Role of Contrast Enhanced Spectral Mammography to Predict Upgrade Rates of Biopsy Proven Atypical Ductal Hyperplasia
Phase: NA
Conditions: Atypical Ductal Hyperplasia
Sponsor: Dana-Farber Cancer Institute

 
 
 
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Protocol Title: Role of Contrast Enhanced Spectral Mammography to Predict Upgrade 
Rates of Biopsy Proven Atypical Ductal Hyperplasia 
 
 
NCT Number:  NCT03505372 
 
 
 
 
12.09.2019 
 

DF/HCC Protocol #: 17-694 
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DF/HCC Protocol #: 17-694 
 
TITLE: Role of Contrast Enhanced Spectral Mammography to predict upgrade rates of 
biopsy proven atypical ductal hyperplasia 
 
Coordinating Center: 
Beth Israel Deaconess Medical Center 
 
Principal Investigator (PI): 
Jordana Phillips, MD 
BIDMC 
330 Brookline Avenue, Boston, MA 02215 
617 667 1630 
617-667-8212 
jphilli2@bidmc.harvard.edu 
 
Other Investigators: 
Priscilla J Slanetz, MD MPH 
BIDMC 
pslanetz@bidmc.harvard.edu 
 
Tejas Mehta, MD MPH 
BIDMC 
tmehta@bidmc.harvard.edu 
 
Vandana Dialani, MD 
BIDMC 
vdialani@bidmc.harvard.edu 
 
Valerie Fein-Zachary, MD 
BIDMC 
vfeinzac@bidmc.harvard.edu 
 
Jane Karimova, MD 
BIDMC 
ekarimov@bidmc.harvard.edu 
 
Michael Fishman, MD 
BIDMC 
mfishma1@bidmc.harvard.edu 
 
Amy Patel, MD 
BIDMC 
apatel21@bidmc.harvard.edu 
 
Rashmi Mehta, MD 
BIDMC 
rmehta3@bidmc.harvard.edu 
 

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Parisa Lotfi, MD 
BIDMC 
plotfi@bidmc.harvard.edu 
 
Ted A. James, MD 
BIDMC 
Tajames@bidmc.harvard.edu 
 
Zahra Karimi 
BIDMC 
zkarimi@bidmc.harvard.edu 
 
 
 

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Study Coordinator:  
Layla Rahimi 
BIDMC 
lrahimi@bidmc.harvard.edu 
 
NCI-Supplied Agent(s):  NA 
 
 
Study Exempt from IND Requirements per 21 CFR 312.2(b).   
 
 
SCHEMA 
 
 
 
 
 
 
 
Breast Biopsy is performed 
(stereotactic, US) 
ADH diagnosed 
CESM performed 
Patients with concurrent 
breast cancer in the same 
quadrant are excluded 
Surgical Excision 
Patients without surgical 
excision 

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TABLE OF CONTENTS 
 
SCHEMA .........................................................................................................................................4 
1. 
OBJECTIVES ......................................................................................................................7 
1.1 
Study Design ............................................................................................................7 
1.2 
Primary Objectives...................................................................................................8 
1.3 
Secondary Objectives...............................................................................................8 
2. 
BACKGROUND .................................................................................................................8 
2.1 
Study Disease(s).......................................................................................................8 
2.2 
Rationale ..................................................................................................................8 
3. 
PARTICIPANT SELECTION .............................................................................................8 
3.1 
Eligibility Criteria ....................................................................................................9 
3.2 
Exclusion Criteria ..................................................................................................10 
3.3 
Inclusion of Women and Minorities ......................................................................10 
4. 
REGISTRATION ..............................................................................................................10 
4.1 
General Guidelines for DF/HCC Institutions ........................................................10 
4.2 
Registration Process for DF/HCC Institutions .......................................................11 
5. 
TREATMENT AND/OR IMAGING PLAN .....................................................................11 
5.1 
Pre-Treatment Criteria ...........................................................................................11 
5.2 
Duration of Follow Up ...........................................................................................11 
5.3 
Criteria for Taking a Participant Off Study ...........................................................11 
6. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................12 
6.1 
Expected Toxicities ................................................................................................12 
6.2 
Adverse Event Characteristics ...............................................................................12 
6.3 
Expedited Adverse Event Reporting ......................................................................13 
6.4 
Expedited Reporting to Hospital Risk Management .............................................13 
6.5 
Routine Adverse Event Reporting .........................................................................14 
7. 
IMAGING AGENT INFORMATION ..............................................................................14 
8. 
STUDY CALENDAR .......................................................................................................14 
9. 
MEASUREMENT OF EFFECT........................................................................................14 
9.2 
Other Response Parameters ...................................................................................15 
10. 
DATA REPORTING / REGULATORY REQUIREMENTS ...........................................15 
10.1 
Data Reporting .......................................................................................................15 
10.2 
Data Safety Monitoring..........................................................................................15 
11. 
STATISTICAL CONSIDERATIONS...............................................................................16 
11.1 
Study Design/Endpoints.........................................................................................16 

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11.2 
Sample Size, Accrual Rate and Study Duration ....................................................17 
11.3 
Interim Monitoring Plan ........................................................................................17 
11.4 
Analysis of Primary Endpoints ..............................................................................17 
11.5 
Analysis of Secondary Endpoints ..........................................................................18 
12. 
PUBLICATION PLAN .....................................................................................................18 
REFERENCES ..............................................................................................................................18 
 
 
 

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1. OBJECTIVES 
 
Our study objective is to determine whether contrast enhanced spectral mammography (CESM) 
can predict which cases of atypical ductal hyperplasia (ADH) diagnosed at core needle biopsy 
will upgrade to breast malignancy at the time of surgical excision. 
 
Hypothesis:  CESM can reliably predict which cases of ADH will upgrade to malignancy at the 
time of surgical excision. 
 
1.1 
Study Design 
 
This is a prospective clinical pilot study evaluating whether CESM can predict upgrade rates to 
malignancy at the time of surgical excision.  All study participants with a diagnosis of ADH on 
core needle biopsy, who will be getting subsequent surgical excision, will have a CESM prior to 
surgical excision.  CESM outcomes will be compared with the surgical outcomes to determine 
whether CESM can predict upgrade to malignancy. 
 
Study Population:  Women > 30 years of age with a diagnosis of ADH identified by ultrasound 
and stereotactic core biopsy who will be getting subsequent surgical excision will be included in 
this study. 
 
Recruitment and Enrollment: No formal publicity of the research study will be performed.  
Subjects will be approached for study participation by a research coordinator after their diagnosis 
of ADH and completed diagnostic work-up for this diagnosis. Interested subjects will then be 
enrolled in the study. 
 
Image acquisition: CESM will be performed according to BIDMC clinical protocols for image 
acquisition. Omnipaque 350 (the standard CT contrast agent) will be used at a dose of 1.5 mL of 
contrast per kilogram of body weight at an injection rate of 3 mL/second to a maximum in dose 
of 150 ml.  The patient’s weight will be confirmed with measurement on a scale by the 
technologists, as is done in clinical practice, and documented on both clinical forms and case 
report forms. 
 
Image interpretation:  Two radiologists will independently interpret the CESM exam.  
Radiologists will have access to all the pertinent prior history and routine imaging. Each 
radiologist will document their interpretation of the biopsy site and up to 2 additional findings 
per exam using the Breast Imaging-Reporting and Data System (BI-RADS). The radiologist will 
also provide a BI-RADS code for the overall exam.  If there is a discrepancy in interpretation for 
any finding, then a third radiologist will be the tie-breaker.  The description of the site of atypia 
will be excluded from the clinical report and will be entered into a research note to be included in 
the online medical record.  This will ensure that the surgeon will not be biased by the CESM 
interpretation of the area of atypia. In addition, all individual and final interpretations will be 
documented in the case report forms.  Incidental findings identified on CESM (defined by >2cm 
away and distinct from the biopsied mass) will be managed according to standard of care.   
 
Pathology:  Two pathologists will review the percutaneous biopsy specimen and the excisional 
biopsy specimen and provide independent interpretations regarding the presence/absence of 

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ADH, DCIS, and invasive cancer.  If there is disagreement, a third pathology will be the tie-
breaker. Final pathology will be recorded on the case report form as well as the online medical 
record. 
 
Surgical Management:  The presumed initial surgical treatment plan will be recorded based on 
the imaging findings at the time of diagnostic imaging.  The final surgical treatment will also be 
recorded.  
 
1.2 
Primary Objectives 
 
To determine whether CESM can predict upgrade rates of biopsy proven ADH at surgical 
excision 
 
1.3 
Secondary Objectives 
 
To evaluate how CESM impacts surgical management of patients diagnosed with ADH 
 
2. BACKGROUND 
 
2.1 
Study Disease(s) 
 
Atypical ductal hyperplasia (ADH) is a common pathology result after percutaneous breast biopsy.  
Although not malignant itself, ADH is viewed as a precursor lesion to breast cancer.  The literature 
reports highly variable upgrade rates of ADH to breast cancer (1-4).  As a result, the standard of 
care is to perform surgical excision on all patients with this diagnosis at biopsy to identify potential 
cancer.  
 
2.2 
Rationale 
 
Preliminary attempts to identify those cases of ADH that will upgrade to cancer using breast MRI 
has been performed and has shown promise (5-9).  CESM is an imaging tool that uses a dual energy 
technique after contrast administration to identify breast cancer.  The exam provides two sets of 
images for interpretation.  One set has the appearance of conventional mammographic images and 
the other highlights areas of contrast uptake, similar to breast MRI.  As a result, a CESM provides 
information on both morphology/density and vascularity, without the need for breast MRI.  This is 
beneficial as CESM is a lower cost, faster, more universally accessible exam than MRI given that it 
is an add-on unit to conventional mammography equipment.  
 
Our objective is to perform a preliminary study to determine whether we can predict upgrade of 
atypia to malignancy using CESM.  The results of this study will drive a larger study on the role of 
CESM in this setting. 
 
3. PARTICIPANT SELECTION 
 
Given that this study involves an FDA approved imaging test that is used in clinical care with a 
well-established risk profile, and does not involve a therapeutic agent or investigational device, 
informed consent will be performed by any member of the study team, including the study 

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coordinator. 
 
3.1 
Eligibility Criteria  
 
3.1.1 Women 
3.1.2 Age, Minimum 30 years.  CESM is an imaging exam that uses radiation and is not 
typically employed in women younger than age 30 due to potentially negative biologic 
effects on glandular breast tissue. 
3.1.3 Participants who had a percutaneous breast biopsy (to include stereotactic, tomosynthesis, 
or ultrasound guided) that revealed ADH 
3.1.4 Participants will be undergoing surgical excision to remove the ADH. 
3.1.5 Participants must have normal organ and marrow function as defined by a GFR ≥60 
mL/min/1.73 m2 to be performed per clinical protocol. 
 
CLINICAL PROCOTOL USED AS REFERENCE FOR THIS STUDY:  
(i)  Patients  ≥65 years without underlying renal insufficiency get GFR tested within 6 months 
of the exam.   
(ii)  Patients < 65 years without underlying renal insufficiency do not require an GFR 
calculation) 
(iii)  Patients  ≥65 years with known underlying renal insufficiency get GFR tested within 1 
month of the exam.   
(iv)  Patients < 65 years with known renal insufficiency get GFR tested within 1 month of the 
exam.   
 
3.1.6 Because of the potential teratogenic effects of radiation, women of child-bearing potential 
must agree to use adequate contraception (hormonal or barrier method of birth control; 
abstinence) prior to study entry, until the CESM is performed.  Should a woman become 
pregnant or suspect she is pregnant, she should inform the study team prior to getting the 
CESM. 
3.1.7 Ability to understand and the willingness to sign a written informed consent document. 
 
 
 
 
 
 
 
 
 
 
 
 

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3.2 
Exclusion Criteria 
 
3.2.1 Participants with a core biopsy diagnosis of atypia with associated malignancy (in the 
same quadrant) will be excluded. 
3.2.2 Participant had a breast MRI that was performed after the diagnosis of ADH but before 
surgical excision 
3.2.3 Participants who have a known allergy to contrast media. 
3.2.4 Participants who have a known severe allergic response to one or more allergens, as 
defined by anaphylaxis. 
3.2.5 Participants with persistent asthma as defined by the National Heart, Lung, and Blood 
Institute. 
3.2.6 Participants with renal insufficiency or failure, as determined by a point of care renal 
function blood test. 
3.2.7 Participants who are breastfeeding are excluded because there is an unknown but potential 
risk for adverse events in nursing infants secondary to contrast administration in the 
mother. 
3.2.8 Participants with the following underlying medical conditions: multiple myeloma, 
myasthenia gravis, dysproteinemias, severe cardiac disease, aortic stenosis, primary 
pulmonary hypertension, cardiac arrythmia, or severe cardiomyopathy.  These underlying 
medical conditions may make the participant more likely to develop a contrast reaction.  
This is based on the ACR contrast manual version 10.3 and hospital policy. 
3.2.9 Participants with thyroid carcinoma or thyroid disease for whom systemic radioactive 
iodine therapy is part of planned diagnostic work-up or treatment within 2 months 
following the contrast mammogram study. 
3.2.10 Participants with a concurrent active illness including, but not limited to, symptomatic 
congestive heart failure, unstable angina pectoris, cardiac arrhythmia, thyroid storm. 
3.2.11 Pregnant women are excluded from this study because CESM uses radiation with the 
potential for teratogenic or abortifacient effects. This will be defined by a urine 
pregnancy test prior to the CESM study. 
 
3.3 
Inclusion of Women and Minorities 
 
Women of all races and ethnic groups are eligible for this trial. 
 
4. REGISTRATION  
 
4.1 
General Guidelines for DF/HCC Institutions 
 
Institutions will register eligible participants in the Clinical Trials Management System (CTMS) 
OnCore. Registrations must occur prior to the initiation of protocol therapy. Any participant not 
registered to the protocol before protocol therapy begins will be considered ineligible and 
registration will be denied. 
 
An investigator will confirm eligibility criteria and a member of the study team will complete the 
protocol-specific eligibility checklist. 
 

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Following registration, participants may begin protocol therapy. Issues that would cause 
treatment delays should be discussed with the Overall Principal Investigator (PI). If a participant 
does not receive protocol therapy following registration, the participant’s registration on the 
study must be canceled. Registration cancellations must be made in OnCore as soon as possible.  
 
4.2 
Registration Process for DF/HCC Institutions 
 
DF/HCC Standard Operating Procedure for Human Subject Research Titled Subject Protocol 
Registration (SOP #: REGIST-101) must be followed.   
 
5. TREATMENT AND/OR IMAGING PLAN 
 
The CESM exam will be performed according to clinical protocol.  Omnipaque 350 (the 
standard CT contrast agent) will be administered at a dose of 1.5 mL of contrast per kilogram of 
body weight at an injection rate of 3 mL/second, according to clinical protocol.  Images will be 
acquired within approximately 2-12 minutes of contrast injection. A low energy and high 
energy image will be acquired of each breast in two projections for a total of four images per 
breast. The voltage will be based on breast tissue thickness and will conform to the 
Mammography Quality Standards Act guidelines for quality control. The total radiation dose of 
CESM has been shown to be approximately 20-80% greater than the dose of a standard 
mammogram (11,12). Please see 1.1 above for the detailed study design.   
 
A clinical report will be generated and entered into the online medical record.  The description 
of the site of atypia will be excluded from the clinical report and will be entered into a research 
note to be included in the online medical record.  This will ensure that the surgeon will not be 
biased by the CESM interpretation of the area of atypia. 
 
All incidental areas identified on the CESM study (>2cm away and distinct from the biopsied mass) 
will be managed according to standard of care. 
 
5.1 
Pre-Treatment Criteria 
 
5.1.1 GFR ≥60 per the clinical protocol.  If a GFR is not available, then a point of care renal 
function test will be performed and reviewed on the day of the exam before the patient 
receives the CESM. 
5.1.2 Negative urine pregnancy test. If the patient is of child-bearing potential, then this will be 
performed and reviewed on the day of the CESM before the patient receives the exam. 
 
5.2 
Duration of Follow Up 
 
Participants will be followed until they have surgical excision for their ADH.  No additional 
follow-up will subsequently be performed unless clinically indicated. 
 
The de-identified imaging data may be used for future undefined research.  This has been 
included in the informed consent document. 
5.3 
Criteria for Taking a Participant Off Study 
 

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Participants will be removed from study when any of the following criteria apply: 
 If surgical excision is not performed within 2 years of the study. 
 Withdrawal of consent for data submission 
 Death 
 
The reason for taking a participant off study, and the date the participant was removed, must be 
documented in the case report form (CRF). 
 
When a participant is removed from protocol therapy and/or is off of the study, the relevant Off-
Treatment/Off-Study information will be updated in OnCore. 
 
6. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial. Given that 
the contrast mammogram will be acquired according to standard of care technique without 
alterations in duration, contrast agent, or contrast type and given that the AE profile for this 
imaging exam is well established, we will not be capturing AEs for the purposes of analysis.  We 
intend to only capture AEs for those patients who initiate phone calls to our department. Should 
a patient contact the research team, the PI or co-investigator will evaluate and decide the best 
management, to include referring patient to the primary care physician for further management 
or sending patient to the emergency department. 
 
The following list of reported and/or potential AEs (Section 7.1) and the characteristics of an 
observed AE (Section 7.2) will determine whether the event requires expedited reporting in 
addition to routine reporting. 
 
6.1 
Expected Toxicities 
 
6.1.1 
Adverse Event List(s) for contrast mammogram 
 
Risk of toxicity is related to the contrast agent that is administered during the imaging 
exam. Risks include allergic, allergic-like, or physiologic type of reaction to the 
contrast agent.  There is also the risk for contrast induced nephropathy. 
 
Risk of toxicity is also related to the risk of biologic harm from radiation 
administered during the exam.  However, this risk is non-measurable during the 
course of this study. 
 
6.2 
Adverse Event Characteristics 
 
 CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 will be utilized for AE reporting.  All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.0.  A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 

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 For expedited reporting purposes only:   
- 
AEs for the agent(s) that are listed above should be reported only if the adverse event 
varies in nature, intensity or frequency from the expected toxicity information which 
is provided. 
- 
Other AEs for the protocol that do not require expedited reporting are outlined in the 
next section (Expedited Adverse Event Reporting) under the sub-heading of Protocol-
Specific Expedited Adverse Event Reporting Exclusions. 
 
 Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
6.3 
Expedited Adverse Event Reporting  
 
6.3.1 Investigators must report to the Overall PI any serious adverse event (SAE) that occurs 
after the initial dose of study treatment, during treatment, or within 30 days of the last 
dose of treatment on the local institutional SAE form.  
 
6.3.2 
DF/HCC Expedited Reporting Guidelines 
 
Investigative sites within DF/HCC will report AEs directly to the DFCI Office for 
Human Research Studies (OHRS) per the DFCI IRB reporting policy.  
 
 
 
 
Attribution 
DF/HCC Reportable AEs 
Gr. 2 & 3 AE 
Expected 
Gr. 2 & 3 AE 
Unexpected 
Gr. 4 AE Expected 
Gr. 4 AE 
Unexpected 
Gr. 5 AE 
Expected or 
Unexpected 
Unrelated 
Unlikely 
Not required 
Not required 
5 calendar days# 
5 calendar days 
24 hours* 
Possible 
Probable 
Definite 
 
Not required 
 
5 calendar days 
 
5 calendar days# 
 
5 calendar days 
 
24 hours* 
# If listed in protocol as expected and not requiring expedited reporting, event does not need to be reported. 
 
* For participants enrolled and actively participating in the study or for AEs occurring within 30 days of the last 
intervention, the AE should be reported within 1 business day of learning of the event. 
 
 
 
6.4 
Expedited Reporting to Hospital Risk Management 
 
Participating investigators will report to their local Risk Management office any participant 
safety reports or sentinel events that require reporting according to institutional policy.  
 

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6.5 
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions to the Overall PI on the 
toxicity case report forms.  AEs reported through expedited processes (e.g., reported to the 
IRB, FDA, etc.) must also be reported in routine study data submissions. 
 
7. IMAGING AGENT INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational or other agents 
administered in this study can be found in Section 7.1. 
 
8. STUDY CALENDAR 
 
 
 
Visit 1a 
 
Screening 
& exam 
Informed Consent 
X 
Medical History  
X 
Urine pregnancy 
Test 
Xb 
Blood Test 
Xb 
Contrast 
Mammogram 
X 
 
a If abnormal findings are detected on the contrast mammogram, there is the potential that 
additional standard of care tests and procedures will need to be performed.  These may occur on 
the same day of the contrast mammogram or at a later date. 
b Blood and urine samples will be taken if standard of care samples are not available. 
 
9. MEASUREMENT OF EFFECT 
 
9.1.1 Methods for Evaluation of Disease on Conventional mammography, ultrasound 
 
Two radiologists will retrospectively and independently review the pre-biopsy 
mammogram and ultrasound that had been performed for clinical purposes.  They will 
each provide a BI-RADS code of the biopsied area based on the combined assessment of 
the relevant pre-biopsy imaging.  If there is a discrepancy in interpretation, then a third 
radiologist will be the tie-breaker. 
 
9.1.2 Methods for Evaluation of Disease on CESM 
 
Two radiologists will prospectively review the CESM, and will use a third as tie-breaker.  
The CESM will be evaluated for the biopsy site and up to two additional findings in 
either breast.  The biopsy site will be evaluated for abnormal findings that would suggest 
malignant involvement such as abnormal enhancement around the biopsy site, abnormal 
calcifications or masses.  The result of the consensus will be documented in the clinical 

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report. 
 
All measurements should be taken and recorded in metric notation using a digital 
measurement tool.  A BI-RADS code will be assigned to each finding.  This code 
provides a probability of malignancy score as well as a management recommendation. 
 
9.1.3 Methods for Evaluation of Disease on Pathology 
 
Each biopsy and surgical excision specimen will be reviewed by two pathologists 
independently to determine the presence of malignancy.  If there is a discrepancy, then a 
third pathologist will be the tie-breaker. 
 
9.2 
Other Response Parameters 
 
9.2.1 Methods for Evaluation of Impact on Surgical Management 
The treatment plan that would be recommended based on imaging at the time of ADH 
diagnosis will be documented on a CRF form.  This will be compared with the final 
treatment plan that is created after the CESM study is performed.  Included in this 
evaluation will be a description of additional procedures initiated by the CESM exam.  
This will include the number of false positive and true positive additional biopsies, 
additional surgical procedures, and additional department visits. 
 
10. DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 
 
10.1 
Data Reporting 
 
10.1.1 Method 
 
Patients will be registered in the Oncore system. Study patient data will be captured in an 
institutional RedCap system designed and maintained by the study team. 
 
10.2 
Data Safety Monitoring 
 
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity 
and accrual data from this study. The committee is composed of clinical specialists with 
experience in oncology and who have no direct relationship with the study. Information that 
raises any questions about participant safety will be addressed with the Overall PI and study 
team. 
 
The DSMC will review each protocol up to four times a year or more often if required to review 
toxicity and accrual data. Information to be provided to the committee may include: up-to-date 
participant accrual; current dose level information; DLT information; all grade 2 or higher 
unexpected adverse events that have been reported; summary of all deaths occurring with 30 
days of intervention for Phase I or II protocols; for gene therapy protocols, summary of all deaths 

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while being treated and during active follow-up; any response information; audit results, and a 
summary provided by the study team. Other information (e.g. scans, laboratory values) will be 
provided upon request.  
 
11. STATISTICAL CONSIDERATIONS 
 
This is a pilot study in which patients with a diagnosis of ADH on percutaneous biopsy will have 
a CESM prior to surgical excision to determine whether CESM can predict upgrade of atypia to 
malignancy.  
 
Based on the literature of breast MRI, which we assume to have similar performance to CESM, 
we would need 130-150 patients to show that the false negative rate is less than 3% with 95% 
confidence to allow CESM to be used for this indication in clinical practice.  Given the 
limitations of recruiting that number of patients, and the absence of any data on this topic for 
CESM, a decision was made to do a pilot study to first determine whether CESM can distinguish 
between benign and malignant pathology.   
 
Therefore:  
Null hypothesis: the proportion of patients with positive CESM findings is the same in the 
malignant and benign groups;  
 
The alternative hypothesis is that the proportion of patients with positive CESM findings is 
different in the malignant and benign groups (two-tailed hypothesis). 
 
11.1 
Study Design/Endpoints 
 
The primary outcome will be whether the biopsy site on CESM is coded as benign or malignant 
and how that correlates with the pathologic diagnosis of the surgically excised specimen, as 
benign or malignant.   
 
The biopsy site and up to 2 additional findings will be coded according to the Breast Imaging-
Reporting and Data System (BI-RADS), ranging from 1-5. An overall code for each exam will then be 
generated that corresponds to the most suspicious finding in the study.  BI-RADS codes 1, 2, and 3 
associated with the corresponding categories of negative, benign findings, and probably benign 
findings will be classified as negative (benign). BI-RADS codes 4 and 5 associated with the 
corresponding categories of suspicious and highly suspicious for malignancy will be classified as 
positive ( malignant).   
 
Negative truth is defined by a benign diagnosis by the final outcome of pathologic review.  
Positive truth is defined by a malignant diagnosis (ductal carcinoma in situ and invasive caner) by 
the final outcome of pathologic review. 
 
The secondary outcome will be to understand the impact of CESM for ADH evaluation on surgical 
management. The pre-CESM and post-CESM final surgical management plans will be compared 
descriptively. 
 

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11.2 
Sample Size, Accrual Rate and Study Duration 
 
For the primary outcome: 
The expected group sizes for 0.05 significance level and 0.9 power, assuming sensitivity of 0.9 and 
specificity of 0.8 (based on aggregate data from multiple studies in the literature, references 6-10), and 
0.2 incidence rate (20% of cases becoming malignant in the sample based on data from our clinical 
practice), suggest 6 patients in the malignant group, 5.5 of whom are expected to have 
positive CESM findings, and 24 patients in the benign group, 5 of whom are expected to have 
positive CESM findings. 
 
Given that we identify 60 number of atypia per year and expect 30% enrollment, we expect 
recruitment to be approximately 1.5 years. 
 
Although we will be calculating CESM’s performance characteristics (including sensitivity, 
specificity, positive predictive value, negative predictive value, and false negative rate), we will not 
be using these performance characteristics as primary objectives in our study as the number of 
participants involved is too small to draw significant conclusions. 
 
For the secondary outcome: This is exploratory and descriptive statistics will be used to evaluate 
the impact of CESM on surgical management of ADH. 
 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
 
Males 
 
Total 
Hispanic or Latino 
5 
+ 
 
= 
 
Not Hispanic or Latino 
25 
+ 
 
= 
 
Ethnic Category: Total of all subjects 
30 
(A1) + 
 
(B1) = 
 
(C1) 
Racial Category 
 
American Indian or Alaskan Native 
0 
+ 
 
= 
 
Asian 
5 
+ 
 
= 
 
Black or African American 
12 
+ 
 
= 
 
Native Hawaiian or other Pacific 
Islander 
0 
+ 
 
= 
 
White 
13 
+ 
 
= 
 
Racial Category: Total of all subjects 
 
(A2) + 
 
(B2) = 
 
(C2) 
 
(A1 = A2) 
 
(B1 = B2) 
 
(C1 = C2) 
 
11.3 
Interim Monitoring Plan 
 
There are no plans to conduct interim monitoring unless requested by the DSMC (see section 
11.2). 
 
11.4 
Analysis of Primary Endpoints 
 

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See sections 11.1 and 11.2 
 
11.5 
Analysis of Secondary Endpoints 
 
See sections 11.1 and 11.2 
 
12. PUBLICATION PLAN 
 
The results should be made public within 24 months of reaching the end of the study. The end of 
the study is the time point at which the last data items are to be reported, or after the outcome 
data are sufficiently mature for analysis, as defined in the section on Sample Size, Accrual Rate 
and Study Duration. If a report is planned to be published in a peer-reviewed journal, then that 
initial release may be an abstract that meets the requirements of the International Committee of 
Medical Journal Editors. A full report of the outcomes should be made public no later than three 
(3) years after the end of the study.  
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