontinuation 
in up to 24% of women over 2 years (4,5).  Knowledge that can be used 
to prevent discontinuation of these important agents because of 
severe AIMSS is urgently needed. 
The NCI Division of Cancer Prevention has recognized AIMSS as a 
priority area for future study. The symptoms are associated with a 
high rate of AI discontinuation and therefore compromise survival 
outcomes at great cost to both patients and society.  Very little is 
known about AIMSS, or how to predict who is at risk for the condition, 
or for discontinuing therapy because of the symptoms.  This study will 
provide a basis for comprehensive assessment of risk factors at the 
patient-reported outcomes, phenotypic, and laboratory levels.  We will 
explore the natural history of AIMSS in different ethnic populations, 
and will validate previously reported genetic determinants of the 
development of AIMSS. 
A common problem with multicenter GWAS studies of very large 
sample size, especially in the absence of measurable diagnostic 
parameters, is inclusion of heterogeneous groups of patients(6).  In 
addition to assessing pharmacogenomic predictors, this study 
involves specification of a pre-defined AIMSS phenotype and 
collection of patient-reported outcomes (PROs).  As such, these data 
will have clinical utility by clarifying the factors associated with 
aromatase inhibitor discontinuation and thus guiding clinicians 
towards interventions to improve adherence. Coupled with other 
studies, the long-term goals are to develop a gene signature that will 
be used to better guide the selection of endocrine interventions for 
patients with breast cancer. 
Etiology and Pathophysiology 
The underlying physiology of AIMSS remains obscure.  A small 
exploratory case control study did not find a role for commonly 
encountered cytokines in AIMSS (7).  The role of estrogen and 
estrogen metabolites remains a possible explanatory variable, as well 
as new cytokines such as IL-17.  This newly described cytokine has 
been implicated in disorders such as rheumatoid arthritis and other 

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autoimmune diseases (8), and has been specifically linked to articular 
nociception in animal models of arthritis(9). 
AIMSS Phenotype:  The large studies to date of AIs (ATAC, BIG I-98, 
E1Z03) have been limited by the absence of a clearly defined 
phenotype for AIMSS (10). Retrospective analyses have provided 
some information that clearly cannot replace (PROs). The lack of 
good prospective PROs represents a major gap as a well-defined 
phenotype is necessary in order to identify useful genomic 
associations.  Methods evaluating possible predictors such as the use 
of MRI of the wrists for tenosynovitis are expensive and have not 
been definitive (11), and patient-reported symptoms are used and may 
represent the most useful clinical phenotype. 
The exemestane and letrozole pharmacogenomics (ELPh) study, 
conducted by the Consortium on Breast Pharmacogenomics 
(COBRA), has provided important data not only regarding the 
prevalence of the symptoms and drug discontinuation but also for 
PRO by using the Health Assessment Questionnaire (HAQ), a 
commonly used rheumatology instrument. Dr. David Flockhart and Dr. 
Vered Stearns of ECOG are co-founders of the COBRA group.  In this 
prospective comparison of exemestane and letrozole, patients were 
randomly assigned to either letrozole or exemestane and were 
evaluated at predefined intervals by study team members and 
referred to a rheumatologist based upon change in HAQ scores and 
pain ratings on a visual analog scale (VAS).  The study showed that 
the predefined symptomatic criteria based on the HAQ and VAS 
successfully provided a means of case definition of an otherwise 
difficult-to-characterize syndrome (4, 5).  Improvement or worsening of 
HAQ score was defined as a decrease or increase, respectively, of 
more than 0.22 based on data provided from the rheumatology 
literature(12). However, the sensitivity, specificity, and generalizability 
of the ELPh clinical criteria for defining AIMSS clearly need to be 
confirmed in a larger cohort of a diverse patient population and in 
other clinical settings. Data from the ELPh study for the first 100 
patients showed that median time to onset of symptoms was 1.6 
months (range 0.4-10 months), and median time to study 
discontinuation (for those who stopped taking AI) was 6.1 months 
(range 2.2-13 months) (4). 
Anastrozole was not studied in the ELPh trial, representing a gap in 
knowledge both as it is a widely prescribed AI, and because 
anastrozole associated musculoskeletal symptoms have not been 
phenotypically characterized with the HAQ.  Furthermore, as the 
patients studied by the ELPh and NCIC Clinical Trials Group MA.27 
(described below) populations are predominantly Caucasian, further 
studies in minority populations are urgently needed.  
Genetic Predictors of AIMSS:  Pharmacogenomic predictors may 
help identify women at risk for AIMSS since genetic variants that are 
associated with AI pharmacokinetics, with the effects of estrogen 
deprivation on bone and other phenotypes have already been 
described. We briefly review recent important findings that emphasize 
the importance of this concept as well as its feasibility.  

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Previous studies by the PI with COBRA investigators identified 
genetic predictors, such as polymorphisms in estrogen receptors 
(ESR), or genes encoding for cytochrome P450 enzymes (CYP), of 
tamoxifen effects. Estrogen receptor subtypes may influence lipid 
metabolism (13) and bone density (14). Furthermore, CYP 
polymorphisms are important in predicting discontinuation of 
tamoxifen (15), and hot flashes (16). Our preliminary data suggest that 
variants in ESR predict development of AIMSS (Manuscript in 
preparation).  These findings provide an important model for 
exploration of genetic predictors of side effects of AIs. Additional 
recent work has identified potential genetic determinants of the 
pharmacokinetics and pharmacodynamics of the AIs that may also 
explain variability in responses to AIs. (17-21). 
The first evidence for the existence of genetic predictors of AIMSS 
came from an analysis of 293 cases and 585 controls from the MA.27 
trial, a large study which compared exemestane and anastrozole. 
Genome wide associations (GWAS) and functional genomic studies 
identified novel single nucleotide polymorphisms (SNPs) and a gene 
related to IL-17 as associated with AIMSS(17). These findings were 
recognized as important and should be confirmed in large prospective 
studies (22). However, few studies conducted or planned to date have 
included a predefined phenotype, PROs or specimens evaluable for 
pharmacogenomics. 
Review of available data from the MA27 and the ELPh studies has 
identified ten SNPs that may be relevant to AIMSS syndrome.  In the 
MA27 dataset, the most striking P values (1E-06) were for three SNPs 
on chromosome 14,  rs7158782, rs7159713, rs2369049, which were 
all close to the T Cell leukemia 1A (TCL1A) gene, a fourth SNP, 
rs11849538, was imputed. The ELPh study also identified the latter 
two SNPs, and four other SNPs. These were rs2296972, the 
serotonin receptor subtype 2A, rs2347868 and rs9340835 associated 
with estrogen receptor 1, and rs4646 associated with CYP19A1. An 
additional two SNPs have been identified in studies of severe large 
joint arthritis. These are rs2234693 in the ESR1 gene, and rs1062033 
in the CYP19A1 gene (22a). 
1.1.2 
Studying the Decision to Discontinue Aromatase Inhibitors 
Compliance is an important issue, as many patients do not fill their 
prescriptions for AIs (23).  The basis for the patient’s decision to 
discontinue AI therapy has not been studied. On the basis of 
anecdotal observations of our community oncologists, patients are 
torn between their fear of recurrence and the perceived burden of 
treatment.  AIs are one of the few agents that have pain as a side 
effect.  Patient answers to questions about their fear of recurrence, 
perceived treatment burden, burden due to co-morbidities, and 
adherence behaviors may provide further insights to patient decision-
making and compliance.  
The significant role of patient reported outcomes as a possible 
determinant in the decision to discontinue AIs was a central finding in 
ECOG 1Z03 and presented by Dr. Lynne Wagner at the 2011 San 

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Antonio Breast Conference (24). Further study of patient reported 
outcomes may lead to robust bedside assessments of the risk of 
discontinuation. 
1.1.3 
Studying the use of paper forms or the PROMIS electronic format for 
data entry 
Collection of patient rated outcomes is a critical component of these 
kinds of studies, and incomplete data collection during follow-up 
represents a major challenge both logistically and to the validity of 
these studies.  The NIH has developed a Web-based system for 
recording patient reported outcomes during clinical trials, the Patient 
Reported Outcomes Management Information System (PROMIS) that 
will enable the efficient collection of patient reported outcomes and 
decrease the logistical burdens on office practices for patients on 
clinical trials. The PROMIS Assessment Center is the web-based 
platform for dissemination of NIH PROMIS measures.  The 
assessment center can be used to administer patient rated outcome 
instruments, monitor accrual, manage data, send reminders to 
patients, be used to deliver custom researcher developed content, 
and has numerous features that support both simple and complicated 
accrual designs (branching, multiple arms, multiple time points, 
etc.).(25)   Dr David Cella, an ECOG member, has been a key 
participant in the development of the PROMIS system and is Director 
of the PROMIS Statistical Center.  Studies undertaken by the 
PROMIS staff have shown there is excellent satisfaction with the 
PROMIS Assessment Center (26) for patients with visual and other 
impairments. There is no charge for using the PROMIS system. Data 
is kept secure behind firewalls. Data that is entered will be the 
property of ECOG and can be downloaded directly to the ECOG 
system. With the current popularity of smart phones in the breast 
cancer patient population, we think the time is ripe to test its’ use in a 
cooperative group trial setting. 
The symptom instruments used will build upon the work in the NIH 
Patient Reported Outcomes project to develop better symptom 
instruments, through use of the PROMIS Physical Function 20 Form 
and the PROMIS Assessment Center.  This will support the 
development of better symptom and quality of life measurements and 
begin to integrate the PROMIS project within the Cancer Cooperative 
Groups.  Experience in using the instruments and the PROMIS 
Assessment Center will lead to new ways for cooperative groups to 
collect patient rated outcome data and reduce attrition. 
Secondary objective 2.2.6 is to assess the feasibility of the on-line 
PROMIS platform for collecting patient-reported outcomes in the 
setting of a cooperative group clinical trial. We plan to make all of the 
patient-reported quality of life instruments available through the 
PROMIS web site. 
 

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2. 
Objectives 
2.1 
Primary Objectives 
To validate previously identified associations between 10 specific single 
nucleotide polymorphisms (SNPs) and discontinuation of treatment with AIs due 
to the development of musculoskeletal symptoms (MSS) among women with 
breast cancer. 
2.2 
Secondary Objectives 
2.2.1 
To determine whether other SNPs in CYP, UGT, Vitamin D, serotonin 
and other receptors are associated with discontinuation of treatment 
due to the development of severe AIMSS.  
2.2.2 
To determine whether other SNPs in CYP, UGT, Vitamin D, serotonin 
and other receptors are associated with the development of other 
potential complications of AI therapy. 
2.2.3 
To develop a gene signature that can identify patients at risk for 
developing severe anastrozole-related AIMSS and other potential 
complications of AI therapy. 
2.2.4 
To determine the epidemiology and predictors of severe AIMSS and 
of AI discontinuation. 
2.2.5 
To describe patient reported outcomes for minority patients with 
breast cancer treated with aromatase Inhibitors (AIs). 
2.2.6 
To assess the utility of the PROMIS system to collect patient reported 
outcomes in a cooperative group study, and validate the PROMIS 
Physical Function 20a form in patients with AIMSS. 
2.2.7 
To develop a model that incorporates patient ratings of treatment 
burden, fear of recurrence and adherence behaviors to describe 
patient decisions to continue or discontinue anastrozole. 
2.2.8 
To collect serum samples for future testing for biomarkers of AIMSS. 
 

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3. 
Selection of Patients 
Each of the criteria in the checklist that follows must be met in order for a patient to be 
considered eligible for this study. Use the checklist to confirm a patient’s eligibility. For 
each patient, this checklist must be photocopied, completed and maintained in the 
patient’s chart. 
In calculating days of tests and measurements, the day a test or measurement is 
done is considered Day 0. Therefore, if a test is done on a Monday, the Monday 
four weeks later would be considered Day 28. 
ECOG Patient No. ____________________________ 
Patient’s Initials (L, F, M) _______________________ 
Physician Signature and Date ___________________ 
NOTE: 
All questions regarding eligibility should be directed to the study chair or 
study chair liaison. 
NOTE: 
Institutions may use the eligibility checklist as source documentation if it has 
been reviewed, signed, and dated prior to registration/randomization by the 
treating physician.  
3.1 
Eligibility Criteria 
3.1.1 
Age ≥ 18 years. 
3.1.2 
Patients must be female and post-menopausal. Post-menopausal will 
be defined as women meeting any of the following criteria: 
· 
≥ 60 years of age; or 
· 
< 60 years of age and amenorrheic for ≥ 12 months prior to day 1 
if uterus/ovaries are intact; or 
· 
< 60 years of age, and the last menstrual period 6-12 months prior 
to day 1, if intact uterus/ovaries and meets biochemical criteria for 
menopause (FSH and estradiol within institutional standard for 
postmenopausal status); or 
· 
< 60 years of age, without a uterus, and meets biochemical criteria 
for menopause (FSH and estradiol within institutional standards 
for postmenopausal status); or 
· 
< 60 years of age and history of bilateral oophorectomy.  Surgery 
must have been completed at least 4 weeks prior to day 1; or 
· 
Prior radiation castration with amenorrhea for at least 6 months. 
NOTE: 
Use of LHRH agonists (e.g., leuprolide or goserelin) is not 
allowed 
3.1.3 
Patients must have estrogen and/or progesterone receptor positive 
histologically confirmed Stage I-III adenocarcinoma of the breast. 
3.1.4 
 Patients must have completed planned local therapy (i.e., definitive 
surgery and radiation therapy) and adjuvant chemotherapy for breast 
cancer prior to registration. In addition, any prior local therapy and 
adjuvant chemotherapy should be completed prior to participant 
completion of baseline PRO instruments (i.e., HAQ, PROMIS Physical 
_____
_____
_____
Rev. 11/13 
Rev. 11/13 
_____

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Function, FACT Breast and ES, etc.) and collection of optional blood 
for banking for future research. 
NOTE: 
Concomitant treatment with ongoing trastuzumab 
(Herceptin®) or other targeted/biologic agents is allowed. 
Concomitant treatment with any other type of 
chemotherapy or hormonal therapy is not allowed. 
3.1.5 
Patients must not have received prior AI therapy with exemestane, 
letrozole, or anastrozole as preoperative/adjuvant therapy or for 
prevention of breast cancer. Prior tamoxifen is allowed. 
3.1.6 
Plan to treat with anastrozole for at least 12 months.  
3.1.7 
ECOG performance status between 0-2. 
3.1.8 
Patients must be disease-free of other prior invasive malignancies for 
≥ 5 years with the exception of curatively-treated basal cell or 
squamous cell carcinoma of the skin or carcinoma in situ of the cervix. 
Prior early stage breast cancers are also allowed as long as prior 
treatment did not include aromatase inhibitors. 
3.1.9 
Patients must not be currently taking (or have taken in the past 6 
months) medication for active, chronic conditions, including 
rheumatoid arthritis, carpal tunnel syndrome, tenosynovitis, systemic 
lupus erythematosus, gout, fibromyalgia, or severe osteoarthritis 
involving the hands, wrists, hips, knees, feet or ankles. This includes 
analgesic medications or medications being taken with the purpose of 
treating pain or that may have an effect on pain (e.g. anti-depressants 
for help with pain or neuropathy, corticosteroid shots for arthritis.) 
(Note: patients taking daily low dose aspirin are allowed to participate 
in this trial.) 
3.1.10 
Patients must not have a prior history of deep vein thrombosis (DVT) 
or pulmonary embolism in the past 5 years. 
3.1.11 
Patients must have worst pain rated as no worse than 3 out of 10 on 
the following question (i.e., a pain score of 0, 1, 2, or 3): “In the past 
week, how much pain have you had on a scale of 0 to 10, where 0 
equals no pain and 10 means the worst pain you can imagine.” 
NOTE: 
This question regarding patient’s pain should be completed 
within one week prior to registration. This question may be 
asked orally prior to consent up to 7 days prior to 
registration; the response will be recorded on the 
registration checklist. 
3.1.12 
Patients must have adequate hepatic, hematologic and renal 
functioning to be able to be administered anastrozole at the discretion 
of the treating physician. 
 
OPTIONAL: 
This signature line is provided for use by institutions wishing to use the 
eligibility checklist as source documentation. 
 
 
 
Physician Signature 
 
Date 
_____
_____
_____
_____
_____
_____
_____
_____
Rev. 11/13 
Rev. 11/13 
Rev. 11/13 
Rev. 4/14 
Rev. 4/14 

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4. 
Registration Procedures 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
Prior to the recruitment of a patient for this study, investigators must be registered 
members of a Cooperative Group.   Each investigator must have an NCI investigator 
number and must maintain an “active” investigator registration status through the annual 
submission of a complete investigator registration packet (FDA Form 1572 with original 
signature, current CV, Supplemental Investigator Data Form with signature, and 
Financial Disclosure Form with original signature) to the Pharmaceutical Management 
Branch, CTEP, DCTD, NCI.  These forms are available on the CTSU Web site (enter 
credentials at https://www.ctsu.org; then click on the Register tab) or by calling the PMB 
at 240-276-6575 Monday through Friday between 8:30 a.m. and 4:30 p.m. Eastern time. 
Each investigator or group of investigators at a clinical site must obtain IRB approval for 
this protocol and submit IRB approval and supporting documentation to the CTSU 
Regulatory Office before they can enroll patients. Study centers can check the status of 
their registration packets by querying the Regulatory Support System (RSS) site 
registration status page of the CTSU member web site by entering credentials at 
https://www.ctsu.org. 
Requirements for E1Z11 site registration: 
CTSU IRB Certification 
CTSU IRB/Regulatory Approval Transmittal Sheet 
Submitting Regulatory Documents 
Before an ECOG Institution may enter patients, protocol specific regulatory documents 
must be submitted to the CTSU Regulatory Office at the following address:   
CTSU Regulatory Office 
Coalition of National Cancer Cooperative Groups 
1818 Market Street, Suite 1100 
Philadelphia, PA 19103 
FAX: (215) 569-0206 
Required Protocol Specific Regulatory Documents 
1. CTSU Regulatory Transmittal Form. 
2. Copy of IRB Informed Consent Document. 
NOTE:  
Any deletion or substantive modification of information concerning risks or 
alternative procedures contained in the sample informed consent 
document must be justified in writing by the investigator and approved by 
the IRB. 
3. A. CTSU IRB Certification Form. 
 
Or 
B. Signed HHS OMB No. 0990-0263 (replaces Form 310). 
 
Or 
 
C. IRB Approval Letter 
NOTE:  
The above submissions must include the following details: 
· 
Indicate all sites approved for the protocol under an assurance 
number. 

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· 
OHRP assurance number of reviewing IRB 
· 
Full protocol title and number 
· 
Version Date 
· 
Type of review (full board vs. expedited) 
· 
Date of review. 
· 
Signature of IRB official 
The CTSU encourages you to go to the following CTSU RSS webpage so that 
more information on RSS2.0 as well as the submission forms can be accessed. 
Log in to  http://www.ctsu.org and click on the Regulatory tab to access the RSS 
webpage. If you have questions regarding regulatory document submission, 
please telephone the CTSU Help Desk at 1-888-823-5923 or E-mail 
CTSUContact@westat.com. Monday through Friday, 9:00am - 8:30pm. 
Patients must not start protocol treatment prior to registration. 
Treatment should start within three working days after registration 
Patient registration can occur only after pre-treatment evaluation is complete, eligibility 
criteria have been met, and the study site is listed as ‘approved’ in the CTSU RSS. 
Patients must have signed and dated all applicable consents and authorization forms. 
All site staff (Lead Group and CTSU Sites) will use OPEN to enroll patients to this study. 
It is integrated with the CTSU Enterprise System for regulatory and roster data and, 
upon enrollment, initializes the patient position in the Rave database. OPEN can be 
accessed at https://open.ctsu.org or from the OPEN tab on the CTSU members’ side of 
the website at https://www.ctsu.org. 
Prior to accessing OPEN site staff should verify the following: 
· 
All eligibility criteria has been met within the protocol stated timeframes. Site staff 
should use the registration forms provided on the group or CTSU web site as a tool 
to verify eligibility. 
· 
All patients have signed an appropriate consent form and HIPAA authorization form 
(if applicable). 
Access requirements for OPEN: 
· 
Site staff will need to be registered with CTEP and have a valid and active CTEP-
IAM account. This is the same account (user id and password) used for the CTSU 
members' web site.  
· 
To perform registrations, the site user must have been assigned the 'Registrar' role 
on the relevant Group or CTSU roster.  
· 
To perform registrations on protocols for which you are a member of the Lead Group, 
you must have an equivalent 'Registrar' role on the Lead Group roster.  Role 
assignments are handled through the Groups in which you are a member  
· 
To perform registrations to trials accessed via the CTSU mechanism (i.e., non-Lead 
Group registrations) you must have the role of Registrar on the CTSU roster. Site 
and/or Data Administrators can manage CTSU roster roles via the new Site Roles 
maintenance feature under RSS on the CTSU members' web site. This will allow 
them to assign staff the "Registrar" role. 
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NOTE: 
The OPEN system will provide the site with a printable confirmation of 
registration and treatment information. Please print this confirmation for your 
records. 
Further instructional information is provided on the OPEN tab of the CTSU members’ 
side of the CTSU website at https://www.ctsu.org or at https://open.ctsu.org. For any 
additional questions contact the CTSU Help Desk at 1-888-823-5923 or 
ctsucontact@westat.com. 
The following information will be requested 
4.1 
Protocol Number 
4.2 
Investigator Identification 
4.2.1 
Institution and affiliate name (Institution CTEP ID) 
4.2.2 
Investigator’s name (NCI number) 
4.2.3 
Cooperative Group Credit 
4.2.4 
Credit Investigator 
4.2.5 
Protocol specific contact information 
4.3 
Patient Identification 
4.3.1 
Patient’s initials (first and last) 
4.3.2 
Patient’s Hospital ID and/or Social Security number 
4.3.3 
Patient demographics 
4.3.3.1 
Gender 
4.3.3.2 
Birth date 
4.3.3.3 
Race 
4.3.3.4 
Ethnicity 
4.3.3.5 
Nine-digit ZIP code 
4.3.3.6 
Method of payment 
4.3.3.7 
Country of residence 
4.4 
Eligibility Verification 
Patients must meet all of the eligibility requirements listed in Section 3. 
4.5 
Additional Requirements 
4.5.1 
Patients must provide a signed and dated, written informed consent 
form. 
NOTE: 
Copies of the consent are not collected by the ECOG 
Coordinating Center. 
4.5.2 
Blood for DNA must be submitted for pharmacogenomic analysis as 
outlined in Section 10. 
4.5.3 
Blood for banking for future research studies should be submitted as 
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NOTE: 
ECOG requires that biological samples submitted from 
patients participating in E1Z11 be entered and tracked via 
the online ECOG Sample Tracking System (STS). See 
Section 10.3. 
NOTE: 
Institutions outside of the United States and Canada must 
confer with the receiving laboratory and the ECOG 
Coordinating Center regarding logistics for submission of 
fresh samples. 
4.5.4 
Data collection for this study will be done in Medidata Rave and in 
Assessment CenterTM. Prior to beginning data entry in Rave, study 
staff must be registered in Medidata and complete the required 
training modules. Study staff will receive an invitation to join the study 
in Rave after evidence of IRB approval is submitted to RSS. 
4.5.5 
Patients will have the option of completing quality of life assessments 
through the PROMIS Assessment Center, a web-based application. 
Prior to registering patients, the site should consider whether there 
are facilities in the clinic for this (e.g., a computer terminal available 
for patient use), or if the patient must make their own arrangements. If 
neither of these options is possible or if the patient prefers, QOL 
assessments can be done using paper forms, with responses entered 
by study staff into Medidata Rave. More information about how to use 
the PROMIS Assessment Center for this study is available at 
www.ecog.org/AIMSS_QOL. 
4.6 
Instructions For Patients Who Do Not Start Assigned Protocol Treatment 
If a patient does not receive any assigned protocol treatment, baseline and 
follow-up data will still be collected and must be submitted through Medidata 
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5. 
Treatment Plan 
5.1 
Administration Schedule 
 Patient receives anastrozole 1 mg po daily, and completes the baseline and 
follow up questionnaires on the PROMIS study website, Assessment Center,TM or 
with pencil and paper.  The questionnaires include Functional Assessment of 
Cancer Therapy (FACT) measures (FACT-General, Breast subscale and 
Endocrine subscale) and HAQ. 
The patient will be asked not to discontinue the medication on her own. When the 
patient develops joint pain or stiffness and calls their treating physician, the 
patient will be encouraged to continue anastrozole medication until seen in an 
office visit. 
5.1.1 
Treatment 
Anastrozole 1 mg, oral, daily for 12 months.  Treatment should start 
within three working days after registration.  The patient will be given 
a pill diary and instructed to complete it and bring it with them to their 
next MD visit. 
5.1.2 
Patients should be instructed that when they develop joint pain or 
stiffness that they should call their MD.  Patients should be 
encouraged to stay on the medication until seen in an office visit.   
MD or provider should see the patient within 2 weeks of the patient’s 
call to assess for the likelihood of rheumatologic disease (joints are 
not red, hot, swollen, or deformed), and determines clinically if the 
patient has AIMSS, and records his/her impression. The patient 
completes the questionnaires.  
Patient discusses with MD whether to continue or discontinue the 
drug or start a treatment for AIMSS. A holiday (defined as a drug-free 
interval of 6 weeks or less) is also an option, as is switching to a 
different AI, tamoxifen, or participating in a treatment study. The MD 
will record the recommendation. 
5.1.3 
If and when the patient decides to discontinue anastrozole, the patient 
will be asked to complete questionnaires. If this was part of a holiday 
plan, the drug will be considered discontinued if the patient refuses to 
restart the medication (off the medication for more than 6 weeks). 
5.1.3.1 
When a patient discontinues the medication, she will be 
asked for the reasons, and asked to rank them.  If pain or 
other symptoms such as stiffness are the first or second 
reason, then it will be considered a discontinuation 
because of AIMSS.  
5.1.3.2 
The MD will check in with the patient 4-6 weeks later to 
see if symptoms have resolved, and if anastrozole is 
discontinued.  The patient will complete questionnaires 
again. 
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5.1.4 
If the patient is to continue anastrozole beyond the 12 months on 
study, a final questionnaire will be completed at the 12 month time 
point. 
NOTE: 
All notations of MD above refer to medical protocol (ie, MD, NP or 
PA); an oncology nurse may also make assessments if felt to be 
qualified by the Principal Investigator. 
5.2 
Adverse Event Reporting Requirements 
5.2.1 
Purpose 
Adverse event (AE) data collection and reporting, which are required 
as part of every clinical trial, are done to ensure the safety of the 
patients enrolled, as well as those who will enroll in future studies 
using similar agents. 
5.2.2 
Terminology 
· 
Adverse Event (AE): Any untoward medical occurrence 
associated with the use of a drug in humans, whether or not 
considered drug related. Therefore, an AE can be ANY 
unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal product, whether or not considered 
related to the medicinal product. 
· 
Attribution: An assessment of the relationship between the 
adverse event and the protocol treatment, using the following 
categories. 
ATTRIBUTION 
DESCRIPTION 
Unrelated 
The AE is clearly NOT related to treatment 
Unlikely 
The AE is doubtfully related to treatment 
Possible 
The AE may be related to treatment 
Probably 
The AE is likely related to treatment 
Definite 
The AE is clearly related to treatment 
· 
CTCAE: The NCI Common Terminology Criteria for Adverse 
Events provides a descriptive terminology that is to be utilized for 
AE reporting.  A grade (severity) is provided for each AE term. 
· 
Expectedness: Expected events are those that have been 
previously identified as resulting from administration of the agent. 
An adverse event is considered unexpected, for expedited 
reporting purposes, when either the type of event or the severity of 
the event is NOT listed in the protocol or drug package insert. 
5.2.3 
Reporting Procedure 
This study requires that expedited adverse event reporting use 
CTEP’s Adverse Event Reporting System (CTEP-AERS). The CTEP’s 
guidelines for CTEP-AERS can be found at http://ctep.cancer.gov. A 
CTEP-AERS report must be submitted electronically to ECOG and the 
appropriate regulatory agencies via the CTEP-AERS Web-based 
application located at http://ctep.cancer.gov. 
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In the rare event when Internet connectivity is disrupted a 24-hour 
notification is to be made by telephone to  
· 
the AE Team at ECOG (617-632-3610) 
· 
the FDA (800-332-1088) 
An electronic report MUST be submitted immediately upon re-
establishment of internet connection. 
Supporting and follow up data:  Any supporting or follow up 
documentation must be uploaded to the Supplemental Data Folder in 
Medidata Rave within 48-72 hours. In addition, supporting or follow up 
documentation must be faxed to the FDA (800-332-0178) in the same 
timeframe. 
NCI Technical Help Desk: For any technical questions or system 
problems regarding the use of the CTEP-AERS application, please 
contact the NCI Technical Help Desk at ncictephelp@ctep.nci.nih.gov 
or by phone at 1-888-283-7457. 
5.2.4 
Expedited Reporting Requirements For Protocol E1Z11 
Commercial Agent: Anastrozole 
Attribution 
Grade 5a 
Unexpected 
Expected 
Possible,  
Probable,  
Definite 
7 calendar days 
7 calendar days 
7 Calendar Days: 
Indicates a full CTEP-AERS report is to be submitted within 7 
calendar days of learning of the event. 
a 
This includes all deaths within 30 days of the last dose of treatment with an 
attribution of possible, probable, or definite. 
NOTE: 
In addition, any death that occurs > 30 days after the last dose of 
treatment and is attributed possibly, probably, or definitely to the 
treatment must be reported within 7 calendar days of learning of the 
event. 
5.2.5 
Other Recipients Of Adverse Event Reports and Supplemental Data 
Adverse events determined to be reportable via CTEP-AERS must 
also be reported by the institution, according to the local policy and 
procedures, to the Institutional Review Board responsible for oversight 
of the patient. 
5.2.6 
Second Primary Cancer Reporting Requirements 
All cases of second primary cancers, including acute myeloid 
leukemia (AML) and myelodysplastic syndrome (MDS), that occur 
following treatment on NCI-sponsored trials must be reported to 
ECOG using Medidata Rave 
· 
A second malignancy is a cancer that is UNRELATED to any prior 
anti-cancer treatment (including the treatment on this protocol).  
Second malignancies require ONLY routine reporting as follows: 
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1. Complete a Second Primary Form within 14 days in Medidata 
Rave 
2. Upload a copy of the pathology report to ECOG via Medidata 
Rave confirming the diagnosis. 
3. If the patient has been diagnosed with AML/MDS, upload a 
copy of the cytogenetics report (if available) to ECOG via 
Medidata Rave. 
· 
A secondary malignancy is a cancer CAUSED BY any prior anti-
cancer treatment (including the treatment on this protocol). 
Secondary malignancies require both routine and expedited 
reporting as follows: 
1. Complete a Second Primary Form within 14 days in Medidata 
Rave. 
2. Report the diagnosis via CTEP-AERS at http://ctep.cancer.gov 
· 
Report under a.) leukemia secondary to oncology chemotherapy, 
b.) myelodysplastic syndrome, or c.) treatment related secondary 
malignancy 
3. Upload a copy of the pathology report to ECOG via Medidata  
Rave and submit a copy to NCI/CTEP confirming the 
diagnosis. 
4. If the patient has been diagnosed with AML/MDS, upload a 
copy of the cytogenetics report (if available) to ECOG via 
Medidata Rave and submit a copy to NCI/CTEP. 
NOTE: 
The ECOG Second Primary Form and the CTEP-AERS 
report should not be used to report recurrence or 
development of metastatic disease. 
NOTE: 
If a patient has been enrolled in more than one NCI-
sponsored study, the ECOG Second Primary Form must 
be submitted for the most recent trial. ECOG must be 
provided with a copy of the form and the associated 
pathology report and cytogenetics report (if available) even 
if ECOG was not the patient's most recent trial. 
NOTE: 
Once data regarding survival and remission status are no 
longer required by the protocol, no follow-up data should 
be submitted via CTEP-AERS or by the ECOG Second 
Primary Form. 
5.3 
Patient Reported Outcome Administration 
5.3.1 
PRO Instruments to be Administered 
Participants will complete the Health Assessment Questionnaire 
(HAQ) and the PROMIS Physical Function 20 to assess AIMSS 
symptoms, the FACT Endocrine Subscale to assess estrogen 
deprivation symptoms, the FACT-Breast to assess breast cancer-
specific concerns, the FACT-General (FACT-G) to assess health-
related quality of life, the Assessment of Survivor Concerns (ASC) to 
assess fear of recurrence, a Treatment Burden scale, and the 
PROsetta Stone Comorbidity Form and SOAPP study Comorbidity 
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Bother Item. Participants will have a choice between completing these 
electronically with the NIH Assessment Center or pencil and paper 
versions of these instruments will be administered to the participants 
during office visits to their oncologist. It should take approximately 30 
minutes for study participants to complete the battery of study 
instruments. 
5.3.2 
PRO Assessment Schedule 
Patients will be assessed according to the following schedule: 
1.) Baseline*  
2.) 3 months 
3.) 6 months 
4.) 9 months 
5.) 12 months 
6.) At the time of symptom onset (if applicable)** 
7.) At the time the patient discontinues taking anastrozole due to 
AIMSS*** 
8.) One month after discontinuing anastrozole due to AIMSS 
The PRO assessment timepoints correspond to the standard office 
visits of routine clinic visits to minimize participant burden. However, 
in the event that a routine clinic visit is not planned or is missed, an 
attempt should be made to complete the questionnaires on schedule, 
either by mail or remote electronic entry. 
* 
The Pain Item on the HAQ will be administered within one week 
prior to registration.  It may be administered orally by staff. 
** When a study participant has AIMSS symptoms, she should make 
an appointment to have a MD/provider visit within 2 weeks of 
onset of symptoms. At this visit it will be determined whether the 
patient has AIMSS and if it is related to anastrozole. The patient 
and her MD/provider will decide on a plan to either continue on 
anastrozole, take a holiday from taking it, or discontinue taking it. 
*** If the patient discontinues taking anastrozole due to AIMSS the 
MD should follow up within 1 month after discontinuation to have 
the patient complete an additional PRO assessment.  All 
participants will continue PRO assessments as scheduled up until 
12 months, including participants who discontinue anastrozole 
early for any reason. 
5.3.3 
PRO Administration Instructions – Using Paper Forms 
5.3.3.1 
The questionnaires must be administered at the time 
points listed above. The patient should be instructed to 
respond to the questionnaires in terms of her experience 
during the timeframe specified on each questionnaire.  
5.3.3.2 
The patient should be asked to read the instructions at the 
beginning of each questionnaire and complete all the 
items.  It is permissible to assist the patient with the 
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completion of the questionnaires as long as the staff 
person does not influence the patient’s responses. 
5.3.3.3 
The questionnaires must be reviewed by the protocol 
nurse or research coordinator as soon as the patient 
completes them to ensure all items were marked 
appropriately.  If more than one answer was marked, the 
patient should be asked to choose the answer which best 
reflects how she is feeling.  If a question was not 
answered, the patient should be asked if she would like to 
answer it.  The patient should always have the option to 
refuse.  If the patient refuses, it should be indicated on the 
questionnaire that she declined to answer the item. 
5.3.3.4 
If the patient cannot complete a questionnaire, or if the 
patient refuses to complete the questionnaire, the reason 
should be noted according to the instructions in the E1Z11 
Forms Completion Guidelines. 
5.3.4 
PRO Administration Instructions – Using Assessment Center ™ 
5.3.4.1 
Electronic administration of PRO will be done using the 
study's website in the PROMIS Assessment Center 
www.assessmentcenter.net/ac1/Assessments/E1Z11. 
5.3.4.2 
Prior to accessing the website, each patient will need to be 
registered by the site. After registering the patient, the site 
staff member will be provided with a username and 
password to be given to the patient. 
5.3.4.3 
Patient-friendly instructions along with additional 
information about electronic submission of PRO can be 
found at www.ecog.org/AIMSS_QOL. 
5.3.4.4 
For patients who complete assessments using the 
Assessment Center, sites will log completion of these 
assessments in Medidata Rave. If the patient needed 
assistance or was unable to complete assessments at a 
given time point, the reason or type of assistance should 
be provided. 
5.3.4.5 
For sites with troubleshooting inquiries regarding the use of 
Assessment Center, the following steps should be 
followed: 1) All sites should direct troubleshooting inquiries 
directly to the E1Z11 Data Associate; 2) ECOG will forward 
unresolved inquiries to Northwestern University research 
staff; 3) Research staff at Northwestern University may 
forward unresolved inquiries to Assessment Center for final 
resolution. NOTE: Assessment Center should not receive 
any troubleshooting inquiries directly from sites. 
5.4 
Dose Modifications 
See Section 5.1 for criteria for dose interruption, discontinuation, and/or 
resumption. The daily dose of anastrozole (1mg po daily) cannot be modified 
when it is taken. 
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5.5 
Concomitant Treatment 
Concomitant treatment with ongoing trastuzumab (Herceptin®) or other 
targeted/biologic agents is allowed; treatment with any other type of 
chemotherapy or hormonal therapy is not allowed. Prior enrollment in any other 
clinical trial during chemotherapy or radiation therapy in the preoperative (i.e., 
neoadjuvant) or adjuvant setting  is not an exclusion as long as all other eligibility 
criteria are met, and the planned assessments on this study can be completed as 
planned. 
The enrollment of a participant in another clinical trial that may randomize to a 
hormonal therapy other than anastrozole or to anastrozole plus another 
therapeutic agent is not allowed. 
Should the participant develop AIMSS and stay on anastrozole, concomitant 
enrollment on to a clinical trial for treatment of AIMSS is allowed (see Supportive 
Care) 
5.6 
Supportive Care 
All supportive measures consistent with optimal patient care will be given 
throughout the study. 
In participants who experience AIMSS, concomitant enrollment in other clinical 
trials evaluating the roles of medications or other interventions in the treatment of 
AIMSS is allowed. Any co-enrollment and interventions must be clearly 
documented in the medical record and reported on the electronic CRF. 
NOTE: 
The co-enrollment of participants to a trial looking to PREVENT the 
development of AIMSS is not allowed. 
5.7 
Duration of Therapy 
Patients will receive protocol therapy for 12 months from registration. After the 
12-month study period is completed, patients should continue to take anastrozole 
or other endocrine therapies in accordance with standard practice guidelines if 
tolerated. 
Patient will receive protocol therapy unless: 
5.7.1 
Extraordinary Medical Circumstances: If at any time the constraints of 
this protocol are detrimental to the patient’s health, protocol treatment 
should be discontinued.  In this event submit data through Medidata 
Rave according to the schedule in the E1Z11 Forms Completion 
Guidelines.   
5.7.2 
Patient withdraws consent. 
5.7.3 
Patient experiences unacceptable toxicity. 
5.7.4 
Prohibited non-protocol therapies are administered. 
5.8 
Duration of Follow-up 
For this protocol, all patients, including those who discontinue protocol therapy 
early, will be followed until the month 12 visit, which should take place 
approximately 1 year (+/- 4 weeks) after the initiation of anastrozole therapy. For 
this protocol, all patients, including those who discontinue protocol therapy early, 
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6. 
Study Measures 
6.1 
Patient Reported Outcome Measures Used In This Study Will Include The 
Following: 
6.1.1 
Health Assessment Questionnaire (HAQ) 
6.1.2 
FACT -G, FACT-Breast subscale and FACT-Endocrine Subscale 
6.1.3 
Assessment of Survivor Concerns (ASC) and Rackovitch Risk 
Perception Scale – will be used to assess fear of recurrence and 
perceived risk of recurrence. 
6.1.4 
Treatment Burden 
6.1.5 
PROsetta Stone Comorbidity Form 
6.1.6 
SOAPP study Comorbidity Bother Item 
6.1.7 
PROMIS Physical Function 20 Form 
6.2 
Patient Reported Outcome Measures To Be Used In This Study 
6.2.1 
HAQ - AI arthralgias are not well defined, and the most careful work to 
date has been done with the Health Assessment Questionnaire (HAQ) 
(27), a patient reported instrument used by rheumatologists, and in the 
ELPh trial organized by COBRA. This instrument is designed for 
patients with more serious and debilitating arthritic conditions, and not 
as sensitive for patients with milder symptoms.  Use of broader 
screening questions may detect milder disability but show ceiling 
effects for severe disability.  We will follow the symptom assessment 
scheme of the COBRA study by Henry et al (4).  This will allow us to 
gain experience with a published approach to case finding in a second 
population of patients, and for both clinical and genomic datasets to 
be compared with the ELPh study,   
6.2.2 
FACT Breast and ES - The FACT-Breast and Endocrine Subscales 
are tailored for patients with breast cancer and includes specific 
questions related to endocrine therapy (28, 29).  The FACT-G measures 
overall health-related quality of life and consists of 4 subscales that 
measure physical, functional, emotional and social well-being. The 
FACT-B Trial Outcome Index (TOI) combines  the Physical well-being 
(PWB) and functional well-being (FWB) subscales of the FACT-G with 
the breast cancer subscale (BCS). The FACT B+ES were used in the 
ATAC trial (30).   Normative data for interpreting results from this study 
will be available from E1Z03 for FACT Breast and ES data. 
6.2.3 
Fear of Recurrence - The Assessment of Survivor Concerns (ASC) is 
a 5-item questionnaire that has 2 subscales – worry about cancer 
recurring (3 items) and worry about general health (2 items). Each of 
the items has a Likert response. In the initial paper, Cronbach’s alpha 
was 0.93 for the cancer worry subscale and 0.72 for the health worry 
subscale. The items are worry about future tests, new cancer, 
recurrence, death, and health.  ECOG has used the 5-item 
Assessment of Survivor Concerns (31) for the TAILORx trial to assess 
fear of recurrence. 
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The Rakovitch Risk Perception Scale asks respondents to describe 
perception of the likelihood of breast cancer recurring in the breast, of 
breast cancer recurring elsewhere, of dying from breast cancer, and 
of dying from other cancers.  It has 4 items (32).   
6.2.4 
Treatment Burden - While many factors may contribute to treatment 
burden, the concept of a single item for global burden has been used 
in European studies by the SAKK group(33). 
6.2.5 
PROsetta Stone Comorbidity Items - Clinical decision-making 
regarding cancer treatment takes on additional complexity in the 
presence of comorbidity (36). Currently, no gold standard exists in the 
measurement of comorbidity in cancer patients(37). Although 
comorbidity is often measured through provider checklists based on 
chart review, patient self-report of comorbidity yields similar 
information and includes chronic conditions that are sometimes 
overlooked on provider chart review. The Prosetta Stone comorbidity 
items have been used across several large NIH-sponsored projects 
(PROMIS, Neuro-QOL, Toolbox) and it has demonstrated good 
reliability and validity. An additional item to address cigarette smoking 
will be included on this measure for this study.  This item is added in 
response to the need for better reporting of tobacco use as a potential 
factor influencing patient outcomes in NCI sponsored clinical trials(38). 
6.2.6 
The SOAPP Study Comorbidity Bother Item - Perception about a 
patient’s capacity to tolerate treatment can influence treatment 
decisions.  In the ECOG SOAPP study (E2Z02), a single item was 
used to assess the degree to which the patient reported being 
bothered by conditions other than cancer. In the breast cancer cohort 
of the SOAPP study, 65.9% of patients reported at least a little bit of 
bother due to comorbidities (39) There was a strong association seen 
between this self-reported bother due to comorbidity and symptom 
burden (40) This single item is thus included to better understand the 
impact of comorbidity in addition to the Prosetta Stone items. 
6.2.7 
PROMIS Physical Function (PF) Short Form 20a - The PROMIS PF 
20a consists of 20 items that assess four subdomains of physical 
function: upper extremity, lower extremity, central, and activity. 
Responses to the 20 items are summed to create one single score. 
The PROMIS PF 20 was developed based on items selected from the 
PROMIS Physical Function 154 item bank. The PROMIS PF 20a 
contains IRT-based items selected from the PROMIS PF 154 item 
bank. The “IRT-based” PROMIS PF20 are selected using IRT 
information content data from over 21,000 subjects to identify the best 
items and minor qualitative input to ensure that all major areas of 
Physical Function/Disability were represented in the instrument, with 
their strongest items. In a study of 451 rheumatoid arthritis patients, 
the PF20 form was comparable to the HAQ (41). The PF20 form has 
not been used in patients with AIMSS and will be validated against the 
HAQ in this study. 
NOTE: 
Please note, Spanish, Korean, Chinese and Japanese 
versions of the FACT-B form will be available on the 
ECOG website. Chinese and Spanish version of the HAQ 
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will be available on the ECOG website.  Also, the Spanish 
version of the PROMIS Physical Function 20-item scale 
will be posted to the ECOG website. 
 

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7. 
Study Parameters 
7.1 
Data Collection 
 
 
Baseline1 
3, 6, 9 and 
12 
months12,17 
Symptom 
onset/At 
diagnosis of 
AIMSS13,17 
At discontinuation 
of Anastrozole 
due to AIMSS12,17 
One month after 
discontinuation of 
Anastrozole due 
to AIMSS14,12,17 
5 Years Post 
Registration16 
Demographics 
X 
 
 
 
 
 
Vital Status 
X 
 
 
 
 
X 
History & Physical Exam, ECOG PS 
X 
 
 
 
 
 
Physical Exam Joints2 
X 
X 
X 
X 
 
 
Routine Blood Tests3 
X 
 
 
 
 
 
Medication Form4 
X 
X 
X 
X 
X 
 
The Stanford Health Assessment 
Questionnaire (HAQ) and PROMIS Physical 
Function- Short Form 20a5,6 
X5 
X 
X 
X 
X 
 
Patient-Reported Comorbidity Checklist 
X 
 
 
 
 
 
Provider Completed Comorbidity Form 
X 
 
 
 
 
 
FACT-G, FACT-B, and FACT-ES6 
X 
X 
X 
X 
X 
 
Quality of Life (QOL) Battery including 
Assessment of Survivor Concerns (ASC), 
Rakovitch Scale, SOAPP Comorbidity Bother, 
and SOAP Treatment Burden6 
X 
X 
X 
X 
X 
 
Physician Questionnaire7  
 
 
X 
X 
 
 
Recurrence Status15 
X 
X 
X 
X 
 
X 
Pill Calendar8 
 
X 
 
X 
 
 
Biological Sample Submissions9 
See Section 10 
 
MANDATORY: Blood for Pharmacogenomics 
(one (1) 10cc yellow top tube)10 
X 
 
 
 
 
 
Blood for Banking for Future Research11 
(serum, [one (1) 10cc red top tube]  
X 
X 
X 
X 
 
 
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1. Baseline assessments and questionnaires must be completed by patients after consent is signed and prior to the start of study treatment, unless 
otherwise noted. 
2. The baseline physical exam is to include physical exam of the joints and should be done within 4 weeks prior to registration. Providers must 
document presence of any joint abnormalities (ie, deformity, edema, joint tenderness, effusions) and if any decrease in range of motion at each 
visit. In follow-up, assessment should include any diagnosis of AIMSS and recommendations on anastrozole dosing. 
3. This refers to blood tests requested by the provider to assess appropriateness to begin hormonal therapy with anastrozole, if the provider would 
routinely perform any tests. There are no routine blood tests specifically required by the study.  
4. Include a list of interventions being used by the patient for pain or AIMSS on the Medication Form. MD/provider may allow the patient to 
complete the medication form as long as they check accuracy after patient completes this form.  
5. Patient’s baseline pain rating must be completed within 7 days prior to registration. The response will be recorded on the registration checklist. 
6. If patients want to use the Assessment Center for completing quality of life assessments, the site should complete the registration prior to asking 
the patient to complete QOL questionnaires so that their case number can be used as an identifier in Assessment Center. The baseline 
assessment should be done prior to starting treatment with anastrozole. For subsequent visits, if participant is not able to complete the 
questionnaires online, paper versions should be given for completion in clinic. 
7. Physician impressions and recommendations regarding AIMSS (stop, continue or holiday) should be recorded on the Physician Questionnaire in 
Medidata Rave. This can be completed by the physician either electronically or on paper, with information transferred to the electronic CRF by 
the study staff. 
8. Patient pill calendar/diary should be completed by patient and collected by the site at 3, 6, 9 and 12 month visits and at the time patient 
discontinues taking anastrozole. 
9. Kits are being provided for the collection and shipment of the blood samples.  Please refer to Section 10.1.2.1 for instructions. 
10. Blood collection for DNA for pharmacogenomics is mandatory as outlined in Section 10. Blood is strongly encouraged to be collected at baseline 
[after registration, prior to treatment] but may be collected at any other time point if unable to collect at baseline. 
11. Blood (serum) should be collected at baseline (after registration, prior to treatment), at three (3) months OR onset of AIMSS (if prior to three [3] 
months), and at twelve (12) months OR discontinuation of anastrozole due to AIMSS. Submit from patients who answer “Yes” to “I agree to 
provide additional blood for research.” 
12. PRO assessments and clinic visits should be completed every 3 months until 1 year (-/+ 4 weeks) after the initiation of anastrozole therapy. In 
the event that anastrozole is discontinued due to AIMSS, two additional PRO assessments will be administered: At the discontinuation of 
Anastrozole due to AIMSS and 1 month after discontinuation of anastrozole due to AIMSS. All participants will complete PRO assessments up 
until 12 months, including participants who discontinue anastrozole early for any reason. 
13. Within two weeks after the patient first reports possible AIMSS, there must be an MD assessment/visit to confirm diagnosis and complete 
PRO's. If the decision is made to discontinue anastrozole due to AIMSS during the same visit as Symptom onset/At diagnosis of AIMSS only 
one additional MD assessment/visit and repeat PROs must occur one month after discontinuation. If discontinuation due to AIMSS occurs on a 
separate visit an MD assessment and PRO's must be done at discontinuation due to AIMSS and one month after discontinuation. 
14. If the decision is made to discontinue anastrozole due to AIMSS prior to 12 months, a one month follow-up visit after discontinuation must be 
completed. 
15. All patients will be followed for recurrence status and survival status until 5 years post study registration.  No specific imaging or other 
assessments are required.  
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12/14 
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16. Follow-up visits should be done yearly until 5 years post registration, starting after the patient has completed the 12 months of patient 
assessments. 
17. If the Symptom assessment(s), At discontinuation of Anastrozole due to AIMSS or 1 month after discontinuation of Anastrozole due to AIMSS 
visits are within one month (+ or -) of any of the regularly scheduled visit (3, 6, 9, 12) only one set of PRO's and one clinic visit are required. The 
Symptom assessment(s), At discontinuation of Anastrozole due to AIMSS and 1 month after discontinuation of Anastrozole due to AIMSS visits 
must trump the 3,6,9 and 12 month post registration visits. 
 
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8. 
Drug Formulation and Procurement 
This information has been prepared by the ECOG Pharmacy and Nursing Committees. 
8.1 
Drug Name Anastrozole 
8.1.1 
Other Names  
Arimidex® 
8.1.2 
Classification  
Antineoplastic agent 
8.1.3 
Mode of Action  
Aromatase inhibitor 
8.1.4 
Storage and Stability  
Store at 20-25° degrees Celsius in a dry environment. 
8.1.5 
Dose Specifics  
1 mg by mouth daily. 
8.1.6 
Preparation  
Oral tablet. Ready to use commercial preparation.  
8.1.7 
Route of Administration  
Anastrozole is taken orally. 
8.1.8 
Incompatibilities  
Not applicable. 
8.1.9 
Availability  
Commercially available. 
8.1.10 
Side Effects  
Vasodilation, hot flushes (flashes), diarrhea, nausea, vomiting, 
asthenia, pain (including back pain), arthritis, arthralgia, fractures, 
increased liver function tests, hypertension, osteoporosis, peripheral 
edema, lymphedema, pharyngitis, depression, rash, insomnia, 
headache, increased cough, dyspnea, fatigue 
8.1.11 
References  
AstraZeneca. Arimidex (anastrozole) tablets prescribing information. 
Wilmington, DE; 2008 Dec. 
 

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9. 
Statistical Considerations 
The primary endpoint is defined as discontinuation of treatment following development of 
AIMSS. A patient will be considered to have developed AIMSS if there is a 20% or 
greater decline in scores on the HAQ instrument from baseline within one year. At the 
time of treatment discontinuation, patients and providers will be asked to rank the 
reasons for treatment discontinuation.  If either the patient or the provider lists pain as 
the first or second-ranked reason and discontinuation is within 3 months of symptom 
escalation, this will be considered an event.  Patients who are lost to follow-up or whose 
reason for discontinuation is unknown will be considered to be event-free.  From 
previous studies, it is estimated that 40% of patients will develop symptoms, and 25% of 
patients will discontinue treatment with AIs within 1 year due to development of 
musculoskeletal symptoms. 
The enrollment plan is designed to assure adequate enrollment of minority (Asian and 
African-American) patients. After 600 patients are enrolled from other racial groups, 
closure of the study to those subgroups will be terminated and accrual will continue 
among only Asian and African-American patients.  When 200 patients are enrolled from 
the first remaining racial subgroup, closure of accrual to that subgroup will terminate and 
all remaining patients will be enrolled from the final remaining subgroup. ECOG Minority 
CCOPs will be strongly encouraged to participate in order to meet targets for minority 
accrual. While not a separate accrual cohort, ethnicity (Hispanic/non-Hispanic) will also 
be considered in the analysis plan. 
The approach we will use to conduct genetic analysis will be a comprehensive one that 
employs a range of technologies to examine germline genetic variants in the DNA of 
women in this study, the goal being to test for simple associations of these variants with 
AIs-induced events. Our GWAS approach builds upon data and techniques from 
genome wide trials already conducted as well as data from candidate gene studies. We 
will use a custom - designed series of variants tested using the ABI Biotrove Open 
Array™ system. This allows robust testing of 100-300 variants with a technology that 
has high reliability and reproducibility, since it is based on simple TaqmanTM technology. 
The Indiana COBRA site has extensive experience in developing chips which can be 
used to screen for complex and difficult-to-identify ESR genotypes, CYP SNPs, and the 
other hypothesized candidate polymorphisms that will be tested for in this trial. The use 
of a flexible but robust technology like this is important since new variants are being 
identified all the time. 
9.1 
Statistical considerations for primary objective of SNP validation 
Patients will be classified into two groups based on whether or not they 
discontinued treatment due to MSS. Hardy-Weinberg equilibrium will be 
evaluated within each racial subset. SNP genotypes will be coded as additive 
effects on the log odds ratio by coding as 0, 1 or 2 for the count of the minor 
allele. Logistic regression will be used to test the association between having a 
minor allele and the log odds of discontinuation of treatment, adjusting for 
covariates.  We plan to enroll 1000 patients and follow them for development of 
symptoms.  Minor allele frequencies reported by Ingle et al. were assumed for 
the 4 SNPs associated with the TCL1A gene, and preliminary results from the 
ELPH study were used to estimate minor allele frequencies associated with the 
ESR gene. A Bonferroni adjustment will be used to account for the simultaneous 
testing of 10 SNPs; a one-sided p-value of 0.0025 will be considered statistically 
significant. For purposes of illustrating statistical power, we assume that Hardy-

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Weinberg equilibrium exists in the allele distribution and that the minor allele is 
associated with higher proportions of discontinuation of treatment due to 
development of symptoms. Table 1 shows the genes, SNPs, and representative 
minor allele frequencies observed in previous studies. Table 2 shows odds ratios 
for the effect of each minor allele that will be detectable with 80% power for 
overall discontinuation rates of 20% or 30% and a range of plausible minor allele 
frequencies, given a sample size of 1000 patients and using a one-sided 
Cochran-Armitage trend test. The table also shows detectable odds ratios for the 
subsets of Caucasian (n=600) and African-American and Asian patients (n=200 
patients each). 
Table 1. SNPs to be validated 
SNP 
Gene 
Rank 
(Ingle) 
Rank 
(ELPH) 
Minor Allele Frequency 
(MAF) 
rs7158782 
TCL1A 
1 
 
0.189 among cases, 0.109 
among controls (0.2 ELPH) 
rs7159713 
TCL1A 
2 
 
0.189 (0.19 ELPH) 
rs2369049 
TCL1A 
3 
4 
0.176 (.18 ELPH) 
rs11849538 
TCL1A 
4 
9 
0.15 (ELPH) 
rs2296972 
HTR2A 
 
1 
0.37 (ELPH) 
rs2347868 
ESR1 
 
2 
0.23 
rs9340835 
ESR1 
 
3 
0.35 
rs2234693 
ESR1 
 
 
0.45 (Riancho) 
rs1062033 
CYP19A1 
 
 
0.44 (Riancho) 
rs4646 
CYP19A1 
 
5 
0.28 
Table 2. Odds Ratios for Effect of Each Minor Allele 
Detectable with 80% Power (Additive Model) 
Proportion Discontinuing MAF N=1000 N=600 N=200 
20% 
10% 
1.88 
2.23 
3.89 
30% 
10% 
1.78 
2.10 
3.65 
20% 
20% 
1.63 
1.87 
2.94 
30% 
20% 
1.55 
1.76 
2.70 
20% 
30% 
1.55 
1.76 
2.66 
30% 
30% 
1.47 
1.65 
2.42 
20% 
40% 
1.52 
1.72 
2.59 
30% 
40% 
1.44 
1.61 
2.33 
9.2 
Secondary Endpoint Analyses 
The association of other SNPs in the ESR, TCL1A, and CYP19A1 genes with 
discontinuation of treatment due to MSS will be explored using a candidate gene 
approach. In this exploratory analysis, the prevalence of treatment 

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discontinuation will be compared between patients who do and do not have the 
variant genotype, modeling the effects as additive, dominant, and recessive.  
Correlations among SNPs will be estimated, and linkage disequilibrium among 
pairs of SNPs will be characterized.   Logistic regression models, with treatment 
discontinuation as the outcome variable, will be used to explore the association 
with SNPs, adjusting for important clinical factors. No adjustment for multiple 
comparisons is planned, but only the top ranking SNPs that were not part of the 
primary validation study will be further explored. 
Other endpoints, including the proportions of patients with treatment 
discontinuation for any reason, the proportion of patients with symptoms 
determined not to be from other known etiologies, and the proportion of patients 
whose symptoms improve when the AI is discontinued, will be similarly explored.  
Time to discontinuation of treatment and time to development of symptoms will 
be explored using proportional hazards models adjusting for significant genotypic 
and clinical predictors.  Kaplan-Meier plots will be used to graphically portray the 
associations. Hispanics are the fastest growing demographic group in the US 
population, and there are 17,100 new breast cancer cases and 2400 breast 
cancer deaths expected in this demographic group in 201237.  The Hispanic 
demographic group may have unique attitudes, beliefs and behaviors related to 
medication adherence with AI.38-40 Exploratory analyses to determine whether 
effects are different in patients with Hispanic ethnicity will also be performed.  
Previous studies have suggested that patients who experience specific adverse 
events associated with endocrine therapy may have improved recurrence-free 
(RFS) and overall survival (OS) compared to those who do not develop these 
symptoms (42,43). RFS ad OS will be described for the entire study population and 
for racial and ethnic subsets. Differences in RFS and OS between patients who 
do or do not develop AIMSS will be explored. 
9.3 
Statistical Considerations For Patient-Reported Outcomes 
We propose to include all 1000 patients in assessment of patient-reported 
outcomes.  Linear mixed effects models will be used to evaluate changes in 
symptoms over time on these instruments.  For purposes of estimating available 
statistical power, we consider a hypothetical analysis comparing changes in 
endocrine symptoms from baseline to 3 months between Caucasian and African-
American patients.  Total score on the FACT-ES (FACT-B plus ES subscale) will 
be calculated.  Psychometric properties of FACT-ES were reported by Fallowfield 
et al. (29).In that report, mean scores of 61.61 at baseline (standard deviation 
6.65) and 57.03 at 12 weeks (standard deviation 9.03) were reported among 32 
women (a decline of 4.52 points).  Table 3 shows statistical power and 
differences in change from baseline that will be detectable assuming a two-sided 
t-test with 5% Type I error, 85% power, baseline standard deviation of 6.65, intra-
patient correlations of 0.4 or 0.6, and QOL completion rates of 90% and 75% 
across the two time points.  There will be good power to detect reasonable 
differences between groups in changes from baseline. 
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Table 3. Detectable Differences for an Example Patient-Reported Outcomes 
Analysis (85% Power) 
Intra-Patient 
Correlation 
Standard 
Deviation 
of Change 
Completion 
Rate 
N 
Caucasian 
Patients 
N 
African-
American 
Patients 
Detectable 
Difference 
0.4 
7.285 
90% 
540 
180 
1.88 
0.6 
5.948 
90% 
540 
180 
1.54 
0.4 
7.285 
75% 
450 
150 
2.06 
0.6 
5.948 
75% 
450 
150 
1.68 
Similar analyses will be done for the FACT-B subscale and for the Trial Outcome 
Index, consisting of the FACT-B subscale along with the FACT-G Physical Well-
being and Functional Well-Being subscales. 
In E1Z03, the quality of life companion study to MA27, patients who reported 
being bothered by side effects of treatment were more likely to discontinue 
treatment.  The impact of patient-reported outcomes, both side effects in general 
and joint pain in particular, on treatment discontinuation will be examined along 
with the genotype information to assess the relative significance of both. 
Patients will be given a choice regarding their preference for submitting QOL 
instruments in paper form or electronically. If 90% or more of patients choose the 
electronic system and if the completion rate among those patients is greater than 
90%, then the web-based system would be considered for future trials. 
If fewer than 90% of patients choose the system but the completion rate among 
these patients is greater than 90%, then the web-based system would be offered 
as an alternative in future trials. 
If the completion rate among web-based users is significantly lower than the rate 
for paper forms, then paper forms would be retained for future studies. Assuming 
that 80% of the 1000 patients opt for the web-based system, there will be 
adequate power (91%) to detect a difference in completion rates of 12% (for 
example, 80% vs. 68%), using a one-sided Fisher’s exact test with 2.5% Type I 
error. Given that access issues may exist in racial subgroups, differences in the 
rates of preference of the on-line system and in the completion rates by racial 
subgroup will be explored. Within minority subgroups there will be 90% power to 
detect a difference in completion rates of 28% (for example, 80% vs. 52%) for 
paper- and web-based processes. A plan to carry electronic capture of QOL data 
forward would not be considered if this was a barrier to participation in minority 
communities. 
As described in Objective 2.2.6 and Section 6.2.7, a goal of the study is to 
validate the PROMIS Physical Function (PF) Short Form 20a in patients with 
AIMSS.  We plan to employ both instruments until 480 English-speaking patients 
have enrolled, assuming that the incidence or AIMSS among these patients is 
25%, resulting in 120 symptomatic patients with assessments on both 
instruments.  Validation will include assessment of internal consistency using 
Cronbach’s alpha.  Test-retest reliability will be assessed by calculating a 
bivariate correlation on scores for the first and second administrations among 
patients whose scores on the HAQ assessment did not change. Associations 
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between scores on the HAQ and the PROMIS PF20a will be used to evaluate 
external validity.  The ability of the instrument to discriminate between patients 
with/without symptoms will also be evaluated.  Assuming 480 patients, a 
completion rate of 90% at 3 months, and 25% of patients with symptoms at 3 
months, there will be adequate power to detect an effect size of .35, using a two-
sided t-test with 90% power and 5% Type I error. 
9.4 
Safety Monitoring 
Interim analyses of toxicity are performed twice yearly for all ECOG studies. 
Reports of these analyses are sent to the ECOG Principal Investigator or Senior 
Investigator at the participating institutions. Expedited reporting of certain 
adverse events is required, as described in Section 5. 
9.5 
Gender and Ethnicity  
Based on prespecified accrual targets the anticipated accrual in subgroups 
defined by gender and race is: 
Ethnic Category 
Gender 
Females 
Males 
Total 
Hispanic or Latino 
100 
0 
100 
Not Hispanic or Latino 
900 
0 
900 
Ethnic Category: Total of all subjects 
1000 
0 
1000 
Racial Category 
American Indian or Alaskan Native 
5 
0 
5 
Asian 
200 
0 
200 
Black or African American 
200 
0 
200 
Native Hawaiian or other Pacific Islander 
5 
0 
5 
White 
590 
0 
590 
Racial Category: Total of all subjects 
1000 
0 
1000 
The accrual targets in individual cells are not large enough for definitive 
treatment comparisons to be made within these subgroups. Therefore, overall 
accrual to the study will not be extended to meet individual subgroup accrual 
targets. 
9.6 
Accrual Rates 
We expect to accrue 500 patients per year for 2 years. Accrual of African 
American and Asian cohorts may take longer, but targeted strategies will be used 
to encourage enrollment to these cohorts. 
 

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10. 
Correlative Studies 
NOTE: 
An informed consent must be signed prior to the submission of any samples, 
including future laboratory studies. 
NOTE: 
ECOG requires that all biological samples submitted be entered and tracked 
via the online ECOG Sample Tracking System. An STS Shipping Manifest 
Form must be generated and shipped with the sample submissions. See 
Section 10.3. 
NOTE: 
Institutions outside of the United States and Canada must confer with the 
receiving laboratory and the ECOG Coordinating Center regarding logistics 
for submission of fresh samples. 
10.1 
DNA Polymorphisms Associated with AIMSS and Discontinuation of Aromatase 
Inhibitors 
Pharmacogenomic predictors may be able to identify women at risk for AIMSS 
since genetic variants have already been identified that are associated with AI 
pharmacokinetics, with the effects of estrogen deprivation on bone and other 
phenotypes. 
The goal of the correlative study is to validate previously identified associations 
between ten specific single nucleotide polymorphisms (SNPs) and 
discontinuation of treatment with aromatase inhibitors (AIs) due to the 
development of musculosketal symptoms (MSS) among women with breast 
cancer. If these associations are confirmed, a marker could be identified that may 
serve as an indicator of increased risk for treatment discontinuation and related 
poor therapeutic outcome. 
10.1.1 
Sample Submission Schedule 
Instructions to order kits are outlined below in Section 10.1.2.1. 
NOTE: 
Due to funding restrictions multiple kit requests are not 
permitted.  Additionally patients must be registered to or 
being worked up for the trial before submitting your kit 
requests. 
Questions are to be directed to the ECOG Immunological Monitoring 
and Cellular Products laboratory (IMCPL) ECOG study coordinator at 
(412) 624-0078. 
10.1.1.1 
Blood for DNA must be collected at baseline (blood is 
strongly encouraged to be collected at baseline [after 
registration, prior to treatment] but may be collected at any 
other time point if unable to collect at baseline)for the 
mandatory genotyping assays outlined in Sections 1.1.2 
and 10.2. 
Dr. David Flockhart’s Laboratory at the Indiana University 
Division of Clinical Pharmacology will perform the analysis. 
10.1.1.2 
Blood (serum) for banking for future research studies 
should be submitted at the following time points: 
· 
Baseline 
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· 
At Three (3) Months OR Onset of AIMSS (if prior to 
three [3] months) 
· 
At Twelve (12) Months OR Discontinuation of 
Anastrozole due to AIMSS 
NOTE: 
Blood samples are to be submitted from 
patients who answer “YES” to “I agree to 
provide additional blood for research.” 
10.1.2 
Sample Preparation Guidelines  
1. At Baseline ONLY the following MUST be submitted: 
· 
One (1) FULL 10 cc YELLOW top ACD tube 
2. At EACH time point listed above in Section 10.1.1.2 please submit 
the following (OPTIONAL): 
· 
One (1) FULL 10 cc RED top tube 
Please completely fill all blood tubes as full as possible. 
Each tube must be clearly labeled to include: 
· 
ECOG protocol number E1Z11 
· 
ECOG five digit patient sequence number 
· 
Patient initials 
· 
Originating institution/investigator name  
· 
Date and time drawn 
· 
Collection time point 
10.1.2.1 
Shipping Kits 
Specimen shipping kits must be requested from the 
IMCPL. Please fax the request using the Shipping Kit 
Request Facsimile Form (Appendix VI) to (412) 623-6625 
or call the IMCPL at (412) 624-0078. Please allow ten days 
for shipment and provide the following information: 
· 
Study Number 
· 
Participating Site Number 
· 
Contact Person and Telephone Number 
The kits will be shipped via FedEx Express Saver. Please 
plan ahead, priority overnight shipment is not possible.  
All blood samples should be shipped the day of collection 
using the shipping kit. Follow shipping instructions 
provided in the kit carefully. 
The shipping kit consists of the following: 
· 
Insulated shipping container and packing material 
· 
FedEx Priority Overnight return label  
· 
Shipping Instructions 
· 
Shipping Kit Request Form 

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10.1.3 
Shipping Procedures  
Log the samples into the ECOG STS the day of shipment. If the STS 
is unavailable, an ECOG Generic Specimen Submission Form 
(#2981) must be submitted with the samples. Once STS is available, 
retroactively log the shipment into STS, using the actual collection and 
shipping dates. 
If the STS is unavailable, notify the IMCPL ECOG study coordinator 
by fax (412-623-6625) using the Specimen Shipment/Requisition 
Form (Appendix V). If you are unable to get through to the laboratory 
by fax, telephone the ECOG study coordinator at (412) 624-0078 and 
provide the tracking number. 
Blood collected into the appropriate tubes should be sealed, wrapped 
and placed in the specimen shipper kit and shipped on the same day 
they are drawn by Federal Express Priority overnight courier using the 
return label provided in the kit. The yellow and red top tubes should 
be refrigerated immediately. Cool packs are not required as the 
Styrofoam shipper should protect the tubes for overnight shipment. 
Shipments must be timed to arrive during normal working hours and 
should be shipped in one box. 
The laboratory will be open Monday through Friday to receive 
samples. Do NOT ship on Fridays or Saturdays, or the day before a 
legal holiday. Ship by overnight courier Monday - Thursday only to: 
Immunologic Monitoring and Cellular Products Laboratory 
University of Pittsburgh Cancer Institute 
UPCI-IMCPL 
ECOG Study Coordinator 
Hillman Cancer Center 
5117 Centre Avenue, L 1.26 
Pittsburgh, PA 15213 
Tel: (412) 624-0078 
Fax: (412) 623-6625 
An STS Shipping Manifest Form must be generated and shipped with 
all sample submissions. 
NOTE: 
Blood should NOT be collected on Fridays. Please contact 
the IMCPL for further instruction. 
10.1.4 
Federal Guidelines for the Shipment of Blood Products: 
Sites should follow IATA regulations for Packaging UN3372 
shipments. Please refer to FedEx guidelines. 
10.2 
Pharmacogenomic Study Methods 
10.2.1 
Specimen Acquisition 
Blood will be collected at baseline using yellow top tubes. Specimens 
will be shipped to the ECOG IMCPL at the University of Pittsburgh 
where DNA will be isolated and stored for subsequent shipment to Dr. 
David Flockhart’s Laboratory at the Indiana University School of 
Medicine for genotyping assays. DNA concentrations will be 
determined using the Picogreen DNA quantification assay (Life 
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Technologies, Inc). This assay is based on the SYBR green 
fluorescence and provides the most accurate total DNA quantification 
measurements. DNA quality will be assessed by 260:280 nanometers 
absorbance and a subset of samples will be run on an agarose gel to 
assure that high quality high molecular weight DNA is being isolated. 
10.2.2 
Assay 
The Flockhart Laboratory will use the OpenArray™ platform for the 
genotyping assays. The instrument to be used has been purchased 
from Applied Biosystems, Inc. The custom designed genotyping 
arrays are mini Taqman™ assays plated on the OpenArrays™ in 33 
nanoliter reaction volumes. The thermocycling is done in an ABI 9600 
thermocycler and the resulting allele specific fluorescence is read in 
the OpenArray™ reader. All equipment and reagents are purchased 
from Applied Biosystems, Inc. (a division of Life Technologies, Inc).  
10.2.3 
Assay Performance 
The Flockhart Laboratory’s previous studies using the OpenArray™ 
format have yielded call rates of >95% with accuracy of >98%. For 
quality control purposes, approximately 10-15% of the samples are re-
genotyped. Concordance rates of >98% are expected, but are usually 
100%. Any discrepancies are resolved by DNA sequencing. Every 
assay contains a no template control (water in place of the DNA 
sample). The assays are not performed in a CLIA laboratory, and thus 
no results will be returned to patients or health care providers. 
10.2.4 
Scoring 
Genotyping data results will yield one of three possible classifications: 
Homozygous wild-type (2 wild-type alleles), heterozygous (1 wild-type 
and 1 variant allele), or homozygous variant (2 variant alleles). The 
classification is determined based on the fluorescent values obtained 
from the allelic discrimination plots of the Taqman™ assays. These 
are standard assays used widely in the field for genotyping. Minor 
allele frequencies are expected to range from 10% to 38% based on 
prior studies in similar populations. This range of frequencies is high 
enough that an association between the polymorphism and the 
phenotype of treatment discontinuation due to AIMSS has potential 
utility. The rate of treatment discontinuation due to AIMSS is expected 
to be 20 to 30%. 
10.3 
ECOG Sample Tracking System 
It is required that all samples submitted on this trial be entered and tracked 
using the ECOG Sample Tracking System (STS). The software will allow the use 
of either 1) an ECOG user-name and password previously assigned (for those 
already using STS), or 2) a CTSU username and password.   
When you are ready to log the collection and/or shipment of the samples 
required for this study, please access the Sample Tracking System software by 
clicking https://webapps.ecog.org/Tst  
Additionally, please note that the STS software creates pop-up windows, so you 
will need to enable pop-ups within your web browser while using the software. A 

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user manual and interactive demo are available by clicking this link: 
http://www.ecog.org/general/stsinfo.html Please take a moment to familiarize 
yourself with the software prior to using the system. 
An STS generated Shipping Manifest Form should be generated and shipped 
with all sample submissions. 
Please direct your questions or comments pertaining to the STS to 
ecog.tst@jimmy.harvard.edu 
10.3.1 
Study Specific Notes 
An ECOG Generic Specimen Submission Form (#2891) will be 
required only if STS is unavailable at the time of sample submission. 
Indicate the appropriate Lab ID # on the submission form: 
· 
0009= ECOG Immunologic Monitoring and Cellular Products 
Laboratory 
· 
The day of shipment, notify the IMCPL ECOG study 
coordinator by fax (412-623-6625) using the Specimen 
Shipment/Requisition Form (Appendix V). If you are unable to 
get through to the laboratory by fax, telephone the ECOG 
study coordinator at (412) 624-0078 and provide the FedEx 
tracking number. 
Retroactively enter all collection and shipping information 
when STS is available. 
10.4 
Banking 
Blood samples collected will be retained at the ECOG IMCPL for use in future 
ECOG approved studies. If future use is denied or withdrawn by the patient, the 
samples will be removed from consideration for use in any future study. 
10.5 
Lab Data Transfer Guidelines 
The data collected or generated on the above mentioned correlative studies will 
be submitted electronically via secure data portal to the ECOG Coordinating 
Center by the central laboratory on a quarterly basis. 
10.6 
Sample Inventory Submission Guidelines 
Inventories of all specimens collected and aliquoted will be submitted 
electronically by secure web application to the ECOG Coordinating Center on a 
monthly basis or upon request by any laboratory holding and/or using specimens 
associated with this study. 
 

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11. 
Electronic Data Capture 
Please refer to the E1Z11 Forms Completion Guidelines for the forms submission 
schedule. Data Collection will be performed in Medidata Rave and in Assessment 
CenterTM. 
This study will be monitored by the CTEP Data Update System (CDUS) version 3.0. 
Cumulative CDUS data will be submitted quarterly from the ECOG Coordinating Center 
to CTEP by electronic means. 
12. 
Patient Consent and Peer Judgment 
Current FDA, NCI, state, federal and institutional regulations concerning informed 
consent will be followed. 
13. 
References 
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Clin.60(5):277-300. 
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et al. American Society of Clinical Oncology clinical practice guideline: update on 
adjuvant endocrine therapy for women with hormone receptor-positive breast 
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3. 
Crew KD, Greenlee H, Capodice J, Raptis G, Brafman L, Fuentes D, et al. 
Prevalence of joint symptoms in postmenopausal women taking aromatase 
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4. 
Henry NL, Giles JT, Ang D, Mohan M, Dadabhoy D, Robarge J, et al. Prospective 
characterization of musculoskeletal symptoms in early stage breast cancer patients 
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Henry NL, Azzouz F, Desta Z, Li L, Nguyen AT, Lemler S, et al. Predictors of 
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Klein C, Lohmann K, Ziegler A. The Promise and Limitations of Genome-wide 
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Henry NL, Pchejetski D, A'Hern R, Nguyen AT, Charles P, Waxman J, et al. 
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2920022. 
8. 
Miossec P, Korn T, Kuchroo VK. Interleukin-17 and type 17 helper T cells. N Engl J 
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Pinto LG, Cunha TM, Vieira SM, Lemos HP, Verri WA, Jr., Cunha FQ, et al. IL-17 
mediates articular hypernociception in antigen-induced arthritis in mice. 
Pain.148(2):247-56. 
10. Baum M, Buzdar A, Cuzick J, Forbes J, Houghton J, Howell A, et al. 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. 2003;98(9):1802-10. 
11. Henry NL, Jacobson JA, Banerjee M, Hayden J, Smerage JB, Van Poznak C, et al. 
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Cancer.116(18):4360-7. PMCID: 2936686. 
12. Wolfe F, Michaud K, Strand V. Expanding the definition of clinical differences: from 
minimally clinically important differences to really important differences. Analyses 
in 8931 patients with rheumatoid arthritis. J Rheumatol. 2005;32(4):583-9. 
13. Hayes DF, Skaar TC, Rae JM, Henry NL, Nguyen AT, Stearns V, et al. Estrogen 
receptor genotypes, menopausal status, and the effects of tamoxifen on lipid 
levels: revised and updated results. Clin Pharmacol Ther. 2010;88(5):626-9. 
14. Henry NL, Nguyen A, Azzouz F, Li L, Robarge J, Philips S, et al. Lack of 
association between oestrogen receptor polymorphisms and change in bone 
mineral density with tamoxifen therapy. Br J Cancer.102(2):294-300. PMCID: 
2816645. 
15. Rae JM, Cordero KE, Scheys JO, Lippman ME, Flockhart DA, Johnson MD. 
Genotyping for polymorphic drug metabolizing enzymes from paraffin-embedded 
and immunohistochemically stained tumor samples. Pharmacogenetics. 
2003;13(8):501-7. 
16. Henry NL, Rae JM, Li L, Azzouz F, Skaar TC, Desta Z, et al. Association between 
CYP2D6 genotype and tamoxifen-induced hot flashes in a prospective cohort. 
Breast Cancer Res Treat. 2009;117(3):571-5. PMCID: 2746261. 
17. Ingle JN, M. L, Wickerham DL, Schaid DJ, Mushiroda T, Kubo M, et al., editors. 
Genome-Wide Associations of Breast Events and Functional Genomic Studies in 
High-Risk Women Receiving Tamoxifen or Raloxifene on NSABP P1 and P2 
Prevention Trials. A Pharmacogenomics Research Network-RIKEN-NSABP 
Collaboration. San Antonio Breast Cancere Symposium; 2010; San Antonio, 
Texas. 
18. Kamdem LK, Liu Y, Stearns V, Kadlubar SA, Ramirez J, Jeter S, et al. In vitro and 
in vivo oxidative metabolism and glucuronidation of anastrozole. Br J Clin 
Pharmacol.70(6):854-69. PMCID: 3014069. 
19. Garcia-Casado Z, Guerrero-Zotano A, Llombart-Cussac A, Calatrava A, 
Fernandez-Serra A, Ruiz-Simon A, et al. A polymorphism at the 3'-UTR region of 
the aromatase gene defines a subgroup of postmenopausal breast cancer patients 
with poor response to neoadjuvant letrozole. BMC Cancer.10:36. PMCID: 
2830181. 
20. Desta Z, Kreutz Y, Nguyen AT, Li L, Skaar T, Kamdem LK, et al. Plasma letrozole 
concentrations in postmenopausal women with breast cancer are associated with 
CYP2A6 genetic variants, body mass index, and age. Clin Pharmacol 
Ther.90(5):693-700. 
21. Kamdem LK, Flockhart DA, Desta Z. In vitro cytochrome P450-mediated 
metabolism of exemestane. Drug Metab Dispos.39(1):98-105. PMCID: 3014267. 
22. Offit K, Robson ME. New pharmacogenomic paradigm in breast cancer treatment. 
J Clin Oncol.28(31):4665-6. 
22 
a Riancho JA, García-Ibarbia C, Gravani A, et al. Common variations in estrogen-
related genes are associated with severe large-joint osteoarthritis: a multicenter 
genetic and functional study. Osteoarthritis Cartilage. 2010;18:927-33. PMID: 
20417295.) 
23. Hershman DL, Kushi LH, Shao T, Buono D, Kershenbaum A, Tsai WY, et al. Early 
discontinuation and nonadherence to adjuvant hormonal therapy in a cohort of 

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8,769 early-stage breast cancer patients. J Clin Oncol.28(27):4120-8. PMCID: 
2953970. 
24. Wagner LI, Zhao F, Chapman J-AW, Cella D, Shepherd LE, Sledge GW, et al., 
editors. Patient-reported predictors of early treatment discontinuation: NCIC 
JMA.27/E1Z03 quality of life tudy of postmenopausal women with primary breast 
cancer randomized to exemestane or anastrozole. San Antonio Breast Cancer 
Symposium; 2011; San Antonio, Texas. 
25. Gershon RC, Rothrock N, Hanrahan R, Bass M, Cella D. The use of PROMIS and 
assessment center to deliver patient-reported outcome measures in clinical 
research. J Appl Meas.11(3):304-14. 
26. Gershon R, Rothrock NE, Hanrahan RT, Jansky LJ, Harniss M, Riley W. The 
development of a clinical outcomes survey research application: Assessment 
Center. Qual Life Res.19(5):677-85. 
27. Bruce B, Fries JF. The Stanford Health Assessment Questionnaire: a review of its 
history, issues, progress, and documentation. J Rheumatol. 2003;30(1):167-78. 
28. Brady MJ, Cella DF, Mo F, Bonomi AE, Tulsky DS, Lloyd SR, et al. Reliability and 
validity of the Functional Assessment of Cancer Therapy-Breast quality-of-life 
instrument. J Clin Oncol. 1997;15(3):974-86. 
29. Fallowfield LJ, Leaity SK, Howell A, Benson S, Cella D. Assessment of quality of 
life in women undergoing hormonal therapy for breast cancer: validation of an 
endocrine symptom subscale for the FACT-B. Breast Cancer Res Treat. 
1999;55(2):189-99. 
30. 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):273-84. 
31. Gotay CC, Pagano IS. Assessment of Survivor Concerns (ASC): a newly proposed 
brief questionnaire. Health Qual Life Outcomes. 2007;5:15. PMCID: 1828718. 
32. Rakovitch E, Franssen E, Kim J, Ackerman I, Pignol JP, Paszat L, et al. A 
comparison of risk perception and psychological morbidity in women with ductal 
carcinoma in situ and early invasive breast cancer. Breast Cancer Res Treat. 
2003;77(3):285-93. 
33. Bernhard J, Maibach R, Thurlimann B, Sessa C, Aapro MS. Patients' estimation of 
overall treatment burden: why not ask the obvious? J Clin Oncol. 2002;20(1):65-72. 
34. Ritchie CS, Kvale E, Fisch MJ. Multimorbidity: an issue of growing importance for 
oncologists. J Oncol Pract.7(6):371-4. PMCID: 3219463. 
35. Sarfati D. Review of methods used to measure comorbidity in cancer populations: 
No gold standard exists. J Clin Epidemiol.65(9): 924-33. 
36. Peters EN, Torres E, Toll BA, Cummings KM, Gritz ER, Hyland A, et al. Tobacco 
assessment in actively accruing national cancer institute cooperative group 
program clinical trials. J Clin Oncol.30(23):2869-75. PMCID: 3410402. 
37. Kvale EA, Manola J, Ritchie CS, Snyder CF, Fisch MF. Concordance between 
patient and clinician regarding perception of comorbidity burden. Supp Care 
Cancer 2012;20(Suppl 1)(S197, Abstract 827 ). 
38. Ritchie C, Manola J, Kvale E, Snyder CF, Fisch M. The relationship between 
symptom burden and perceived comorbidity in outpatients with common solid 
tumors. J Clin Oncol. 2012;30 suppl(Abst 6080). 
Rev. Add5 

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39. Fries JF, Krishnan E, Rose M, Lingala B, Bruce B. Improved responsiveness and 
reduced sample size requirements of PROMIS physical function scales with item 
response theory. Arthritis Res Ther.13(5):R147. PMCID: 3308075.  
40. CuzickJ, Sestak I, Cella D, et al. Treatment-emergent endocrine symptoms and the 
risk of breast cancer recurrence: a retrospective analysis of the ATAC trial.  Lancet 
Oncol 2008; 9: 1143-1148. 
41. Fontein DBY, Seynaeve C, Hadji P, et al. Specific adverse events predict survival 
benefit in patients treated with tamoxifen or aromatase inhibitors: an International 
Tamoxifen Exemestane Adjuvant Multinational Trial analysis.  J Clin Oncol 2013; 
31: 2257-2264. 
 
Rev. 11/13 
Rev. 11/13 

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Appendix I 
 
Informed Consent Template for Cancer Treatment Trials (English Language) 
[Deleted in Addendum #3] 
INFORMED CONSENT INTENTIONALLY REMOVED FROM 
PROTOCOL DOCUMENT 
Appendix I was removed from the protocol document in Addendum #3 and is posted as a 
separate document on the ECOG website. This was removed from the protocol to comply 
with NCI formatting guidelines. 
Rev. 4/14 
Rev. 4/14 

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Appendix II 
 
Patient Thank You Letter 
We ask that the physician use the template contained in this appendix to prepare a letter 
thanking the patient for enrolling in this trial. The template is intended as a guide and can 
be downloaded from the ECOG web site at http://www.ecog.org. As this is a personal 
letter, physicians may elect to further tailor the text to their situation. 
This small gesture is a part of a broader program being undertaken by ECOG and the 
NCI to increase awareness of the importance of clinical trials and improve accrual and 
follow-through. We appreciate your help in this effort. 
 ________________________________________________________________________  
 
[PATIENT NAME] 
[DATE] 
[PATIENT ADDRESS] 
 
 
Dear [PATIENT SALUTATION], 
 
Thank you for agreeing to take part in this important research study. Many questions 
remain unanswered in cancer.  With the help of people like you who participate in clinical 
trials, we will achieve our goal of effectively treating and ultimately curing cancer. 
We believe you will receive high quality, complete care. I and my research staff will 
maintain very close contact with you. This will allow me to provide you with the best care 
while learning as much as possible to help you and other patients. 
On behalf of [INSTITUTION] and the Eastern Cooperative Oncology Group, we thank 
you again and look forward to helping you. 
 
 
Sincerely, 
 
 
 
 
[PHYSICIAN NAME] 
 
 

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Appendix III 
 
Patient Pill Calendar 
 
 
Pill Calendar Directions 
1. Take your scheduled dose of each pill. 
2. If you forget, the missed pills will not be taken later. 
NOTE: 
Local study teams may use a different calendar format as long as drug 
dates/doses are recorded for study reporting/data completion. 
 
 

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Patient Pill Calendar 
This is a calendar on which you should record taking the study tablet, anastrozole. You should 
take your anastrozole as directed by your doctor. Write in the date and your initials for each day 
during the month you took anastrozole. If you develop any side effects, please record them and 
anything you would like to tell the doctor in the space provided. 
DAY 
Date 
Patient 
Initials 
Number of 
pills taken 
Did you 
take brand 
or generic 
anastrozole 
Side effects (including unusual 
symptoms), other medications 
you have taken, or other notes 
for your doctor. 
Month Day 
Year 
 
 
1 
 
 
 
 
 
 
 
2 
 
 
 
 
 
 
 
3 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
5 
 
 
 
 
 
 
 
6 
 
 
 
 
 
 
 
7 
 
 
 
 
 
 
 
8 
 
 
 
 
 
 
 
9 
 
 
 
 
 
 
 
10 
 
 
 
 
 
 
 
11 
 
 
 
 
 
 
 
12 
 
 
 
 
 
 
 
13 
 
 
 
 
 
 
 
14 
 
 
 
 
 
 
 
15 
 
 
 
 
 
 
 
16 
 
 
 
 
 
 
 
17 
 
 
 
 
 
 
 
18 
 
 
 
 
 
 
 
19 
 
 
 
 
 
 
 
20 
 
 
 
 
 
 
 
21 
 
 
 
 
 
 
 
22 
 
 
 
 
 
 
 
23 
 
 
 
 
 
 
 
24 
 
 
 
 
 
 
 
25 
 
 
 
 
 
 
 
26 
 
 
 
 
 
 
 
27 
 
 
 
 
 
 
 
28 
 
 
 
 
 
 
 
29 
 
 
 
 
 
 
 
30 
 
 
 
 
 
 
 
31 
 
 
 
 
 
 
 
 

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Appendix IV 
 
ECOG Performance Status 
PS 0 
Fully active, able to carry on all pre-disease performance 
without restriction 
PS 1 
Restricted in physically strenuous activity but ambulatory and 
able to carry out work of a light or sedentary nature e.g. light 
house work, office work. 
PS 2 
Ambulatory and capable of all self-care but unable to carry out 
any work activities.  Up and about more than 50% of waking 
hours. 
PS 3 
Capable of only limited self-care, confined to bed or chair more 
than 50% of waking hours. 
PS 4 
Completely disabled.  Cannot carry on any self-care.  Totally 
confined to bed or chair. 
 

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Appendix V 
 
Specimen Shipment Requisition Form 
ECOG – PROTOCOL E1Z11 
It is required that samples submitted from patients participating in E1Z11 be entered and 
tracked via the online ECOG Sample Tracking System. This form is used only in the event that 
the STS is inaccessible and then the shipments are to be logged in retroactively, indicating the 
actual dates of collection and shipment. 
Immunologic Monitoring and 
Cellular Products Laboratory 
UPCI Research Pavilion at the Hillman Cancer Center 
Room L 1.26 
5117 Centre Avenue 
Pittsburgh, PA  15213-1863 
Tel: 412-624-0078 
Fax: 412-623-6625 
 
Call the IMCPL ECOG Study Coordinator at 412-624-0078 with questions on shipping. 
Please complete the following information and include this form in the shipment. 
Specimen 
 
 
 
 
 
Specimen 
Collection Date __ __/__ __/__ __ 
 
 
Collection Time: ____ ____:____ ____ 
mm    dd        yy 
 (24 hour clock) 
Time Points (check one): 
 
Baseline 
One (1) ACD yellow top tube, One (1) red top tube 
 
Month 3 
 
One (1) red top tube  
 
(or onset of AIMSS) 
 
Month 12 
One (1) red top tube 
 
(or discontinuation of treatment) 
ECOG Patient Sequence Number:  ________________________   ECOG Patient Initials: __________ 
 
Last   First 
Clinical Site:_______________________________   Site Contact: ____________________________ 
Telephone Number:  _________________________    Fax Number: ___________________________ 
Federal Express® Air Bill No.: _________________________  Date of Shipment: ________________ 
Ship specimens by overnight express to arrive the next morning unless otherwise directed by the 
protocol. Do NOT ship on Friday or Saturday, or the day before a legal holiday. 

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Shipping Checklist: (kits will be shipped / delivered to you from UPCI IMCPL upon request) 
____ Label vials with patient initials/ECOG sequence number, and date and time of draw. 
____ Seal, wrap, and place specimen tubes in specimen shipper kit. 
____ STS Shipping Manifest Form. Make a copy for your records and place the original form 
inside the specimen shipper kit. 
 
To be completed by IML Staff: 
IML Study Number 
IML Accession Number: 
Specimen Type received (if different from above): 
Specimen Acceptability: 
Comment: 
 
 
This message is intended only for the use of the individual or entity to which it is addressed and may 
contain information that is privileged, confidential, and exempt from disclosure under applicable law.  If 
the reader of this message is not the intended recipient or the employee or agent responsible for 
delivering the message to the intended recipient, you are hereby notified that any dissemination, 
distribution, or copying of this communications is strictly prohibited.  If you have received this 
communication in error, please notify us immediately by telephone and return the original facsimile to 
us at the above address via the U.S. Postal Service.  Thank you. 

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Appendix VI 
 
Shipping Kit Request Facsimile Form 
ECOG – PROTOCOL E1Z11 
Immunologic Monitoring and 
Cellular Products Laboratory 
UPCI Research Pavilion at the Hillman Cancer Center 
Room L 1.26 
5117 Centre Avenue 
Pittsburgh, PA  15213-1863 
Tel: 412-624-0078 
Fax: 412-623-6625 
To: 
ECOG Study Coordinator 
 
 
 
 
Fax: 412-623-6625 
From:  
 
Name: _______________________________ 
 
 
 
Institution:____________________________ 
 
 
 
Telephone: ____________________________ 
 
 
 
Fax:  _________________________________ 
Number of Kits Requested:  
Baseline (1RT/1ACD) _______________                      
Month 3/Onset of AIMSS (1RT) 
______________ 
Month 12/End of Treatment (1RT) ______________ 
Shipping Address: 
_______________________________________ 
 
 
 
_______________________________________ 
 
 
 
________________________________________ 
 
 
 
________________________________________ 
PLEASE ALLOW 10 WORKING DAYS FOR RECEIPT OF SHIPPING KITS 
NOTE: 
To order collection and shipping kits for E1Z11, patients must be registered to or in 
the process of being worked up for the E1Z11 trial. Due to funding restrictions 
institutions cannot order multiple collection and shipping kits in advance.