Comparing an Operation to Monitoring, With or Without Endocrine Therapy (COMET) Trial For Low Risk DCIS: A Phase III Prospective Randomized Trial
Phase: NA
Conditions: DCIS, Ductal Carcinoma in Situ
Sponsor: Alliance Foundation Trials, LLC.

 
 
 
Date: 05/02/24 
 
Version#: 7 
ALLIANCE FOUNDATION TRIALS (AFT)  
 
 
PROTOCOL NUMBER 
AFT – 25 
 
 
COMPARING AN OPERATION TO MONITORING, WITH OR WITHOUT ENDOCRINE THERAPY (COMET)  
FOR LOW-RISK DCIS:  A PHASE III PROSPECTIVE RANDOMIZED TRIAL 
 
Protocol Version: 7 
Protocol Version Date: 05/02/2024 
 
 
ClinicalTrials.gov Identifier: NCT02926911 
 
 
 
Study Chair
E. Shelley Hwang MD, MPH
Duke University
465 Seeley Mudd Building
Durham, NC 27705
           
 
 
Patient-Reported Outcomes (Study Co-Chair)
Ann Partridge MD, MPH
Dana-Farber Cancer Institute
450 Brookline Ave 
Boston, MA 02215 
             
 
 
Correlative Science Chair 
Imaging Chair 
Alastair Thompson, ALCM, MBChB, MD, FRCSEd(Gen)
Section Chief, Breast Surgery  
Division of Surgical Oncology 
Baylor College of Medicine 
7200 Cambridge Street 
Houston, Texas 77030 
 
 
 
Pathology Chair (1) 
Sunil Badve, MD, FRCPath 
Department of Pathology and Laboratory Medicine 
Emory University School of Medicine 
1364 Clifton Road NE, Room H184  
Atlanta, GA 30322 
   
Lars Grimm, MD, MHS, FSBI
Associate Professor of Radiology 
Duke Cancer Institute 
2 Seeley Mudd Building 
10 Bryan Searle Drive 
Durham, NC 27705 
 
 
Patient Advocate 
Elizabeth Frank 
Patient Advocate 
80 Park Street 
Apt#75 
Brookline MA 02446 
 
 

 
 
 
 
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Pathology Chair
Stuart Schnitt, MD 
Professor of Pathology 
Harvard Medical School 
Brigham and Women’s Hospital 
Boston, MA 
 
 
 
Faculty Statistician 
Terry Hyslop, PhD 
Professor of Biostatistics 
Thomas Jefferson University 
833 Chestnut St 
Philadelphia, PA, 19107 
 
 
 
Sponsor Principal Investigator 
Evanthia Galanis, MD 
Alliance Foundation Trials, LLC 
221 Longwood Avenue, Room 122 
Boston, MA 02115 
   
   
 
AFT Biorepository at Washington University
Mark A. Watson, M.D., Ph.D. 
Assoc. Prof. Pathology and Immunology 
Washington University School of Medicine 
Box 8118 660 S. Euclid Ave 
St. Louis MO. 63110 
 
 
Sponsor Executive Officer 
Anna Weiss, M.D. 
Assoc. Prof. - Department of Surgery, 
Oncology  
University of Rochester Medical Center 
601 Elmwood Ave, Box SURG 
Rochester, NY 14642 
 
 
 
 
 

 
 
 
 
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Table of Contents 
 
1. 
BACKGROUND INFORMATION 
11 
1.1. 
Overview of Ductal Carcinoma in Situ and Patient Population 
11 
1.1.1 
Overview of Ductal Carcinoma in Situ 
11 
1.1.2 
Current Treatment Approach Indication 
11 
1.2. 
Study Rationale 
12 
1.2.1 
Omitting Surgery for Ductal Carcinoma In Situ 
12 
1.2.2 
Role of Endocrine Therapy for DCIS 
13 
1.3. 
Study Design 
14 
1.4. 
Study Design Rationale 
14 
1.5. 
Study Agents 
16 
1.6. 
Risks and Benefits 
17 
 
2. 
OBJECTIVES AND ENDPOINTS 
17 
2.1. 
Primary Objectives 
18 
2.2. 
Secondary Objectives 
18 
2.2.1 
Quality of Life and Psychosocial Outcomes 
18 
2.2.2 
Clinical Outcomes 
18 
2.3. 
Endpoints 
18 
2.3.1 
Primary Endpoint 
18 
2.3.2 
Secondary Endpoints 
18 
2.3.3 
Exploratory Endpoints 
18 
 
3. 
PATIENT SELECTION/POPULATION 
19 
3.1. 
Inclusion Criteria 
19 
3.2. 
Exclusion Criteria 
20 
3.3. 
Inclusion of Women and Minorities 
21 
 
4. 
METHOD OF TREATMENT ASSIGNMENT/PATIENT NUMBERING 
21 
4.1. 
Stratification Factors 
21 
4.2. 
Treatment Assignment 
21 
4.3. 
Treatment Blinding 
21 
 
5. 
TREATMENT PLAN 
21 
5.1. 
Surgery Arm 
21 
5.1.1 
Baseline 
21 
5.1.2 
Treatment 
21 
 
5.1.2.1 Surgery 
21 
 
5.1.2.2. Radiotherapy 
21 
 
5.1.2.3 Endocrine Therapy 
21 
 
5.1.2.4 Use of Genomic Health DCIS Score 
22 
 
5.2. 
Active Monitoring (AM) Arm 
22 
5.2.1 
Baseline 
22 
5.2.2 
Treatment 
22 

 
 
 
 
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5.2.2.1 Surgery 
22 
 
5.2.2.2 Endocrine Therapy 
22 
                      5.2.2.3 Use of Genomic Health DCIS Score                                                                                  23 
5.3. 
Monitoring in Surgery and AM Arms 
23 
5.3.1 
Pre-Treatment Criteria 
23 
5.3.2 
Diagnosis of Ipsilateral Breast Events 
24 
5.3.3 
Diagnosis of Contralateral Breast Events 
24 
5.3.4 
Survival 
25 
 
6. 
STUDY ASSESSMENTS AND PROCEDURES 
25 
6.1. 
Assessment Types 
25 
6.1.1 
Clinical Examination Assessment Plan 
25 
6.1.2 
Imaging Assessment Plan 
26 
6.1.3 
Patient-Reported Outcomes 
26 
 
7. 
STUDY ASSESSMENT TABLE 
28 
 
8. 
ADVERSE EVENTS 
32 
8.1. 
Adverse Events - General Overview 
32 
8.1.1 
Routine Adverse Event Reporting 
32 
8.1.2 
Solicited Adverse Event Reporting                                                                                                32 
8.1.3                 Expedited Adverse Event Reporting 
33 
8.1.4 
Severe Adverse Event Reporting Requirements 
33 
 
 
9. 
DATA COLLECTION AND MANAGEMENT 
34 
9.1. 
Data Collection and Submission 
34 
9.2. 
Data Confidentiality 
34 
 
10. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
34 
10.1. 
Overview of the Study Design 
34 
10.2. 
Sample Size, Accrual Time and Study Duration 
35 
10.3. 
Stratification Factors 
38 
10.4. 
Data Safety Monitoring Board (DSMB) Reporting 
38 
10.5. 
Supplementary/Secondary Analysis Plans 
38 
10.6. 
Duration of Follow-Up 
39 
10.7. 
Survival Follow-Up 
39 
10.8. 
Criteria for Taking a Patient Off Study 
39 
10.9. 
Study Monitoring (Reports, Summaries) 
40 
10.10. 
Data and Safety Monitoring (Inc. Interim Reports from the statistical team) 
40 
 
11. 
GENERAL REGULATORY CONSIDERATIONS AND CREDENTIALING 
40 
11.1. 
Compliance with Trial Enrollment and Results Posting Requirements 
40 
11.2. 
Regulatory and Ethical Compliance 
40 
11.3. 
Informed Consent 
41 
11.4.             Responsibilities of the Investigator/IRB/IEC/REB 
41 

 
 
 
 
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11.5. 
Protocol Deviations 
42 
11.6. 
Protocol Amendments 
42 
11.7. 
Retention of Records (Inc. study Documentation and record keeping) 
42 
11.8. 
Data Confidentiality 
42 
11.9. 
Database Management and Quality Control 
42 
11.10. 
Site Auditing 
43 
11.11. 
Data and Safety Monitoring Board 
43 
11.12. 
Regulatory Reporting 
44 
11.13. 
Audits and Inspections 
44 
11.14. 
Publication of Study Protocol and Results 
44 
 
12. 
BIOSPECIMEN COLLECTION 
45 
12.1. 
Sample Collection 
45 
12.2. 
Sample Shipping 
45 
12.3. 
Specimen Banking and Archiving 
46 
 
13. 
FUTURE BIOMEDICAL RESEARCH                                                                                                      46 
 
14. 
IMAGING REPOSITORY 
47 
14.1. 
Image Collection 
47 
 
REFERENCES 
                                                                                                                                48 
  
 
 
 
 
 

 
 
 
 
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1. BACKGROUND INFORMATION  
 
1.1  Overview of Ductal Carcinoma in Situ and Patient Population 
 
1.1.1 
Overview of Ductal Carcinoma in Situ  
Ductal Carcinoma in Situ (DCIS): potential risks and burdens.  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 will detect ductal carcinoma in situ, or DCIS,1 considered the earliest detectable form 
of pre-breast cancer. Approximately 51,000 women in the United States will be diagnosed with DCIS this 
year alone, almost all of these diagnoses made in completely asymptomatic individuals.2 DCIS is 
characterized by a proliferation of malignant cells confined to the milk ducts of the breast.3 Unlike invasive 
breast 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 breast cancer.4,5 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.   
DCIS was rarely diagnosed prior to widespread use of screening mammography.  Although mammography 
has been shown to reduce overall breast cancer mortality by over 20%,6 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 pre-cancerous conditions 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.7-11 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.12 
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,13,14 have garnered intense 
interest, anxiety, and scrutiny from patients, their families, and other health care stakeholders. 
There is a general consensus that much of this burden derives from the treatment of DCIS. Currently, 
almost all DCIS is treated aggressively with surgery despite the fact that other similar conditions (such as 
Lobular Carcinoma in Situ and Atypical Ductal Hyperplasia) are not; of those treated, the majority may not 
benefit if they would not have developed invasive breast cancer. An alternative to surgery is active 
monitoring (AM). Currently, only 3% of women in the United States with DCIS opt for AM. Thus, there has 
been global interest to address the issue of whether AM would be sufficient for women at low risk of 
progression to invasive breast disease. 
 
1.1.2 
Current Treatment Approach Indication 
Current gaps in evidence. Current treatment options routinely offered for DCIS include surgery 
(lumpectomy or mastectomy), radiation (radiation or none) and/or hormonal therapy according to 
National Comprehensive Cancer Network (NCCN) treatment recommendations.15 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.16  Among the 97% of women with DCIS treated with 

 
 
 
 
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surgery, neither randomized trials or retrospective studies to date have shown a survival advantage of any 
treatment option over another.16 To date, none of the treatment options has ever been compared in a 
rigorous fashion to AM. 
Moreover, the impact of surgery and AM 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,17 the clinical outcomes and patient reported 
outcomes (PRO) of active monitoring have never been studied. Thus women face a tremendous burden 
of uncertainty when considering the tradeoffs of surgery or AM for DCIS.18,19  
 
1.2  Study Rationale 
Overdiagnosis and overtreatment resulting from mammographic screening have been estimated to be as 
high as 1 in 4 patients diagnosed with breast cancer,20-23 although the absence of standard definitions for 
measuring overdiagnosis has led to much uncertainty around this estimate.24 The national health care 
expenditure resulting from false positive mammograms and breast cancer overdiagnosis has been 
estimated to approach $4 billion annually.25 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 persistent pain at the surgical site, with estimates 
ranging from 25-68%.26-29 Importantly, persistent pain after lumpectomy may be as prevalent as that after 
total mastectomy.26,27,30 Persistent postsurgical pain is rated by patients as the most troubling symptom,31 
leading to disability and psychological distress, and is often resistant to management;32 Although 
prospective population-based data have demonstrated significant patient and surgical focus on pain with 
remarkably high levels of chronic pain 4 and 9 months after breast surgery, much of these data have been 
collected in women with invasive breast cancer, with little data directly relevant to patients with DCIS. 
 
1.2.1 
Omitting Surgery for Ductal Carcinoma in situ 
There are minimal data on the natural history of patients diagnosed with DCIS, with most published 
studies presenting retrospective reviews of missed diagnoses. They relate to an era of very different 
qualities of imaging and biopsy and do not include active monitoring by mammography. Many of the 
patients described in these series would not be eligible for the COMET trial and almost all presented 
symptomatically. 
There has been interest in recent years in active monitoring for low risk DCIS, in part based upon the 
recognition of the tremendous biological heterogeneity in the group of conditions defined as “DCIS.” 
Clearly, the most controversial approach to the management of DCIS is “active monitoring,” based on the 
philosophy that the goal of DCIS treatment should be directed towards prevention or early detection of 
invasion rather than “treatment” of the DCIS lesion. The approach is based on the contention that current 
treatment for DCIS and early stage invasive breast cancer are not significantly different for hormone 
receptor-positive DCIS, and that the morbidity of treatment could be reserved for those patients who 
show a rapid tempo of DCIS. Much along the lines of active monitoring for early stage prostate cancer, 
intervention would only be undertaken with clinical progression, in the form of increased extent of DCIS 
or clinical evidence of invasion. 
In a small retrospective study of a cohort of patients who elected to delay surgery for DCIS, 9 of 14 patients 
either had clinical stability without intervention or had surgery which revealed DCIS without invasion.33 In 
Europe, this strategy has culminated in a recently initiated randomized clinical trial which offers active 

 
 
 
 
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monitoring for women with low risk DCIS. Critical to such an approach is a physician-patient relationship 
which includes a well-informed patient, clear communication of treatment options and risks, and mutual 
commitment to close and regular monitoring.  
The first prospective clinical trial randomizing patients with low risk DCIS (age >45, grade 1 or 2 DCIS) to 
active monitoring with or without endocrine therapy was initiated in the UK in 2014.  Named the “LORIS” 
study, the trial is aimed to determine how invasive breast cancer incidence, and overall/invasive breast 
cancer-specific survival are impacted with monitoring alone.34  In the United States, the COMET study will 
aim to address this question in a cohort of low risk, ER-positive HER2-negative DCIS. 
  
1.2.2 
Role of endocrine therapy for DCIS 
Most of the published literature on endocrine therapy for DCIS relates to the effect of endocrine therapy 
in the adjuvant setting. There is evidence from one placebo-controlled trial, NSABP B-2435, that in pre- 
and post-menopausal patients treated for DCIS with lumpectomy and adjuvant radiotherapy, tamoxifen 
reduces the risk of ipsilateral local recurrence by 30% and of contralateral breast cancer by 50%.36 The 
absolute risk at 5 years of any (invasive or non-invasive) breast cancer event is small (tamoxifen arm 8% 
and placebo arm 13%). Survival was not influenced by treatment.  
A subsequent randomized controlled trial with a more complex design37 examined the use of tamoxifen 
versus no adjuvant therapy following complete local excision of DCIS in the absence or presence of 
radiotherapy. In the absence of radiotherapy, tamoxifen was again associated with a 30% overall 
reduction in breast events through reduction in DCIS recurrence and contralateral DCIS and invasive 
breast cancer. Tamoxifen was however ineffective in preventing ipsilateral invasive recurrence. In the 
presence of radiotherapy, tamoxifen appeared ineffective. Survival was not impacted by radiotherapy or 
tamoxifen in this trial, with breast cancer accounting for only 20% of all deaths (2% breast deaths and 11% 
overall deaths).  
Recently, anastrozole, an aromatase inhibitor, has been compared to tamoxifen in two large randomized 
trials enrolling post-menopausal women with DCIS.  In NSABP B-35 which enrolled 3104 post-menopausal 
women who had undergone lumpectomy to clear margins and adjuvant radiation for DCIS, anastrozole 
treatment was associated with a small but statistically significant improvement in breast cancer free 
interval compared to tamoxifen (HR 0.73 [95% CI 0.56-0.96]. p=0.023), although disease-free survival was 
the same at 120 months (HR 0.89 [95% CI 0.75-1.07], p=0.21).38  Among women <60 in this study (n=1447), 
anastrozole was associated with significant improvements in breast cancer-free interval (BCFI) and 
disease-free survival (DFS) compared to tamoxifen, HR 0.53 (95%CI 0.35-.080) and HR 0.69 (95% CI 0.51-
0.93), respectively.  However, IBIS II, which enrolled 2980 post-menopausal women with DCIS who had 
undergone lumpectomy to clear margins +/- radiation, failed to demonstrate an improvement with the AI 
compared with tamoxifen (HR 0.89 [95% CI 0.64-1.23], p=0.49).39     
Two studies have reported the effect of preoperative endocrine therapy in DCIS.  Boland and colleagues 
evaluated women who discontinued exogenous hormonal therapy between the time of DCIS diagnosis 
and surgery (14-41 days).  A reduction in Ki67, ER and PR was observed in this group.40 In a 3-month 
neaodjuvant trial of endocrine therapy for DCIS, postmenopausal women on letrozole had significant 
reduction of PR, and Ki67 as well as increase in CD68-positive cells.41 Combined evidence from adjuvant, 
preoperative trials supports the suggestion that endocrine therapy may have a primary role in this setting. 
 
1.3  Study Design 

 
 
 
 
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The proposed study is a Phase III large pragmatic randomized trial comparing an operation to monitoring, 
with or without endocrine therapy for low risk DCIS. 
The two treatment arms are patients undergoing surgery or AM. The use of radiotherapy following surgery 
will be also recorded. 
 
1.4 Study Design Rationale 
The overarching hypothesis of the study is that management of low-risk DCIS using an active monitoring 
(AM) approach does not yield inferior invasive breast cancer or quality of life outcomes compared to 
surgery. The two arms of the trial were initially referred to as “active surveillance” and “guideline-
concordant care”. However, the study team decided that “active monitoring” was a more proactive and 
appropriate term than “active surveillance”, and that “surgery” better described the primary treatment 
that patients would receive - as opposed to “guideline-concordant care”, a term that many patients found 
difficult to understand. 
The primary comparator groups are “surgery” and “active monitoring (AM)” groups for biopsy confirmed 
diagnosis of low-risk DCIS (see Eligibility Criteria) (date of diagnosis is defined as the date of the first 
pathology report that diagnosed the patient with DCIS). As a pragmatic study, patients randomized to the 
surgery group will choose any of the NCCN standard treatment options for DCIS15 (with or without 
endocrine therapy), as they have all been shown to yield comparable breast cancer-specific survival.16,42 
Patients randomized to the AM group choose either AM without endocrine therapy, or AM with endocrine 
therapy, and adherence/duration of therapy noted. Randomization will be stratified based on the 
following factors: age at diagnosis: <55, 55-65, >65; maximum diameter of microcalcifications: <2cms, 2-
5cms, >5cms; DCIS nuclear grade: I or II. We will collect whether the patient has had prior surgical excision 
for the index diagnosis; this variable will be used for subset analysis and not stratification. 
Given the numerous variables for which stratification is not planned, selection biases may occur. Thus, 
key covariates will be collected and included in the analysis to help overcome and adjust for inherent 
treatment biases expected within study arms. All eligible patients must be willing to undergo either 
surgery or AM prior to randomization, and must not have contraindication for surgery.  
Selection of patient-centered outcomes. For this proposal, patient-centered outcomes have been divided 
into two broad categories: clinical outcomes and patient-reported outcomes. We selected the endpoints 
based on the following criteria abstracted from data in response to the following questions posed to 
stakeholders during the grant preparation process: 1) is this endpoint important for patients and 
stakeholders? 2) is this endpoint evaluable during the study period? 3) will this endpoint lead to improved 
understanding of whether and for which patients AM has a favorable risk/benefit assessment?  
We will test the association of PRO data with all breast events, including invasive or recurrent breast 
disease in the surgery arm, tumor progression in the AM arm, and decision to undergo surgery in the AM 
arm despite absence of clinical change. 
PRO surveys composed of validated measures will be administered at pre-specified time points during the 
study; a brief overview is provided below (see Appendix for full description of scales and survey 
administration schedule). We will collect PROs identified as salient issues to women with DCIS in our prior 
survey (see Appendix), including items specific to arm and breast symptoms, body image, and decision-
making.   

 
 
 
 
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We have carefully considered the burdens and barriers of the survey in conjunction with our patient 
advocate stakeholders. In so doing, we selected the number of survey items to reduce survey burden 
while not detracting substantially from the scientific goals. We anticipate that patients will be able to 
complete the full survey in approximately 30 minutes. To ensure that there is no excessive burden to 
patients as well as to test content flow and clarity, all surveys will be piloted with patient advocates prior 
to trial initiation. The surveys will be provided in print and online versions and will include the following 
measures (available in both English and Spanish versions): 
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.96-98 
Medical and Family history: We will survey women about their family history of breast/ovarian history. 
We will assess co-morbidities using the Self-Administered Co-morbidity Questionnaire (based on 
Charlson Co-morbidity Index and other comorbidity indices).44 
Adherence to hormonal therapy: We will measure adherence to hormonal therapy using a Medication 
Adherence measure based on work from Voil et al. Specifically, we will adapt Part 1 of the two-part 
measure of medication adherence, which includes 3 items that evaluate the extent of non-adherence over 
the past week.45,46 
Quality of Life (QOL): We will use the SF-3643 to measure health-related QOL. A modified 19-item version 
of the Breast Cancer Prevention Trial (BCPT) Symptom Checklist will evaluate commonly reported 
menopausal symptoms.47 The Breast-Q, a validated instrument to evaluate outcomes following surgery, 
will be used to evaluate satisfaction with appearance, body and self-image, and sexual functioning.48 Four 
items from the Quality of Life in Adult Cancer Survivors (QLACS) scale will be adapted to evaluate 
frequency (1=never; 7=always) of worries about DCIS, including concerns about future breast events and 
death from DCIS.76 The presence, severity, and functional impact of pain will also be evaluated. 
Neurosensory symptoms will be assessed using 7 items from the Breast Cancer Pain Questionnaire 
(BCPQ);.27,49,50. We will also use the Brief Pain Inventory, a well-validated general measure of pain and 
disability worst pain, least pain, and interference.95 
Utility: The EQ-5D-5L will be used to generate and evaluate QALYs. The EQ-5D-5L is a summary measure 
of health status for use in evaluating health and healthcare and includes five functional dimensions 
(mobility, self-care, usual activities, pain/discomfort, anxiety/depression) plus a visual analog scale (EQ-
VAS) that asks participants to assess how good or bad their health is today on a 0 (worst health imaginable) 
-100 (best health imaginable) scale.78, 81 
Complementary therapies: We will utilize a revised form of the CAM Questionnaire used by Burstein et 
al. to assess women’s use of complementary therapies. 80 
Health behaviors/lifestyle factors: Health behaviors, including physical activity, 81-85 smoking,86-88 alcohol 
use,87, 90 and diet, 91-94- will be evaluated using items selected from the Alliance Patient Questionnaire that 
is currently being piloted (Alliance A191401). 
Emotional/Psychological: To assess generalized anxiety, we will use the State Trait Anxiety Inventory 
(STAI) scale.51 Depressive symptoms will be evaluated with the Center for Epidemiologic Studies 
Depression Scale (CES-D-10).77 The CES-D-10 will be scored automatically by PRO Core when it is 
completed online by the patient or when it is data entered by study staff at DFCI. If a participant scores 

 
 
 
 
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10 or greater, indicative of potential depression, the PRO Core system will automatically send an email to 
the site principal investigator, so that symptoms can be addressed as needed. In addition, site study 
personnel who log in to PRO Core will be able to see the flagged survey alert. Site study personnel must 
complete a brief form in Pro Core indicating that the flagged survey alert has been seen and triaged as 
appropriate. We will assess feelings of uncertainty using the Intolerance of Uncertainty Scale (Short-
form), which has been used in studies of active monitoring in the prostate cancer setting.72-74 Coping will 
be evaluated using the Brief COPE, a shortened form of the COPE Inventory, inclusive of 28 items (14 
subscales).75 
Decision-making: Four items (The SURE scale) adapted from the Decisional Conflict Scale will be used to 
measure patients’ uncertainty about participating in the COMET trial.78, 79  The Decision Regret Scale will 
measure how women perceived their DCIS treatment/management decision including decision to 
participate in the trial.52 Sources of information about DCIS management options will be assessed using 
items adapted from a prior study of surgical decision-making.53  
Knowledge and Risk Perceptions: DCIS and breast cancer knowledge will be measured with items adapted 
from the Breast Cancer Surgery Decision Quality Instrument (BCS-DQI) as well as questions developed 
specifically for a study that assessed DCIS knowledge and risk perceptions.54,55,100 We will assess risk 
perceptions in women with DCIS using questions developed by Lerman and Croyle56 that were used in a 
prior study of psychosocial outcomes in women with DCIS.18 
Financial burden: We will adapt items from the National Health Interview Survey57 and the Cancer 
Outcomes Research and Surveillance (CanCORS) Caregiver Study58 to assess financial burden and to 
estimate out of pocket expenses attributed to their DCIS diagnosis. 
 
1.5  Study Agents 
There are no drugs included within the arms of the trial as experimental agents, although the use of 
endocrine agents (tamoxifen or aromatase inhibitors) as adjuvant therapy within both arms of the trial 
are encouraged to be considered and adherence be recorded. Such endocrine agents have many decades 
of use in standard clinical practice and have extensive safety profiles.  In the setting of DCIS, tamoxifen in 
both pre- and post-menopausal women is associated with reduction in the risk of ipsilateral and 
contralateral breast cancer events.  Recent studies comparing the aromatase inhibitor anastrozole to 
tamoxifen in post-menopausal women have revealed that the aromatase inhibitor is similarly to slightly 
more effective with regard to efficacy.   
Side effects and adverse events do vary between the two agents and this factor may be the rationale for 
choosing one agent over the other in post-menopausal women (for premenopausal women, tamoxifen is 
the primary hormonal therapy option).38,59 Risks of tamoxifen include but are not limited to hot flashes, 
night sweats, vaginal discharge, premature cataracts as well as more serious but rare risks of uterine 
cancer and thrombosis. Risks of anastrozole include but are not limited to hot flashes, night sweats, 
vaginal dryness, musculoskeletal symptoms as well as increased risk of osteoporosis and fractures.  Recent 
patients reported outcomes data from the NSABP B-35 trial comparing adjuvant tamoxifen to anastrozole 
in post-menopausal women with DCIS suggested that women treated with tamoxifen had increased 
severity of vasomotor symptoms, bladder control and gynecologic symptoms compared to women 
treated with anastrozole who reported increased severity of musculoskeletal and vaginal symptoms.38,59 
Of note, benefits were greatest in women under 60, particularly for women receiving anastrozole, but in 

 
 
 
 
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both arms these younger women reported had significantly worse vasomotor, vaginal and gynecologic 
symptoms as well as more weight gain.   
 
1.6  Risks and Benefits 
Surgery is, by definition, the prevailing standard of care for DCIS. The risks associated with surgical 
management of a breast lesion are well documented and include, but are not limited to, surgical and 
anesthetic side effects and/or complications; side effects and complications of subsequent radiotherapy 
following breast conservation therapy, if utilized; side effects and complications of endocrine therapy, if 
prescribed and taken. All local treatments may also be associated with a negative impact on cosmesis. 
For surgery, the potential benefits (while uncertain on an individual patient basis) include reduced 
incidence of invasive breast cancer and reduced recurrence of DCIS or invasive breast disease.  For 
endocrine therapy the impact on ipsilateral DCIS or recurrence/invasive breast cancer is uncertain, 
although there is a clear population-based reduction in contralateral DCIS and invasive breast cancer. 
For AM, the risk of progression of DCIS to more extensive involvement of the breast or to developing 
invasive breast cancer is a key clinical outcome of the trial.  The greatest potential risk to patients is posed 
by the delay in diagnosis of invasive breast cancer as a result of understaging on core biopsy.  Among 
women who are diagnosed with low or intermediate grade DCIS without invasive breast cancer on core 
biopsy, the estimate of upstaging to invasive cancer upon surgical excision ranges from 0-20% in published 
literature.60-62  One recent study,62 reported a 0% upstaging among women who would have fulfilled 
criteria for the LORIS trial, indicating that a low risk subgroup could be identified.  The impact of a delay 
in diagnosis of invasive breast cancer or the development of invasive breast cancer while undergoing 
monitoring is thought to pose a low risk to patients if detected at an early stage, although this has not 
been definitively shown. 
Additional risks to study participation include potential distress and loss of privacy when answering 
questions when filling out the surveys.  While the direct responses to the survey will not be shared 
with the participants’ medical team directly, we will alert the study team (registering physician and study 
coordinator at site) if a participant scores 10 or greater indicative of substantial depressive symptoms on 
the CES-D-10.   
 
2 
OBJECTIVES AND ENDPOINTS 
This trial will compare both clinical outcomes and PRO between patients treated with surgery versus AM 
for biopsy-proven DCIS  
Primary study outcomes. Endpoints were selected in two broad categories of 1) Clinical Outcomes defined 
as those disease- and treatment-related outcomes to be collected by research staff from primary source 
documentation, and 2) Patient Reported Outcomes (PRO) which will include comprehensive domains of 
QOL and psychosocial outcomes collected from patient surveys. 
 
2.1  Primary Objectives 
The hypothesis is based upon a non-inferiority endpoint that 2-year rate of invasive breast cancer 
diagnosis is not inferior in the AM group compared to the surgery group.  The estimate of invasive breast 
cancer upstaging (i.e. identified at the time of surgery) is 10% in the surgery group.  Non-inferiority will be 

 
 
 
 
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declared if the 2-year detection of invasive breast cancer in the AM group does not exceed 15% (based on 
statistical estimates).   
 
2.2  Secondary Objectives 
 
2.2.1 
 Quality of life and psychosocial outcomes:  
The secondary hypothesis is based upon a non-inferiority endpoint that 2-, 5-, 6, 8, 10 health-related 
quality of life, rate of anxiety, and rate of depression are not inferior in the AM group compared to the 
surgery group.   
 
2.2.2 
Clinical outcomes: 
The secondary hypothesis is based upon a non-inferiority endpoint that 2-, 5-, 7- and 10-year rates of 
mastectomy, contralateral invasive breast cancer, and survival (both overall survival and invasive 
breast cancer-specific survival) are not inferior in the AM group compared to the surgery group.  
 
2.3 Endpoints  
 
2.3.1 
Primary endpoint:  Proportion of new diagnoses of ipsilateral invasive breast cancer in surgery 
and AM arms at follow up of 2-years.  
 
2.3.2 
Secondary endpoints:   
 
Quality of life and psychosocial outcomes; 
o Health related QOL at baseline, 6 months, 1 year, annually year 2-6, biannually thereafter. 
o Anxiety/depression at baseline, 6 months, 1 year, annually year 2-6, biannually thereafter. 
o Coping at baseline 
o Intolerance of uncertainty at baseline and 2 years 
 
Clinical outcomes 
o Mastectomy rate at 2, 5, 7 and 10 years  
o Breast conservation rate at 2, 5, 7 and 10 years  
o Contralateral invasive breast cancer rate at 2, 5, 7 and 10 years  
o Overall survival and invasive breast cancer-specific survival at 2, 5, 7, and 10 years  
o Ipsilateral invasive breast cancer rate in surgery and AM arms at 5, 7 and 10 years  
 
2.3.3 
Exploratory endpoints:   
 
Breast MRI utilization at 2, 5, 7 and 10 years  
 
Breast biopsy rate at 2, 5, 7 and 10 years  
 
Radiation rate at 2, 5, 7 and 10 years  
 
Chemotherapy rate at 2, 5, 7 and 10 years  
 
Self-reported co-morbidity at baseline, 6 months, 1 year, annually year 2-6, biannually thereafter. 
 
Adherence to hormonal therapy at 6 months, 1 year, annually year 2-6, biannually thereafter. 
 
Health behavior/lifestyle factors at 6 months and 2 years 
 
Symptoms, pain, body image, sexual function at baseline, 6 months, 1 year, annually year 2-6, 
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 
Quality of decision making at baseline and 2 years 
 
Decisional regret at 1 year, annually year 2-6, biannually thereafter. 
 
Knowledge and risk perceptions at baseline and 2 years 
 
Decisional conflict at baseline  
 
Financial burden at 6 months 
 
Employment status at baseline, 6 months, 1 year, annually year 2-6, biannually thereafter. 
 
Use of complementary therapies at 6 and 24 months 
 
 
3 
PATIENT SELECTION/POPULATION 
The trial population will reflect that of patients undergoing treatment for DCIS at participating ALLIANCE 
sites that have representation from all race/ethnicities and socioeconomic classes; the study population 
will reflect this diversity and thus improve generalizability to the overall population of women diagnosed 
with DCIS. Study participants will be patients at participating ALLIANCE sites who present for a treatment 
consultation for a new DCIS diagnosis and who are considered at low risk. Patients for randomization will 
be required to meet the inclusion criteria outlined at 3.1.  
 
3.1 Inclusion Criteria 
 
 
Diagnosis of unilateral, bilateral, unifocal, multifocal or multicentric DCIS without invasive breast 
cancer (date of diagnosis defined as the date of the first pathology report that diagnosed the patient 
with DCIS) OR: atypia verging on DCIS OR: DCIS + LCIS (mix and/or separate locations in the same 
breast) 
 
A patient who has also had a lumpectomy or partial mastectomy with margins positive for DCIS (i.e. 
<2mm/ink on tumor) as part of their treatment for a current DCIS diagnosis is eligible (post-excision  
mammogram required at enrollment to establish a new baseline) 
 
No previous DCIS or invasive breast cancer in ipsilateral breast 5 years prior to current DCIS diagnosis 
 
40 years of age or older at time of DCIS diagnosis  
 
ECOG performance status 0 or 1 
 
No contraindication for surgery 
 
Baseline imaging (must include dimensions): 
o unilateral DCIS:  contralateral normal mammogram  6 months of registration and ipsilateral 
breast imaging  120 days of registration (must include ipsilateral mammogram; can also 
include ultrasound or breast MRI) 
o bilateral DCIS:  bilateral breast imaging  120 days of registration (must include bilateral 
mammogram; can also include ultrasound or breast MRI) 
o DCIS s/p lumpectomy:  post excision mammogram on side of excision 60 days of registration 
 
Pathologic criteria: 
o All grade I DCIS (irrespective of necrosis/comedonecrosis) 
o All grade II DCIS (irrespective of necrosis/comedonecrosis) 
o Absence of invasion or microinvasion 
o Diagnosis of DCIS confirmed on core needle biopsy, vacuum-assisted biopsy or surgery  120 
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o ER(+) and/or PR(+) by IHC (≥ 10% staining or Allred score ≥ 4) unless atypia verging on DCIS in 
which case biomarker criterion does not apply  
o HER2 0, 1+, or 2+ by IHC if HER2 testing is performed  
 
Histology slides reviewed and agreement between two clinical pathologists (not required to be at 
same institution) that pathology fulfils COMET eligibility criteria. In cases of disagreement between 
the two pathology reviews about whether the case fulfils the eligibility criteria, a third pathology 
review will be required. 
 
At least two sites of biopsy for those cases where individual mammographic extent of calcifications 
exceeds 4 cm, with second biopsy benign or both sites fulfilling pathology eligibility criteria (ER/PR 
testing required for second biopsy) 
 
Amenable to follow up examinations 
 
Ability to read, understand and evaluate study materials and willingness to sign a written informed 
consent document 
 
Reads and speaks Spanish or English 
 
3.2  Exclusion Criteria 
 
 
All grade III DCIS 
 
Male DCIS 
 
Concurrent diagnosis of invasive or microinvasive breast cancer in either breast 
 
Documented mass on examination or mass/hypoechoic area on imaging at site of DCIS prior to biopsy 
yielding diagnosis of DCIS, with exception of: subsequent lumpectomy or partial mastectomy (with 
positive DCIS margins i.e. <2mm/ink on tumor) followed by a post-surgery MMG; fibroadenoma at a 
distinct/separate site from site of DCIS; or diagnosis of mass/hypoechoic area as a cyst or a papilloma. 
In cases of uncertainty about whether the mass was present on physical examination prior to biopsy, 
the following criteria should be applied: if mammogram noting abnormal findings is diagnostic MMG 
= symptomatic/if mammogram noting abnormal findings is screening MMG = asymptomatic. If a 
patient has a mass on imaging that is biopsied (worked-up) and does not show invasive breast cancer, 
they are eligible. If a patient has a mass on initial MMG that is not seen on subsequent MMG, they 
are eligible (if initial mass occurred due to additional work-up).  
 
Any color/bloody nipple discharge (ipsilateral breast) 
 
Mammographic finding of BIRADS 4 or greater within 6 months prior to registration at site of breast 
other than that of known DCIS, without pathologic assessment  
 
Use of investigational cancer agents within 6 weeks prior to diagnosis of DCIS 
 
Any serious and/or unstable pre-existing medical, psychiatric, or other existing condition that would 
prevent compliance with the trial or consent process 
 
Pregnancy. If a woman has been confirmed as pregnant, she will not be eligible to take part in the 
trial. If she suspects there is a chance that she may be pregnant, a pregnancy test should be 
undertaken, although a pregnancy test for all women of child-bearing potential is not mandatory. In 
addition, if a woman becomes pregnant once registered to the trial, she can continue to be followed 
(endocrine therapy is not a mandatory requirement of the study). 
 
Documented history of prior tamoxifen, aromatase inhibitor, or raloxifene use in the 6 months prior 
to registration. 
 
Current use of exogenous hormones (i.e. oral progesterone) 
 

 
 
 
 
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3.3  Inclusion of Women and Minorities 
Technically, women of all races and ethnic groups are eligible for this trial. However, the trial is currently 
limited to English- and Spanish-speaking patients only. 
 
4 
METHOD OF TREATMENT ASSIGNMENT  
 
4.1  Stratification Factors 
Randomization will be stratified based on the following factors: age at diagnosis: <55, 55-65, >65; 
maximum diameter of microcalcifications: <2cms, 2-5cms, >5cms; DCIS nuclear grade: I or II. We will 
collect whether the patient has had prior surgical excision for the index diagnosis; this variable will be 
used for subset analysis and not stratification. 
 
4.2  Treatment Assignment 
The study is designed to provide a 1:1 randomization of all patients to surgery or AM.   
 
4.3  Treatment Blinding 
Given the nature of the two study arms, there will be no treatment blinding. 
 
5 
TREATMENT PLAN 
 
5.1  Surgery Arm 
 
5.1.1 
Baseline  
Baseline data will be collected, to include details of medical history, and details of recommended surgical 
therapy, including whether patient would be a candidate for lumpectomy. 
 
5.1.2 
Treatment  
 
5.1.2.1 
Surgery  
Patients randomized to the surgery arm will undergo appropriate surgery for DCIS according to local 
guidelines. It is expected that patients will complete definitive surgery within 60 days of randomization. 
Data on all related surgical procedures, including data on immediate or delayed breast reconstruction, 
will be collected. 
 
5.1.2.2 
Radiotherapy  
The recommendation for post-surgical radiotherapy should be decided following surgery and prescribed 
according to standard local protocols. The use of post-surgical radiotherapy is not mandated within the 
trial. However, data on the use of radiotherapy will be collected.  
 
5.1.2.3 
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The use of endocrine therapy is not mandatory within the trial but will be discussed with each patient on 
the surgery arm. Selection of endocrine therapy will be determined based on provider recommendations 
and patient preferences and administered for a maximal duration of 5 years.  If applicable, data on the 
use of endocrine therapy (type, duration, adherence, and side effects) will be captured at each visit. 
 
Participants in the surgery arm of the study will meet with a provider to discuss the option of endocrine 
therapy following surgery, including side effects of treatment.  The provider can be either a surgical 
oncologist or medical oncologist who is informed regarding endocrine systemic treatment options for 
DCIS. If the patient elects endocrine therapy, it will be prescribed by the treating physician following 
surgery according to standard dosing and schedule used for routine breast cancer chemoprevention. 
Prescriptions will be provided directly to the patient or to the pharmacy of patient’s choice and will not 
be provided by the study.   
All follow up and monitoring will be conducted according to the standard of care of each provider and 
institution, dependent on whether the patient elects or declines endocrine therapy.  The provider will also 
exercise their best clinical judgment regarding the necessity for baseline laboratory testing (e.g. liver 
function tests, triglycerides) and imaging (e.g. bone scan) as determined by the institution’s and individual 
provider’s routine standard of care.  
 
5.1.2.4 
Use of Genomic Health DCIS Score 
The use of the Genomic Health DCIS Score is allowed within both arms of the trial if requested by the 
patient or her clinician but will not be used to determine eligibility for the trial. 
 
5.2  Active Monitoring (AM) Arm  
 
5.2.1 
Baseline  
Baseline data will be collected, to include details of medical history and medication use. 
 
5.2.2 
Treatment  
 
5.2.2.1 
Surgery 
Patients in the Active Monitoring arm will not undergo primary surgery and will only undergo surgery if 
there is documentation of invasive breast progression requiring surgical intervention.  If the patient opts 
for surgery in the absence of invasive breast progression, they will be considered as having declined the 
arm to which they were specifically randomized (see Section 11.2); in this case they will be offered an 
option to continue to complete follow-up. 
 
5.2.2.2 
Endocrine Therapy  
The use of endocrine therapy is not mandatory within the trial but will be discussed with each patient on 
the AM arm. Selection of endocrine therapy will be determined based on provider recommendations 
and patient preferences and administered for a maximal duration of 5 years.  If applicable, data on the 
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Participants in the AM arm of the study will meet with a provider to discuss the option of endocrine 
therapy, including side effects of treatment.  The provider can be either a surgical oncologist or medical 
oncologist who is informed regarding endocrine systemic treatment options for DCIS. If the patient elects 
endocrine therapy, it will be prescribed by the treating physician according to standard dosing and 
schedule used for routine breast cancer chemoprevention. Prescriptions will be provided directly to the 
patient or to the pharmacy of patient’s choice and will not be provided by the study.   
All follow up and monitoring will be conducted according to the standard of care of each provider and 
institution, dependent on whether the patient elects or declines endocrine therapy.  The provider will also 
exercise their best clinical judgment regarding the necessity for baseline laboratory testing (e.g. liver 
function tests, triglycerides) and imaging (e.g. bone scan) as determined by institution and individual 
provider routine standard of care.  
5.2.2.3 
Use of Genomic Health DCIS Score 
The use of the Genomic Health DCIS Score is allowed within both arms of the trial if requested by the 
patient or her clinician but is not used to determine eligibility for the trial. 
 
5.3  Follow-up protocol in Surgery and AM Arms  
 
5.3.1 
Pre-Treatment Criteria 
There are no specific pre-treatment laboratory criteria for participation in this trial.  However, it is 
anticipated that at minimum, patients will undergo routine blood tests prior to surgery or initiation of 
endocrine therapy according to standard of care, consisting of CBC, electrolytes, BUN, creatinine, and 
glucose.  Additional lab tests may be obtained at the discretion of the care team subject to standard 
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5.3.4 
Survival  
If the patient is in clinical follow up years 0-5, sites must report patient deaths by completing the Patient 
Status form and Adverse Event forms immediately upon being made aware of the event. If the patient is 
in clinical follow up years 6-10 or survival follow up only, the patient status form needs to be completed 
annually. 
 
6. STUDY ASSESSMENTS AND PROCEDURES 
Close follow up of outcomes in each group is critical to the validity of the proposed comparisons. Following 
registration and consent at the initial clinic visit, baseline demographic information and data regarding 
clinical presentation will be collected. All clinical outcome data will be collected by a trained clinical 
research assistant who has received GCP and HIPAA training. All registered patients will be asked to 
complete the baseline survey on paper after they have been registered (but prior to being randomized), 
with the follow-up surveys completed at specified time-points (either on-line or on paper) (see Section 
7.1.3 Patient-Reported Outcomes describing the procedures for survey data collection.) Once registered 
to the trial, patients will be randomized to one of the treatment arms within four weeks; the monitoring 
period will start on the date of registration.  
 
                   6.1. Assessment Types 
6.1.1 
Clinical Examination Assessment Plan 
For both the surgery and AM groups, required clinical follow-up years 1-5 will consist of: 
 
Clinical examination including history and physical examination every 6 months.  
 
Unilateral mammography (MMG) of the affected breast every 12 months in the surgery arm; not 
required if patient has had mastectomy of the affected breast. 
 
Unilateral mammography (MMG) of the affected breast every 6 months in the AM arm.    
 
MMG of the unaffected breast every 12 months in both arms; not required if patient has had 
mastectomy of the unaffected breast. 
 
All mammograms should be performed within 4 weeks of each clinic visit. 
For the surgery and AM groups, required clinical follow-up years 6-10 consists of: 
o Clinical examination including history and physical examination every 12 months (both arms).  
o Bilateral mammogram every 12 months (both arms) (mammogram not required if patient has had 
mastectomy of both the index and the unaffected breast).  
o For patients on the AM arm, the study does not require 6-monthly MMG after the 5-year 
timepoint. However, the decision about whether to continue 6-monthly MMG should be at the 
discretion of the patient in consultation with their treating physician. 
o The study does not recommend the use of endocrine therapy after the 5-year timepoint. 
However, the decision about whether to continue ET should be at the discretion of the patient in 
consultation with their treating physician. 
Standardized case report forms will be completed for each scheduled study visit. In the surgery group, 
treatment data, including surgery and radiation if received, will be collected. For both groups, the use of 
endocrine therapy will be recorded. We will also collect clinical outcomes, including procedures, 
interventions, and recurrence history since the last visit. More frequent clinic visits or additional imaging 
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and pathology reports as well as the primary source image data will be uploaded to the ALLIANCE central 
imaging data submission portal.  
6.1.2 
Imaging Assessment Plan 
Clinical criteria for DCIS progression and indications for biopsy or treatment will be left to the best clinical 
judgment of the treating provider, together with the patient. Pragmatic clinical criteria requiring 
additional work up include the following:  
 
New breast mass on clinical examination in either breast 
 
Other new breast signs including nipple/skin retraction, nipple discharge, breast edema/erythema in 
either breast. 
Radiographic criteria for DCIS progression and indications for biopsy or treatment will be left to the best 
clinical judgment of the treating provider, together with the patient and breast imagers at each site. 
Pragmatic radiographic criteria for biopsy recommendation during follow up are the following:  
 
New mass/architectural distortion*/density* on mammogram in either breast according to *ACR 
Breast Imaging Reporting and Data System (BI-RADS) for mammography in assessment of masses and 
calcifications.63  
 
Increase in extent of calcifications ≥ 5mm in at least one dimension compared to the most recent prior 
MMG in the index breast. 
 
New suspicious findings on other radiologic studies (US, MRI) in either breast (i.e. hypoechoic area). 
For all routine mammograms, patients will be informed of the result of the mammogram within 1 week 
of the date of the mammogram. If a patient fails to schedule or keep a mammogram appointment, a 
second appointment will be scheduled. If the patient fails to keep the second appointment, the patient 
will be contacted by telephone. The site research team must make every effort to ensure that patient 
contact details are up to date. 
Diagnostic or surgical procedures other than those required by the protocol, as well as any change in 
management (e.g. participant in AM arm wishes to proceed with surgery in the absence of clinical and/or 
radiographic progression or participant in surgery arm decides not to proceed with surgery) and reason 
for change will be recorded, along with the findings prompting the recommendation or decision. In 
addition, any recommendations for management declined by the patient will also be recorded. 
6.1.3 
 Patient Reported Outcomes 
Survey instruments for the project have been carefully selected to provide the most relevant patient 
centered outcomes (see Section 1.3). Questionnaire packets will be completed at baseline, 6, 12, 24, 36, 
48, 60, 72, 96, and 120 months; a gap year letter will be sent to participants at months 84 and 108 (the 
years when a survey packet is not being sent) from UNC PRO Core in the same way that they receive the 
survey packets (either by email or by mail). This patient-reported outcome data collection will be 
conducted using the PRO Core survey platform, which enables web-based questionnaire completion, 
automated email reminders, data entry of paper forms, and tracking of participant survey completion. 
Surveys will be available in English or in Spanish. Language preference for each participant will be noted 
in PRO Core at baseline and can be changed throughout the study. Detailed information (screenshots, 
etc.) about how to use PRO Core for this study is provided in the training slide deck. The baseline 
questionnaire will be completed on paper after the patient has registered for the study (but prior to 
randomization). It will be data-entered into PRO Core by the site study staff and a copy will be kept on 
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The 6-, 12-, 24-, 36-, 48-, and 60-month follow-up questionnaires must be completed within an 8-week 
survey window, which begins on the scheduled survey date and ends 8 weeks later on the survey 
expiration date; the 72-month follow-up questionnaire must be completed within a 52-week survey 
window, which begins on the scheduled survey date and ends 52 weeks later on the survey expiration 
date; the 96-, and 120-month follow-up questionnaires must be completed within a 16-week survey 
window, which begins on the scheduled survey date and ends 16 weeks later on the survey expiration 
date. All these dates are indicated in PRO Core. The follow-up questionnaires will be completed online if 
the participant has an email address and regular internet access (i.e., checking email at least once a week). 
It will be completed on paper if the participant does not have email and regular internet access, or if the 
participant prefers to complete it on paper. However, all follow-up questionnaires should be completed 
using the electronic version if possible. Alternatively, the site study coordinator may call the participant 
and collect the data via phone interview (i.e. reading the questionnaire to the participant and marking 
their answers on the paper questionnaire form). 
The participant’s preferred method of contact for the follow-up surveys (e.g., mailed paper survey or 
emailed survey link) and their contact information (e.g., mailing address or email address, respectively) 
must be noted in PRO Core at baseline and can be changed throughout the study. Participants who are 
completing the follow-up questionnaires online will be emailed a unique link to the web-based 
questionnaire. For the 6-, 12-, 24-, 36-, 48-, and 60-month follow-up questionnaires, the email will be sent 
automatically by the PRO Core system on the scheduled survey date, and again at 2, 4, and 6 weeks 
thereafter if the questionnaire has not been completed; for the 72-month follow-up questionnaire, the 
email will be sent automatically by the PRO Core system when the survey becomes available (e.g., on the 
scheduled survey date), and again every 2 weeks thereafter up to 7 times if the questionnaire has not 
been completed; for the 96-, and 120-month follow-up questionnaires, the email will be sent 
automatically by the PRO Core system on the scheduled survey date, and again at 2, 4, 6, 8, 10, 12, and 
14 weeks thereafter if the questionnaire has not been completed. 
Participants who are completing the follow-up questionnaires on paper will be mailed a questionnaire 
packet within the first week of the scheduled survey date. The packet will contain the questionnaire and 
a stamped envelope addressed to the data entry staff at DFCI who will scan and upload a copy of the 
questionnaire into PRO Core, and subsequently enter the data into PRO Core. Sites that have tablet or 
desktop computers in their clinic available for patients to use privately and securely may have patients 
complete the baseline and follow-up questionnaires online during their clinic visit.  If the site is going to 
have the participant complete the questionnaire on paper in clinic, a copy of the questionnaire can be 
printed from the website of AFT.  If a participant needs to complete a follow-up questionnaire at a clinic 
visit, site staff should update the participant’s survey mode in PRO Core prior to the scheduled survey 
date.  
  
Each participant’s survey completion must be monitored by the site study staff through the tracking and 
reporting functionality of PRO Core. For the 6-, 12-, 24-, 36-, 48-, and 60-month follow-up questionnaires, 
site study staff will call participants who have not completed an online survey or returned a paper survey 
by week four, to provide a reminder and to answer any questions; for the 72-month follow-up 
questionnaire, site study staff will call participants who have not completed an online survey or returned 
a paper survey every 4 weeks for up to 12 weeks from when the survey became available to provide a 
reminder and to answer any questions; for the 96-, and 120-month follow-up questionnaires, site study 
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four, week eight, and week twelve, to provide a reminder and to answer any questions. Survey completion 
rates will be reviewed on a monthly basis by the investigative team for the duration of the study. 
Participants who have opted to complete the questionnaires online will be emailed a reminder about their 
upcoming annual/bi-annual follow-up questionnaire approximately 2 months before that time as a 
reminder, engagement and retention strategy.  In this correspondence, we will also remind participants 
about the website and thank them for their continued contributions to the study. Participants who have 
opted to complete the questionnaire on paper will not be mailed a reminder because the paper 
questionnaire packet itself is substantial and includes text thanking them for their continued contribution 
to the study.     
Engagement with the DCIS Website: We will assess engagement with the website associated with this 
study (cometstudy.org) by asking participants on the baseline survey to tell us how they heard about the 
study, whether they knew about the cometstudy.org website, whether they have visited the website, and 
if so, whether they found the content useful.  We will also have detailed data on use of the website that 
will be used to assess rate of engagement with the website. Although these variables are not key 
outcomes, these data will provide some indication of the role of the website component of this research 
and help to inform future research, care and communication efforts surrounding both DCIS and clinical 
trials in general. 
 
 
7. STUDY ASSESSMENT TABLE 
Laboratory and clinical parameters during treatment are to be followed using individual institutional 
guidelines and the best clinical judgment of the responsible physician. There are no mandatory lab tests 
required for this study; if no labs are drawn per physician discretion (based on routine site practice), that 
is acceptable. It is expected that patients on this study will cared for by physicians experienced in the 
treatment and supportive care of patients on this trial.  Date of registration is Day 1 on study. 

 
 
 
 
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8. ADVERSE EVENTS 
 
            8.1. Adverse Events - General Overview 
Per the International Conference of Harmonization (ICH) guidelines, an adverse event (AE) is defined as 
any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have to have a causal relationship with this 
treatment. An adverse event can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a 
medicinal product or protocol-specified procedure, whether or not considered related to the medicinal 
product or protocol-specified procedure.   
 
8.1.1 
Routine Adverse Event Reporting 
For the COMET study, patients will receive surgery, radiation therapy, or hormonal therapy. The toxicity 
profiles of these standard treatments for DCIS have been well described.   
Adverse event (AE) data collection and reporting, are done to ensure the safety of patients enrolled in the 
study. AEs will be reported from study entry until 5 years after registration.  
Preexisting conditions will be recorded as part of medical history during Screening.   Any new AEs or 
increase of a documented preexisting condition from screening/history will be recorded from the time of 
study registration through the end of year 5 on study. AEs are reported in a routine manner at scheduled 
times according to the study calendar in section 8. All AEs are entered into the eCRFs in Rave. 
The following are regarded as expected AEs for the purpose of the study:  
 
AEs related to image-guided biopsy 
 
AEs relating to adjuvant treatment for primary breast cancer or recurrence, such as AEs relating 
to endocrine therapy (examples include tamoxifen, anastrozole)   
 
AEs relating to radiotherapy such as hematoma, wound infection or seroma  
 
AEs relating to surgery such as hematoma, wound infection, or seroma. 
If an AE occurs that does not meet the criteria above the AE should be reported in RAVE. To report any 
AEs other than those listed on the Adverse Events: Solicited form, answer “Yes, and reportable adverse 
events occurred” to the question “Were (other) adverse events assessed during this reporting period?” at 
the bottom of the eCRF.  This will roll out the Adverse Events: Other form in the same folder in Rave for 
the reporting of these other AEs. 
 
Some AEs may not be assessed if tests or procedures are not specifically required within the protocol. 
 
AEs should be reported so that they can be monitored and compared between groups, it is unlikely that 
AEs will be related to active monitoring, due to the minimal nature of this treatment. Therefore, it is 
expected that AEs will frequently be considered “unrelated to active monitoring”. Detection of invasive 
disease is not an AE, thus this should be recorded elsewhere in the CRF. 
 
8.1.2 
Solicited Adverse Event Reporting 
 

 
 
 
 
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Adverse event data collection and reporting, which are required as part of every clinical study are 
done to ensure the safety of patients enrolled in the studies as well as those who will enroll in future 
studies with similar treatments. Adverse events are reported in a routine manner at scheduled times 
according to the study calendar in Table 1. For this study, the Forms “Adverse Events: Solicited” and 
“Adverse Events: Other” are used for routine AE reporting in RAVE. AE reporting is only required 
during years 1-5 of the study (it is not required years 6-10).  
 
Solicited Adverse Events: The following adverse events are considered “expected” and their 
presence/absence should be solicited and severity graded at each reporting period. 
 
 
Allergic Reaction 
 
Arthralgia 
 
Fever 
 
Hot Flashes 
 
Myalgia 
 
Acute Coronary Syndrome 
 
Ischemia Cerebrovascular 
 
Hypertension 
 
Nausea 
 
Fracture 
 
Osteoporosis 
 
Cholesterol (High) 
 
8.1.3 
Expedited Adverse Event Reporting 
Investigators are required by Federal Regulations to report serious adverse events as defined in the table 
below. Investigators are required to notify the AFT and their Institutional Review Board if a patient has a 
reportable serious adverse event. The descriptions and grading scales found in the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4 will be utilized for AE reporting.  The CTCAE is 
identified 
and 
located 
on 
the 
CTEP 
website 
at: 
ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. All appropriate treatment areas 
should have access to a copy of the CTCAE.  SAEs must be entered into Rave as applicable within 24 hours 
of learning of the event.  This will allow the safety monitor to review the information and assess the safety 
of the patient.  
 
8.1.4 
Severe Adverse Event Reporting Requirements 
 
Severe Adverse Events (SAEs) will be reported from study entry until 5 years after registration. 
 
REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS  
NOTE:  Investigators MUST immediately report to the sponsor (AFT) ANY Serious Adverse Events, whether or not they 
are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
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10.2 Sample Size, Accrual Time and Study Duration 
 
Power and Sample Size Considerations. Sample size for this study was estimated using a 2-group test of 
non-inferiority of proportions, with the 2-year invasive breast cancer rate in the surgery group assumed 
to be 0.10 based on published studies.61,62 The non-inferiority margin assumed was 0.05. Based on a 1-
sided un-pooled z-test, with alpha=0.05, a sample size of n=446 per group will have 80% power64 to detect 
the specified non-inferiority margin. The proportion of patients who decline the arm to which they are 
specifically randomized can diminish the estimate of treatment difference, and could also widen the 
confidence bounds, but the analytical approaches proposed here aim to diminish the impact on bias of 
the treatment difference. With a 3-year duration of accrual and 2 additional years of follow-up, we 
anticipate approximately 148 total events. 
 
Analysis of Primary Outcome (See below for outcomes definitions).  This trial was designed anticipating 
non-acceptance of arm allocation, and the proportion of patients that do not accept their arm allocation 
can lead to bias in estimates of treatment differences.  Thus, we plan to complete several analyses of the 
primary outcome, reporting the primary intent to treat (ITT) analysis as well as sensitivity analyses that 
are intended to reduce the bias in estimation of treatment difference in this setting. 
 
We assume that a clinically acceptable difference in 2-year invasive cancer diagnosis rate in order to 
conclude non-inferiority is 5%.  Cumulative incidence curves will be used to estimate the invasive cancer 
diagnosis rates over time, and at the 2-year point, the difference in rates will be estimated and a 1-sided 
upper confidence bound of (AM-GCC) will be computed, using methods described by Austin.65 We will 
conclude that AM is not inferior to Surgery if the upper confidence bound on the risk difference at 2 years 
is less than 5%.   
 
ITT Analysis.  The ITT analysis of 2-year invasive cancer diagnosis rate will be conducted using all patients, 
as randomized, and will be completed using Kaplan-Meier estimates, stratified by group, combined with 
the Greenwood’s confidence interval.  The difference in invasive cancer risks will be computed from the 
Cox model with treatment at 2 years, with a 1-sided 95% confidence interval of the difference (AM-GCC) 
computed.   
 
Sensitivity analyses.  Several sensitivity analyses are planned, including a per protocol analysis, as treated 
analysis, an instrumental variable analysis, as well as a principal stratification analysis.68,69 The sensitivity 
analysis will account for loss of follow-up, rejection of randomization allocation and withdrawals, and pre-
randomization factors influencing rejection of randomization, described in further detail below.  
 
Intent-to-treat (ITT) analysis is typically the standard in reporting results of clinical trials. However, in the 
presence of rejection of randomization allocation (here defined as selecting surgery when randomized to 
AM, and choosing AM when randomized to surgery), ITT results can be biased;66-68 similarly per protocol 
(PP) and as-treated (AT) analyses could yield biased estimates, especially since these analyses may no 
longer maintain balance achieved by randomization. Cuzick et al66 outline an approach to measure 
treatment effect among compliers, which follows the randomization (e.g. ITT), but assures that the 
estimates are not diluted by allocation changes. Thus, studies using this approach are similarly powered 
to ITT analysis, but provide appropriately wider confidence limits, which will be critical in a non-inferiority 
study. Principal stratification approaches can improve upon the width of confidence intervals and can 

 
 
 
 
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allow for covariate adjustment to aid in this improvement. Additionally, the covariates can aid in 
identifying subgroups with differential clinical response or treatment preference. 
We recognize the potential to lose patients to follow-up; yet, we consider approaches that could still 
provide some level of information for all patients who were randomized. Dunn et al67 describe 
instrumental variable methods with inverse probability weighting for missing data and latent class models 
as two approaches to deal with loss to follow-up.  Each approach makes assumptions, most of which are 
feasible for this trial, but we will report the assumptions as well as the comparative analyses in the 
literature and disseminate findings. We will also assess sensitivity to departures from these assumptions 
through simulation studies. 
At interim time-points as the study is enrolling, we plan to assess the level of withdrawal from the study 
completely, as well as the level of rejection of allocation or later changes in treatment (can only occur in 
Active Monitoring arm). We will utilize these levels to carry out simulation studies, but with parameters 
based upon ranges around our observations during the trial enrollment in order to assess our ability to 
maintain unbiased results of the treatment differences, particularly in the context of a non-inferiority 
setting. We will also implement sensitivity to the assumptions made in these simulations, including 
missing data mechanism (MD-5). If all of the approaches are generally equal in reducing bias, we will 
report on the approach that maintains alpha level and appropriate non-inferiority conclusion as our 
primary focus, but will also report the other approaches as comparators. The simulation results will be 
reported as evidence supporting conclusions, when applicable.   
Participant subgroups and planned subgroup analyses. We hypothesize that both clinical outcomes and 
PRO measures may be dependent upon treatment arm and patient characteristics. Pre-specified 
subgroups for assessment of heterogeneity of treatment effect will include (1) endocrine therapy (yes/no 
as well as duration of therapy); (2) choice of surgery (lumpectomy or mastectomy); (3) receipt of radiation 
(yes/no); (4) mode of monitoring (q 6 month MMG versus additional imaging, i.e. ultrasound or MRI); (5) 
race (African-American women compared to white women; other minorities will also be assessed for HTE, 
but precision is likely to be low); (6) menopausal status (pre-or post-menopausal, as reported by the 
patient); (7) baseline risk of invasive breast cancer based on modified Gail Score; (8) burden of co-
morbidities at diagnosis which will impact the magnitude of clinical benefit derived from surgery for DCIS. 
These subgroup analyses will be completed using methods described by Austin65 to estimate the average 
treatment effect (ATE) and the average treatment effect for the treated (ATT), using adjusted Cox models.  
The ATE would answer the question about how outcomes would change if a policy was instituted that all 
patients eligible for either therapy were only offered the “experimental therapy”, which here is Active 
Monitoring.  We also consider the use of time-dependent methods for endocrine therapy and receipt of 
radiation therapy, using the Austin approaches as well, with time-dependent covariates in the Cox models.  
 
Definitions of outcomes 
Subsequent local breast events (SLBE) events are coded as one of the following types:  
- 
iINV: Ipsilateral invasive in-breast cancer (includes chest wall recurrence) 
- 
iCIS: Ipsilateral in situ in-breast cancer  
- 
cINV: Contralateral invasive in-breast cancer (includes chest wall recurrence) 
- 
cCIS: Contralateral in situ in-breast event cancer 
- 
iLX: Ipsilateral lymph node cancer 
- 
cLX: Contralateral lymph node cancer 
 

 
 
 
 
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Planned subgroup analyses (NCDB Special Study). The large DCIS registry developed through 
collaboration with the National Cancer Database (NCDB) will allow for the continued collection of long-
term outcomes for patients as well as for the comparison of primary and secondary outcomes (when 
measurable in NCDB) for AM versus surgery amongst those patients who are randomized and accept their 
arm allocation versus those patients who are randomized but do not accept their arm allocation versus 
patients not registered or randomized to COMET, but who generally meet our broad inclusion criteria for 
the trial. Patients will be identified from all study sites during the time interval of COMET accrual. These 
analyses will be from predominantly non-randomized patients, so we plan to utilize observational study 
approaches for analyses. We will use full regression models (logistic or Cox model, dependent upon 
outcome measure) to control for potential confounders, including pathology, age, race, academic versus 
community setting, among others. As in other analyses, we will utilize inverse-probability weighting to 
handle missing data.70  
Analyses of long-term outcomes. Analyses of long-term outcomes will follow the approaches outlined 
above, modifying the year of rate calculations, accordingly. PRO data will utilize longitudinal linear mixed 
models over time, following appropriate scoring and transformation, if needed. 
10.3 Stratification Factors 
Randomization will be stratified based on the following factors:  
o Age at diagnosis: <55, 55-65, >65 
o Maximum diameter of microcalcifications: <2cms, 2-5cms, >5cms 
o DCIS nuclear grade: I or II 
We will collect whether the patient has had prior surgical excision for the index diagnosis; this variable 
will be used for subset analysis and not stratification. 
 
10.4 Data Safety Monitoring Board (DSMB) Reporting  
The COMET trial will be subject to bi-annual formal review at the Alliance Foundation DSMB meetings.  At 
each meeting we will utilize a template report formulated for use in Alliance trials, with appropriate 
modifications for the COMET follow-up study.   
 
 
10.5 Supplementary/Secondary Analysis Plans 
Planned Analysis for PRO data: For analyses of PRO endpoints, we will use t-tests and ANOVA to compare 
unadjusted mean scores for health-related PRO measures at baseline. We will use linear mixed-effects 
models to assess change in these domains over time. Among women who are allocated to surgery, we will 
examine differences by surgery type (e.g., lumpectomy followed by radiation vs. unilateral mastectomy 
vs. bilateral mastectomy) and compare changes between these groups over time. 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 allow 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 surgery and AM groups. We plan to measure risk perceptions and knowledge 
again at 2 years and will assess change between the two time points in each group using t-tests (e.g., for 
continuous scores) and McNemar’s test (e.g., proportion correctly perceiving their risk).  
 

 
 
 
 
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10.6 Duration of Follow-Up 
Participants in both arms of the study will be followed for 10 years from time of registration.  For the 
surgery and AM groups, required monitoring years 1-5 consists of the following: 
 
Clinical examination including history and physical examination every 6 months. 
 
Unilateral mammography (MMG) of the affected breast every 12 months in the surgery arm; not 
required if patient has had mastectomy of the index breast. 
 
Unilateral mammography (MMG) of the affected breast every 6 months in the AM arm. 
 
MMG of the unaffected breast every 12 months; not required if patient has had mastectomy of the 
unaffected breast 
After 5 years, participants in both arms will undergo physical examination and bilateral mammogram 
every 12 months; mammogram is not required if patient has had mastectomy of both the index and the 
unaffected breast (for additional information on required clinical follow-up (years 6-10), see Section 
7.1.1.).  
 
10.7 Survival Follow up  
Any study participant can choose to withdraw from the study at any time for any reason, including no 
specified reason.  Patients in the surgery arm cannot opt for the AM arm after surgery, but in the event 
that a patient withdraws from the study, the date of withdrawal and reason for withdrawal will be 
recorded.  The patient will be censored in time-to-event analyses at the date of withdrawal from the study 
Patients in the AM arm may choose to either withdraw from the study or opt to proceed with surgery at 
any time.  In the event that a patient in the AM arm opts to proceed with surgery in the absence of invasive 
progression, the date of withdrawal and reason for withdrawal will be recorded.   As for the surgery arm, 
in the event that a patient withdraws from the study, the patient will be censored at the date of 
withdrawal from the study. 
Patients in the AM arm with progression to invasive breast cancer are required by the study protocol to 
proceed with surgery for their invasive breast cancer.  Patients who have invasive breast progression and 
do not wish to have surgery will continue to remain in follow up with their invasive cancer event recorded, 
at the time of invasive breast progression for the primary analysis. For further exploratory analyses, the 
lack of surgery for these patients will be recorded.    
For patients who choose to no longer be followed per the protocol schedule, the patient can choose to 
enter the Survival Follow-up Phase. Survival data, ongoing adjuvant therapies and subsequent disease 
progression data will be collected during this phase of the study every 12 months for 10 years from 
registration. Telephone contact is acceptable as well as medical record review.  
 
Follow-up will be discontinued early due to:  
• 
Patient Death  
• 
Patient Withdrawal of consent for all follow-up  
• 
Patient deemed lost to follow-up  
 
 
10.8 Criteria for Taking a Patient Off Study 

 
 
 
 
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Patients will be recorded at the time of death from any cause, and depending upon cause, may contribute 
to an invasive cancer event.  Date and cause of death will be recorded.  Patients lost to follow up will be 
defined as those patients for whom clinical data is not available for ≥ 24 months.  Those patients will be 
censored at 24 months from last contact. 
 
10.9 Study Monitoring (Reports, Summaries) 
Enrollment and AE/SAE reports will be completed every 6 months from study initiation and submitted to 
the AFT office and the DSMB.   
 
10.10 
Data and Safety Monitoring 
Interim Reports from the statistical team will be generated for the Data and Safety Monitoring Board 
(DSMB), as per the safety monitoring plan.  
 
 
11 GENERAL REGULATORY CONSIDERATIONS AND CREDENTIALING (ETHICAL CONSIDERATIONS AND 
ADMINISTRATIVE PROCEDURES) 
 
                    11.1. Compliance with Trial Enrollment and Results Posting Requirements 
 
The trial and its results are subject to the requirements for submission to the Clinical Trials Data Bank, 
http://www.clinicaltrials.gov.  Information posted will allow patients to identify potentially appropriate 
trials for their health-related conditions and pursue participation by calling a central contact number for 
further information on appropriate trial locations and trial site contact information. 
 
                    11.2. Regulatory and Ethical Compliance 
 
By signing the protocol, the investigator agrees to treat all of the information that is provided with the 
strictest confidentiality and to require the same of his/her personnel as well as the IRB. Study documents 
(protocols, investigator`s brochures, eCRFs, etc.) provided by the AFT will be stored in an appropriate 
manner in order to ensure confidentiality. The information provided to the investigator by AFT must not 
be made available to other parties without a direct written authorization by the aforesaid parties, with 
the exception of the extent to which disclosure is necessary in order to obtain informed consent from the 
patients who wish to participate in the study. 
 
This study will be conducted in compliance with the study protocol, subsequent amendment(s) and with 
the study-specific manuals/guidelines, if applicable. These documents ensure that the ICH E6 guideline 
for Good Clinical Practice is maintained as well as compliance with the principles of the Declaration of 
Helsinki (World Medical Association), or the laws and regulations of the country in which the research is 
conducted, whichever afford the greater protection to the individual. The study will comply with the 
requirements of the ICH E2A guideline (Clinical Safety Data Management: Definitions and Standards for 
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By signing the study protocol the investigator agrees to comply with the instructions and procedures 
described therein and thus to adhere to the principles of good clinical practice, which these instructions 
and procedures reflect. 
 
                   11.3. Informed Consent 
 
If potential participants wish to speak with a patient advocate about the trial or any other aspect of the 
study, they will be provided with the contact details of a member of the COMET Patient Leadership Team 
(PLT). All participants (both potential and registered) will be provided with access to educational materials 
specifically designed by the PLT to inform them about the study, as well as to support decision making 
between options allowed in each arm following randomization.  
 
It is the responsibility of the Investigator, or a person designated by the Investigator (if acceptable by local 
regulations), to obtain written Informed Consent from each patient participating in this study, after 
adequate explanation of the aims, methods, anticipated benefits, and potential hazards of the study. This 
information must be provided to the patient prior to undertaking any trial-related procedure which is not 
part of the routine clinical management of the patient (i.e. would not be indicated outside the study). 
 
It is the investigator’s responsibility to obtain the signed Informed Consent Form, and a signature from 
the person conducting the informed consent discussion, prior to undertaking any trial-related procedure. 
The proposed Informed Consent Form must comply with the ICH GCP guideline and regulatory 
requirements 
 
                    11.4. Responsibilities of the Investigator/IRB/IEC/REB 
 
The regulatory requirements for the Investigator can be found in Subpart D of 21CFR312(21CFR 312.60: 
General Responsibilities of Investigators) and in ICH E6 Section 4.  
Additional requirements are also outlined in the Statement of Investigator Responsibilities (Form FDA 
1572) and the Site Services Agreement.  Alliance Foundation Trials, LLC (AFT) will supply the protocol and 
subsequent amendments. 
 
The Investigator is responsible for ensuring all patients are informed about the study and that written 
consent is obtained prior to the conduct of any study related procedures. In addition, the Investigator is 
responsible for reviewing all health-related information collected for each study patient in order to 
identify any safety related issues/adverse events (AE).  
 
As specified in 21CFR 312.62 (Investigator Record Keeping and Record Retention) and ICH E6 Sections 4.9 
and 8, the Investigator is responsible for ensuring that their study staff maintains and retains all study 
related documentation, including but not limited to: signed Informed Consent forms, medical records that 
are applicable for this study and source documents, the protocol, Institutional Review Board (IRB) 
approvals, relevant IRB and Sponsor correspondence, and assorted regulatory documents.  The 
Investigator is responsible for retaining and keeping safe all patient related documentation.  In order to 
do this, the site staff will complete electronic case report forms (eCRFs) (see Appendix 1) in a timely 
manner. Due to the limited nature of the study protocol signature pages, medical licenses, IRB member 
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                    11.5. Protocol Deviations 
 
The investigator is responsible to document and explain any deviations from the approved protocol. The 
investigator should promptly report any deviations that might impact patient safety and data integrity to 
AFT and if locally applicable, to the respective IRB in accordance with local IRB policies and procedures.  
 
A deviation is a departure from the protocol.   If deviations are discovered by the data manager, other 
member of study staff or otherwise, they will be discussed with the Investigator and study staff. 
 
                    11.6. Protocol Amendments 
 
Any modifications to the protocol or the Informed Consent Form which may impact on the conduct of the 
study, potential benefit of the study, or may affect patient safety, including changes of study objectives, 
study design, patient population, sample sizes, study procedures, or significant administrative aspects will 
require a formal amendment to the protocol. Such amendment will be released by AFT, agreed by the 
investigator(s) and approved by relevant IRBs prior to implementation. A signed and dated statement that 
the protocol, any subsequent relevant amended documents and the Informed Consent Form have been 
approved by relevant IRBs must be provided to AFT before the study is initiated.  
 
Administrative changes of the protocol are minor corrections and/or clarifications that have no effect on 
the way the study is to be conducted. These administrative changes will be released by the AFT, agreed 
by the investigator(s) and notified to the IRB.  
 
                    11.7. Retention of Records (Study Documentation, record keeping, and retention of records) 
 
Any records and documents relating to the conduct of this study and the distribution of ICFs, eCRFs, PRO 
data, must be retained by the study chair until notification by AFT, or for the length of time required by 
relevant national or local health authorities, whichever is longer. After that period of time, the documents 
may be destroyed, subject to local regulations. No records may be disposed of without the written 
approval of AFT. Written notification should be provided to AFT prior to transferring any records to 
another party or moving them to another location. 
 
                    11.8.  Data Confidentiality  
 
Patient medical information, both associated with biologic specimens or not, is confidential and may only 
be disclosed to third parties as permitted by the ICF (or separate authorization for use and disclosure of 
personal health information) which has been signed by the patient, unless permitted or required by law. 
Data derived from biologic specimen analysis on individual patients will in general not be provided to 
study investigators unless a request for research use is granted. The overall results of any research 
conducted using biologic specimens will be available in accordance with the effective AFT policy on study 
data publication. 
 
                    11.9. Database Management and Quality Control 
 
The Site Principal Investigator and/or his/her designee will prepare and maintain adequate and accurate 
participant case histories with observations and data pertinent to the study. 

 
 
 
 
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Rave EDC will be used for this study. The study data will be transcribed by study-site personnel from the 
source documents onto an eCRF, and transmitted in a secure manner to AFT within the timeframe agreed 
upon between the sponsor and the study site. The electronic file will be considered to be the eCRF. 
 
The Clinical Research Coordinator (CRC) or designated study site personnel will complete the eCRF within 
5 days following a subject visit and queries are to be addressed within 5 days from the date issued. 
Subjects will not be identified by name in the study database or on any study documents to be collected 
by the AFT (or designee), but will be identified by a site number, subject number. 
 
In accordance with federal regulations, the Investigator is responsible for the accuracy and authenticity 
of all clinical and laboratory data entered onto ergs. Each eCRF must be reviewed for accuracy by the 
Investigator, corrected as necessary, and then approved. 
 
At study completion, when the database has been declared to be complete and accurate, the database 
will be locked.  
 
After data have been entered into the study database, a system of computerized data validation checks 
will be implemented and applied to the database on a regular basis. After upload of the data into the 
clinical study database they will be verified for accuracy and consistency with the data sources. Queries 
are entered, tracked, and resolved through the EDC system directly. The study database will be updated 
in accordance with the resolved queries.  All changes to the study database will be documented. 
 
At critical junctures of the protocol (e.g., production of interim and final reports), data for analysis is locked 
and cleaned per established procedures. 
 
If the Investigator becomes unable for any reason to continue to retain study records for the required 
period (eg, retirement, relocation), AFT should be prospectively notified. The study records must be 
transferred to a designee acceptable to AFT, such as another investigator, another institution, or to AFT 
itself. The Investigator must obtain AFT’s written permission before disposing of any records, even if 
retention requirements have been met. 
 
                    11.10. Site Auditing 
 
The Investigator grants permission to AFT (or designee), and appropriate regulatory authorities to conduct  
auditing of all appropriate study documentation. Investigator sites may be audited by AFT under the AFT 
site audit program. 
 
                    11.11. Data and Safety Monitoring Board (DSMB) 
 
The Alliance Foundation Trials Data Safety Monitoring Board (DSMB) will be monitoring this study to 
ensure objectivity and the safety of participants. The DSMB will meet twice each year either by face-to-
face meeting or by teleconference. At each meeting, the study will be reviewed for safety and progress 
toward completion. When appropriate, the DSMB will also review formal interim analyses of the outcome 
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recommendations for changes to the study will be circulated to investigators in the form of addenda to 
this protocol document.  
 
Reports provided to the DSMB will include accrual data, adverse events, and results of interim analyses 
when available. In determining whether the trial should be continued, the DSMB will consider the results 
of each interim analysis, as described above. The DSMB will also consider the evidence regarding safety, 
i.e. adverse events, and the feasibility of completing the trial, i.e. the accrual rate. Weighing the adverse 
events and the feasibility of study completion is complex and therefore no particular cut-offs of these 
measurements are provided in advance. The DSMB will use its discretion in weighing these 
measurements. 
 
                    11.12. Regulatory Reporting 
 
It is the responsibility of the investigator and the research team to ensure that serious adverse events are 
reported according to the Code of Federal Regulations, Good Clinical Practices (GCP), the protocol 
guidelines, AFT’s guidelines, and Institutional Review Board (IRB) policy. As this is an IND exempt study, 
some regulations do not apply. 
 
                    11.13. Audits and Inspections 
 
To enable evaluations and/or audits from regulatory authorities or AFT, the Investigator agrees to keep 
records, including the identity of all participating subjects (sufficient information to link records, e.g., 
eCRFs and hospital records), all original signed informed consent forms, copies of all eCRFs, safety 
reporting forms, source documents, and detailed records of treatment disposition, and adequate 
documentation of relevant correspondence (e.g., letters, meeting minutes, telephone calls reports).  The 
records should be retained by the Investigator according to  local regulations, or as specified in the Clinical 
Trial Agreement, whichever is longer, but at a minimum, all study documentation must be retained for 2 
years after the last marketing application approval in an ICH region or after at least 2 years have elapsed 
since formal discontinuation of clinical development of AFT-25. 
                   
 
                   11.14. Publication of Study Protocol and Results 
 
Initial results of the study will be published following analysis performed once a follow up time of 2 years 
has been achieved.  Additional planned analyses at 5-, 7- and 10-year follow up will be conducted and 
reported. Publication in the instance of early termination will depend upon the number of patients 
accrued at the time of termination. A plain-language study result summary will also be produced and 
distributed to trial participants and public venues, including clinicaltrials.gov. 
 
Alliance Foundation Trials, LLC prioritizes the timely presentation and publication of study results. 
Publications and any kind of presentations of results from the study shall be in accordance with accepted 
scientific practice, academic standards and customs and must be approved in writing by AFT as the 
sponsor of this trial. No investigator may present or publish any portion of this trial without written 
approval from AFT.  
 
 

 
 
 
 
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12. BIOSPECIMEN COLLECTION 
 
Biospecimen collection is a required component of this protocol, in order to perform future correlative 
science objectives.  Please see the COMET (AFT-25) Correlative Science Manual for additional details 
with regard to sample processing, labeling, and shipping. 
 
                   12.1 Sample Collection 
 
Consent for biospecimen collection will be required of all study participants.  Once consent is obtained, 
the study site will request the FFPE tissue samples from: 1) the diagnostic core or vacuum-assisted biopsy 
of the primary DCIS or surgical excision specimen of the DCIS from those patients who entered the study 
after initial excision; and 2) diagnostic core or vacuum-assisted biopsy or surgical excision specimen of the 
invasive breast cancer, if diagnosed.  
 
Each site will submit a representative paraffin block up to four weeks after registration and also up to four 
weeks after a further event (DCIS or invasive breast cancer) occurs; sites will also submit a block up to four 
weeks after a biopsy where benign breast disease is diagnosed.  If a block cannot be submitted, 20 
unstained tissue slides will be requested.  If it is not deemed possible to submit 20 slides in the 
pathologist’s or histologist’s best judgement, as many slides as possible will be sent without compromising 
the diagnostic integrity of the block. 
 
In addition, for patients registered before August 14, 2020, 24 ml peripheral blood (or as much as can 
reasonably be drawn) will be collected for cell-free tumor DNA analysis and constitutional DNA from white 
blood cells (1 x 8ml Whole Blood/2 x 8ml Plasma for cfDNA in three separate tubes), up to four weeks 
after registration and will be collected up to four weeks after a further event (DCIS or invasive breast 
cancer) occurs and up to four weeks after a biopsy where benign breast disease is diagnosed. For patients 
registered after August 14, 2020,  32 ml peripheral blood (or as much as can reasonably be drawn) will be 
collected for cell-free tumor DNA analysis and constitutional DNA from white blood cells (1 x 8ml Whole 
Blood/3 x 8ml Plasma for cfDNA in four separate tubes), up to four weeks after registration and annually 
thereafter. This amount of blood will also be collected up to four weeks after a further event (DCIS or 
invasive breast cancer) occurs and up to four weeks after a biopsy where benign breast disease is 
diagnosed. Specialized blood collection and shipping materials will be provided to enrolling sites. 
 
                   12.2 Specimen Tracking System Specimen Submission Instructions 
 
Specimens for patients registered on this study must be logged and shipped using the online Alliance 
Foundation Trials Specimen Tracking System (AFT.BioMS). All institutions may access this system via the 
Alliance Foundation Trials Web site (https://alliancefoundationtrials.org). 
 
A copy of the Shipment Packing Slip produced by the AFT.BioMS System must be printed and placed in 
the shipment with the specimens.  USE OF THE SPECIMEN TRACKING SYSTEM IS MANDATORY AND ALL 
SPECIMENS MUST BE LOGGED AND SHIPPED VIA THIS SYSTEM.  For procedural help in logging and shipping 
specimens, please refer to the AFT.BioMS User Guide, which can be accessed via the Help link on the 
AFT.BioMS web site.  To report technical problems with the AFT.BioMS, such as login issues or application 
errors, and/or for further assistance using the application, please email the AFT.BioMS helpdesk at 
. 

 
 
 
 
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                   12.3 Sample Shipping  
 
The AFT Biorepository at Washington University will be the lead correlative study center for this 
retrospective tissue-based study. Collaborating sites will send FFPE tissue slides and peripheral blood 
samples (as described above) for central archiving and storage. 
 
A method of shipping that is secure and traceable will be used. Extreme heat precautions will be taken 
when necessary.  
 
Collaborating sites will send FFPE samples for analysis to the following address: 
 
AFT Biorepository at Washington University 
c/o Siteman Cancer Center Tissue Procurement Core 
425 S. Euclid Avenue 
BJCIH Building, Room 5120 
St. Louis, MO 63110-1005 
 
 
 
13. Future Biomedical Research 
 
Submission of biospecimens is a required component of this trial and an integrated part of the consent 
process.  In the event that it is physically impossible to submit required biospecimens, however, patients 
may still be enrolled to the trial without biospecimen submission.  Biospecimens will be used to address 
future biomarker correlative science questions that are relevant to this treatment trial.  This may include 
genomic and epigenomic analysis, central histopathology review, immunohistochemical studies, and 
other molecular biomarker studies.  All collected biospecimens will be stored in the Alliance Foundation 
Biorepository (AFB), a CAP-accredited biorepository at Washington University in St. Louis, until 
biospecimen accrual and clinical follow-up is sufficiently complete to allow for the design and execution 
of specific correlative analyses using ‘state-of-the-art’ analytical platforms that will be available at that 
time. 
 
Such biomarker research will address emergent questions not described elsewhere in this protocol. The 
objective of collecting specimens for future biomedical research is to explore and identify biomarkers that 
inform the scientific understanding of disease and/or their therapeutic treatments in the context of this 
trial. Proposals for future correlative research will undergo rigorous scientific, programmatic, and 
statistical review by AFT, and biospecimens will only be released to those investigators who have obtained 
appropriate regulatory approval and demonstrate adequate funding to successful complete proposed 
research aims. AFT will ensure that all collected specimens are used only for approved research protocols. 
 
Anonymized (de-identified) data generated from biospecimens used for future correlative research, 
including somatic and constitutional (germline) genomic data, may be shared with other researchers or 
deposited in a publicly accessible or controlled-access data repositories. Correlative study results and data 
will not be returned to individual patients. 
 

 
 
 
 
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14. IMAGING REPOSITORY 
 
                   14.1 Image Collection 
 
Image collection is a required component of this protocol, in order to perform future correlative science 
objectives.   
 
From the date of this protocol revision, collaborating sites will submit ALL mammograms to the Imaging 
and Radiation Oncology Core (IROC) Quality Assurance Review Center (QARC). If breast ultrasound, 
breast MRI, contrast-enhanced mammography, and/or image guided breast biopsies is performed 
during the surveillance or study period, those images with corresponding reports are also requested for 
submission.   
 
In addition, a request will be made to submit ALL retrospective imaging previously undertaken at each 
site for AFT-25 that has not been required for QARC submission under previous versions of the protocol.  
 
If a core/vacuum-assisted biopsy or surgical procedure is performed for a finding identified during follow 
up on either the AM or surgery arm, the last diagnostic mammogram that immediately predates the 
core/vacuum-assisted biopsy or surgical excision (with positive DCIS margins) will be requested for each 
event.  Four standard screening views as well as all diagnostic views, including all magnification views are 
requested.  
 
Image Type 
Status 
Required 
Ship To 
Mammography 
 
Screening and diagnostic 
mammogram immediately 
predating diagnostic 
core/vacuum-assisted 
biopsy or surgical biopsy 
(with positive DCIS 
margins)  
Four standard screening 
views plus all diagnostic 
and magnification views 
Quality Assurance 
Review Center 
Mammography 
 
Diagnostic mammogram 
immediately predating 
core/vacuum-assisted 
biopsy or surgical biopsy 
(with positive DCIS 
margins) performed for a 
finding identified during 
follow up 
Four standard screening 
views plus all diagnostic 
and magnification views 
Quality Assurance 
Review Center 
 
Diagnostic imaging data may be submitted in digital/electronic format on CD-ROM to QARC, although 
submission via sFTP is preferred; duplicate films or printouts will not be collected.   De-identified digital 
mammograms will be in DICOM format with PHI redacted. Screen-film mammograms will be digitized 
using mammography grade scanners, with PHI blocked during scanning or digitally cropped out after 
scanning. De-identification will be performed with procedures approved by each institution’s IRB and/or 
information security office.  It will be emphasized that the software used to de-identify images does not 
remove the date of the scan. Other PHI will be replaced with the protocol number and Patient Study ID.  
 

 
 
 
 
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Collaborating sites will also provide a copy of mammography reports for the images, with PHI redacted 
except for exam date in month/year. This will be provided electronically in each subject’s image folder.  
These files may also be submitted in digital/electronic format on CD-ROM to QARC, although submission 
via sFTP is preferred. Multiple studies for the same patient may be submitted on one CD/DVD; however, 
only one patient will be submitted per CD/DVD. QARC will be available for questions or more information. 
 
Digital data submission instructions including instructions for obtaining a sFTP account, can be found at 
www.QARC.org, following the link labeled digital data. Alternatively, if submission via sFTP is not feasible, 
the imaging may be burned to a CD and mailed to QARC at the address below, as explained in the prior 
paragraphs. 
 
All images and reports should to be shipped to the address below: 
 
IROC Rhode Island QA Center - QARC 
UMass Chan Medical School 
640 George Washington Highway 
Building B, Suite 201 
Lincoln, RI 02865-4207 
 
 
 
NOTE: If protocol therapy is discontinued early then QARC must be notified of the reason(s) and the 
date the patient stopped therapy. The notification must be submitted in writing via email to: 
 or 
. 
 
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