Pre-Operative Window of Adjuvant Endocrine Therapy to Inform Radiation Therapy Decisions In Older Women With Early-Stage Breast Cancer
Phase: PHASE2
Conditions: Breast Cancer Female
Sponsor: Shayna Showalter, MD

Pre-Operative Window of Adjuvant Endocrine Therapy to Inform Radiation Therapy Decisions in 
Older Women with Early-Stage Breast Cancer    
Version Date: 21 February 2023 
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PRE-OPERATIVE WINDOW OF ADJUVANT ENDOCRINE THERAPY 
TO INFORM RADIATION THERAPY DECISIONS IN OLDER WOMEN 
WITH EARLY-STAGE BREAST CANCER 
Protocol ID: POWER 
National Clinical Trial (NCT) Identified Number:  NCT04272801 
Funded by: American Cancer Society – IRG and National Institutes of 
Health (R21 grant) 
Version Date: 21 February 2023 
Confidentiality Statement 
The information contained in this document is the property of the University of Virginia Cancer Center 
Office of Clinical Research and the Human Immune Therapy Center.  Distributing, copying, or 
disclosing information contained in this document requires prior authorization from the University of 
Virginia Cancer Center, except that this document may be disclosed to the appropriate institutional 
review boards or other regulatory agencies as required by law.   

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Key Roles and Study Governance 
 
Multi-Site Principal 
Investigator 
 
Shayna L. Showalter, MD 
University of Virginia Health System 
Department of Surgery 
Office phone: (434) 982-0840 
Fax: (434) 297-5362 
snl2t@virginia.edu 
 
Participating Institutions 
University of Virginia 
Trish Millard, MD  
Principal Investigator 
Office phone: (434) 982-3210 
tas9g@virginia.edu 
 
VCU Massey Cancer Center 
Kandace P. McGuire, MD FACS 
Principal Investigator 
Office phone: 1-804-828-9325 
Kandace.McGuire@vcuhealth.org  
 
Biostatistician: 
Gina Petroni, PhD 
grp4c@virginia.edu 
Data Coordinating Center 
University of Virginia School of Medicine, Clinical Trials 
Office, Multisite Clinical Research Office (MCRO) 
 
Amy Smith 
(434)-243-2270 
ajb6bb@virginia.edu  
 
 
 
 

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STATEMENT OF COMPLIANCE ...................................................................................... 5 
ABBREVIATIONS .............................................................................................................. 6 
 
PROTOCOL SUMMARY ............................................................................................ 8 
1.1 
SYNOPSIS .............................................................................................................. 8 
1.2 
SCHEMA ............................................................................................................... 10 
 
INTRODUCTION ....................................................................................................... 11 
2.1 
STUDY RATIONALE ............................................................................................... 11 
2.2 
BACKGROUND ...................................................................................................... 11 
2.3 
SUMMARY ............................................................................................................ 14 
2.4 
RISK/BENEFIT ASSESSMENT ................................................................................ 15 
 
OBJECTIVES AND ENDPOINTS ............................................................................. 16 
 
STUDY DESIGN ........................................................................................................ 16 
4.1 
OVERALL DESIGN ................................................................................................. 16 
4.2 
JUSTIFICATION FOR DOSE .................................................................................... 17 
4.3 
END OF STUDY DEFINITION .................................................................................. 17 
 
STUDY POPULATION .............................................................................................. 18 
5.1 
INCLUSION CRITERIA ............................................................................................ 18 
5.2 
EXCLUSION CRITERIA ........................................................................................... 18 
5.3 
JUSTIFICATION FOR STUDY POPULATION .............................................................. 18 
5.4 
LIFESTYLE CONSIDERATIONS ............................................................................... 19 
5.5 
SCREEN FAILURES ............................................................................................... 19 
5.6 
STRATEGIES FOR RECRUITMENT AND RETENTION ................................................ 19 
 
STUDY INTERVENTION .......................................................................................... 19 
6.1 
DESCRIPTION OF STUDY INTERVENTION(S) ........................................................... 19 
6.2 
DOSING AND ADMINISTRATION ............................................................................. 20 
6.3 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY ......................................... 21 
6.4 
STUDY INTERVENTION COMPLIANCE ..................................................................... 21 
6.5 
REGISTRATION AND TREATMENT ALLOCATION ...................................................... 21 
6.6 
CONCOMITANT THERAPY ...................................................................................... 22 
 
STUDY CLOSURE, STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION OR WITHDRAWAL ....................................................................... 23 
7.1 
STUDY DISCONTINUATION AND CLOSURE ............................................................. 23 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL .................................................... 23 
7.3 
PROCEDURES FOR DISCONTINUATION OF STUDY INTERVENTION .......................... 24 
7.4 
LOST TO FOLLOW-UP ........................................................................................... 24 
 
STUDY ASSESSMENTS AND PROCEDURES ...................................................... 24 
8.1 
CLINICAL ASSESSMENTS ...................................................................................... 24 
8.2 
PARTICIPANT QUESTIONNAIRES ........................................................................... 25 
8.3 
RECURRENCE AND SURVIVAL ............................................................................... 27 
 
DATA AND SAFETY MONITORING PLAN ............................................................. 27 

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9.1 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ............................................. 27 
9.2 
REPORTING EVENTS TO PARTICIPANTS ................................................................ 31 
9.3 
UNANTICIPATED PROBLEMS ................................................................................. 31 
9.4 
DATA BREACH ...................................................................................................... 32 
9.5 
PROTOCOL DEVIATION ......................................................................................... 33 
9.6 
PARTICIPANT WITHDRAWALS/DROPOUTS PRIOR TO STUDY COMPLETION ............. 34 
10 
STATISTICAL CONSIDERATIONS ..................................................................... 34 
10.1 
STUDY DESIGN OVERVIEW ................................................................................... 34 
10.2 
ENDPOINTS, STATISTICAL HYPOTHESES AND ESTIMATION .................................... 34 
10.3 
SAMPLE SIZE DETERMINATION ............................................................................. 34 
10.4 
ACCRUAL ............................................................................................................. 35 
10.5 
STATISTICAL ANALYSES ....................................................................................... 35 
11 
REGULATORY AND OPERATIONAL CONSIDERATIONS ............................... 36 
11.1 
REGULATORY AND ETHICAL CONSIDERATIONS ..................................................... 36 
11.2 
DATA HANDLING AND RECORD KEEPING .............................................................. 40 
11.3 
PUBLICATION AND DATA SHARING POLICY ............................................................ 40 
11.4 
CONFLICT OF INTEREST POLICY ........................................................................... 40 
12 
REFERENCES ...................................................................................................... 42 
 
APPENDICES ........................................................................................................ 46 
APPENDIX 1:  SCHEDULE OF EVENTS ............................................................................... 47 
APPENDIX 2:  PROTOCOL AMENDMENT HISTORY ............................................................. 49 
APPENDIX 3:  THE BRIEF ILLNESS PERCEPTION QUESTIONNAIRE (BIP-Q)........................ 52 
APPENDIX 4: BELIEFS ABOUT MEDICINES QUESTIONNAIRE .............................................. 54 
APPENDIX 5:  PERCEIVED SENSITIVITY TO MEDICINE SCALE ............................................ 57 
APPENDIX 6:  UVA BREAST CANCER BELIEF SURVEY ...................................................... 59 
APPENDIX 7: EORTC QLQ ............................................................................................. 61 
APPENDIX 8:  CENTER FOR EPIDEMIOLOGIC STUDIES DEPRESSION SCALE REVISED........ 65 
APPENDIX 9: BREAST CANCER PREVENTION TRIAL SYMPTOM CHECKLIST ....................... 67 
APPENDIX 10: ADHERENCE QUESTIONS .......................................................................... 69 
APPENDIX 11: TREATMENT DECISION SURVEY ................................................................ 71 
APPENDIX 12: DECISIONAL CONFLICT SCALE .................................................................. 73 
APPENDIX 13: DECISION REGRET SCALE ......................................................................... 75 
 
 
 

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STATEMENT OF COMPLIANCE 
The trial will be conducted in accordance with International Conference on Harmonisation Good 
Clinical Practice (ICH GCP) and the applicable United States (US) Code of Federal Regulations 
(CFR), and the NIH Terms and Conditions of Award. The Principal Investigator will assure that no 
deviation from, or changes to the protocol will take place without prior approval from the 
Institutional Review Board (IRB), except where necessary to eliminate an immediate hazard(s) to 
the trial participants. All personnel involved in the conduct of this study have completed Human 
Subjects Protection. 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the IRB for review and approval.  Approval of both the protocol and the consent form 
must be obtained before any participant is enrolled.  All changes to the consent form will be IRB 
approved; a determination will be made regarding whether a new consent needs to be obtained 
from participants who provided consent, using a previously approved consent form.  
 
 
 
 
 
 
 
 
Sponsor/Lead Principal Investigator 
 
______________________ _______________________ _________ 
Name (print)  Signature  Date 
 
Investigator 
 
_______________________ _________________________  _________ 
Name (print)  Signature  Date 
 

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ABBREVIATIONS 
AE 
Adverse Event 
AI  
Aromatase Inhibitor 
BCS 
Breast Conservation Surgery 
BCT 
Breast Conservation Surgery followed by Radiation Therapy 
BCPT-SCL 
Breast Cancer Prevention Trial Symptom Checklist 
BIPQ 
Brief Illness Perception Questionnaire 
BMQ 
Beliefs about Medicines Questionnaire 
CESD 
Center for Epidemiologic Studies Depression Scale 
CESD-R 
Center for Epidemiologic Studies Depression Scale Revised 
CFR 
Code of Federal Regulations 
CONSORT 
Consolidated Standards of Reporting Trials 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
DCC 
Data Coordinating Center 
DCS 
Decisional Conflict Scale 
DHHS 
Department of Health and Human Services 
DRS 
Decision Regret Scale 
DSMB 
Data Safety Monitoring Board 
DRE 
Disease-Related Event 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Forms 
ELPh 
Exemestane and Letrozole Pharmacogenetics 
EORTC 
European Organisation for Research and Treatment of Cancer 
EuroQOL VAS EuroQOL Visual Analog Scale 
ER 
Estrogen Receptor 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Amendments Act of 2007 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
GMP 
Good Manufacturing Practices 
HADS 
Hospital Anxiety and Depression Scale 
HIPAA 
Health Insurance Portability and Accountability Act  
HRQoL 
Health-related quality of life 
IB 
Investigator’s Brochure 
IBTR 
Ipsilateral Breast Tumor Recurrence 
ICH 
International Conference on Harmonisation  
ICMJE 
International Committee of Medical Journal Editors 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
ISO 
International Organization for Standardization 
ITT 
Intention-To-Treat 
MOP 
Manual of Procedures 
NCCN 
National Comprehensive Cancer Network 

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NCT 
National Clinical Trial 
NIH  
National Institutes of Health 
OHRP 
Office for Human Research Protections 
PI 
Principal Investigator 
PR 
Progesterone Receptor 
Pre-ET 
Pre-operative endocrine therapy 
PRO 
Patient Reported Outcomes 
PSM 
Perceived Sensitivity to Medicine Scales 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SMC 
Safety Monitoring Committee 
SOA 
Schedule of Activities 
SOM 
School of Medicine 
SOP 
Standard Operating Procedure 
RT 
Radiation Therapy 
UP 
Unanticipated Problem 
US 
United States 
UVA MCRO 
University of Virginia Multisite Clinical Research Office 
VAS 
Visual Analog Scale 
 
 
 

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 PROTOCOL SUMMARY 
1.1 
Synopsis  
Title: 
Pre-Operative Window of Adjuvant Endocrine Therapy to Inform 
Radiation Therapy Decisions in Older Women with Early-Stage Breast 
Cancer 
Study 
Description:  
 
 
 
 
 
 
 
 
This is a prospective multisite exploratory study for women ≥ 65 years 
of age with early stage estrogen receptor positive (ER+) breast cancer.  
These individuals will be treated with 3 months of pre-operative 
endocrine therapy (pre-ET) with assessment of tolerance to the 
endocrine therapy by patient reported outcome (PRO) measures. The 
results of this study will be used to develop an algorithm for treatment 
recommendations in early stage geriatric breast cancer patients.   
The following will be assessed: 
1) The results of the tolerance assessments will change the 
treatment recommendations and decisions regarding adjuvant 
radiation therapy (RT); 
2) Tolerance of pre-ET as measured by PROs will be predictive of 
long-term adjuvant endocrine therapy adherence;  
3) Use of 3 months of pre-ET endocrine therapy in order to assess 
tolerance to the endocrine therapy will not negatively impact 
surgical completion. 
Objectives & 
Endpoints 
Objectives 
Endpoints 
Primary 
 
 To assess whether pre-ET changes 
an individual’s preference for 
adjuvant radiation treatment 
 To assess whether pre-treatment 
with endocrine therapy changes the 
surgical oncologist’s preference for 
adjuvant radiation treatment 
 Radiation preference question 
for participant pre and post 
pre-ET treatment 
 
 Radiation preference question 
for the surgical oncologist pre 
and post pre-ET treatment 
 
Secondary 
 
 To obtain preliminary estimates to 
assess whether patient reported 
outcomes during pre-ET treatment 
are predictive of long-term adjuvant 
endocrine therapy adherence 
 For those participants who agree to a 
radiation oncologist consultation, to 
assess whether pre-treatment with 
endocrine therapy changes the 
radiation oncologist’s preference for 
adjuvant radiation treatment 
  PRO assessments 
 
 
 
 
 Radiation preference question 
for the radiation oncologist pre 
and post pre-ET treatment 
 
 To obtain preliminary data on the 
effect of pre-ET on decision 
outcomes for adjuvant therapy after 
BCS 
 PRO assessments  
Exploratory 
 

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 To obtain exploratory data on 
recurrence-free survival and overall 
survival 
 Recurrence-free survival and 
survival through 24 months 
Study 
Population: 
 
Women ≥65 years of age with a diagnosis of clinical stage I, ER+, 
progesterone positive (PR+) or negative (PR-), and HER2 non-
amplified invasive breast cancer and clinically negative nodes. Any 
invasive breast cancer histologic subtype may be enrolled. 
Phase: 
Pilot study 
Description of 
Sites/Facilities 
Enrolling 
Participants: 
Participants will be enrolled at the University of Virginia Health System 
and Virginia Commonwealth University 
Description of 
Study 
Intervention: 
Participants enrolled to the study will receive 3 months of endocrine 
therapy (e.g. tamoxifen or aromatase inhibitors (AIs) such as letrozole, 
anastrozole, or exemestane).  The choice and dose of endocrine 
therapy will be at the discretion of the treating medical oncologist. 
Study Duration: 62 months  
Participant 
Duration: 
30 months 
Note that before IRB approval of protocol v01-26-22, this study was referred to as “Breast 52.” 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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1.2 
Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
Please see Appendix 1 for a complete list of activities 
 
 
 
 
 
 
 
 
 
 
 
 
Women 65 years of age with stage1 ER+ breast cancer eligible for upfront breast 
conserving surgery (BCS). 
Obtain informed consent  
Screen potential participants by inclusion and exclusion criteria 
 
Pre-operative endocrine therapy  
Days 2-90 
BCS 
Within 2-8 weeks after stopping pre-operative endocrine therapy 
 
Perform baseline assessments; initiation of pre-operative endocrine therapy 
(Day 1) 
Radiation therapy for a subset of participants  
Complete time course will be determined per 
standard clinical care 
Adjuvant endocrine therapy (On study up to 2 years)  
Initiation of endocrine therapy will occur 1 - 90 days after 
surgery or radiation therapy, whichever is later (Visit 1) 
 
Additional visits (V2-4) scheduled for 6, 12, and 24 months 
after Visit 1 

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  INTRODUCTION 
2.1 
Study Rationale  
Breast cancer is the most common cancer diagnosed in women in the United States and almost 
half of newly diagnosed breast cancer cases are in women 65 years and older1. Given this large 
number of geriatric breast cancer patients, it is paramount that research be conducted in this 
population so that treatment recommendations can be tailored to specific geriatric considerations. 
Historically, early stage breast cancer patients were treated with breast conserving surgery (BCS), 
followed by adjuvant radiation therapy (RT; delivered in the immediate postoperative period) and 
endocrine therapy (for 5-10 years) - both of which are known to decrease the risk of recurrence. 
However, recent data from randomized controlled trials in women ≥ 65 - 70 years of age with 
estrogen receptor (ER) positive, node negative, small (≤ 3cm) breast cancers have shown that 
omission of adjuvant radiation following BCS does not result in a decreased survival2-4. Despite 
these findings and inclusion of criteria for omission of radiation in NCCN guidelines, studies show 
that RT is still frequently used after BCS in this population5-7. There is increasing opinion that 
offering radiation to this patient population should be considered overtreatment. However, RT 
omission has not been widely accepted because of the concern that adherence to endocrine 
therapy is higher in the clinical trial setting than what is reported in clinical practice8,9, and therefore 
adjuvant radiation therapy is offered to ensure acceptable recurrence rates. Without patient-level 
data regarding tolerance to endocrine therapy, physicians and patients are unable to make 
informed decisions regarding omission of RT.  The rationale for this prospective analysis is to 
collect data on pre-ET tolerance as a criterion to better inform decision making on RT omission in 
the immediate post-operative period and to identify criteria to guide future additional adjuvant 
treatment. 
2.2 
Background  
 Breast Conservation Therapy is a Standard Treatment for Early Stage Breast Cancer  
Early stage breast cancer is treated with surgery (mastectomy or BCS).  There is no difference in 
long term survival between mastectomy and breast conservation therapy (BCS followed by 
radiation therapy (RT); BCT), and BCT is the preferred treatment approach based on decreased 
morbidity and higher associated quality of life10,11. Traditionally, a key part of BCS is the 
recommendation for adjuvant whole breast RT to decrease the risk of local recurrence12-14. 
Adjuvant RT is delivered in the immediate post-operative period as there is evidence of increased 
risk of local failure if RT is delayed beyond 8 weeks15-17.  Patients with hormone receptor positive 
breast cancer are treated with adjuvant endocrine therapy (tamoxifen or an AI), which is typically 
started upon completion of RT. The duration of endocrine therapy is at least 5 years with evidence 
for extended duration in higher risk patients18. Adjuvant endocrine therapy is proven to decrease 
local recurrence, distant recurrence, and prolong survival 19.  
 Breast Cancer Incidence and Mortality in Geriatric Patients 
The incidence of breast cancer is increasing as the population ages and nearly half of new 
diagnoses of breast cancer are in women ≥65 years of age.  Thus,  treatment specific to the 
geriatric population is increasingly relevant1. Elderly breast cancer patients have been shown to 
be more likely to have favorable tumor characteristics including lower histologic grade and 
hormone receptor positivity20,21. Despite this, there is evidence that suggests that increasing age 
is associated with higher disease-specific mortality22. Importantly, elderly breast cancer patients 

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compared to younger patients are known to be  more likely to have deviations from standard of 
care in surgical management and adjuvant radiation, chemotherapy, and endocrine therapy 
management23. These non-standard treatment approaches for geriatric breast cancer patients 
reflect both physician recommendations and patient preference.  Elderly patients are therefore 
both under- and over- treated in regards to established treatment recommendations, with each 
possibly contributing to higher rates of disease specific mortality. More studies are needed in the 
geriatric breast cancer population that will allow for age-specific evidence-based algorithms to 
guide clinical decision making. 
 Treatment of Early Stage Breast Cancer in Geriatric Patients 
Radiation omission is a proven treatment option for older patients with low risk breast cancers, 
but implementation rates are low. Many trials have explored the utility of adjuvant radiation in 
hormone receptor positive early stage breast cancer and, while use of adjuvant RT leads to a 
decrease in ipsilateral breast tumor recurrence (IBTR), there is no difference in survival when 
compared to patients that omit RT3,4,12-14,24. Current NCCN breast cancer guidelines indicate that 
adjuvant radiation may be omitted in patients 70 years or older with ER+, clinically node negative, 
T1 tumors who will receive adjuvant endocrine therapy18. This recommendation comes primarily 
from the evidence provided by two large, randomized clinical trials in geriatric patients3,4.  
 
Cancer and Leukemia Group B (CALGB) 9343  
In CALGB 9343, 636 geriatric women with clinical stage 1, ER+ breast cancer were 
randomly assigned to adjuvant treatment with tamoxifen plus RT or tamoxifen alone3. Long 
term follow up (median 12.6 years) confirmed 98% of patients in the RT plus tamoxifen 
arm and 90% of patients in the tamoxifen alone arm were free from local and regional 
recurrence with no difference in time to local or regional recurrence, frequency of 
mastectomy, breast cancer specific survival, time to distant metastasis, and overall 
survival2.  Therefore, the authors concluded that RT has no significant impact on survival, 
and RT omission is a reasonable choice for low risk, ER+ breast cancer patients ≥ 70 years 
who take adjuvant endocrine therapy after BC.  
 
Prime II 
The PRIME II trial included 1326 geriatric women aged 65 years or older with ER+, node 
negative, T1-2 tumors treated with BCS and adjuvant endocrine therapy.  Individuals were 
randomized to receive RT or no RT. Patients treated with adjuvant RT and endocrine 
therapy had an IBTR of 1.3% and those treated with adjuvant endocrine therapy without 
RT had an IBTR of 4.1% with median follow up of 5 years. There was no difference in 
regional recurrence, distant metastases, contralateral breast cancers, or new breast 
cancers and 5 year overall survival was 93.3% in both groups4. The authors concluded 
that postoperative RT resulted in a significant reduction in IBTR, but that the 5 year IBTR 
was low enough for omission of RT to be a rational treatment approach for select patients. 
Updated 10-year results were reported at the 2020 San Antonio Breast Cancer 
Symposium and confirm previous findings of increased local recurrence of 9.8% vs 0.9%, 
but no difference in overall survival25.     
The results of these two trials resulted in updates to the NCCN guidelines in 2004, which included 
the option for omission of RT in women over the age of 70 with ER+ T1N0 breast cancer who will 
take adjuvant endocrine therapy. However, despite these recommendations, implementation of 
RT omission is low5,7 and many providers still view RT omission as substandard care6. The 

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reasons for why providers do not offer RT omission is multifactorial. Providers overestimate the 
life expectancy of patients6 and believe that healthy patients over age 70 do not fit the population 
of the CALGB 9343 study. In fact, the patients in CALGB 9343 were healthier and lived longer 
than women in the general population of similar ages2.  A key part of the design of CALGB 9343 
and PRIME II trials was that all patients were recommended to be treated with adjuvant endocrine 
therapy. Adjuvant endocrine therapy is shown to not only decrease distant recurrence, but also 
IBTR12-14. When recommending BCS with omission of immediate postoperative RT, neither the 
provider nor the patient knows whether the patient will tolerate and adhere to prescribed 
endocrine therapy.  Early insight regarding an individual patient’s tolerance and predicted 
adherence to endocrine therapy has potential to assist physicians to better formulate treatment 
plans and will allow patients to better accept and follow these recommendations. This would result 
in a patient specific treatment plan and decrease the risk of either over or under treatment of early 
stage breast cancer in the geriatric population.   
 Adherence to Endocrine Therapy in the Geriatric Population  
Adherence to endocrine therapy in clinical practice is low.  Non-adherence to endocrine therapy 
as documented in large adjuvant endocrine therapy trials is estimated between 23-28%, but it is 
even higher in studies examining non-adherence in clinical practice8,9. A systematic review of 
adherence to adjuvant endocrine therapy in clinical practice shows that adherence at 5 years 
ranges from 32 -73%.  Within this systematic review, reports of 5-25% of women on AIs 
discontinued treatment within the first two years9. At year 5, 47.1% of patients discontinued 
tamoxifen and 31.3% discontinued AI treatment26. Non-adherence to adjuvant endocrine therapy 
results in increased recurrence and mortality27  Capturing reasons for non-adherence is 
challenging with studies often reporting on demographic factors, but not identifying patient 
experience factors such as tolerability of the medication or a patient’s perception of risk and 
benefit of therapy. Demographic factors identified as predictive of non-adherence include younger 
age, type of surgery (BCS), more comorbid conditions, and African American race28.   
 
There is a need to better define health related quality of life (HRQOL) and patient reported factors 
for non-adherence within clinical practice.  Intolerable patient side effects is the most common 
patient reported reason for endocrine therapy non-adherence29 with musculoskeletal symptoms 
being the primary reported toxicity leading to AI discontinuation26,30. Musculoskeletal side effects 
are estimated to occur in up to 50% of patients on adjuvant AI treatment31. The Exemestane and 
Letrozole Pharmacogenetics (ELPh) trial was a multicenter, prospective randomized study 
comparing adjuvant exemestane and letrozole that included patient reported outcomes (PROs) 
and adherence data. Within this study, 32.6% of patients discontinued adjuvant AI (median follow 
up 15.5 months +/- 9 months) with the primary reason being musculoskeletal symptoms. Of the 
entire study population, 24.4% discontinued adjuvant AI because of musculoskeletal symptoms.  
The median time to treatment discontinuation was 6.4 months32.  
 Tolerance as a Predictor of Non-Adherence to Endocrine Therapy. 
The ELPh trial reported on PROs and examined whether early changes in PROs predict AI 
discontinuation. In this study, health-related quality of life (HRQoL) was assessed using the 
EuroQOL Visual Analog Scale (EuroQOL VAS), depression was assessed using the Center for 
Epidemiologic Studies-Depression (CESD) tool, anxiety was assessed with the anxiety subscale 
of the Hospital Anxiety and Depression Scale (HADS), and symptom burden was assessed using 
the Breast Cancer Prevention Trial Symptom Checklist (BCPT-SCL). The BCPT-SCL was 
analyzed by symptom clusters of weight/body image, vasomotor, vulvovaginal, musculoskeletal, 

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cognitive, and mood. The PROs were assessed at regular intervals on adjuvant AI therapy. The 
musculoskeletal symptom burden assessment was noted to be rising at month 1 and significantly 
higher by month 3 and month 6 (p = 0.023, p = 0.033). Of the examined PROs, rising 
musculoskeletal scores and decreasing HRQOL scores were found to predict discontinuation of 
AI33. This study demonstrates that side effects develop early in patients on AIs and are predictive 
of early discontinuation and non-adherence. In the present study, we plan to assess if this can be 
looked at in a brief course of pre-ET to predict long term tolerance and adherence of adjuvant 
endocrine therapy. 
 Relevant Clinical Experience 
The traditional approach to treatment of early stage breast cancer is local management with 
surgical resection via lumpectomy followed by adjuvant radiation and adjuvant endocrine therapy. 
There is significant clinical evidence that endocrine therapy can be safely and effectively used in 
a neoadjuvant approach in postmenopausal women34. Historically, neoadjuvant endocrine 
therapy was studied as a treatment approach for an elderly patient population that was not well 
suited to neoadjuvant chemotherapy or even surgery35. However, additional studies completed 
include multiple randomized trials that included healthier and younger postmenopausal patients 
randomized to neoadjuvant endocrine therapy or neoadjuvant chemotherapy. These studies have 
shown similar response rates between the two arms of treatment and improved toxicity profile in 
the endocrine therapy arms36-38. On the basis of this evidence, the NCCN Breast Cancer 
guidelines include “Neoadjuvant endocrine therapy alone may be offered to those with strongly 
hormone receptor-positive tumors”18. While there is mounting clinical evidence for the use of 
neoadjuvant endocrine therapy in postmenopausal women with strongly ER positive breast 
cancer, the relatively small numbers within the trials and uncertain best endocrine therapy 
regimens in this setting has limited the routine use of this approach for a fit patient in clinical 
practice. It is for this reason that the present study is being conducted as an investigational 
approach.  
2.3 
Summary 
The present study is designed to assess whether a three month course of pre-ET is an appealing, 
safe, and informative strategy to assist in formulating treatment regimens for geriatric breast 
cancer patients. The ultimate goal of our research is to develop a novel and comprehensive tool 
that will allow patients and providers to make informed decisions about treatment regimens for 
early stage breast cancer patients. Our future intention is to expand upon this research by using 
the PROs in combination with other factors such as demographic and breast cancer 
histopathologic characteristics to generate a tool for recommendations on treatment for geriatric 
patients. This tool will guide decisions on breast surgery, adjuvant radiation, and choice of 
endocrine therapy and it will be based on evidence specific to the early stage geriatric breast 
cancer patient. This work may ultimately change the established order treatment is given to 
geriatric breast cancer patients and it will allow for patient-specific treatment plans without leading 
to under or overtreatment.   
 
 
 

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2.4 
Risk/Benefit Assessment   
 Known Potential Risks  
The present study is felt to be of low risk of harm to potential participants. All patients will be 
recommended for standard breast conservation treatment based on available evidence and 
clinical practice guidelines. The potential for radiation omission is a current standard approach for 
patients eligible for this study and all patients will be counseled on the potential benefits and risks 
of radiation as in standard in clinical practice. The use of endocrine therapy is well established as 
a mainstay in ER positive breast cancer treatment and in general is a safe and effective practice. 
As noted in section 2.2.6, neoadjuvant endocrine therapy is a proven safe and effective treatment 
strategy. Within the present study, patients will be treated with a limited duration of pre-ET as a 
tool for better informing future treatment decisions. The present study is not intended to 
demonstrate that pre-ET is a more efficacious approach than upfront surgery, but rather that the 
information gained from the early exposure will ensure informed patient and physician decisions 
regarding adjuvant radiation therapy importance. 
 Known Potential Benefits  
 
Breast cancer patients that opt for BCT are recommended to initiate breast RT within 4-12 weeks 
after completion of surgery. Adjuvant endocrine is not initiated until after completion of radiation. 
Therefore, providers and patients are currently forced to make a decision regarding RT without 
knowledge about endocrine therapy tolerance. This leads to the potential for omission of RT and 
nonadherence to endocrine therapy and a resultant higher risk of IBTR. 
 
Data from prospective randomized controlled trials supports the omission of breast RT in elderly 
patients with early stage ER positive tumors.  The patients in these trials were all treated with 
adjuvant endocrine therapy.  However, outside of clinical trials, it is well established that 
adherence to adjuvant endocrine therapy is low and especially in elderly patients.  The proposed 
study will provide necessary data regarding utilization of a short course of pre-ET  to guide 
recommendations for post-operative RT.   
 
While it is widely known that NCCN guidelines include RT omission for ER positive early stage 
breast cancer patients over 70, providers are not routinely offering this5. Within the present study, 
we propose a new treatment approach to try to better inform patients and providers on the 
decision to give or omit adjuvant RT. By treating patients with pre-ET for three months and 
assessing tolerance, the provider and the patient will have the opportunity for an informed 
discussion about the adjuvant treatment plan. Providers can educate patients on the role of 
endocrine therapy in decreasing IBTR with emphasis on the importance of this for patients 
omitting RT. Patients will know what sort of side effects they will experience on endocrine therapy 
and better assess their willingness and ability to tolerate five or more years of the medication. The 
goal is that careful assessment of PRO measurements while on three months of pre-ET can help 
the patient and provider better predict adherence to adjuvant endocrine therapy.  Ultimately, this 
could result in a patient specific treatment plan that would decrease the risk of either over or under 
treatment of their disease. 
 Assessment of Potential Risks and Benefits  

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The present study is felt to be of low risk of harm to potential participants and may result in patient 
specific treatment plans that either decrease the risk of either over or under treatment of breast 
cancer in the geriatric population. 
 OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary 
 
 To assess whether pre-ET changes 
an individual’s preference for 
adjuvant radiation treatment 
 To assess whether pre-treatment 
with endocrine therapy changes the 
surgical oncologist’s preference for 
adjuvant radiation treatment 
 
 Radiation preference question for 
participant pre and post pre-ET 
treatment 
 
 Radiation preference question for the 
surgical oncologist pre and post pre-
ET treatment 
 
Secondary 
 
 To obtain preliminary estimates to 
assess whether patient reported 
outcomes during pre-ET are 
predictive of long-term adjuvant 
endocrine therapy adherence 
 For those participants who agree to a 
radiation oncologist consultation, to 
assess whether pre-treatment with 
endocrine therapy changes the 
radiation oncologist’s preference for 
adjuvant radiation treatment 
  PRO assessments 
 
 
 
 
 Radiation preference question for the 
radiation oncologist pre and post pre-
ET treatment 
 
 To obtain preliminary data on the 
effect of pre-ET on decision 
outcomes for adjuvant therapy after 
BCS 
 PRO assessments 
Exploratory 
 
 To obtain exploratory data on 
recurrence-free survival and overall 
survival 
 Recurrence-free survival and survival 
through 24 months 
 
 STUDY DESIGN  
4.1 
Overall Design 
This is a multicenter study of pre-ET tolerance to inform treatment decisions for adjuvant radiation 
in geriatric individuals with early stage, ER+ breast cancer.  Study therapy will include 90 days of 
pre-ET.  Endocrine therapy options may include tamoxifen or AI (letrozole, anastrozole, or 
exemestane) and choice of endocrine therapy will be at the discretion of the treating physician.  
Following pre-ET, all individuals will undergo BCS.  After BCS, enrolled participants and their 
physicians (surgical oncology, radiation oncology, and medical oncology) will finalize an adjuvant 
radiation and adjuvant endocrine therapy plan. Participants recommended for and accepting 
adjuvant RT will complete this as planned and then be recommended to re-start on adjuvant 

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endocrine therapy.  Participants who do not have radiation will be recommended to restart on 
endocrine therapy after surgery. The choice and duration of adjuvant endocrine therapy will be 
determined by the treating medical oncologist. All participants regardless of their adjuvant therapy 
will be followed. Genomic profiling of the tumor may be performed if deemed clinically indicated 
by the treating medical oncologist and any recommended adjuvant chemotherapy will be 
completed prior to resumption of endocrine therapy in the adjuvant setting. 
The primary objective is to assess whether pre-treatment with endocrine therapy changes an 
individual’s or the surgical oncologist’s preference for adjuvant radiation treatment. The secondary 
objective is obtain preliminary information to assess whether tolerance of pre-ET predicts 
adherence to adjuvant endocrine therapy.  
Baseline assessment of patient beliefs and attitudes will be assessed using the Brief Illness 
Perception Questionnaire (BIPQ), the Beliefs about Medicines Questionnaire (BMQ) and BMQ 
Endocrine therapy subscale (BMQ ET), the Perceived Sensitivity to Medicine Scale (PSM), the 
Decision Regret Scale (DRS), and an additional novel survey of breast cancer and breast cancer 
medication specific patient beliefs.  
Tolerance of pre-ET will be assessed using validated PRO assessments. Baseline and serial 
assessment of PROs will be conducted using the EORTC Quality of Life Questionnaire (QLQ-
C30 and QLQ-BR23), the Breast Cancer Prevention Trial Symptom Checklist (BCPT-SCL), and 
the Center for Epidemiologic Studies Depression Scale Revised (CESD-R).  
The Decision Regret Scale will be used to assess the effect of pre-ET on decision outcomes for 
adjuvant therapy after breast conservation surgery.  
Adherence will be monitored throughout the endocrine therapy treatment period using patient 
report.  
Up to 83 individuals will be enrolled. 
4.2 
Justification for Dose 
Each of the endocrine therapy drugs will be used at standard doses described in the drug labels. 
Radiation therapy will be completed in accordance with standard clinical practice.  
4.3 
End of Study Definition 
Primary completion date is the date that the final participant is examined or receives an 
intervention for the purposes of final collection of data for the primary outcome, whether the clinical 
study concluded according to the pre-specified protocol or was terminated.  
Study completion date is the date the final participant is examined or receives an intervention for 
purposes of final collection of data for the primary and secondary outcome measures and adverse 
events (for example, last participant’s last visit), whether the clinical study concludes according to 
the pre-specified protocol or is terminated.  
Collection and analysis of exploratory data may extend beyond the study completion date. The 
study may remain open with the IRB during this time. 

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 STUDY POPULATION 
5.1 
Inclusion Criteria 
In order to be eligible to participate in this study, an individual must meet all of the following criteria: 
1. Provision of signed and dated informed consent form 
2. Stated willingness to comply with all study procedures and availability for the duration of 
the study  
3. ECOG performance status 0-2 
4. Females, aged ≥ 65 years  
5. Diagnosed with anatomic stage I, ER positive, PR positive or negative, and HER2 non 
amplified invasive breast cancer and clinically negative nodes; any invasive breast cancer 
histologic subtype may be enrolled 
6. Tumor size ≤ 2 cm 
7. Patient has elected BCS as surgical choice 
8. Eligible to receive tamoxifen or an aromatase inhibitor 
9. Ability to take oral medication and be willing to adhere to the endocrine therapy for the 3 
month period prior to BCS 
10. Agreement to adhere to Lifestyle Considerations (see Section 5.4) throughout study 
duration 
 
5.2 
Exclusion Criteria 
An individual who meets any of the following criteria will be excluded from participation in this 
study: 
 
1. Prior or current use of endocrine therapy for  breast cancer 
2. History of ipsilateral breast radiation 
3. Pregnancy or lactation 
4. Has a known additional malignancy that is progressing or requires active treatment.  
Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the 
skin that has undergone potentially curative therapy or in situ cervical cancer. 
5. Current or planned use of a strong CYP2D6 inhibitor (e.g. Fluvoxamine, Paroxetine) and 
is not able to receive an endocrine therapy agent that does not use the CYP2D6 pathway.  
 
5.3 
Justification for Study Population 
Each year, nearly half of newly diagnosed breast cancer cases are in women 65 years and older.  
Recent data from randomized controlled trials have shown that omission of adjuvant radiation 
following BCS does not result in a decreased survival in women 65+ years old with estrogen 
receptor (ER) positive, node negative, small (≤ 2 cm) breast cancers. Despite these findings and 
inclusion of criteria for omission of radiation in NCCN guidelines, studies show that RT is still 
frequently used after BCS in this population5-7.  Without patient-level data regarding tolerance to 
endocrine therapy physicians and patients are unable to make informed decision regarding 
omission of RT.  This study is limited to women ≥ 65 years of age to develop treatment 

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recommendations that can be tailored to specific geriatric considerations.  On the basis that the 
initial studies supporting the omission of radiation in the geriatric population were conducted in 
women and that the surgical plans and side effect profiles from endocrine therapies differ between 
men and women, men will be excluded from this initial pilot study.  
 
5.4 
Lifestyle Considerations 
Individuals will be educated on potential interactions between the endocrine therapies and other 
drugs.  The prescribing information will be referenced by the treating physician to identify potential 
interactions. If a potential interaction exists (e.g. use of another strong CYP2D6 inhibitor with the 
use of tamoxifen), alternative endocrine therapies may be considered for the individual or the 
individual may be prescribed an alternative CYP2D6 inhibitor for the treatment of other conditions. 
5.5 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical trial but are 
not entered in the study. A minimal set of screen failure information is required to ensure 
transparent reporting of screen failure participants, to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements (for NIH studies) and to respond to queries 
from regulatory authorities. Minimal information includes demography, screen failure details, 
eligibility criteria, and any serious adverse events (SAEs). 
5.6 
Strategies for Recruitment and Retention 
Potentially eligible participants will be identified by treating clinicians. Participants who are 
interested in participating will have a consultation with a medical oncologist to discuss pre-ET. 
 STUDY INTERVENTION 
6.1 
Description of Study Intervention(s)  
 Endocrine Therapy 
The choice of endocrine therapy will be determined by the medical oncologist.  All endocrine 
therapy drugs are commercially available and will be prescribed at doses consistent with those 
described in the product label.   
On the basis of the following criteria, the principal investigator has determined that the study 
meets the criteria for IND exemption.   
1. The study is not intended to support FDA approval of a new indication or a 
significant change in the product labeling.  
The present study is not intended to get a new FDA approval for any of the included 
endocrine therapy drugs.  
 
2. The study is not intended to support a significant change in the advertising for the 
product.  
The present study is not intended to result in a change in the advertising for any of the 
included endocrine therapy drugs.  

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3. The investigation does not involve a route of administration or dosage level or use 
in a patient population or other factor that significantly increases the risks (or 
decreases the acceptability of the risks) associated with the use of the drug 
product.  
Each of the included endocrine therapy drugs within the present study will be used at 
standard dosing, route of administration and schedule as indicated in the package inserts. 
The only change of use from the label is that the endocrine therapy will be administered 
as 3 months of pre-ET in addition to adjuvant therapy recommended for at least 5 years. 
While the endocrine therapy labels do not include pre-ET use, there is sufficient clinical 
evidence in the literature documenting the safety of pre-ET in hormone receptor positive 
breast cancer. This has been prospectively studied and deemed to be an appropriate 
treatment approach in selected patients. Based on these studies, the NCCN Breast 
Cancer guidelines include a line stating that “Neoadjuvant endocrine therapy alone may 
be offered to those with strongly hormone receptor-positive tumors.” It is the investigator’s 
opinion that three months of pre-ET does not result in increased risk to the targeted patient 
population of ER positive breast cancer patients.  
 
4. The study is conducted in compliance with institutional review board (IRB) and 
informed consent regulations set forth in parts 56 and 50 (21 CFR parts 56 and 
50).  
The present study is submitted for internal review by both the Protocol Review Committee 
and the IRB and will be monitored closely. 
 
5. The study is conducted in compliance with § 312.7 (promotion and charging for 
investigational drugs).  
The present study is conducted in compliance with promotion and charging for 
investigational drugs. 
 Radiation Therapy 
Radiation therapy will be administered in accordance with standard clinical practice.   
6.2 
Dosing and Administration 
 Endocrine Therapy 
The dosing and administration of endocrine therapy will be in accordance with the drug label for 
each drug prescribed by the medical oncologist. 
Individuals will not switch endocrine therapies during pre-operative endocrine therapy; however, 
an individual may stop endocrine therapy at any time during pre-operative therapy.  Individuals 
who stop neo-adjuvant therapy prior to 90 days may still be eligible to receive adjuvant endocrine 
therapy.  
Individuals may take different endocrine therapies during neo-adjuvant and adjuvant therapy.  

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Individuals may also switch endocrine therapies (e.g. switch from an aromatase inhibitor to 
tamoxifen) during adjuvant therapy.   
 Radiation Therapy 
The dosing and administration of radiation therapy will be in accordance with standard clinical 
practice guidelines for the treatment of breast cancer. 
 Dose Modifications and Delays for Endocrine Therapy 
Dose Modifications 
No dose modifications of endocrine therapy are permitted. 
Dose Delays 
Neo-adjuvant Endocrine Therapy 
No dose delays will be prescribed during pre-operative endocrine therapy.   
Adjuvant Endocrine Therapy 
Individuals may temporarily discontinue adjuvant endocrine therapy if recommended by the 
treating medical oncologist. Interruptions in adjuvant endocrine therapy should not last longer 
than 12 weeks per year. This is based on evidence from the SOLE trial in which patients on 
intermittent endocrine therapy (defined as at least 9 months per year) had no difference in survival 
compared to those on continuous endocrine therapy39.  
6.3 
Preparation/Handling/Storage/Accountability 
 Acquisition and Accountability 
All endocrine therapy drugs will be commercially available. Individuals will receive a prescription 
for the endocrine drugs and the drugs will be dispensed from a licensed pharmacy. The cost of 
the drugs will be billed to the participant or the participant’s insurance provider.   
 Formulation, Appearance, Packaging, and Labeling 
Details may be found in the prescribing information for each endocrine therapy drug. 
 Product Storage and Stability 
Details may be found in the prescribing information for each endocrine therapy drug.   
6.4 
Study Intervention Compliance 
Participants will be asked about compliance with taking endocrine therapies as part of patient 
reported outcomes. 
6.5 
Registration and Treatment Allocation 
All participants must sign the consent form prior to determination of eligibility for this study.    

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When a site is ready to enroll a patient, the following documentation must be scanned and emailed 
to the UVA Coordinating Center:  
 
Patient and staff signed signature page of the current informed consent form 
(ICF)  
 
Completed Inclusion/Exclusion checklist demonstrating subject eligibility  
 
Supporting documentation needed to confirm eligibility (lab results, scan results 
etc.)  
Consult with the MCRO for instructions on sending this information. The Coordinating Center will 
consult with the Overall Study PI if questions arise in confirming eligibility. The UVA Coordinating 
Center will communicate the subject number to the enrolling site. 
Registration will occur following verification of eligibility by the treating physician. 
Participants who are consented and accrued to the study should be registered in OnCore in 
accordance with the Clinical Trial Management System Policy via the UVa OnCore Resources 
link in OnCore. General guidelines are available in the OnCore User Manual and Data Entry 
Guide.  
Participants should receive their first study treatment within 2 weeks of registration. 
Treatment allocation to receive either radiation and adjuvant endocrine therapy or adjuvant 
endocrine therapy after BCS will be discussed with participants during the process of informed 
consent.  At enrollment and at the pre-operative visit, the surgical oncologist will be asked the 
radiation recommendation survey question (section 8.2.2). If the patient is seen by UVA radiation 
oncology during this time, the radiation oncologist will be asked the radiation recommendation 
survey question at enrollment and at the time of the pre-operative visit (section 8.2.2).  The 
participant will also answer a radiation preference survey question at enrollment and at the pre-
operative visit (section 8.2.2).  Individuals will proceed with/without radiation and adjuvant 
endocrine therapy per standard clinical practice. 
This study does not involve any randomization, blinding or masking procedures.  Participants will 
be told which treatment they are receiving. 
6.6 
Concomitant Therapy 
For this protocol, a prescription medication is defined as a medication that can be prescribed only 
by a properly authorized/licensed clinician. The participant should be asked about all medications 
that were administered ≤ 28 days prior to screening and throughout study treatment.  
 Prohibited Concomitant Medications 
 
Endocrine therapy not prescribed for the treatment of the breast cancer 
 
Current use of strong CYP2D6 inhibitors if participant is receiving tamoxifen.   
 Rescue Medicine/Supportive Care 
Any reported side effects from the endocrine therapy should be managed by the treating 
physicians per usual standard of care. This includes recommendations for non-medication 

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supportive interventions such as acupuncture, physical therapy, etc. Physicians may also choose 
to prescribe additional medication with evidence for improving endocrine therapy side effects such 
as venlafaxine, duloxetine, or Nonsteroidal anti-inflammatory drugs. Any prescription medications 
will be prescribed per package labeling. Patients on endocrine therapy should have any routine 
standard of care monitoring as recommended by the treating oncologist. This includes annual 
LFT evaluation and annual gynecology evaluation for patients on tamoxifen if recommended by 
treating oncologist. This includes periodic assessment of bone density and appropriate treatment 
of low bone density as recommended by the treating oncologist.  
 STUDY CLOSURE, STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION OR WITHDRAWAL 
7.1 
Study Discontinuation and Closure 
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause.  Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to the investigator and funding 
agency.  If the study is prematurely terminated or suspended, the Principal Investigator (PI) will 
promptly inform the Institutional Review Board (IRB) and will provide the reason(s) for the 
termination or suspension.  Study participants will be contacted, as applicable, and be informed 
of changes to study visit schedule. 
  
Circumstances that would warrant termination or suspension include, but are not limited to: 
 
 
Determination of unexpected, significant, or unacceptable risk to participants  
 
Demonstration of efficacy that would warrant stopping    
 
Insufficient compliance to protocol requirements 
 
Data that are not sufficiently complete and/or evaluable 
 
Determination of futility 
 
For safety related concerns, the study may resume once concerns about safety, protocol 
compliance, and data quality are addressed, and satisfy the Principal Investigator, IRB, and Data 
and Safety Monitoring Committee. 
 
Participants receiving study treatment at the time of study discontinuation should complete 
procedures described in section 7.3. 
 
7.2 
Participant Discontinuation/Withdrawal  
Participants are free to withdraw from participation in the study at any time upon request. 
A participant’s study treatment would be discontinued for the following reasons: 
 
 
If any clinical adverse event (AE), laboratory abnormality, or other medical condition or 
situation occurs such that continued participation in the study would not be in the best 
interest of the participant per the discretion of the principal investigator. 
 
Disease progression which requires discontinuation of the study intervention 

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 
If the participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation 
 
Participant decision to withdraw from study treatment and/or the study 
 
Initiation of prohibited intervention or medication 
 
Dose delays beyond those permitted in section 6.2.3 
The reason for participant discontinuation or withdrawal from study treatment will be recorded 
on the CRF. Participants who sign the informed consent and who are registered will not be 
replaced.  Participants that withdraw from the study (not only from study treatment, but all 
study follow-up) will not be contacted for any further study visits. 
7.3 
Procedures for Discontinuation of Study Intervention 
Discontinuation from endocrine therapy or radiation therapy does not mean discontinuation from 
the study, and remaining study procedures should be completed as indicated by the study 
protocol.  If a clinically significant finding is identified (including, but not limited to changes from 
baseline) after enrollment, the investigator or qualified designee will determine if any change in 
participant management is needed. Any new clinically relevant finding will be reported as an 
adverse event (AE). 
The data to be collected and procedures to be completed at the time of study intervention 
discontinuation are included in the schedule of events (Appendix 1).  
7.4 
Lost to Follow-Up 
A participant will be considered lost to follow-up if she fails to return for 3 scheduled visits and is 
unable to be contacted by the study site staff. The study staff will attempt to contact the participant 
up to 3 times. 
The following actions must be taken if a participant fails to return to the clinic for a required study 
visit: 
 
The site will attempt to contact the participant and reschedule the missed visit within 4 
weeks and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain if the participant wishes to and/or should continue in the study. 
 
Before a participant is deemed lost to follow-up, the investigator or designee will make 
every effort to regain contact with the participant by phone.  
 
These contact attempts should be documented in the study file.  
 
Should the participant continue to be unreachable, she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
 
 STUDY ASSESSMENTS AND PROCEDURES 
8.1 
Clinical Assessments  
The study team will have access to tests and procedures conducted prior to the study that were 
completed as part of an individual’s standard clinical care.  These include information about 
medical history, results from prior physical exams or laboratory tests, pathology reports, and clinic 
notes.   

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The following evaluations will be performed on an outpatient basis.  Please refer to Appendix 1 
for the schedule of activities. 
 Exams and Evaluations 
The following will be performed by a licensed clinician: 
 
Medical History 
 
Physical Exam -Breast exam and axillary lymph node exam.  
 
Vital signs (pulse, blood pressure)  
 
Start and stop dates of pre-ET and adjuvant endocrine therapy; reason for 
discontinuation  
 Assessment of Adverse Events 
Each participant will be evaluated by a licensed clinician at each study visit.  The NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 5 will be used for the characterization 
and grading of adverse events.  
Toxicities will be captured from the exams and evaluations. For each AE, date of onset, duration, 
grade, and attribution will be noted in the individual’s study chart, or study documents, or in the 
clinic note and will be entered in the UVA Cancer Center database.   
In the event of an AE, appropriate action will be taken to ensure adequate care for the participant.  
If the participant is still on protocol, treatment delay or withdrawal from the protocol will be 
considered according to the protocol guidelines (section 6.2.3). 
8.2 
Participant Questionnaires  
 Patient Belief Surveys 
Baseline data regarding patient beliefs and perceptions about their breast cancer and endocrine 
therapy will be collected prior to starting pre-ET.  
The Brief Illness Perception Questionnaire (BIPQ, Appendix 3) is a 9 item scale that measures 
patients’ beliefs about their illness including consequences, timeline, personal control, treatment 
control, identity, coherence, emotional response, and causes40. Responses are on a 10 point 
Likert scale and patients also identify 3 causes of their breast cancer.  
The Beliefs about Medicines Questionnaire (BMQ) is an 8 item scale that measures patients’ 
beliefs about medicines using a 5-point Likert scale41. The BMQ-ET (Appendix 4) is an adapted 
version of the BMQ that includes 10 questions on a 5 point Likert scale that assess patients’ 
beliefs about their endocrine therapy42. The BMQ-ET will be assessed at baseline.  
The Perceived Sensitivity to Medicine Scale (PSM, Appendix 5) is a 5 item assessment of 
patients’ perceived sensitivity to medications at baseline using a 5 point Likert scale43.  
The UVA Breast Cancer Belief Survey (Appendix 6), a novel series of questions regarding 
patient beliefs about breast cancer and breast cancer medications, will also be administered. 

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 Radiation Preference Questions 
The patient and the surgical oncologist will answer the radiation preference question at enrollment 
and at the pre-operative visit. If the patient has a radiation oncology consultation on or before Day 
1, the radiation oncologist will answer the radiation preference question at Day 1 and at the pre-
operative visit per Appendix 1.  Answers to questions are measured on a 4 point Likert scale. 
Before IRB approval of protocol version 01-27-2021, radiation preference questions were asked 
at a post-operative visit and not the pre-operative visit. Subjects who have had their pre-operative 
visit but not their post-operative visit after protocol v 01-27-2021 is IRB approved should have 
their radiation preference questions asked post-operatively to ensure that this data point is 
collected.  
Enrollment Patient Question:  Based on the conversations you have had with your breast cancer 
doctors thus far, how likely are you to decide to do radiation after your surgery? 
1 = Extremely Unlikely 
2 = Unlikely 
3 = Likely 
4 = Extremely Likely 
Enrollment Surgical/Radiation Oncologist Question:  Based on your current knowledge of this 
patient’s breast cancer and discussions with her about her treatment plan, how would you 
characterize the strength of your recommendation for adjuvant radiation therapy? 
1 = Extremely weak 
2 = Weak 
3 = Strong 
4 = Very Strong 
Pre-operative Patient Question: Based on the conversations you have had with your breast 
cancer doctors thus far and your experience with the breast cancer medicine taken before 
surgery, how likely are you to decide to do radiation after your surgery? 
1 = Extremely Unlikely 
2 = Unlikely 
3 = Likely 
4 = Extremely Likely 
Pre-operative Surgical/Radiation Oncologist Question: Based on your current knowledge of this 
patient’s breast cancer, discussions with her about her treatment plan, and her experience with 
pre-ET, how would you characterize the strength of your recommendation for adjuvant radiation 
therapy? 
1 = Extremely weak 
2 = Weak 
3 = Strong 
4 = Very Strong 
 Patient Reported Outcome Surveys 
Patient reported outcomes will be assessed as indicated in Appendix 1.  
Health related quality of life (HRQOL) will be assessed using the EORTC QLQ-C30 and QLQ-
BR23 (Appendix 7), which is a validated and reliable 53 question assessment of general health 
and wellbeing44.  
Depression will be assessed using the Center for Epidemiologic Studies Depression Scale 
Revised (CESD-R, Appendix 8), which is a 20 item assessment to measure symptoms of 
depression in nine different groups as defined by the American Psychiatric Association Diagnostic 
and Statistical Manual, fifth edition. The score ranges from 0 to 60 and scores greater than 16 
indicate depressive symptoms45.  

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General symptom burden while on endocrine therapy will be assessed using the Breast Cancer 
Prevention Trial Symptom Checklist (BCPT-SCL, Appendix 9) in which 47 symptoms are 
assessed on a scale of 0 to 4 (high burden) with plans to follow symptom clusters used in the 
ELPh trial of weight/body image, vasomotor, vulvovaginal, musculoskeletal, cognitive, and 
mood33,46,47. 
Data will be collected on patient adherence to endocrine therapy using patient report via two 
simple questions (Appendix 10).  
 Treatment Decision Survey 
A survey to assess treatment decision will be given as indicated in Appendix 1. The survey can 
be found in Appendix 11. 
 Decisional Conflict and Decision Regret Scales 
The Decisional Conflict Scale (DCS)48 and Decision Regret Scale (DRS)49 are patient reported 
outcome surveys that will be used to assess subjects’ perceptions related to their medical choices 
(Appendix 12 and Appendix 13). The DRS does not need to be completed at baseline because it 
relates to past decisions related to a medical choice (radiation and endocrine therapy) that is not 
made at baseline. 
8.3 
Recurrence and Survival 
Recurrence is defined as a biopsy-proven diagnosis of breast cancer in the index quadrant of the 
previously treated breast cancer. Patients will be evaluated routinely post-treatment to assess for 
local recurrence, loco-regional recurrence, contralateral breast cancer recurrence and distant 
disease. Clinical breast exams will be performed per standard of care every 3-6 months by the 
treating physicians. Mammography will be performed annually if patient is still eligible for breast 
cancer screening based on standard practice guidelines and images will be reviewed for evidence 
of recurrence. 
 DATA AND SAFETY MONITORING PLAN  
In the following section, there are references to “days”, “calendar days”, and “working days”.  
References to “days” should be interpreted as calendar days.  Working days include Monday 
through Friday with the exception of the following federal holidays (New Year’s Day, Marin Luther 
King Jr.’s birthday, Washington’s birthday, Memorial Day, Independence Day, Labor Day, 
Columbus Day, Veteran’s Day, Thanksgiving Day, Christmas Day).  Please note that the 
difference in reporting between the FDA required reporting (10 working days) and the UVA IRB 
requirement of 10 calendar days for Unanticipated Adverse Device Effects (UADEs)(for device 
studies only).  For reporting to the IRB, follow the more conservative guideline (e.g. calendar 
days). 
9.1 
Adverse Events and Serious Adverse Events 
 Definition of Adverse Events (AE) 

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Adverse event means any untoward medical occurrence associated with the use of an 
intervention in humans, whether or not considered intervention-related (21 CFR 312.32 (a)). 
 Definition of Serious Adverse Events (SAE) 
An adverse event (AE) or suspected adverse reaction is considered "serious" if, in the view of 
either the investigator or sponsor, it results in any of the following outcomes:  
 
death,  
 
a life-threatening adverse event,  
 
inpatient hospitalization or prolongation of existing hospitalization,  
 
a persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions, or  
 
a congenital anomaly/birth defect.  
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the participant and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse. 
Note: A planned medical or surgical procedure is not, in itself, an SAE 
 Classification of an Adverse Event 
9.1.3.1 Severity of Event 
The NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5 will be used for 
the characterization and grading of adverse events.  
9.1.3.2 Relationship to Study Intervention 
All adverse events (AEs) must have their relationship to study intervention assessed by the 
clinician who examines and evaluates the participant based on temporal relationship and his/her 
clinical judgment. The degree of certainty about causality will be graded using the categories 
below. In a clinical trial, the study product must always be suspect.  
 
Definitely Related – There is clear evidence to suggest a causal relationship, and other 
possible contributing factors can be ruled out. The clinical event, including an abnormal 
laboratory test result, occurs in a plausible time relationship to study intervention 
administration and cannot be explained by concurrent disease or other drugs or 
chemicals. The response to withdrawal of the study intervention (dechallenge) should be 
clinically plausible. The event must be pharmacologically or phenomenologically definitive, 
with use of a satisfactory rechallenge procedure if necessary. 
 
 
Probably Related – There is evidence to suggest a causal relationship, and the influence 
of other factors is unlikely. The clinical event, including an abnormal laboratory test result, 
occurs within a reasonable time after administration of the study intervention, is unlikely 

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to be attributed to concurrent disease or other drugs or chemicals, and follows a clinically 
reasonable response on withdrawal (dechallenge). Rechallenge information is not 
required to fulfill this definition. 
 
 
Possibly Related – There is some evidence to suggest a causal relationship (e.g., the 
event occurred within a reasonable time after administration of the trial medication). 
However, other factors may have contributed to the event (e.g., the participant’s clinical 
condition, other concomitant events). Although an AE may rate only as “possibly related” 
soon after discovery, it can be flagged as requiring more information and later be upgraded 
to “probably related” or “definitely related”, as appropriate. 
 
Unlikely to be related – A clinical event, including an abnormal laboratory test result, 
whose temporal relationship to study intervention administration makes a causal  
 
relationship improbable (e.g., the event did not occur within a reasonable time after 
administration of the study intervention) and in which other drugs or chemicals or 
underlying disease provides plausible explanations (e.g., the participant’s clinical 
condition, other concomitant treatments). 
 
 
Not Related – The AE is completely independent of study intervention administration, 
and/or evidence exists that the event is definitely related to another etiology. There must 
be an alternative, definitive etiology documented by the clinician. 
9.1.3.3 Expectedness 
Pre-operative Endocrine Therapy 
The Principal Investigator will be responsible for determining whether an adverse event (AE) is 
expected or unexpected.  An AE will be considered unexpected if the nature, severity, or 
frequency of the event is not consistent with the risk information previously described for the study 
intervention in the prescribing information for each drug. 
 Time Period and Frequency for Event Assessment and Follow-Up 
 
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the 
attention of study personnel during study visits and interviews of a study participant presenting 
for medical care, or upon review by a study monitor. 
 
All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured 
on the appropriate case report form (CRF). Information to be collected includes event description, 
time of onset, clinician’s assessment of severity, relationship to study product (assessed only by 
those with the training and authority to make a diagnosis), and time of resolution/stabilization of 
the event. All AEs occurring while on study must be documented appropriately regardless of 
relationship. All AEs will be followed to adequate resolution. 
 
Any medical condition (including a laboratory abnormality) that is present at the time that the 
participant is screened will be considered as baseline and not reported as an AE. However, if the 

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study participant’s condition deteriorates at any time during the study, it will be recorded as an 
AE.  
Changes in the severity of an AE will be documented to allow an assessment of the duration of 
the event at each level of severity to be performed. AEs characterized as intermittent require 
documentation of onset and duration of each episode. 
A member of the study team will record all reportable events with start dates occurring any time 
after informed consent is obtained until 30 days (for non-serious AEs) or anytime (for SAEs 
considered related to the study intervention) after the last day of neo-adjuvant endocrine therapy, 
or until another therapy is started.  At each study visit, the investigator will inquire about the 
occurrence of AE/SAEs since the last visit.  Events will be followed for outcome information until 
resolution or stabilization. 
 Adverse Event Reporting 
AEs must be recorded into the University of Virginia Cancer Center (UVA Cancer Center) 
database per guidelines in Table 1. 
Table 1:  Recording Guidelines for UVA  
Cancer Center Database 
 
 
 Serious Adverse Event Reporting 
 
Medium Risk Studies 
Reporting requirements for AEs that occur within 30 days of the last dose of protocol specified treatment 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 & 5 
 
Expected 
and 
unexpected 
 
Expected 
 
Unexpected 
Expected 
 
Unexpected 
Expected 
Unexpected 
Without 
hospitalization 
With 
hospitalization 
Without 
hospitalization 
With 
hospitalization 
Unrelated 
Unlikely 
Not 
required 
Not 
required 
Not 
required 
OnCore 
30 days 
OnCore 
15 days 
OnCore 
30 days 
OnCore 
15 days 
OnCore 
15 days 
OnCore 
15 days 
Possible 
Probable 
Definite 
OnCore 
30 days 
OnCore 
30 days 
OnCore 
15 days 
OnCore 
30 days 
OnCore 
15 days 
OnCore 
15 days 
OnCore 
15 days 
OnCore 
15 days 
OnCore 
(24-hrs)* 
7 days 
*Enter into Cancer Center database within 24 hours if unexpected and definitely related to protocol specified treatment 
Hospitalization defined as an inpatient hospital stay or prolongation of a hospital stay equal to or greater than 24 hours 

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The study clinician will report to the sponsor any serious adverse event, whether or not considered 
study intervention related, including those listed in the protocol or drug labels, and must include 
an assessment of whether there is a reasonable possibility that the study intervention caused the 
event. Study endpoints that are serious adverse events (e.g., all-cause mortality) must be 
reported in accordance with the protocol unless there is evidence suggesting a causal relationship 
between the drug and the event (e.g., death from anaphylaxis). In that case, the investigator must 
immediately report the event to the sponsor. 
 
All serious adverse events (SAEs) will be followed until satisfactory resolution or until the site 
investigator deems the event to be chronic or the participant is stable. Other supporting 
documentation of the event may be requested by the UVA Multisite Clinical Research Office (UVA 
MCRO/Sponsor) and should be provided as soon as possible 
 
Site Reporting Requirements 
 
 
Report to the UVA MCRO within 24 hours from the time the study team received 
knowledge of the event according to UVA MCRO requirements.  
 
Report to your IRB in accordance with your IRB guidelines.  
 
Multi-Site Principal Investigator / UVA MCRO Reporting Requirements 
 
 
The Sponsor (or the UVA MCRO on behalf of the sponsor)  is responsible for notifying the 
UVA IRB-HSR of any event resulting in death that is deemed DEFINITELY related to 
(caused by) study within 24 hours from the time the study team received knowledge of the 
event.  Report using IRB Online and by telephone. 
 
 
The Sponsor (or the UVA MCRO on behalf of the sponsor) is responsible for notifying the 
UVA IRB-HSR of any serious, unexpected, related adverse event within 7 calendar days 
from the time the study team receives knowledge of the event. Timeline includes 
submission of signed hardcopy of AE form.  Report using IRB online.   
9.2 
Reporting Events to Participants 
If there is any new information relevant to the participant’s willingness to continue to participate in 
the study, such as if there are new risks of the study treatment identified that were not included 
on the consent form that the participant signed, the study team will contact the participant to 
discuss this information. If the participant is still receiving study treatment, the study team will 
present the participant with an updated consent and confirm that he or she wants to continue 
receiving study treatment. The Principal Investigator will determine whether new risks are 
applicable to participants who are in follow-up, whether participants need to be notified, and 
whether re-consenting is required. 
9.3 
Unanticipated Problems 
 Definition of Unanticipated Problems (UP) 
 

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The Office for Human Research Protections (OHRP) considers unanticipated problems 
(UPs)(may include a data breach) involving risks to participants or others to include, in general, 
any incident, experience, or outcome that meets all of the following criteria: 
 
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures 
that are described in the protocol-related documents, such as the Institutional Review 
Board (IRB)-approved research protocol and informed consent document; and (b) the 
characteristics of the participant population being studied; 
• 
Related or possibly related to participation in the research (“possibly related” means there 
is a reasonable possibility that the incident, experience, or outcome may have been 
caused by the procedures involved in the research); and 
• 
Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. 
 Unanticipated Problem Reporting 
To satisfy the requirement for prompt reporting, UPs will be reported using the following timeline:   
 
Site Reporting Requirements 
 
UPs that are SAEs will be reported in accordance with the guidelines for SAE reporting. 
 
 
UPs that are not adverse events, protocol deviations or data breaches (see section 9.4.2 
for reporting for data breaches)  
o Report to the UVA MCRO within 2 calendar days from the time the study team 
receives knowledge of the event.  
o Report to your IRB of record in accordance with your IRB guidelines.   
 
Multi-Site Principal Investigator/UVA MCRO/Study Team Reporting Requirements 
 
Report UPs that are not adverse events or protocol deviations to the UVA IRB-HSR within 
7 calendar days from the time the study team receives knowledge of the event.  Report 
using the Unanticipated Problem Report form. 
 
 
All UPs will be reported to appropriate institutional officials (as required by an institution’s 
written reporting procedures), the supporting agency head (or designee), and the Office 
for Human Research Protections (OHRP) in accordance with institutional policies. 
 Reporting Unanticipated Problems to Participants 
If during the course of the study there is an unanticipated problem that affects current or past 
participants, affected participants will be contacted if needed. 
9.4 
Data Breach 
 Definition of Data Breach 
An unauthorized acquisition, access, or use of protected health information (PHI) that 
compromises the security or privacy of such information. 

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 Reporting a Data Breach 
 
Site Reporting Requirements 
 
Report to the UVA MCRO within 24 hours from the time the study team receives 
knowledge of the event.  
 
 
Report to your IRB of record in accordance with your IRB guidelines.   
 
Multi-Site Principal Investigator (or UVA MCRO on behalf of the sponsor) Reporting 
Requirements 
 
Report to the UVA Corporate Compliance and Privacy Office as soon as possible and no 
later than 24 hours from the time the incident is identified.  Report by telephone. 
 
 
Report to ITC if the breach involves electronic data.  Report as soon as possible and no 
later than 24 hours from the time the incident is identified.  Refer to the following for details:  
http://security.virginia.edu/report-information-security-incident. 
 
 
Report to UVA police if the breach includes such things as stolen computers.  Report by 
telephone. 
 
9.5 
Protocol Deviation 
 Definition of Protocol Deviation 
A protocol deviation is defined as any change, deviation, or departure from the study design or 
procedures of a research project that is NOT approved by the institution’s IRB prior to its initiation 
or implementation, OR deviation from  standard operating procedures, Good Clinical Practices 
(GCPs), federal, state or local regulations. Protocol violations may or may not be under the control 
of the study team or site staff. These protocol violations may be major or minor violations. 
 Reporting of a Protocol Deviation 
It is the responsibility of the site investigator to use continuous vigilance to identify and report 
deviations. All deviations must be addressed in study source documents. 
Site Reporting Requirements 
 
Report major deviations to the UVA MCRO within 4 calendar days from the time the study 
team receives knowledge of the event. Consult the MCRO for instructions on recording 
minor deviations. 
 
 
Report to your IRB of record in accordance with your IRB guidelines.   
(For sites that use the UVA IRB-HSR as the IRB of record, the UVA MCRO will report to 
the UVA IRB-HSR as required—see sponsor reporting requirements)   
 
Multi-Site Principal Investigator Reporting Requirements 

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 
Report to the UVA IRB-HSR major deviations within 7 calendar days from the time the 
study team received knowledge of the event.  Report using the Protocol Deviation and 
Protocol Exception Reporting Form. 
 
For minor deviations, please reference the UVA IRB-HSR website for tips for recording minor 
deviations 
9.6 
Participant Withdrawals/Dropouts Prior to Study Completion 
Participants who withdraw consent and those dropping out of the study secondary to an AE will 
be reported to the IRB yearly on the IRB continuation form. 
10 STATISTICAL CONSIDERATIONS  
10.1 Study Design Overview 
This is a prospective multicenter study to obtain preliminary information on whether pre-treatment 
with endocrine therapy changes preference for adjuvant radiation treatment as considered by the 
participant or the surgical oncologist. In addition, we aim to capture a range of patient reported 
outcomes over time to explore the possibility that these measures will be useful predictors of 
adherence to post-operative endocrine therapy. 
10.2 Endpoints, Statistical Hypotheses and Estimation 
Assessment of the primary study objectives will be based upon answers to the radiation 
preference question for study participants and surgical oncologists separately. Change in 
preference is measured as a binary variable (yes/no) with a coding of ‘yes’ if answers between 
the pre-op and on-study (baseline) response differ (no to yes; or yes to no). No difference in 
response is coded as ‘no’. 
Hypothesis test 1: To determine if pre-treatment with endocrine therapy changes participant 
preference for adjuvant radiation treatment in the participant study population by at least 10% with 
a one-sided binomial test.  
Hypothesis test 2: To determine if pre-treatment with endocrine therapy changes surgical 
oncologist preference for participant specific adjuvant radiation treatment in the participant study 
population by at least 10% with a one-sided binomial test. 
Estimation: To estimate the association of pre-treatment PRO measures on the probability of long-
term adjuvant endocrine therapy adherence. 
10.3 Sample Size Determination 
Sample size estimation is based upon accruing a sufficient number of participants to assess the 
primary objective separately for participants and surgical oncologist responses with an overall 
one-sided 10% type I error rate (5% for each individual test). Accrual of 70 evaluable participants 
provides 90% power to test for a change in adjuvant radiation treatment preference between the 
pre-op visit and on-study in the participant study population from a null difference of 5% to an 
alternative of at least 15% with a target one-sided 5% level binomial test (by exact numeration). 
Accrual of 70 evaluable participants also provides 90% power to independently test for a change 

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in adjuvant radiation treatment preference of the surgical oncologist between the pre-op visit and 
on-study in the participant study population from a null difference of 5% to an alternative of at 
least 15% with a one-sided 5% level binomial test. For fixed target size and power, the detectable 
difference increases from 10% to 15% when the assumed null varies within the expected range 
of 5% to 20%. 
This is a pilot study to obtain preliminary data to estimate which if any PRO measures are 
associated with adherence to post-operative endocrine therapy. With n=70, a logistic regression 
of the dependent variable of adherence or not to endocrine therapy by year 2 on a continuous 
PRO measure score achieves 80% power at a 5% significance level to detect an odds ratio of 2 
when the probability of adherence is 25%. These error rate estimates assume no adjustment for 
multiple comparisons among the different PRO.  
10.4 Accrual 
Maximum target sample size is estimated at 83 eligible participants which adjusts for a 15% lost 
to follow-up/dropout rate. In 2018 and 2017, 70 and 78 patients, respectively, met the basic 
inclusion criteria at UVA. Assuming 60% of future patients will agree to enroll in the study, target 
accrual to the study should be achieved in less than two years. 
10.5 Statistical Analyses 
10.5.1 Analysis populations 
 
a) Safety: All study participants who start protocol defined pre-ET. 
b) Primary objective: All eligible study participants who start protocol defined pre-ET for which 
there is an answer to both the on-study and pre-op radiation question.  A participant is 
considered ‘eligible’ if she satisfies all inclusion and exclusion criteria. 
c) Secondary objective for adherence: All eligible study participants who start protocol defined 
pre-ET and who provide PRO measures at on-study and have information on post-op 
adherence to endocrine therapy. 
d) Secondary objective for radiation oncologist’s preference: The subset of eligible study 
participants who start protocol defined pre-ET for which there is an answer to both the on-
study and pre-op radiation question from a radiation oncologist. 
 
10.5.2 Analyses 
Primary analyses will not adjust for center. Summary measures will be described overall and by 
center. Demographics and baseline characteristics will be described for all study participants. 
Characteristics to be examined include: race/ethnicity, age, performance status, stage, ER, PR 
and HER-2 status, histologic subtype, tumor size date of diagnosis. 
Adverse events will be coded based upon the NCI CTCAE v5.0. Safety will be reported by 
frequency and severity of adverse events.  
The primary analysis will be based upon responses from a) study participants and b) surgical 
oncologists to the radiation questions, separately, without adjustment for center. For each 
response group, the proportion of responses that differ from the pre-op visit compared to the on-
study (baseline) response (yes to no; or no to yes) will be calculated along with 95% confidence 
intervals. For each group, we will test that pre-ET resulted in a change in preference for adjuvant 

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radiation therapy in more than 10% of participants compared to no change with a one-sided 5% 
level exact binomial test.  
Graphical methods will be used to display the PRO outcomes over time. On the most basic level, 
logistic regression models with adherence to post-op endocrine therapy at 2 years as the 
dependent outcome and the range of PRO measurement as independent factors will be used to 
obtain initial estimates of the predictive value of the protocol defined PRO to determine 
adherence. Other exploratory repeated measures models will be explored to determine if changes 
over time are also associated with determination of non-adherence. Exploratory analyses could 
include the assessment of PRO for quality adjusted life years or healthy-year equivalents. In all 
exploratory models, individual or simultaneous associations will be deemed promising for factors 
with p < 0.1. 
The secondary analysis related to the radiation oncologist’s preference will be based upon the 
subset of pre and post pre-ET responses from for the consulting radiation oncologist. The 
proportion of responses that differ from the pre-op visit compared to the on-study (baseline) 
response by at least one point (in either direction) will be calculated along with a 95% confidence 
interval. 
Descriptive summaries and simple tabulations will be used to describe results from the preliminary 
data on justification of participant response for those whose preference changed. 
At final analysis the Product-Limit method of Kaplan & Meier will be used to estimate recurrence-
free survival and overall survival, along with 90% CIs. Recurrence-free survival is defined as the 
time from start of pre-ET to time of recurrence or death from any cause, whichever occurred first. 
Participants who do not experience an event (recurrence or death) will be censored at date of last 
clinical assessment. Overall survival is defined as the time from start of pre-ET to time of death 
from any cause. Participants who do not experience an event (death) will be censored at date of 
last contact. 
10.5.3 Interim Analyses and Pausing Guidelines 
There will be no planned interim analyses for testing the primary hypotheses. Participants will be 
monitored for adherence to pre-ET and for pre/post response data capture. Pre-operative ET 
treatment adherence is expected to be close to 100% thus an indication of a lower rate would be 
cause for pause. After accrual of 50% of eligible participants, if the upper limit of a 90% CI around 
the adherence rate does not contain 80% then the study will be paused to assess the cause, 
which may result in no modification, study modification or closure. Similarly, the study will be 
monitored for any indication that use of 3 months of pre-ET negatively impacts surgical completion 
with the same decision guideline. 
11 REGULATORY AND OPERATIONAL CONSIDERATIONS 
11.1 Regulatory and Ethical Considerations 
 Informed Consent Document  
Consent forms will be written in accordance with federal regulations and will be reviewed and 
approved by the IRB-HSR prior to use.  Participants will be given a consent form to review and a 

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member of the study team will be available to answer any questions.   Informed consent will be 
obtained from each participant prior to conducting any study-specific procedures or administering 
study treatment. 
Signed consent forms and other research records will be retained in a confidential manner.  
 Consent Procedures and Documentation 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in 
the study and continues throughout the individual’s study participation. Consent forms will be 
Institutional Review Board (IRB)-approved and the participant will be asked to read and review 
the document. A member of the study team will explain the research study to the participant and 
answer any questions that may arise. A verbal explanation will be provided in terms suited to the 
participant’s comprehension of the purposes, procedures, and potential risks of the study and of 
their rights as research participants.  Participants will have the opportunity to carefully review the 
written consent form and ask questions prior to signing. The participants should have the 
opportunity to discuss the study with their family or surrogates or think about it prior to agreeing 
to participate. The participant will sign the informed consent document prior to any procedures 
being done specifically for the study. Informed consent may be done via Telemedicine. Results 
from procedures completed prior to consent for standard of care purposes may be used for 
research purposes. Participants must be informed that participation is voluntary and that they may 
withdraw from the study at any time, without prejudice. A copy of the informed consent document 
will be given to the participants for their records. The informed consent process will be conducted 
and documented in the source document (including the date), and the form signed, before the 
participant undergoes any study-specific procedures. The rights and welfare of the participants 
will be protected by emphasizing to them that the quality of their medical care will not be adversely 
affected if they decline to participate in this study. 
 Confidentiality and Privacy  
Participant confidentiality and privacy is strictly held in trust by the participating investigators and 
their staff. This confidentiality is extended to cover testing of biological samples and genetic tests 
(if applicable) in addition to the clinical information relating to participants. Therefore, the study 
protocol, documentation, data, and all other information generated will be held in strict confidence. 
Consents will be maintained in a confidential manner in accordance with the code of federal 
regulations and HIPAA. When possible, specimens will be coded with IDs (not MRN or name). 
No information concerning the study or the data will be released to any unauthorized third party 
without prior written approval of the Principal Investigator.  
All research activities will be conducted in as private a setting as possible. 
The study monitor, other authorized representatives of the Principal Investigator, representatives 
of the Institutional Review Board (IRB), or regulatory agencies may inspect all documents and 
records required to be maintained by the investigator, including but not limited to, medical records 
(office, clinic, or hospital) and pharmacy records for the participants in this study. The clinical 
study site will permit access to such records. 
The study participant’s contact information will be securely stored at each clinical site for internal 
use during the study. At the end of the study, all records will continue to be kept in a secure 

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location for as long a period as dictated by the reviewing IRB, Institutional policies, or sponsor 
requirements. 
Study participant research data, which is for purposes of statistical analysis and scientific 
reporting, will be transmitted to and stored in OnCore. This will not include the participant’s contact 
or identifying information. Rather, individual participants and their research data will be identified 
by a unique study identification number. The study data entry and study management systems 
used by the University of Virginia Cancer Center, Office of Clinical Research research staff will 
be secured and password protected.  
To further protect the privacy of study participants, a Certificate of Confidentiality will automatically 
be issued by the National Institutes of Health (NIH) and an application is not necessary.  This 
certificate protects identifiable research information from forced disclosure. It allows the 
investigator and others who have access to research records to refuse to disclose identifying 
information on research participation in any civil, criminal, administrative, legislative, or other 
proceeding, whether at the federal, state, or local level. By protecting researchers and institutions 
from being compelled to disclose information that would identify research participants, Certificates 
of Confidentiality help achieve the research objectives and promote participation in studies by 
helping assure confidentiality and privacy to participants. 
 Future Use of Stored Specimens and Data  
Data collected for this study will be analyzed and stored at the University of Virginia.  
At the end of the study, all study data will be archived and maintained by the PI in accordance 
with institutional policies. 
 Safety Oversight and Monitoring 
The University of Virginia Cancer Center Data and Safety Monitoring Committee (CC DSMC) will 
provide oversight of the conduct of this study.  The CC DSMC will report to the UVA Protocol 
Review Committee (PRC). 
The UVA CC DSMC will review the following: 
 
All adverse events 
 
Audit results 
 
Application of study designed stopping/decision rules 
 
Whether the study accrual pattern warrants continuation/action 
 
Protocol violations 
The UVA CC DSMC will meet every month for aggregate review of data.  Tracking reports of the 
meetings are available to the PI for review.  Issues of immediate concern by the DSMC are 
brought to the attention of the Principal Investigator (and if appropriate to the PRC and IRB) and 
a formal response from the Principal Investigator is requested.  Per the UVA Cancer Center NIH 
approved institutional plan, this study will be audited approximately every 6 months.  The audit 
may include direct access to source data/documents. 

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Any study under the purview of the University of Virginia HSR-IRB is subject to review. Studies 
are chosen for Post-approval Monitoring either a) at random or b) requested by a study team 
member or any member of the IRB-HSR.   
 
The purpose of Post-approval Monitoring audits is to ensure that documentation of clinical 
research studies is of the highest quality, verify protocol adherence, and ensure that all Federal 
and local rules concerning clinical research are being fulfilled.  Post-approval monitoring is done 
by staff within the office of the Vice President for Research (VPR) in accordance with their 
Standard Operating Procedures. The conduct of an on-site review may include but is not limited 
to: 
 
requests for progress reports from investigators, 
 
examinations of research records, including signed informed consent documents, protocol 
modifications, and unexpected, serious, and/or related adverse experience reports, 
 
contacts with research subjects, or 
 
observation of the consent process and/or research procedures. Examples of when 
observation of the consent process could occur are: 
 
Full board IRB determines during review of a project that a conflict of interest exists 
such that the informed consent process should be observed by a neutral party; 
 
IRB is made aware of a complaint or concern with regard to the informed consent 
process; or 
 
IRB determines as a result of the monitoring process that the consent process is 
insufficient and education/training is required for conduct of consent. 
 
Additionally, clinical site monitoring is conducted to ensure that the rights and well-being of trial 
participants are protected, that the reported trial data are accurate, complete, and verifiable, and 
that the conduct of the trial is in compliance with the currently approved protocol/amendment(s), 
with International Conference on Harmonisation Good Clinical Practice (ICH GCP), and with 
applicable regulatory requirement(s).  
 
The UVA Coordinating Center will implement ongoing monitoring activities for this 
study to ensure that Participating Institutions are complying with regulatory and 
protocol requirements, data quality, and subject safety. Monitoring will occur before 
the clinical phase of the protocol begins, continue during protocol performance and 
through study completion. 
 
• 
Monitoring may be conducted either remotely or on-site.  For remote visits, each 
institution will be required to provide redacted source documents for review or 
appropriate access to the EMR. The UVA MCRO will provide the Participating 
Institution with a follow-up letter following completion of the monitoring  visit which 
should be maintained in the site regulatory files.  The schedule for monitoring may 
be adjusted according to subject accrual and data quality.  The Investigator will be 
notified in advance of each visit. 
 
• 
Independent audits may be conducted by each institution according to institutional 
guidelines. Results of these audits may be requested by the UVA Coordinating 
Center. 
 Quality Assurance and Quality Control 

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The clinical site will perform internal quality management of study conduct and data, 
documentation and completion according to institutional policies. 
Quality control (QC) procedures will be implemented beginning with the data entry system and 
data QC checks that will be run on the database will be generated. Any missing data or data 
anomalies will be communicated to the study team for clarification/resolution. 
 
Following written Standard Operating Procedures (SOPs), the monitors will verify that the clinical 
trial is conducted and data are generated and biological specimens are collected, documented 
(recorded), and reported in compliance with the protocol, International Conference on 
Harmonisation Good Clinical Practice (ICH GCP), and applicable regulatory requirements (e.g., 
Good Laboratory Practices (GLP), Good Manufacturing Practices (GMP)).  
 
The investigational site will provide direct access to all source data/documents, and reports for 
the purpose of monitoring and auditing, and inspection by local and regulatory authorities. 
11.2 Data Handling and Record Keeping  
 Data Collection and Management Responsibilities  
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the 
site investigator. The investigator is responsible for ensuring the accuracy, completeness, 
legibility, and timeliness of the data reported.  
All source documents should be completed in a neat, legible manner to ensure accurate 
interpretation of data.   
Data will be collected using a password-protected, centralized electronic case report form called 
ON-line Clinical Oncology Research Environment = Oncore.] Data recorded in the electronic case 
report form (eCRF) derived from source documents should be consistent with the data recorded 
on the source documents.  
 Study Records Retention  
Record retention will be in accordance with IRB-HSR and institutional policies. 
11.3 Publication and Data Sharing Policy 
This trial will be registered at clinicaltrials.gov, and results information from this trial will be 
submitted to clinicaltrials.gov. In addition, every attempt will be made to publish results in peer-
reviewed journals.  This study will be conducted in accordance with the National Institutes of 
Health (NIH) Public Access Policy, which ensures that the public has access to the published 
results of NIH funded research. It requires scientists to submit final peer-reviewed journal 
manuscripts that arise from NIH funds to the digital archive PubMed Central upon acceptance for 
publication. 
11.4 Conflict of Interest Policy 
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical.  Therefore, any actual conflict of interest of persons who have 

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a role in the design, conduct, analysis, publication, or any aspect of this trial will be disclosed and 
managed. Furthermore, persons who have a perceived conflict of interest will be required to have 
such conflicts managed in a way that is appropriate to their participation in the design and conduct 
of this trial.  The study leadership in conjunction with the institution has established policies and 
procedures for all study group members to disclose all conflicts of interest and will establish a 
mechanism for the management of all reported dualities of interest. 
 
 
 
 

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41..Horne R, Weinman J: Patients' beliefs about prescribed medicines and their role in adherence 
to treatment in chronic physical illness. J Psychosom Res 47:555-67, 1999 
42..Brett J, Hulbert-Williams NJ, Fenlon D, et al: Psychometric properties of the Beliefs about 
Medicine Questionnaire-adjuvant endocrine therapy (BMQ-AET) for women taking AETs 
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evaluation of validity and reliability. Br J Health Psychol 18:18-30, 2013 
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and the center for epidemiological studies depression scale for detecting depression in women 
with breast or gynecologic cancer. Gen Hosp Psychiatry 36:74-80, 2014 
46..Ganz PA, Day R, Ware JE, Jr., et al: Base-line quality-of-life assessment in the National 
Surgical Adjuvant Breast and Bowel Project Breast Cancer Prevention Trial. J Natl Cancer Inst 
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47..Stanton AL, Bernaards CA, Ganz PA: The BCPT symptom scales: a measure of physical 
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48..O'Connor AM: Validation of a decisional conflict scale. Med Decis Making 15:25-30, 1995 
49..Brehaut JC, O'Connor AM, Wood TJ, et al: Validation of a decision regret scale. Med Decis 
Making 23:281-92, 2003 
 
 

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 APPENDICES 
 

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Appendix 1:  Schedule of Events 
a Patient reported outcome surveys should be completed prior to first dose of endocrine therapy. 
b Radiation therapy will be scheduled and administered in accordance with standard clinical practice and as recommended by the treating radiation-oncologist. 
c For patients who do not tolerate pre_ET and discontinue early, they will continue to be followed as indicated in the schedule above beginning at the pre-op visit.  
Procedures 
Screening 
Pre_ET Periodc  
 
Pre-Op Visit 
Surgeryj 
 
Radiation 
Adjuvant Treatment Period 
Timeframe 
≤ 21 days 
prior to 
registration 
unless 
otherwise 
noted 
Day 1 
Day 
30 
(+/- 7 
d) 
Day 
90 
(+/- 7 
d) 
 
 
 
2-8 weeks 
after Day 90j  
 
Visit 1 
(1-90 days after 
surgery, 
chemotherapy 
completion,  or RT 
completion b 
whichever is later)  
Visit 2 
(6 months 
after visit 1) 
 (+/- 30 d) 
Visit 3 
(12 months 
after visit 1) 
 (+/- 30 d) 
Visit 4 
(24 months 
after visit 1) 
 (+/- 30 d) 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
Physical exam /vitals 
X 
 
X 
X 
X 
 
 
X 
X 
X 
X 
Endocrine Therapy 
 
Taken daily as directedi 
 
 
 
--Taken daily as directedd-- 
BCS 
 
 
 
 
 
X 
 
 
 
 
 
Radiation Therapy 
 
 
 
 
 
 
Xb 
 
 
 
 
Adverse event review and 
evaluation 
 
 
X 
X 
Xg 
 
 
 
 
 
 
Patient Beliefs Qs 
 
X 
 
 
 
 
 
 
 
 
 
PRO Surveys 
 
Xa 
X 
X 
 
 
 
X 
X 
X 
X 
Treatment Decision Survey 
 
 
 
 
 
 
 
X 
 
 
 
Subject RT preference 
question 
 
X 
 
 
X 
 
 
 
 
 
 
Surgeon RT preference 
question 
 
Xh 
 
 
X 
 
 
 
 
 
 
Radiation Oncologist RT 
preference question 
 
Xf,h 
 
 
Xf 
 
 
 
 
 
 
Decisional Conflict Scale 
 
X 
 
 
X 
 
 
 
 
 
 
Decision Regret Scale 
 
 
 
 
 
 
 
 
X 
X 
X 
Recurrence/Survivale 
 
 
 
 
 
 
 
X 
X 
X 
X 

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d Some individuals may choose to refuse adjuvant endocrine therapy, but will continue to be followed as indicated in the schedule above. Some Individuals will 
continue beyond 24 months of endocrine therapy as directed by their oncologist based on standard of care recommendations.  
e Tumor imaging will not be required at visits 1-4 to assess recurrence.  Recurrence will be assessed using data from breast examinations conducted during the visit 
and prior results from imaging completed as part of standard clinical practice. 
f This is not applicable if participant has not been seen by Radiation Oncology prior to starting pre-ET (radiation oncology consultation on or before Day 1). 
g After the day 90 visit but prior to surgery. 
h Questionnaire to be completed on day 1 or within +7 days.  
i After the day 90 visit, participants may continue the pre-operative endocrine therapy until 2 weeks before surgery per clinician discretion based on standard of care 
recommendations for the pre-operative treatment. 
j Participants need to be off endocrine therapy for at least 2 weeks and no more than 8 weeks prior to surgery

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Appendix 2:  Protocol Amendment History 
 
Version 
Date 
Description of Change  
Brief Rationale 
V25 February 2023 
Title page, Statement of Compliance: 
Updated to add NIH as a funding 
source and to require following the 
terms and conditions of the award 
11.1.3: Added language regarding a 
Certificate of Confidentiality 
11.3: Added language regarding 
abiding by the NIH Public Access 
Policy 
The study has received an NIH 
R21 grant to fund the study  
8.2.5: Added a sentence excluding 
the DRS from baseline 
The decision that is of interest 
hasn’t occurred yet at baseline 
1.2 Schema: Changed “14” to “1 - 90” 
days after surgery or radiation for 
adjuvant endocrine therapy 
Internal consistency 
V24 June 2022 
Revised TOC and made formatting 
changes 
To correct TOC and formatting 
In Section 6.6, removed language 
indicating 
the 
concomitant 
medications need to be recorded in 
the case report forms 
To reduce study team burden by 
reducing extraneous information 
collection  
V23 March 2022 
In the study calendar, revised the 
follow-up Visit 1 to broaden the 
window from 60 days +/- 30 days to 
any time 1-90 days past surgery, 
chemotherapy completion,  or RT 
completion, whichever is later. 
 
To align with clinical practice 
V26 January 2022 
Updated TOC and made formatting 
revisions  
To correct formatting 
Changed the title of the study from “A 
Pilot Study of Neoadjuvant Endocrine 
Therapy 
Tolerance 
to 
Inform 
Treatment Decisions for Adjuvant 
Radiation in Geriatric, Early Stage 
ER+ 
Breast 
Cancer” 
to 
“Pre-
Operative 
Window 
of 
Adjuvant 
Endocrine 
Therapy 
to 
Inform 
Radiation Therapy Decisions in Older 
Women 
with 
Early-Stage 
Breast 
Cancer.” Changed the Study ID from 
“Breast 52” to “POWER” 
To differentiate this study from a 
different study with a similar title, 
and to give the study a more 
recognizable ID.  
Added information to include sites 
external 
to 
UVA. 
This 
includes 
additional 
reporting 
requirements, 
addition of information for VCU, and 
addition of information regarding the 
MCRO 
To expand this study in allowing 
additional sites to participate in 
this clinical trial 

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Replaced “neoadjuvant” with “pre-
operative endocrine therapy (pre-
ET)” in most places when referencing 
this study therapy 
For clarity 
Added 
language 
to 
the 
first 
secondary endpoint 
Clarity 
Added a secondary endpoint to 
include assessment of the effect of 
pre-ET on decisional outcomes for 
adjuvant therapy after BCS 
To 
expand 
the 
study 
endpoints/objectives  
Removed UVA-specific language 
from Section 5.6 regarding process 
for recruitment.  
To allow external site(s) to follow 
their established procedures 
Clarified that radiation oncologists 
should see subjects on or at Day 1 to 
answer the radiation preference 
questions, and that the questions 
should be answered at Day 1 and at 
the pre-operative visit. 
Clarity 
Added the Decisional Conflict Scales 
and Decision Regret Scale to the 
study, including in the calendar and 
appendices 
To assess subjects’ perceptions 
related to their medical decisions 
Added a Treatment Decision Survey 
at Day 1 of adjuvant therapy and 
added this survey to the appendix 
To 
assess 
why 
participants 
made 
decisions 
about 
their 
treatment 
Removed the mild, moderate, and 
sever grading guidelines in section 
9.1.3.1 
AEs should be graded according 
to the CTCAE. Events that do not 
have their own term should be 
graded with the “other” category 
In Section 10.2, clarified that the pre-
op 
and 
on-study 
responses 
measuring change in preference can 
be no to yes or yes to no 
Clarity 
In the study calendar, lengthened the 
window for Visit 1 in the adjuvant 
treatment period and clarified the 
timeframe for this visit relative to 
chemotherapy completion 
For clarity, and to make the 
calendar easier to follow 
In the study calendar, clarified with a 
footnote that after the day 90 visit, 
participants may continue the pre-
operative endocrine therapy until 2-8 
weeks before surgery based on 
clinician 
discretion 
and 
SOC. 
Clarified that the surgery should 
occur 2-8 weeks after Day 90. Fixed 
a footnote at Rad Onc RT preference 
day 1 (changed from “i” to “h). 
Clarified footnote “h” to specify that 
the 
footnote 
applies 
to 
the 
questionnaires. Added footnote “j” to 
Surgery 
visit 
to 
clarify 
that 
participants 
should 
be 
off 
of 
For clarity and correctness.  

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endocrine therapy for at least 2 
weeks and no longer than 8 weeks 
prior to surgery. 
 
In the study calendar, expanded the 
visit timeframe windows to 30 days 
for adjuvant treatment visits 2, 3, and 
4 
To 
reduce 
unnecessary 
restrictions  
V27 January 2021 
Updated TOC 
To reflect shifted page numbers 
Formatting 
revisions 
throughout 
document  
To correct formatting 
Updated the title sheet with the NCT 
number 
To update NCT information 
In Sections 1, 2 and 5, updated the 
Prime II data and changed age 
inclusion criteria from females ≥ 70 to 
females ≥ 65 
To 
reflect 
updated 
data 
presented from the PRIME II trial 
which includes patients ages 65 
and above 
In Sections 6.5, 8.2.2, 10, and 13,  
revised the schedule of the radiation 
preference questions to occur at the 
pre-op visit instead of the post-op 
visit 
To increase compliance with this 
study procedure 
In Section 11.1.2, added that consent 
may occur via Telemedicine 
To 
allow 
for 
the 
use 
of 
telemedicine 
In Appendix 1 Schedule of Events, 
added physical exam/vitals to the 
Pre-Op Visit 
Physical exam/vitals are part of 
the pre-op visit (standard of care) 
In Appendix 1 Schedule of Events 
and schema, removed the Post-Op 
visit  
Visit is not needed, as no study 
procedures are performed at the 
Post-Op visit 
In Section 13 (Appendix 10), updated 
the adherence questions 
To 
update 
the 
adherence 
questions 
V18 March 2020 
Listed additional radiation oncologist 
sub-investigators on the coverpage. 
To address secondary endpoint 
regarding radiation oncologist 
RT therapy preference 
Updated TOC. 
To address use of CESD-R and 
sections shifted with described 
revisions 
CESD-R added in abbreviations, 
section 4.1, 8.2.3 and appendix 8. 
To 
replace 
the 
HADS 
for 
assessment of depression 
Added details regarding radiation 
oncologist RT preference questions 
in synopsis, section 3, 6.5, 8.2.2 and 
appendix 1. 
To address secondary endpoint 
regarding radiation oncologist 
RT therapy preference 
Added 
pre-operative 
visit 
and 
footnotes in appendix 1  
To address AE assessment prior 
to surgery and RT preference 
questions window 
Added “not applicable” response 
option in appendix 10 question 1 
regarding how often subjects take 
ET. 
For day 1 of pre-ET and visit 1 of 
adjuvant ET 
Reformatted surveys in appendix 3, 
4, 5, and 6.  
To improve readability and mimic 
participant surveys. 

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V04 November 2019 
Table 1 (recording guidelines for 
high-risk studies) was revised to 
include 
recording 
guidelines 
for 
medium risk studies. 
Updated page numbers in TOC 
The PRC reviewed this study 
and determined the study meets 
the criteria for a medium risk 
study. 
 
 
Formatting 
revisions 
throughout 
document 
 
Formatting corrections 
Updated page numbers in TOC 
Sections shifted with described 
revisions 
 
 
 
 
 
Appendix 3:  The Brief Illness Perception Questionnaire (BIP-Q) 
Broadbent E, Petrie KJ, Main J, Weinman J. The Brief Illness Perception Questionnaire. J of Psycho Res 
2006;60: 631-637. 
For the following questions, please circle the number that best corresponds to your views: 
How much does your illness affect your life? 
 
No affect at 
all 
 
0 
 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
7 
 
8 
 
9 
 
10 
Severely 
affects my 
life 
How long do you think your illness will continue? 
 
A very 
short time 
 
0 
 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
7 
 
8 
 
9 
 
10 
 
Forever 
How much control do you feel you have over your illness? 
 
Absolutely 
no control 
 
0 
 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
7 
 
8 
 
9 
 
10 
Extreme 
amount of 
control 
How much do you think your treatment can help your illness? 
 
Not at all 
 
0 
 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
7 
 
8 
 
9 
 
10 
 
Extremely 
helpful 
How much do you experience symptoms from your illness? 

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How much does your illness affect you emotionally (e.g. does it make you angry, scared, upset or 
depressed)? 
Not at all 
affected 
emotionally 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Extremely 
affected 
emotionally 
 
Please list in rank-order the three most important factors that you believe caused your illness. The most 
important causes for me: 
 
1.                                                                                                            
 
2.                                                                                                            
 
3.                                                                                                            
 
 
 
 
 
 
 
No  
symptoms 
at all 
 
0 
 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
7 
 
8 
 
9 
 
10 
Many 
severe 
symptoms 
How concerned are you about your illness? 
 
Not at all 
concerned 
 
0 
 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
7 
 
8 
 
9 
 
10 
 
Extremely 
concerned 
How well do you feel you understand your illness? 
Don’t 
understand 
at all 
 
0 
 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
7 
 
8 
 
9 
 
10 
 
Understand 
very clearly 

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Appendix 4: Beliefs about Medicines Questionnaire 
 
General: 
 
Horne R, Weinman J. Patients beliefs about prescribed medicines and their role in adherence to treatment in 
chronic physical illness. J Psycho Res 1999;47(6): 555-567. 
For the following questions, please circle the number that best corresponds to your views: 
 
1. Doctors use too many medicines. 
1 
Strongly 
Disagree 
2 
Disagree 
3 
Uncertain 
4 
Agree 
5 
Strongly Agree 
2. People who take medicines should stop their treatment for a while every now and again. 
1 
Strongly 
Disagree 
2 
Disagree 
3 
Uncertain 
4 
Agree 
5 
Strongly Agree 
3. Most medicines are addictive. 
1 
Strongly 
Disagree 
2 
Disagree 
3 
Uncertain 
4 
Agree 
5 
Strongly Agree 
4. Natural remedies are safer than medicines. 

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Endocrine Therapy: 
Brett J et al. Psychometric properties of the Beliefs about Medicine Questionnaire-adjuvant endocrine therapy 
(BMQ-AET) for women taking AETs following early-stage breast cancer. Health Psychol Open 2017:1-8  
1 
Strongly 
Disagree 
2 
Disagree 
3 
Uncertain 
4 
Agree 
5 
Strongly Agree 
5. Medicines do more harm than good. 
1 
Strongly 
Disagree 
2 
Disagree 
3 
Uncertain 
4 
Agree 
5 
Strongly Agree 
6. All medicines are poisons. 
1 
Strongly 
Disagree 
2 
Disagree 
3 
Uncertain 
4 
Agree 
5 
Strongly Agree 
7. Doctors place too much trust on medicines. 
1 
Strongly 
Disagree 
2 
Disagree 
3 
Uncertain 
4 
Agree 
5 
Strongly Agree 
8. If doctors had more time with patients, they would prescribe fewer medicines. 
1 
Strongly 
Disagree 
2 
Disagree 
3 
Uncertain 
4 
Agree 
5 
Strongly Agree 
9. My health depends on my hormone treatment. 
1 
Strongly 
Disagree 
2 
Disagree 
3 
Uncertain 
4 
Agree 
5 
Strongly Agree 
10. My life will be impossible without my hormone treatment. 
1 
Strongly 
Disagree 
2 
Disagree 
3 
Uncertain 
4 
Agree 
5 
Strongly Agree 
11. Without my hormone treatment I will be very ill. 

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1 
Strongly 
Disagree 
2 
Disagree 
3 
Uncertain 
4 
Agree 
5 
Strongly Agree 
12. My health in the future will depend on my hormone treatment. 
1 
Strongly 
Disagree 
2 
Disagree 
3 
Uncertain 
4 
Agree 
5 
Strongly Agree 
13. Having to use my hormone treatment worries me. 
1 
Strongly 
Disagree 
2 
Disagree 
3 
Uncertain 
4 
Agree 
5 
Strongly Agree 
14. I sometimes worry about the long-term side effects of my hormone treatment. 
1 
Strongly 
Disagree 
2 
Disagree 
3 
Uncertain 
4 
Agree 
5 
Strongly Agree 
15. My hormone treatment is a mystery to me. 
1 
Strongly 
Disagree 
2 
Disagree 
3 
Uncertain 
4 
Agree 
5 
Strongly Agree 
16. My hormone treatment will disrupt my life. 
1 
Strongly 
Disagree 
2 
Disagree 
3 
Uncertain 
4 
Agree 
5 
Strongly Agree 
17. I sometimes worry about becoming too dependent on my hormone treatment. 
1 
Strongly 
Disagree 
2 
Disagree 
3 
Uncertain 
4 
Agree 
5 
Strongly Agree 
18. My hormone treatment protects me from getting worse. 
1 
Strongly 
Disagree 
2 
Disagree 
3 
Uncertain 
4 
Agree 
5 
Strongly Agree 

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Appendix 5:  Perceived Sensitivity to Medicine Scale 
Horne R, Faasse K, et al. The perceived sensitivity to medicines (PSM) scale: an evaluation of validity and 
reliability. Br J Health Psychol 2012;18 (1):18-30. 
 
1. My body is very sensitive to medicines. 
1 
Strongly 
Disagree 
2 
Disagree 
3 
Uncertain 
4 
Agree 
5 
Strongly Agree 
2. My body overreacts to medicines. 
1 
Strongly 
Disagree 
2 
Disagree 
3 
Uncertain 
4 
Agree 
5 
Strongly Agree 
3. I usually have stronger reactions to medicines than most people. 
1 
Strongly 
Disagree 
2 
Disagree 
3 
Uncertain 
4 
Agree 
5 
Strongly Agree 
4. I have had a bad reaction to medicines in the past. 
1 
Strongly 
Disagree 
2 
Disagree 
3 
Uncertain 
4 
Agree 
5 
Strongly Agree 
5. Even very small amounts of medicines can upset my body. 

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For the following questions, please circle the number that best corresponds to your views: 
 
 
 
 
 
 
1 
Strongly 
Disagree 
2 
Disagree 
3 
Uncertain 
4 
Agree 
5 
Strongly Agree 

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Appendix 6:  UVA Breast Cancer Belief Survey 
For the following questions, please circle the number that best corresponds to your views: 
1. I worry a lot about a return of breast cancer at some point in my life. 
1 
Strongly 
Disagree 
2 
Disagree 
3 
Agree 
4 
Strongly 
Agree 
2. Getting breast cancer again would be devastating to me. 
1 
Strongly 
Disagree 
2 
Disagree 
3 
Agree 
4 
Strongly 
Agree 
3. The side effects of a medicine prescribed by my doctor are important when I consider if I will 
continue taking the medicine. 
1 
Strongly 
Disagree 
2 
Disagree 
3 
Agree 
4 
Strongly 
Agree 
4. If I know a medication can help lower my risk of getting breast cancer again, I will continue to 
take it even if I have side effects. 
1 
Strongly 
Disagree 
2 
Disagree 
3 
Agree 
4 
Strongly 
Agree 
Most medicines prescribed by your doctor can have side effects. Sometimes these side effects are very 
minor and sometimes they can be severe. Thinking about the medicine that will be prescribed for your 
cancer please consider how the side effect would impact you taking the medicine. 
 
For each possible side effect please circle whether you would stop for mild, moderate, or severe 
symptoms or whether you would not stop at all. 
Joint pains, 
general aches, 
muscle 
stiffness… 
Mild 
Moderate 
Severe 
I would not stop 
Vaginal dryness, 
pain with 
intercourse, 
difficulty with 
bladder control… 
Mild 
Moderate 
Severe 
I would not stop 

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Weight gain, 
unhappy with 
appearance of my 
body… 
Mild 
Moderate 
Severe 
I would not stop 
Difficulty 
concentrating, 
forgetfulness, 
easily distracted… 
Mild 
Moderate 
Severe 
I would not stop 
Nausea, 
vomiting… 
Mild 
Moderate 
Severe 
I would not stop 

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Appendix 7: EORTC QLQ 
 
 

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Appendix 8:  Center for Epidemiologic Studies Depression Scale Revised 
 
 
 
Below is a list of the ways you might have 
felt or behaved. Please check the boxes to 
tell me how often you have felt this way in 
the past week or so. 
LAST WEEK 
Nearly 
Not at all 
or 
Less than 
1 day 
1-2 
days 
3-4 
days 
5-7 
days 
every 
day for 2 
weeks 
My appetite was poor. 
□ 
□ 
□ 
□ 
□ 
I could not shake off the blues. 
□ 
□ 
□ 
□ 
□ 
I had trouble keeping my mind on what I was doing. 
□ 
□ 
□ 
□ 
□ 
I felt depressed. 
□ 
□ 
□ 
□ 
□ 
My sleep was restless. 
□ 
□ 
□ 
□ 
□ 
I felt sad. 
□ 
□ 
□ 
□ 
□ 
I could not get going. 
□ 
□ 
□ 
□ 
□ 
Nothing made me happy. 
□ 
□ 
□ 
□ 
□ 
I felt like a bad person. 
□ 
□ 
□ 
□ 
□ 
I lost interest in my usual activities. 
□ 
□ 
□ 
□ 
□ 
I slept much more than usual. 
□ 
□ 
□ 
□ 
□ 
I felt like I was moving too slowly. 
□ 
□ 
□ 
□ 
□ 
I felt fidgety. 
□ 
□ 
□ 
□ 
□ 
I wished I were dead. 
□ 
□ 
□ 
□ 
□ 
I wanted to hurt myself. 
□ 
□ 
□ 
□ 
□ 
I was tired all the time. 
□ 
□ 
□ 
□ 
□ 
I did not like myself. 
□ 
□ 
□ 
□ 
□ 
I lost a lot of weight without trying to. 
□ 
□ 
□ 
□ 
□ 
I had a lot of trouble getting to sleep. 
□ 
□ 
□ 
□ 
□ 
I could not focus on the important things. 
□ 
□ 
□ 
□ 
□ 
 
 

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Eaton WW, Muntaner C, Smith C, Tien A, Ybarra M. Center for Epidemiologic Studies Depression Scale: Review 
and revision (CESD and CESD-R). In: Maruish ME, ed. The Use of Psychological Testing for Treatment Planning 
and Outcomes Assessment. 3rd ed. Mahwah, NJ: Lawrence Erlbaum; 2004:363-377. 
 

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Appendix 9: Breast Cancer Prevention Trial Symptom Checklist 
EVERYDAY PROBLEMS DURING THE PAST 4 WEEKS 
 
We are interested in knowing how much you have been bothered by any of the following problems during the 
PAST 4 WEEKS. (Circle one number on each line.  If you do not have the problem, circle “not at all”.) 
 
 
 
 
1.   Hot flashes………………………………………………. 
0 
1 
2 
3 
4 
2.   Nausea…………………………………………………... 
0 
1 
2 
3 
4 
3.   Vomiting………………………………………………... 
0 
1 
2 
3 
4 
4.   Difficulty with bladder control when laughing or crying. 
0 
1 
2 
3 
4 
5.   Difficulty with bladder control at other times…………... 
0 
1 
2 
3 
4 
6.  Vaginal dryness.………………………………………… 
0 
1 
2 
3 
4 
7.  Pain with intercourse..……………...…………………… 
0 
1 
2 
3 
4 
8.  General aches and pains..…………..….………………... 
0 
1 
2 
3 
4 
9.  Joint pains…………………...……………………..…… 
0 
1 
2 
3 
4 
10.  Muscle stiffness……...………………………………… 
0 
1 
2 
3 
4 
11.  Weight gain……………………………………………. 
0 
1 
2 
3 
4 
12.  Unhappy with the appearance of my body...…………... 
0 
1 
2 
3 
4 
13.  Forgetfulness...………………………………………… 
0 
1 
2 
3 
4 
14.  Night sweats...…………………………………………. 
0 
1 
2 
3 
4 
15.  Difficulty concentrating...……………………………... 
0 
1 
2 
3 
4 
16.  Easily distracted...……………………………………... 
0 
1 
2 
3 
4 
17.  Arm swelling (lymphedema)...…….………………….. 
0 
1 
2 
3 
4 
18.  Decreased range of motion in arm on surgery side...….. 
0 
1 
2 
3 
4 
Slightly 
Moder-
ately 
Quite a 
bit 
Extremely 
Not at 
all 
During the past 4 weeks, how much were you bothered by: 

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Stanton, A. L., Bernaards, C. A., & Ganz, P. A.  (2005). The BCPT Symptom Scales:  A measure of physical 
symptoms for women diagnosed with or at risk for breast cancer.  Journal of the National Cancer Institute, 97, 
448-456. 
 
 
 

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Appendix 10: Adherence Questions 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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UVA IRB-HSR 22040: POWER Trial 
Health-Related Quality of Life Questionnaires 
 
Adherence Questions 
In an average week, how often do you take your hormone treatment for breast cancer? Choose the best answer 
from the options below? Note: On Day 1, please mark N/A 
 
Every Day 
(7 out of 7 days) 
Most Days 
(5 out of 7 Days) 
Some Days 
(3-4 out of 7 Days) 
Rarely 
(1-2 out of 7 Days) 
I stopped taking it.
 
        N/A 
 
At this time, how likely is it that you will complete the entire recommended duration (i.e. 7-10 years) of your 
hormone treatment for breast cancer? 
 
1 
=Extremely Unlikely 
2 
=Unlikely 
3 
=Likely 
4 
=Extremely Like

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Appendix 11: Treatment Decision Survey 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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UVA IRB-HSR 22040: POWER Trial 
Treatment Decision Questionnaire 
 
1. Why did you decide to have or not to have radiation therapy? 
 
 
 
 
 
 
 
2. Why are you deciding to restart or not to restart the endocrine therapy pill? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix 12: Decisional Conflict Scale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Decisional Conflict Scale (DCS) 
 
My difficulty in making this choice 
A. Which treatment option do you prefer? Please check one.  
            ☐    Surgery only (no radiation and no endocrine therapy after surgery) 
             ☐      Surgery plus radiation therapy alone (no radiation after surgery) 
             ☐    Surgery plus endocrine therapy alone (no radiation after surgery) 
             ☐    Surgery plus radiation therapy AND endocrine therapy 
             ☐    Unsure 
B. Considering the option you prefer, please answer the following questions: 
 
 
AM O’Connor, Decisional Conflict Scale. @ 1993 [Updated 2005]. Available from www.ohri.ca/decisionaid. 
 
 
 
 
 
 
 
 
 
 
 

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Appendix 13: Decision Regret Scale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Decision Regret Scale 
Please think about the decision you made about the treatment of your breast cancer (radiation 
and endocrine therapy) after talking to your doctors. Please show how you feel about these 
statements by circling a number from 1 (strongly agree) to 5 (strongly disagree).