PORTAL: Patient-reported Outcomes After Routine Treatment of Atypical Lesions
Phase: NA
Conditions: Breast Cancer
Sponsor: Dana-Farber Cancer Institute

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PORTAL:  Patient-reported Outcomes after Routine Treatm ent of Atypical Lesions 
Protocol version:   May 16, 2019 
 
PORTAL:  Patie nt-re porte d Outcomes afte r Routine Treatme nt of Atypical Lesions 
NCT03070236 
Docum ent Approved Date: May 20, 2019 
 
TABLE OF CONTENTS 
 
1.0  
INTRODUCTION 
1.1 OVERVIEW 
1.2 BACKGROUND AND SIGNIFICANCE 
2.0  
OBJECTIVES 
 
 
2.1 RELATIONSHIPS OF AIMS TO SIGNIFICANCE OF PROPOSED STUDY 
 
 
2.2 HYPOTHESIS AND SPECIFIC AIMS 
3.0  
RESEARCH SUBJECT SELECTION 
4.0  
RESEARCH SUBJECT ENTRY 
5.0  
STUDY DESIGN AND METHODS 
5.1  
DESIGN/STUDY TYPE 
5.2  
SELECTION OF INSTRUM ENTS 
5.3  
DESCRIPTION OF SURVEY METHODS 
5.4  
DATA COLLECTION 
5.5  
DESCRIPTION OF STUDY PROCESS 
 
5.5.1 SURVEY ADMINISTRATION 
 
5.5.2 SPECIAL CONCERNS 
 
5.5.3 COMPENSATION 
5.6  
ADVERSE REACTIONS AND THEIR MANAGEMENT 
 
 
 
5.61 REPORTING ADVERSE OR UNANTICIPATED EVENTS 
 
 
 
5.6.2 ANTICIPATED REACTIONS 
 
 
 
5.6.3 REACTION MANAGEMENT 
6.0  
STATISTICAL ANALYSIS 
 
 
6.1 
PRIMARY AND SECONDARY ENDPOINTS 
 
 
6.2 
SAMPLE SIZE AND STATISTICAL POWER 

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PORTAL:  Patient-reported Outcomes after Routine Treatm ent of Atypical Lesions 
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6.3 
ANALYSIS PLAN:  GENERAL APPROACH 
 
 
6.4 
MANAGEMENT OF MISSING DATA  
7.0  
REFERENCES 
8.0  
APPENDICES 
8.1  
APPENDIX A. INVITATION LETTER & RESPONSE FORM 
8.2  
APPENDIX B.1 PATIENT SURVEY  
• APPENDIX B.2 (1)-BREAST-Q-BREAST CONSERVING SURGERY (BCS)-
LUMPECTOMY 
• APPENDIX B.2 (2)-BREAST-Q-MASTECTOMY WITH RECONSTRUCTION 
• APPENDIX B.2 (3)-BREAST-Q-MASTECTOMY WITHOUT 
RECONSTRUCTION 
• APPENDIX B.2 (4)-BREAST-Q-MASTECTOMY PRE-OP-BIOPSY 
• APPENDIX B.3 TTO (TREATMENT TRADE OFF) 
8.4  
APPENDIX C. ELEM ENTS OF CONSENT (FOR ONLINE SURVEY) 
8.5  
APPENDIX D. VERBAL CONSENT (TELEPHONE SURVEY) 
8.6     APPENDIX E. SCREENING QUESTIONS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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PORTAL:  Patient-reported Outcomes after Routine Treatm ent of Atypical Lesions 
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PROTOCOL TITLE 
 
PORTAL:  Patient-reported Outcomes after Routine Treatment of Atypical Lesions 
 
1.0 INTRODUCTION 
 
1.1 Overview 
 
Ductal Carcinoma in Situ (DCIS): A disease of screening with potential risks and burdens 
 
DCIS was rarely diagnosed prior to widespread use of mammography.  Although mammography has 
been shown to reduce overall breast cancer mortality by over 20%,1 there is growing concern that for 
some patients, particularly those with DCIS, breast cancer screening may unintentionally cause harm by 
introducing additional procedures, promoting anxiety, and detecting cancers that may never cause 
illness. Advances in epidemiology and cancer biology have shown that the group of diseases currently 
deemed “cancers” are actually many conditions with enormous variation in biologic behavior, and that 
screening uncovers some conditions that may never impact a person’s overall health if left undetected.2-6 
The term “overdiagnosis” has been used to define these conditions including DCIS, that look like early 
cancer, but are not destined to cause symptoms or death during a patient’s lifetime.7 Attempts to resolve 
the controversy that has grown around the best management of these overdiagnosed conditions, 
including calls to remove the word “cancer” from their description,8,9 have garnered intense interest, 
anxiety, and scrutiny from patients, their families, and other healthcare stakeholders. 
There is a general consensus that much of this burden derives from the treatment of DCIS. Currently, 
almost all DCIS is treated aggressively according to guideline-concordant care (GCC); of those treated, 
the majority may not benefit if they would not have developed cancer. An alternative to GCC is active 
surveillance (AS). Currently, only 3% of women in the United States with DCIS opt for AS (if given the 
choice). However, in order to consider AS as a future treatment option for DCIS, it is imperative that 
long-term health and quality of life (QOL) outcomes resulting from AS are critically evaluated. 
 
The overarching goal for this study is to evaluate the benefits and harms of currently accepted GCC for 
DCIS compared to an AS strategy using cross-sectional patient survey data.  The primary outcomes will 
be diagnosis of cancer and severity of chronic pain. The study will also provide rigorous comparative 
evidence regarding other outcomes of importance to patients including treatment-free survival, quality 
of life, anxiety, fear of another breast event such as DCIS or invasive breast cancer (IBC) in the affected 
breast/chest wall, or more rarely, elsewhere in the body (a.k.a recurrence), or a new primary breast 
cancer in the other breast. Additionally, body image associated with AS will be compared to that of 
GCC to further evaluate the benefits and harms of treatment versus AS for DCIS. 
 
It is anticipated that the study will significantly facilitate the understanding of DCIS, its treatments, and 
outcomes of those treatments, which will benefit future patients. Therefore, the societal benefit could be 
substantial. 
 
1.2 Background and rationale 

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Annually, approximately 65 million women undergo mammographic screening in the United States at a 
cost of over 13 billion dollars. Almost one in 1300 mammograms (.08%) will detect ductal carcinoma in 
situ, or DCIS,10 traditionally considered the earliest detectable form of breast cancer. Over 62,000 
women in the United States will be diagnosed with noninvasive breast cancer this year alone (87% of 
which is DCIS, totaling over 53,000 cases per year).   Almost all of these diagnoses are made in 
completely asymptomatic individuals.5 DCIS is characterized by a proliferation of malignant cells 
confined to the milk ducts of the breast.11 Unlike invasive cancer, DCIS cells remain trapped within the 
breast duct and therefore have little potential to spread to distant organ sites and cause symptoms or 
death. Without treatment, it is estimated that only 20-30% of DCIS will progress to invasive cancer.12,13 
However, once diagnosed, over 97% of women are treated according to current guidelines with a 
combination of surgery, radiation and hormonal therapy treatments similar to those recommended to 
patients with invasive breast cancer. This is different than treatments for other breast conditions, such as 
atypical ductal hyperplasia (ADH) or lobular carcinoma in situ (LCIS), which are also known to confer 
an increased risk of breast cancer. 
Impact of DCIS on the health of individuals and populations.  
Overdiagnosis and overtreatment resulting from mammographic screening have been reported to be as 
high as 1 in 4 patients (25%) diagnosed with breast cancer,14-17 although the absence of standard 
definitions for measuring overdiagnosis has led to much uncertainty around this estimate.18 The national 
health care expenditure resulting from false positive mammograms and breast cancer overdiagnosis has 
been estimated to approach $4 billion annually.19 There is general consensus that much of this burden 
derives from the treatment of DCIS; for those estimated 40,000 women per year whose DCIS may never 
have progressed even without treatment, medical intervention can only harm. In those women who 
undergo surgical management of DCIS, there is risk of developing a number of short and long-term 
adverse events and side effects ranging from complications of anesthesia and loss of work due to 
treatment, to cosmetic changes and persistent pain at the surgical site. Importantly, pain after 
lumpectomy may be as prevalent as that after total mastectomy with estimates ranging from 25-60%.20-22 
Persistent postsurgical pain is rated by patients as the most troubling symptom,23 leading to disability 
and psychological distress, and is often resistant to management;24 notably, much of these data have 
been collected in women with cancer, not DCIS.25 
 
Atypical ductal hyperplasia (ADH) is a model of active surveillance for breast conditions. 
Since over 97% of women receive treatment for their disease immediately upon diagnosis, it has been 
difficult to evaluate the outcomes of an AS strategy for DCIS.26 However, there are other analogous 
clinical scenarios in which women are identified to be at increased risk for breast cancer, and are 
routinely offered close surveillance.  One such example is atypical ductal hyperplasia (ADH) which, 
much like DCIS, is often diagnosed on a biopsy performed for a mammographic abnormality. ADH is 
found in approximately 10% of all benign breast biopsies, and is associated with the highest future risk 
of breast cancer among all benign diagnoses.27 It shares many histologic features with low grade DCIS 
for which it is often mistaken, even by specialized breast pathologists.28 The lifetime cumulative risk of 
invasive cancer among women with ADH has been reported to approach 15% at 25 years (Figure 1a), 
equivalent to approximately half the risk for invasive cancer in women not recognized to have DCIS and 
who were thus managed with biopsy alone (Figure 1b). 29-32  The treatment recommendation for women 
with ADH is not surgery or radiation but rather close or active surveillance, usually with the option of 
endocrine therapy such as tamoxifen to reduce risk of subsequent invasive cancer.29 

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Lobular neoplasia (LN) is another example of a risk marker for invasive breast cancer.  
Lobular neoplasia is characterized by the proliferation of uniform rounded cells which arise from the 
terminal ductal lobular units. These cells have relatively little cytoplasm, are dis-cohesive, and may 
spread along the ducts in a Pagetoid fashion. If the cells occupy and distend more than 50% of the acini, 
the condition is termed lobular carcinoma in situ (LCIS), otherwise it is termed atypical lobular 
hyperplasia (ALH).33  Although the distinction between the two conditions is one of degree, the more 
extensive changes seen in LCIS are associated with a higher risk of subsequent malignancy than occurs 
in ALH.  Previous studies have suggested that LN is predominantly a condition found in pre-menopausal 
women. A study of women registered on the Surveillance, Epidemiology and End Results (SEER) 
database in the US shows a 38% increase in the incidence of what in the SEER database is termed LCIS 
between 2000 and 2009, from 2.0/100,000 to 2.75/100,000 in females aged 18-80.34 Two previous 
studies of the SEER database35,36 suggest that there has been a three to four-fold increase in LCIS 
diagnoses since 1978 (women with ALH were not included in these studies), predominantly among 
post-menopausal women. This increase is explained, at least in part, by the increasing use of screening 
mammography and the increasing proportion of women who undergo percutaneous needle biopsy in the 
investigation of screen-detected abnormalities, particularly microcalcifications. 
 
A recent study of 1060 women with LCIS reported bilateral synchronous LCIS in only 2% of cases,37 
and in the same series none of the 56 women who underwent bilateral prophylactic mastectomy were 
reported as having bilateral LN, although six had contralateral occult cancers (three invasive carcinomas 
and three DCIS). Lobular neoplasia has long been regarded as a marker for an increased risk of 
subsequent malignancy rather than as a precursor. The known increase in breast cancer risk in both 
breasts has been cited as a justification for this view. However, more recently, the hypothesis has 
emerged that, at least in some women, LN may be a non-obligate precursor of invasive malignancy.38 
The risk of malignancy appears to be higher in LCIS than ALH, estimated to be 8-10 times and 4-5 
times background incidence respectively.39 
There is evidence for tamoxifen to reduce the risk of invasive cancer in women with LCIS by 56% in the 
NSABP P-1 study published in 199840 and raloxifene to have a similar protective effect. 41 
Chemoprevention has also been shown to reduce the risk of invasive cancer in a recently published 
longitudinal study.37 
Thus, we propose that the recommended management of women with ADH and LCIS or ALH is a 
model for what an active surveillance (AS) approach would be for DCIS including close follow-up and 
the option of chemoprevention.  
 
Current gaps in evidence.  
In 2009, the National Cancer Institute (NCI) convened a State-of-the-Science conference that identified 
the most critical research questions around DCIS, including investigations on the impact of DCIS on 
QOL and trials evaluating the comparative effectiveness of DCIS treatment strategies.42  Further, the 
American Cancer Society and National Institutes of Health (NIH) published the summary of an NCI 
DCIS Workshop in 2010 that reviewed current issues in DCIS and identified risk communication as a 
priority area for future study.43 However to date, data remain lacking in all of these areas.  
 
Current treatment options routinely offered for DCIS include surgery (lumpectomy or mastectomy), 

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radiation (radiation or none) and hormonal therapy (Table 1).  Increasingly, some women choose to 
undergo bilateral mastectomy.44  These options constitute GCC according to National Comprehensive 
Cancer Network (NCCN) treatment recommendations.45 Between 1991 and 2010, 23.8% of women 
diagnosed with DCIS in the United States underwent mastectomy, 43% lumpectomy with radiation, and 
26.5% lumpectomy without radiation, based on data from the Surveillance, Epidemiology, and End 
Points Registry.26  Among the 97% of women with DCIS treated with GCC, neither randomized trials or 
retrospective studies to date have shown a survival advantage of any treatment option over another.26 To 
date, none of the treatment options has ever been compared to AS. 
 
Moreover, the impact of GCC and AS for DCIS on quality of life have not been carefully evaluated. 
Although research suggests that over 40% of women who are provided risk/benefit information 
regarding DCIS treatment would consider non-surgical management,46 the clinical outcomes and patient 
reported outcomes (PRO) of active surveillance have never been studied. Thus women (and their 
doctors) face a tremendous burden of uncertainty when considering the tradeoffs of GCC or AS for 
DCIS.47,48   This is likely compounded by the relative lack of information and heterogeneity in opinions 
regarding the optimal treatment of DCIS.43,49 
 
Potential for study to improve health care and outcomes.  
This year in the United States alone, approximately 50,000 women will undergo treatment for DCIS, of 
whom only 20-30% may benefit. Evidence to compare clinical outcomes and patient reported outcomes 
between GCC and AS is critically needed to reduce the harms and understand the trade-offs of GCC 
versus AS for DCIS. This project will provide clear, objective, evidence-based information for patients, 
health care providers and other stakeholders regarding the benefits and harms of DCIS treatment.  
Moreover, this project will create a path forward for mitigating the potential for overtreatment of other 
screen-detected conditions.  
 
2.0 OBJECTIVES 
2.1 Relationship of aims to significance of the proposed study.  
The overarching goal for this study is to evaluate the benefits and harms of currently accepted GCC for 
DCIS compared to an active surveillance (AS) strategy using cross-sectional patient survey data.  The 
broad, long-term objective of this project is to enable patients with DCIS, with their doctors, to make 
Table 1. Guide line concor da nt care (GCC) and Active surveillance (AS) options for DCIS. A ll 
treatm ents offered as part of publishe d guide lines mand ate surgical excision to negative marg ins and 
considera tion for adjuva nt radiatio n or endocrin e therapy.  

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informed decisions about their care based on the highest possible quality evidence about DCIS 
treatment, including those treatment options that fall outside of current GCC.  
 
 
2.2 Hypothesis and Specific Aims: 
  
We hypothesize that there are differences in patient-centered clinical outcomes and Patient Reported 
Outcomes (PROs) between women who choose GCC versus AS, and that these differences can be 
compared using advanced analytic methods to allow for the expected treatment selection biases between 
groups.  
 
The specific aims of this study are the following: 
 
Aim 1.  Compare patient-reported outcomes (PROs) between patients diagnosed with ductal 
carcinoma in situ (DCIS) who received GCC to patients diagnosed with DCIS who underwent AS 
as well as those diagnosed with atypical ductal hyperplasia (ADH), and lobular carcinoma in situ 
LCIS/atypical lobular hyperplasia (ALH) (as proxies for DCIS active surveillance (AS) group) in a 
cross-sectional patient cohort at 6 selected study sites.  
 
PROs will be collected from surveys administered to patients diagnosed for either DCIS, ADH, LCIS, or 
ALH between January 1, 2012 and June 30, 2017 at each of six study sites:  Duke University Medical 
Center (DUMC), Dana-Farber Cancer Institute (DFCI), MD Anderson Cancer Center (MDACC), 
Massachusetts General Hospital (MGH), Newton Wellesley Hospital (NWH), and Dana-Farber/Brigham 
and Women’s Cancer Center (DF/BWCC) in clinical affiliation with South Shore Hospital (DFCI @ 
SSH). We are planning for survey data collection to begin in September 2017, but will officially 
commence upon IRB approval at each recruiting site. MDACC received their site’s IRB approval on 
December 6, 2017 and has now been added to the DFCI IRB as a site. MDACC will now complete 
applicable study procedures as outlined in this protocol.  DUMC received their site’s IRB approval on 
February 27, 2018 and has now been added to the DFCI IRB as a site.  Duke will now complete study 
procedures as outlined in this protocol.  MGH has been added to the DFCI IRB as a site.  MGH will now 
complete study procedures as outlined in this protocol.  DFCI @ SSH has been added to the DFCI IRB 
as a site.  DFCI @ SSH will now complete study procedures as outlined in this protocol.  The DFCI 
study team will complete all patient recruitment steps for DFCI @ SSH.  NWH has been added to the 
DFCI IRB as a site.  NWH will now complete study procedures as outlined in this protocol. 
 
Once enrollment begins at a site, the recruitment and survey phases will take place over an 18-month 
period, or until we reach our enrollment goal. Medical records will be accessed through the duration of 
the recruitment phase, which we anticipate will be completed in 2019, to look for potentially eligible 
patients for this study. The primary study outcome will be postoperative pain, assessed on a 10-point 
Likert Scale as well as on the pain burden index.  In addition, other PRO instruments will be 
administered to evaluate QOL measures including symptom assessment, decision quality, body image, 
and anxiety to better understand the overall benefits and harms of a GCC approach versus an AS 
approach. 
 
Aim 2.  Measure the incremental utility of GCC compared to AS according to a preference-based 
quality-adjusted life year metric (QALY).   

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We have developed an 8-item questionnaire based on a time trade off model to collect a preference-
based measure of health on the cohort in Aim 1.  This tool will be included in the patient survey and data 
collected from this tool will be used to compare a standardized health utility measure of GCC versus AS.  
This deliverable will allow patients and stakeholders to better weigh the benefits and tradeoffs of each 
approach. 
 
3.0 RESEARCH SUBJECT SELECTION:  
This study will be conducted at 6 NCI Comprehensive Cancer Center sites (DUMC, DFCI, MDACC, 
MGH, NWH, and DFCI @ SSH).  Additional study sites may be considered to enhance accrual.  
The GCC group will be those patients diagnosed with DCIS and treated according to one of the standard 
treatment options for DCIS (Table 1).  Importantly, since only 2-3% of all women diagnosed with DCIS 
are offered and/or undergo active surveillance, there are insufficient numbers of women with DCIS 
solely electing AS to compare with women treated according to GCC, even across 3 large volume 
cancer centers. Therefore, we decided to add to our DCIS AS group, those patients who have a similarly 
high breast cancer risk based on a diagnosis of ADH, ALH, or LCIS for whom the routine 
recommendation is active surveillance. The ADH/ALH/LCIS group will thus serve as an additional 
proxy for the DCIS active surveillance group, since these risk lesions are managed with a follow up and 
surveillance approach as could be applied if AS were to be used for low risk DCIS. This design will 
allow the most relevant comparison of PROs between GCC and AS strategies for conditions associated 
with increased breast cancer risk.  
English and Spanish speaking patients diagnosed for either: DCIS, ADH, ALH and/or LCIS between 
2012 and 2016 will be included. Each site has a large patient volume of DCIS cases treated and specific 
expertise in studying a DCIS patient population.  Moreover, the sites have unique and complementary 
patient populations, with a large African American population treated at DUMC (26.7% of all patients 
with DCIS treated 2011-2013) and a sizable Hispanic population treated at MDACC (12.8% of all 
patients with DCIS treated 2011-2013). 
 
Eligibility Criteria.  Patients treated at DUMC, DFCI, MDACC, MGH, NWH, or DFCI @ SSH with a 
diagnosis of DCIS, LCIS, ADH, or ALH who are also: 
• Age 18 or more at index diagnosis 
• Diagnosed with DCIS, LCIS, ADH, or ALH (the most recent, highest risk lesion is the “index 
lesion”) between January 1, 2012 and June 30, 2017 
• Able to read either English or Spanish and able to provide written (via paper), verbal consent or 
on-line informed consent 
• Treated and followed at one of the study sites (including affiliated network sites) and for whom 
treatment and surveillance data are available, for at least 1 year of follow up after date of 
diagnosis 
• Participants with bilateral synchronous or metachronous disease (DCIS, LCIS, ADH, ALH) are 
eligible 
 
Exclusion criteria  
• Ever had a diagnosis of invasive or microinvasive breast cancer 
• DCIS prior to index lesion or history of progressive/recurrent DCIS after treatment 
• Other cancers (excluding non-melanoma skin cancer) diagnosed within 5 years prior to index 

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lesion, including concurrent invasive cancer diagnosis and up to the present time of participant’s 
approach to invitation into the study 
• Patients identified by treating physician as being unsuitable for contact 
 
4.0 RESEARCH SUBJECT ENTRY 
 
All activities will be conducted through the 6 study recruitment sites, who will handle all eligibility for 
their own site’s patients. The DFCI main study site will screen and recruit for its own patients as well as 
for DFCI @ SSH patients.  Patients will be recruited individually to the trial. All women with DCIS, 
LCIS, ADH or ALH newly diagnosed between January 1, 2012 and June 30, 2017 and treated at one of 
the 6 designated study sites will be identified systematically at each study site using cancer registry and 
clinic, radiology, and pathology record review.  We will collect consecutive cases in a retrograde fashion 
starting from June 30, 2017 to January 1, 2012 until we have collected 900 DCIS cases and 300 LCIS, 
ADH, or ALH cases.   
In order to assess eligibility and initiate entry into the study chart review necessary for Aim 1 of the 
study, we will request approval of a waiver of informed consent and a waiver of HIPPA. Once approved, 
a research coordinator at each site will review clinic, radiology, pathology, and tumor registry lists to 
screen for potential candidates, and identify potentially eligible patients. We will extract the following 
from the medical record for potential participants: 
• Name 
• Contact information (i.e. mail address, phone number and/or email address)  
• Age 
• Race/Ethnicity 
• Date and type of last biopsy  
• Date and type of last surgery   
• How lesion identified and relevant mammography 
• Pathologic features of the disease on core biopsy (if DCIS: grade, necrosis, ER, PR/HER2 if 
done, size, microinvasion) 
• Type of subsequent evaluation of lesion (excision, surgery etc.) and any subsequent breast 
pathology or procedure 
• Any adjuvant treatment 
• Date and vital status at last follow-up; we will plan to complement this with a National Death 
Index (NDI)/Institutional database look to make sure potential participants are available before 
contacting them. 
 
Sites responsible for screening patients and their affiliates will use the eligibility information above for 
their patients to determine eligibility. We will also use these data to describe the patient population and 
the disease characteristics of these non-invasive breast lesions at diagnosis.   
 
For each eligible case determined through this rigorous review, the institutional attending physician will 
be notified by email about the study and the plans to invite the patient to participate in the survey 
study. Staff at each study site or the lead site for affiliates will contact the treating physician to ask them 
to indicate if they have any concerns about contacting this patient for the study. If the local treating 
physician does not indicate any potential problems with the selected patient’s participation within 2 
weeks, then the study coordinator at each site will verify the mailing address for each eligible patient. 

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Each site will send their own potential patients the study invitation letter (Appendix A) which will 
include information about the study, provide study contact information, and ask patients to respond, and 
if interested in participating in the study, write their email address, or alternative form of contact. 
Because people are busy and may respond to different forms of communication (i.e. calls, notes, letters, 
etc.), the local study team will follow up with 3 additional contacts over an 8-week time period (2 weeks 
(recontact), 4 weeks (call/resend) and 8 weeks (call/resend) to allow for sufficient time to respond.  The 
DFIC study team will pilot two patient outreach materials from Patient Advocates—two brief notes— 
added to the invitation letter and survey to one hundred patients to test improved response and 
participation outcome.  One or both of these outreach material, if proven effective, may be continued 
past the pilot one hundred patients.  At the end of the recruitment period when no further new surveys 
are to be initiated, the DFCI study team will inform by mail, email, or phone any new patient who 
indicates interest to complete a survey that the study is closed and no new surveys will be initiated. 
 
The DFCI study team has found this to be acceptable and desired in past survey research they have 
conducted. As noted above, initial contact will be made by each recruiting site for their own patients 
(e.g. MDA study team will contact MDA patients, Duke study team will contact Duke patients and 
DFCI study team will contact DFCI patients). Collaborating institutions may use waivers of consent and 
authorization to access patient study records to determine eligibility, collect data from the medical charts 
and to initiate patient contact for the prospective survey. The names and contact information of all 
women who agree to participate for the prospective component of this study (the survey) will be sent 
from the local team (MDACC, Duke, MGH, NWH, or DFCI @ SSH) to the DFCI study team. The 
DFCI study team will conduct all consenting and survey initiation/follow up, as described in section 
5.5.1.  
 
The DFCI study coordinator then will initiate the survey (Appendix B) online, paper or over the phone 
as requested by the participant. The majority of the surveys will be conducted in English, although a 
Spanish language paper version of Survey B.1 and B.2 will be available. There will be 3 potential 
recontact timepoints by the DFCI study staff to participants who do not complete the survey:  2 weeks 
(recontact), 4 weeks (call/resend) and 6 weeks (call/resend) from the initial mailing.   
 
There are 3 modes in which an English-speaking patient can elect to complete the prospective survey: 
online, paper or phone. A Spanish speaking patient will have the paper survey available to select.  
Depending on the way the survey is completed, consent will be obtained accordingly. Please see section 
5.5.1 for additional details.  
 
Each site or the lead for an affiliate will track their own patients for eligibility and desire to participate 
(Appendix A). Sites will then pass contact information and approved CRF information for respondents 
who affirm interest on Appendix A to DFCI study staff. DFCI study staff then will follow up with 
patients for consenting and survey participation. See 5.5 Description of the study process for additional 
survey completion detail.  
 
DFCI study staff will register all consenting participants (DF/HCC and non-DF/HCC) in the Clinical 
Trials Management System (CTMS) OnCore as required by DF/HCC SOP REGIST-101, but 
registration will occur once a consent has been obtained (paper consent, online elements of consent, 
verbal consent depending on modality of participant completion) and once the survey has been 
completed.  

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DFCI study staff will complete an eligibility checklist according to DF/HCC SOP REGIST-104, for all 
women who initiate a survey (any modality). If a participant completes a survey via RedCap, study staff 
will print out the page showing she checked the box saying she agrees to the elements of consent as the 
documentation of her consent. For participants who complete by paper, DFCI study staff will have 
participants sign an informed consent document. DFCI study staff will keep documentation of verbal 
consent for those giving consent over the telephone. DFCI study staff will collect and store participant 
consent forms and eligibility checklists.  The Coordinating Center will provide a study number for all 
enrolled participants.   
 
5.0 STUDY DESIGN AND METHODS 
 
5.1 Design /study type 
 
This is a one-time, cross-sectional, patient survey study where the overarching goal is to evaluate the 
benefits and harms of currently accepted GCC vs. AS (including patients with DCIS undergoing AS, as 
well as patients with ADH or LCIS/ALH as a proxy) for DCIS.  
 
5.2 Selection of Instruments 
 
Rationale for participant selection and survey methodology. Although we recognize that issues of 
decision-making and treatment selection are more salient closer to the date of diagnosis when these 
decisions take place, the short timeframe of the project period limits the number of cases that could be 
identified and surveyed within the timeframe of the study.  Therefore, we are reviewing contemporary 
cases diagnosed from 2012 to 2016 for eligibility.  The advantage of this design is that it allows us to 
assess QOL after diagnosis and treatment in a large group of patients, and provides a more cost-effective 
approach compared to rapid case ascertainment.  Moreover, this design will allow collection of our 
primary endpoint of persistent, rather than postoperative, pain among the participants, as well as several 
secondary endpoints, including health-related and psychosocial QOL, anxiety, depression, and 
intolerance of uncertainty among patients at a range of time in follow-up. 
 
Survey instrument/predictors:  
 
Screening questions: We will ask participants for their first date of DCIS/ADH/LCIS/ALH diagnosis; 
if they have had additional breast lesions since that initial breast lesion diagnosis; and if she has had any 
malignancy, other than non-melanoma skin cancer. Please see Appendix E (Screening questions) for 
reference.  
 
Socio-demographics: Women will be asked about their race, education, employment and financial 
status using items selected from the Alliance Patient Questionnaire that is currently being piloted 
(Alliance A191401), adapted to include an item on employment status that has been tested previously in 
a breast cancer population and is going to be added to the next version of the Alliance Patient 
Questionnaire. 
 
Financial burden: We will adapt items from the National Health Interview Survey50 and the Cancer 
Care Outcomes Research and Surveillance (CanCORS) Study51 to assess financial burden and impact on 

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employment-related metrics (e.g., sick leave, unpaid time off work).   
 
Medical, treatment, and family history: We will survey women regarding their treatment history, 
including surgery type, radiation, and hormonal therapy use and adherence52,53, as well as family history 
of breast/ovarian history. Specifically, we will adapt Part 1 of the Voils two-part measure of medication 
adherence, which includes 3 items that evaluates the extent of non-adherence over the past week. 52,53  
 
We will assess co-morbidities using the Self-Administered Co-morbidity Questionnaire (based on 
Charlson Co-morbidity Index and other comorbidity indices).54  
 
Pain:  the presence, severity, and functional impact of pain will be recorded as the primary QOL 
endpoint. The primary endpoint will be highest pain severity measured on a 10-point Likert scale and 
Pain Burden Index as measured by the Breast Cancer Pain Questionnaire (BCPQ). The BCPQ includes 
assessment of pain severity, pain frequency (how many days/week), and pain location (breast, arm, side, 
axilla), from which a Pain Burden Index (PBI) can be calculated.22,55,56 The BCPQ also includes 
questions about other body pain, seeking medical help for pain, and painkiller use. We will also use the 
Brief Pain Inventory, a well-validated general measure of pain and disability, worst pain, least pain, and 
interference with activities. 
 
Knowledge: Among patients with DCIS only, DCIS and breast cancer knowledge will be measured with 
items adapted from the Breast Cancer Surgery Decision Quality Instrument (BCS-DQI), an instrument 
designed to evaluate the quality of breast cancer treatment decisions.57 A series of true/false questions 
used in a prior survey of women with DCIS58 will also be used to assess knowledge of facts specific to a 
DCIS diagnosis and treatment; items will be adapted for patients with an ADH/LCIS/ALH diagnosis. 
 
Decision-making: Treatment goals and preferences will be assessed with the BCS-DQI which includes 
items designed to measure individual patient goals and concerns. 57 Four items (The SURE scale) 
adapted from the Decisional Conflict Scale will be used to measure patients’ uncertainty about which 
treatment and factors contributing to uncertainty.59,60 The 5 item Decision Regret Scale will be used to 
measure decisional regret.61 Patient perception of the decision process will be assessed using an adapted 
version of the Control Preferences Scale.62,63 Communication with physicians and sources of 
information about DCIS/ADH/LCIS/ALH management options will be assessed using items from a 
prior study of surgical decision-making.64  
 
Risk perceptions: We will assess risk perceptions in women with DCIS, LCIS/ALH or ADH using 
questions developed by Lerman and Croyle65 that have previously been used to measure risk perceptions 
in women with DCIS.47 This will ultimately be compared to actual risk of their condition based on 
published data. 
 
Quality of Life (QOL): We will use the SF-12 to measure health-related QOL.66 A modified 19-item 
version of the Breast Cancer Prevention Trial (BCPT) Symptom Checklist will be used to evaluate 
commonly reported menopausal symptoms.67 The Breast-Q, a validated instrument to evaluate outcomes 
following surgery, will be used to evaluate satisfaction with appearance, self-image, and sexuality.68 
Four items from the Quality of Life in Adult Cancer Survivors (QLACS) will be adapted to evaluate 
frequency (1=never; 7=always) of worries about DCIS, including concerns about future breast events 
and death from DCIS.69 

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Emotional/Psychological: To assess generalized anxiety, we will use the short-form version of the State 
Trait Anxiety Inventory (STAI) scale.70 We will use the Center for Epidemiologic Studies Depression 
(CES-D) Scale to evaluate depressive symptoms.71 Additionally, we will assess feelings of uncertainty 
using the Intolerance of Uncertainty Scale (Short-form), which has been used in studies of active 
surveillance in the prostate cancer setting.72-74 
Time-trade-off (TTO):72-74 We will use the QALY metric to compare tradeoffs of GCC versus AS for 
DCIS as determined by preference-based, as opposed to cost-based, utilities in this patient population. 
QALYs are derived by multiplying the length of time in a given health state with the health utility 
(utility weighting) of the given disease/health state.  Thus, there are two primary inputs to a QALY 
calculation: the years of extended life with a given treatment and the health-related quality of life 
associated with both a pre- and post-treatment state.  The general approach to determining QALYs for a 
given intervention uses the valuation of unaffected individuals to derive societal values for certain 
disease states.  The time trade-off (TTO) model is a method developed specifically for use in health care 
evaluations and has been validated against the SG method. Respondents choose between perfect health 
with shorter life expectancy or poorer health but with longer life expectancy.  The TTO tool will include 
an 8-item questionnaire.  
 
Treatment risk trade off:75,76  
6 additional items adapted from a prior study of treatment preferences, that will ask women to assume a 
hypothetical risk of developing breast cancer and ask them to quantify the amount of risk reduction it 
would take for them to choose a particular surgical option (e.g., lumpectomy + radiation, mastectomy). 
 
We anticipate that the entire one-time survey will take participants approximately 30-40 minutes to 
complete. The survey has been pilot tested with patient advocates to ensure that the survey content is 
presented in a clear and understandable format and that it is not overly burdensome to respondents. A 
participant’s active duration on study is the length of time to complete this single survey.   
 
 
5.3 Description of the Survey Methods 
 
We will use a multi-center, cross-sectional patient survey design to systematically collect and compare 
PROs in patients in the GCC or AS groups. All participants will be asked to complete a one-time, 
REDCap online survey or a mailed paper survey, depending on patient preference, and a telephone-
administered version will be available if necessary.  
 
5.4 Data Collection 
 
PRO data to be collected is described in detail above (Section 5.2). Additional data will be abstracted 
from the medical record beyond what is needed to determine eligibility, including prior history of breast 
surgery (lumpectom y, mastectomy, reduction/augm entation, implants, or other surgery, 
axillary surgery) and known high risk predisposition (e.g., BRCA 1 or 2 positive, prior history of 
radiation to the chest. 
 
5.5 Description of the study process 
 
5.5.1 Survey Administration 

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Protocol version:   May 16, 2019 
 
We will recruit approximately 900 women with DCIS matched 3:1 to women with ADH or LCIS/ALH 
(proxies for AS group) or DCIS choosing AS identified at 6 geographically and demographically distinct 
study sites:  DUMC, DFCI, MDACC, MGH, NWH, and DFCI @ SSH. Any patients who have selected 
AS for DCIS will specifically be identified and contacted for inclusion in the study. Enrolled patients 
will be asked to complete a one-time survey. The recruitment and survey phases will take place over an 
18-month period once enrollment begins. We anticipate data cleaning and analysis will last 6 months. 
 
The study coordinator at each site or the lead for an affiliate site will verify the mailing address and/or 
email address for each eligible patient, then local study staff will send an invitation letter and response 
form (Appendix A). The invitation letter and response form will include information about the study, 
study coordinator contact information, and will ask participants to send the local site their email address 
in order to receive the link to the study materials including an online elements of consent information 
page and online survey (Appendix B), or their address to receive the consent and survey (Appendix B) 
via mail. The contact information of all women who agree to participate in the study will be sent from 
the local study team to the DFCI study team to contact potential participants to initiate the consenting 
and survey process (Appendix B). In DFCI’s initial application, it was requested and approved, to have a 
waiver of documentation of consent for people who complete the survey online or on the phone. 
 
Web-based 
The REDCap survey can be accessed from any computer that has internet; the place of completion will 
be at the discretion of the participant. Prior to the survey questions in REDCap, participants will read 
and respond to the screening questions (Appendix E) to determine eligibility before moving to a next 
page which contains the elements of informed consent (Appendix C). If a participant is ineligible to 
participate in the study, she will not be able to move on to the informed consent information page.  If the 
participant is eligible, she will proceed to the informed consent information page and then to the survey 
itself (Appendix B).  
 
Print survey 
As an alternative to the on-line survey, patients will be provided the option to complete a survey by 
mail, or by phone. If completing by mail method, the patient will be mailed two copies of the paper 
consent, and asked to sign one of the copies and return with the completed survey.  The paper version of 
the survey (Appendix B) will be sent with the screening questions (Appendix E) as a cover page along 
with the two copies of the paper informed consent form. If the participant answers the screening 
questions (Appendix E) and is ineligible, she will be instructed to stop and return Appendix E in the 
enclosed pre-paid, pre-stamped envelope. If the participant is eligible, she will be asked to sign one copy 
of the consent and return it along with the completed screening questions (Appendix E) as well as the 
completed survey (Appendix B), which will be attached to one-another for the paper version. 
 
Phone survey 
If completing by phone, the study team will first verbally introduce the study, then will administer the 
screening questions (Appendix E). If the participant is ineligible, study staff will not continue onto the 
survey. If the participant is eligible, the study coordinator will administer and document verbal consent 
(Appendix D) and subsequently administer the patient survey (Appendix B).  
 
The online survey will be programmed in REDCap with appropriate skip patterns, and the paper version 

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Protocol version:   May 16, 2019 
will have clear instructions in order to reduce missing data. The paper copy of the survey is submitted as 
Appendix B. There will be 10 different versions of TTO questions in paper and in REDCap. Participants 
will be assigned to different versions of TTO (Treatment Trade Off) by the DFCI study team on a rolling 
basis (e.g. first participant will receive the first version, second participant will receive the second 
version, and so on). TTO survey is submitted as Appendix G. Patient advocates have piloted both the 
online and written form of the survey.  If the survey needs to be further revised, the study team will 
submit an amendment at DFCI and upon IRB approval, external sites will submit through local IRBs.  
Once the survey has been finalized, it will be disseminated to participants by the DFCI study team. 
 
Methods and Frequency of follow-up: In order to reach a broad sample of patients who may be eligible 
for this study, the local study team will mail an initial letter (Appendix A) to a prospective patient. 
Because people are busy and may respond to different forms of communication (i.e. calls, brief insert 
notes, letters, etc.), the local study team will follow up with 3 additional contacts over an 8-week period 
to allow for sufficient time to respond. The DFIC study team will pilot two patient outreach materials 
from Patient Advocates—two brief notes— added to the invitation letter and survey to one hundred 
patients to test improved response and participation outcome.  One or both of these outreach material, if 
proven effective, may be continued past the pilot one hundred patients. The DFCI study team has found 
this to be acceptable and desired in past survey research they have conducted. Participants who do not 
respond to Appendix A- Invitation letter and response form will be contacted at:  2 weeks (recontact), 4 
weeks (call/resend) and 8 weeks (call/resend). If a participant returns Appendix A, her contact 
information and select case report form (CRF) information will be sent to the DFCI study team. Please 
see section 4.0 for the patient contact procedure after the study has closed to respond to patients who 
indicate interest to complete a new survey.  
 
As outlined above, depending on modality of survey completion, the DFCI study team will collect the 
information as she is eligible, including: the screener, consent information and survey via her preferred method. 
There will be 3 potential recontact timepoints by the DFCI study staff to obtain consent/screener/survey from 
potential participants who do not complete the survey: 2 weeks (recontact), 4 weeks (call/resend) and 6 weeks 
(resend) from the initial contact. Participants who prefer to complete the survey via telephone will be mailed a 
copy of the paper survey and contacted up to 3 times to schedule the call to complete the survey.  
Translation of surveys. The surveys will be offered in English, although a Spanish translation of Survey 
B.1 and B.2 will be available in paper format for mailing to patients. Translated documents will be 
submitted for IRB review prior to implementation. We will follow a method that ensures comparable 
levels of validity, reliability and cultural meaning. First, the English version will be translated into 
Spanish. Bilingual staff will then review the translation. We have expertise on the study team to lead this 
task. Certificates of translation will be obtained and submitted to the IRB with the translated material.  
Native speakers of other languages will be able to participate through a medical interpreter.  All patients 
for whom English is not their primary language who have questions about the survey or study will also 
be able to utilize our institutional interpreter services. 
 
5.5.2 Special Concerns 
 
Data Security. The web-based survey has been developed in Research Electronic Data Capture 
(REDCap), a secure web-based software system that is compliant with HIPAA standards. Available to 
Duke, DFCI, MDACC, MGH, NWH, and DFCI @ SSH faculty, REDCap is commonly used for 
building and managing online databases and surveys. REDCap provides researchers with features that 

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facilitate both analytic and administrative competencies. These includes automated data download to 
Excel and common statistical packages (SPSS, SAS, Stata, R), a built-in project calendar, a scheduling 
module, and branching logic and range checks to reduce the potential of errors. Ad hoc reporting tools 
are available including frequencies and reports that can be generated at any time. The REDCap data 
centers are monitored 24/7 by an experienced team of engineers. They offer data redundancy through 
replicated databases and offer daily secure offsite backups. 
 
Data Privacy. Only administrators, designated study staff, and customer/technical support managers will 
have access to survey data which will be stored in a password protected account.  A written request from 
the patient to permanently remove all response data from the account will be answered in no more than 
two business days. If requested, all files, database records, and backups of this data will be destroyed. 
Data cannot be recovered after this is performed. 
 
Participant data that is collected and stored in REDCap can be archived, which takes it offline and 
removes it from the DFCI study staff’s list of projects. Once archived, it can only be accessed again by 
clicking the Show Archived Projects link at the bottom of the My Projects page.   
 
 
 
5.5.3 Compensation 
 
As part of the informed consent process, participants will be notified that they will be offered a gift card 
worth $20 as a token of appreciation for completion of the survey.  This gift card will be mailed to them 
by Dana-Farber Cancer Institute study staff after survey completion. 
 
5.6 Adverse Reactions and Their Management 
 
5.6.1 Reporting Adverse or Unanticipated Events 
Should there be a loss of confidentiality, reporting to the IRB will be performed in accordance with 
required policies.  
 
5.6.2 Anticipated Reactions  
 
The survey being administered entails minimal physical and psychological risk on the part of the 
participants; however, it is also possible that answering certain questions might cause some distress. The 
CES-D will be scored within a week of receipt.  Patients scoring ≥ 16 will be mailed a letter developed 
by Patient Advocates, Study PIs, and the CRC Staff within one calendar month providing support 
resources. 
 
There is the potential loss of confidentiality, which will be managed by adherence to HIPAA regulations 
at all study sites. 
 
 
5.6.3 Reaction Management 
 
It is possible that answering questions related to breast conditions may cause anxiety. In the letter of 
introduction, women are notified that they are free to skip any questions they do not want to answer.  

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Protocol version:   May 16, 2019 
Additionally, women are advised to contact their physicians or a study representative with any questions 
or concerns. If necessary, study staff will provide information on counseling services to patients that 
request assistance. 
 
All members of the study team will be required to complete Human Subjects Protection Training. This 
requirement may be met by completing the NIH course, the CITI (Collaborative Institutional Training 
Initiative) program or another course as required by the member institution.  
 
6.0 STATISTICAL ANALYSIS 
 
6.1 Primary and secondary endpoints 
 
Endpoints were selected with the input of patient stakeholders in the general categories of: 1) breast 
cancer and health-related clinical outcomes including pulmonary, cardiovascular, other cancer, and  
hematologic disease), and 2) Patient Reported Outcomes (PRO) which will include comprehensive 
domains of QOL and psychosocial outcomes, with a primary focus on pain and physical symptoms.  
 
6.2 Sample size and statistical power 
 
Importantly, published data indicate that patients undergoing lumpectomy with radiation report 
comparable levels of pain and sensory disturbances as those undergoing mastectomy.56 Thus, these 
treatment groups will be grouped together in the initial analysis, then a stratified analysis will be 
performed.  Preliminary data among 582 women undergoing either lumpectomy or mastectomy indicate 
that the mean persistent pain intensity after breast surgery is 2.61 (DS 4.24).55 Given a sample size of 
900 patients in the GCC group and 300 in the AS group, we will be able to detect with 90% power at a 
level of 0.05 (2-sided) a difference in pain intensity score of 2 (from 2.61 to 0.61), which has been 
deemed to be a clinically meaningful difference.  
 
Based upon the number of unique cases diagnosed with DCIS at each site between 2010 and 2013, we 
estimate that at all 6 study sites combined, approximately 1500 women will have been diagnosed with 
DCIS between January 1, 2012 and June 30, 2017 and will be eligible to participate.  Our response rate 
in prior survey studies has been approximately 60% using the approach we will adapt to the current 
study; thus, we anticipate that about 900 women with DCIS will be accrued and will complete the 
survey across all study sites.  These patients will be matched 3:1 to participants diagnosed with ADH or 
LCIS/ALH undergoing active surveillance. DCIS participants will be matched 3:1 to ADH/LCIS/ALH 
participants, based on matching criteria of age within 5 years, year of diagnosis, and study site.  
Additional matching criteria such as race, income, highest education level attained, and family history of 
breast cancer will be considered based upon stakeholder input during the protocol preparation process. 
 
6.3 Analysis Plan: General Approach.  
 
We will conduct descriptive analyses to profile the samples, including examination of proportions, 
means, and medians, as well as estimates of variability such as standard errors, ranges, and confidence 
intervals.  We will identify outlying observations.  Continuous data distributions will be evaluated for 
appropriateness of scale, and normal score transformations will be used where appropriate.   Appropriate 
summary statistics, histograms, scatter plots, or one- or two-way contingency tables for women of each 

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Protocol version:   May 16, 2019 
ethnic group will be computed.  These analyses will be followed by bivariate analyses to examine the 
pairwise relationships among variables under examination.  Demographic data will be compared for the 
respondents and non-respondents using chi-square or t-tests to assess selection bias. In addition to 
baseline disease and socio-demographic data, information relating to other treatment (e.g., endocrine 
treatment, radiation) as well as co-morbidities will be collected, allowing us to control for potential 
confounding by these factors. We will also analyze the decision-making, DCIS knowledge, and risk 
perception data at baseline and compare these domains between the GCC and ADH/LCIS/ALH/AS 
groups.  We will also systematically collect and evaluate and report on the upstaging rates and 
associated details from initial diagnosis of DCIS. 
 
6.4 Management of missing data: As with all studies there is a risk of biased statistical inference with 
missing data and we will adhere closely to standards put forth by the National Research Council. 77 We 
will include details about missing patient data in all tables in subsequent analyses, and include a 
comparison of baseline characteristics of patients with and without missing data. We will carefully 
consider whether data missingness is random or whether missingness may be attributable to a certain 
factor and therefore not random (e.g., older women may be less likely to answer questions). We will 
assess non-response bias by comparing available characteristics in both patients and providers (e.g., 
practice type) among responders and non-responders. 
 
 
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