Comparison of Abbreviated Breast MRI and Digital Breast Tomosynthesis in Breast Cancer Screening in Women With Dense Breasts
Phase: NA
Conditions: Asymptomatic
Sponsor: ECOG-ACRIN Cancer Research Group

 
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Table of Contents 
 
1. 
Statistical Analysis Plan (SAP) ................................................................................................................................. 2 
2. 
Study Protocol ........................................................................................................................................................ 15 
 
 
 

 
 
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1. Statistical Analysis Plan (SAP) 
 
 
 
EA1141: Comparison of Abbreviated Breast MRI and Digital Breast Tomosynthesis in Breast Cancer 
Screening in Women with Dense Breasts 
 
Statistical Analysis Plan (SAP) 
 (10/10/2019) 
 
 
 
Study Chair: 
Study Co-chairs: 
 
 
Protocol Statistician: 
Protocol Epidemiologist:       
 
Data Manager: 
Project Manager: 
 
 
 
 
Christopher Comstock, MD 
Christiane Kuhl, MD 
Gillian Newstead, MD 
 
Constantine Gatsonis, PhD 
Ilana Gareen, PhD 
 
Melissa Tepper, MS 
Sharon Mallett, MS  
 
 
 
 
Prepared by Bradley S. Snyder, MS 
 
 
 
ECOG-ACRIN Biostatistics Center  
Center for Statistical Sciences  
Brown University Box G-S121-7  
121 South Main Street  
Providence, RI 02912  
tel: 401-863-9181 
 
 
 
 

 
 
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Table of Contents 
 
I. 
Introduction ......................................................................................................................................................... 4 
II. 
General Principles ............................................................................................................................................... 4 
III. 
Study Objectives ................................................................................................................................................. 4 
IV. 
Study Population and Design .............................................................................................................................. 5 
V. 
Sample Size Considerations ................................................................................................................................ 7 
VI. 
Changes from the Original Protocol ................................................................................................................... 7 
VII. 
Analysis Sets ....................................................................................................................................................... 8 
VIII. Eligibility ............................................................................................................................................................ 8 
IX. 
Analysis Definitions ........................................................................................................................................... 8 
A. 
Primary and Secondary Endpoints ........................................................................................................ 8 
B. 
Exploratory Post Hoc Endpoints ........................................................................................................ 10 
X. 
Demographics and Risk Score Summary .......................................................................................................... 11 
XI. 
Statistical Analysis ............................................................................................................................................ 12 
A. 
Statistical Analysis of the Primary Endpoint ...................................................................................... 12 
B. 
Statistical Analysis of Secondary Endpoints ...................................................................................... 12 
C. 
Statistical Analysis of Exploratory Post Hoc Endpoints ..................................................................... 12 
D. 
Adjustment for Multiplicity of Comparisons ...................................................................................... 13 
XII. 
References ......................................................................................................................................................... 14 
 
 
 

 
 
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I. 
Introduction 
This Statistical Analysis Plan (SAP) for EA1141 is based on the protocol version dated February 26, 2018 
(amendment 4), and describes details on statistics and analyses to be reported in the primary paper, which will 
include the primary aim, secondary aim #1(a), and secondary aim #2.  Other secondary aims are not included in 
this SAP, and will be addressed in separate publications in the future as data become available. A complete list of 
study objectives can be found in section III of this document. 
 
 
II. 
General Principles 
The analysis and statistical reporting will be conducted by the ECOG-ACRIN Biostatistics Center Office located at 
Brown University.  All analyses will be performed using SAS version 9.4, or R version 3.4.4, or higher. 
 
 
III. 
Study Objectives 
The primary objective of EA1141 was to compare the rate of detection of invasive cancers between the initial 
abbreviated breast MRI (year 0 AB-MR) and the initial digital breast tomosynthesis (year 0 DBT). 
 
Secondary objectives include: 
• 
#1: To compare the positive predictive value of biopsy, call back rates, and short-term follow up rates after 
AB-MR and DBT on both (a) the initial (year 0) screening, and (b) 1 year follow up (year 1) studies. 
• 
#2: To estimate and compare the sensitivity and specificity of AB-MR and DBT, using the 1 year follow up 
to define a reference standard. 
• 
#3: To compare patient-reported short-term quality of life related to diagnostic testing with AB-MR and 
DBT using the Testing Morbidities Index. 
• 
#4: To compare willingness to return for testing with AB-MR vs DBT within the recommended screening 
interval, and to explore factors associated with willingness to return for screening. 
• 
#5: To compare the tumor biology of invasive cancers and DCIS detected on AB-MR and DBT. 
• 
#6: To estimate the incident cancer rate during the 3 years following the year 1 AB-MR/DBT when patients 
return to standard screening. 
 
 

 
 
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IV. 
Study Population and Design 
Participants must be women of age 40 to 75 years with mammographically dense breasts [ACR BI-RADS lexicon 
categories c or d (heterogeneous or extreme fibroglandular tissue) on their most recent prior screening] who are 
scheduled for routine screening DBT; must be asymptomatic for breast disease; must be able to undergo breast MRI 
with contrast enhancement; and, must agree to not undergo screening ultrasound of the breast for the duration of the 
one-year study imaging period.  Participants must not be pregnant or breast-feeding; must not have previously had a 
breast MRI or molecular breast imaging (MBI, MIBI); must not have undergone a screening breast ultrasound within 
12 months prior to randomization; must have no known breast cancer (DCIS or invasive cancer); must not be currently 
undergoing treatment for breast cancer; must not be planning surgery for a high risk lesion; must not be taking 
chemoprevention for breast cancer; and, must not be suspected of being at high-risk for breast cancer as defined by 
the ACS breast MR screening recommendations (lifetime risk of 20-25%).  A complete listing of all study inclusion 
and exclusion criteria can be found in section 3 of the study protocol. 
 
All patients will undergo both DBT and AB-MR within 30 days following registration. Generally, the DBT and AB-
MR will be performed on the same day and interpreted by two different radiologists, each blinded to the other modality.  
However, DBT and AB-MR can be performed within 24 hours of each other, as long as each radiologist remains 
blinded to the results of the other modality.  Patients will be randomized to the order of which study is performed first. 
If DBT is the first test, any additional imaging (spot compression/magnification view and/or ultrasound) recommended 
from the screening DBT views should be completed and a final recommendation recorded on the DBT imaging data 
forms by the interpreting radiologist prior to the AB-MR. If AB-MR is performed first, the results should be recorded 
on the AB-MR imaging data forms prior to DBT. No biopsy should be performed until both the DBT and AB-MR 
have been completed. All suspicious findings on either the DBT or AB-MR should be biopsied regardless of the 
recommendation of the other modality. If the same suspicious lesion is detected on both DBT and AB-MR, the 
interpreting radiologists will determine the best modality for biopsy guidance. High risk lesions on core biopsy, such 
as ADH and LCIS, will be managed as per local site standard practice.  All women will undergo DBT and AB-MR at 
1 year in the same order as the baseline (year 0) DBT and AB-MR, and will be followed for 3 years after the year 1 
AB-MR/DBT when patients return to standard screening. 
 
In addition, patients will be recruited at the time of randomization into the patient reported outcomes portion of the 
study, and will be asked to complete forms approximately 2 weeks after the baseline (year 0) screening. 
 
 
 
 

 
 
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The study schema is as follows: 
 
 
Women ages 40-75 with 
dense breasts already 
scheduled for routine 
screening DBT
R
A
N
D
O
M
I
Z
A
T
I
O
N
Arm A (DBT First)
Years 0 and 1 DBT followed by 
AB-MR. 
Year 0 PRO/QOL assessments 
to be completed approximately 2 
weeks after screenings.  
Accrual Goal= 1450
1.
Suspicious lesions detected on one or both of the modalities at the Year 0 or 1 time points will be biopsied as per local standard 
practice.
2.
Tissue collection and analysis for all cancers detected.
Arm B (AB-MR First)
Years 0 and 1 AB-MR followed 
by DBT. 
Year 0 PRO/QOL assessments 
to be completed approximately 2 
weeks after screenings.  
Return to routine mammographic 
screening and follow for 3 years

 
 
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V. 
Sample Size Considerations 
We are not aware of previous studies comparing AB-MR to DBT. Our choice of plausible values for the additional 
yield of AB-MR at the baseline (year 0) screen was based on a recent comparative study of MRI to FFDM, which 
reported an additional yield of about 12/1000 invasive cancers in a population of women at average risk 1,2.  We 
conservatively assumed that the difference in yield between AB-MR and DBT would be smaller, and computed the 
sample size required to detect a difference as low as 9/1000. The following table presents computations of the 
required sample size to ensure power 90% using a two-sided McNemar’s test of level 0.05, and for a range of values 
of the difference in detection rates and total rates of discordant pairs. Based on these computations, we selected a 
sample size of 1363 cases with complete data from both tests and pathology. This sample size is needed to ensure 
power 90% for a difference in the rates of invasive cancer detection of 9/1000 when the discordant pair rate is in the 
middle of the range. Assuming that adequate information to evaluate the primary endpoint will not be available on 
up to 6% of cases, a sample size of 1450 will provide power 90% to compare the diagnostic yield in invasive cancer 
between the two modalities. Women that complete either only the AB-MR or only the DBT, but not both studies at 
baseline (year 0), will not be included in the analysis. 
 
Power 
Sample size 
Difference in invasive 
cancer rates  
(AB-MR –DBT) 
Proportion of 
discordant cases 
0.90 
1191 
0.009 
0.010 
0.90 
1363 
0.009 
0.011 
0.90 
1552 
0.009 
0.012 
0.90 
1057 
0.010 
0.011 
0.90 
1197 
0.010 
0.012 
0.90 
949 
0.011 
0.012 
 
 
VI. 
Changes from the Original Protocol 
The original protocol (dated April 18, 2016) has undergone 4 amendments:   
 
Amendment 1 (dated November 15, 2016) amended the inclusion/exclusion criteria to exclude patients with prior 
molecular breast imaging (MBI, MIBI); mandated a pregnancy test be done within 2 weeks prior to randomization 
in women suspected of being pregnant, or unsure of their pregnancy status; and clarified blood sample submissions.     
 
Amendment 2 (dated January 26, 2017) corrected a typographical error in the inclusion/exclusion criteria, 
specifically clarifying that patients must have mammographically dense breasts (ACR BI-RADS lexicon categories 
c or d) on their most recent prior screening.  
 
Amendment 3 (dated July 25, 2017) loosened protocol criteria to allow the AB-MR and DBT screening exams to be 
done up to 24 hours apart, as long as the exams were still performed in the indicated randomized order; defined an 
allowable window for year 1 screening (no less than 11 months to no more than 13 months from baseline (year 0) 
screening); mandated and clarified that patients were to have follow-up contact through a phone call at 6 months (+/- 
1 month) after the baseline screening, and immediately prior to the year 1 screening, and every 6 months (+/-1 
month) thereafter for 3 years post year 1 screening; further clarified optional fast scanning for AB-MR for 
participating sites; and further clarified that the mandated pregnancy test for women uncertain of pregnancy status 
would be per local site standard of practice.   
  

 
 
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Amendment 4 (dated February 26, 2018) updated CTSU and Medidata RAVE language, updated the CTCAE 
version, clarified language regarding submission to TRIAD, and clarified language regarding tissue collection and 
follow-up contact. 
VII. 
Analysis Sets 
This section defines patient subsets which will be referred to throughout the remainder of the document.   
 
Enrolled Set:  All subjects registered to the trial, regardless of eligibility. 
 
Analysis Set:  All eligible subjects with both the baseline (year 0) AB-MR and the baseline (year 0) DBT 
completed.  In particular, the following patients are excluded: 
• 
Ineligible patients (i.e. patients documented to have failed the protocol inclusion/exclusion criteria) 
• 
Patients which did not complete either the baseline (year 0) AB-MR or the baseline (year 0) DBT, or both. 
 
A study flowchart showing the derivation of the analysis set, as well as patient exclusions, will be prepared.   
 
 
VIII. 
Eligibility 
Documented ineligibility will be tabulated, along with the reasons for failed inclusion/exclusion criteria.  In 
addition, the number of eligibility waivers, and reasons for waiver, will be summarized, if applicable.  
 
 
IX. 
Analysis Definitions 
 
The primary endpoint is the invasive cancer detection rate based on the baseline (year 0) screening for each 
modality.  Secondary endpoints to be reported in the manuscript will be assessed for the baseline screening. For each 
modality we will estimate and compare, (a) sensitivity, (b) specificity, (c) positive predictive value (PPV) of biopsy, 
and (d) additional imaging recommendation rate.  Exploratory, pre-specified endpoints will include (a) the overall 
(invasive and DCIS) cancer detection rate, (b) interval cancer rate, (c) lesion-level estimated PPV of biopsy, (d) 
local stage of cancers detected, and (e) characteristics of cancers based on histopathological and immuno-
histochemical information.  Definitions of these endpoints are provided below. 
A. Primary and Secondary Endpoints 
i. Invasive cancer detection rate:  For both modalities, invasive cancer detection will be defined at the patient-
level.  For DBT, the numerator will consist of the number of patients with at least one lesion scored as BI-
RADS 3, 4 or 5 on the Tomosynthesis YR-0 Lesions form, with subsequent pathology for that lesion 
verifying invasive disease on either the Needle Biopsy Pathology form or the Surgical Biopsy Pathology 
form; the denominator will consist of the number of patients screened.  Similarly, for AB-MR, the 
numerator will consist of the number of patients with at least one lesion scored as BI-RADS 3, 4 or 5 on the 
MRI YR-0 Lesions form, with subsequent pathology for that lesion verifying invasive disease on either the 
Needle Biopsy Pathology form or the Surgical Biopsy Pathology form; the denominator will consist of the 
number of patients screened. 
 
ii. Sensitivity/specificity: Per protocol, institutions were to conduct patient follow-up at 6 months (+/- 1 month) 
and 12 months (+/- 1 month, but prior to year 1 screening), consisting both of patient contact (by telephone) 
to ask regarding breast cancer status, as well as record assessment at the local institution.  These data were 
captured on the Follow-up Patient Questions form and the RA Follow-up Records Assessment form.  The 
reference standard will be defined as follows.  Subjects with breast cancer (invasive or DCIS) detected on 
the year 0 screening, or with breast cancer (invasive or DCIS) reported at any time from the year 0 to the 

 
 
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year 1 screening based on follow-up data, will be considered reference standard positive.  Patients with no 
breast cancer reported up to the time of the year 1 screening will be considered reference standard negative.  
However, subjects which are not imaged at year 1, and which have <11 months of patient follow-up (<330 
days) post year 0 screening will be considered to have incomplete reference standard. 
 
Patient-level estimates of sensitivity and specificity will then be reported as follows.  Sensitivity will be 
estimated as the fraction of reference standard positive subjects for whom the imaging modality result is 
positive (BI-RADS 3-5), and where the location of the positive imaging finding is matched to the location of 
the cancer indicated by the reference standard.  Specificity will be estimated as the fraction of reference 
standard negative subjects for whom the imaging modality result was negative (BI-RADS 1-2). 
 
iii. PPV of biopsy.   
For DBT, PPV of biopsy will be defined and reported at the patient-level.   
a. 
The numerator will consist of the number of patients with DCIS or invasive disease (reported 
on either the Needle Biopsy Pathology form or the Surgical Biopsy Pathology form) resulting 
from a DBT finding recommended for biopsy.  The denominator will consist of the number of 
patients recommended for biopsy which received a biopsy.  Patients recommended for biopsy 
will consist of those patients with at least one lesion rated BI-RADS 4 or 5 on the 
Tomosynthesis YR-0 Lesions form, with biopsy recommended on the Final Management – 
Tomo Lesions form (either “Stereotactic-guided core biopsy”, “Ultrasound-guided core biopsy”, 
“MR-guided core biopsy”, or “Surgical biopsy”).   
 
In a similar manner, for AB-MR, PPV of biopsy will be defined and reported at the patient-level. 
b. The numerator will consist of the number of patients with DCIS or invasive disease (reported 
on either the Needle Biopsy Pathology form or the Surgical Biopsy Pathology form) resulting 
from an AB-MR finding recommended for biopsy.  The denominator will consist of the number 
of patients recommended for biopsy which received a biopsy.  Patients recommended for 
biopsy will consist of those patients with at least one lesion rated BI-RADS 4 or 5 on the MRI 
YR-0 Lesions form, with biopsy recommended on the Final Management – MRI Lesions form 
(either “Stereotactic-guided core biopsy”, “Ultrasound-guided core biopsy”, “MR-guided core 
biopsy”, or “Surgical biopsy”).   
 
iv. Additional imaging recommendation rate:  This metric will combine the call-back rate and the short term 
followup (STFU) rate, both defined below.  As the concept of a call back does not apply for AB-MR, we 
will define the additional imaging recommendation rate at the patient-level for purposes of comparison 
between the modalities.  For DBT, the additional imaging recommendation rate will consist of a 
recommendation of either a call back or STFU.  For AB-MR, the additional imaging recommendation rate 
will consist of a recommendation of STFU. 
 
a. 
Call back rate:  For DBT, call back will be defined at the patient-level.  A call back consists of a 
Yes response to either, or both, of the following questions on the Tomosynthesis YR-0 
Interpretation form: 
 
o 
“Were additional diagnostic views performed to evaluate a possible finding on the 
screening views?” 
o 
“Was targeted Ultrasound performed to evaluate a finding on DBT?” 
 
To calculate the call back rate for DBT, the numerator will consist of the number of patients 
with a call back and the denominator will consist of the number of patients screened.  For AB-

 
 
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MR, the definition of call back does not apply; accordingly, call back rate will not be estimated 
for AB-MR. 
 
b. Short-term follow up rate:  For both modalities, short-term follow up (STFU) will be defined at 
the patient-level.  For DBT, STFU consists of at least one lesion rated BI-RADS 3 on the 
Tomosynthesis YR-0 Lesions form; for MRI, STFU consists of at least one lesion rated BI-
RADS 3 on the MRI YR-0 Lesions form.  To calculate the STFU rate, for each modality, the 
numerator will consist of the number of patients with STFU and the denominator will consist of 
the number of patients screened.     
B. Exploratory Endpoints 
i. 
Overall cancer detection rate:  This metric will be defined identically to the invasive cancer detection rate, 
except that both DCIS and invasive cancers will contribute to the count.   
ii. Interval cancer rate:  Any cancer (invasive or DCIS) which was not detected on the baseline (year 0) 
screening, or from associated STFU from the baseline (year 0) screening, but which was reported based on 
subsequent patient follow-up prior to the year 1 screening will be defined as an interval cancer.  
 
iii. PPV of biopsy at the lesion-level:   
For DBT, PPV of biopsy will be defined and reported at the lesion-level.   
a. 
Test-positive (T+) will be defined as a lesion rated BI-RADS 4 or 5 on the Tomosynthesis YR-0 
Lesions form, with biopsy recommended on the Final Management – Tomo Lesions form (either 
“Stereotactic-guided core biopsy”, “Ultrasound-guided core biopsy”, “MR-guided core biopsy”, 
or “Surgical biopsy”), and with biopsy performed.  Disease-positive (D+) will be defined as a 
lesion recommended for biopsy with pathology of DCIS or invasive disease as reported on 
either the Needle Biopsy Pathology form or the Surgical Biopsy Pathology form.  PPV of biopsy 
for DBT will then be calculated as the ratio of disease-positive lesions to test-positive lesions, 
i.e. as the conditional probability P(D+/T+).    
In a similar manner, for AB-MR, PPV of biopsy will be defined and reported at the lesion-level. 
b. Test-positive (T+) will be defined as a lesion rated BI-RADS 4 or 5 on the MRI YR-0 Lesions 
form, with biopsy recommended on the Final Management – MRI Lesions form (either 
“Stereotactic-guided core biopsy”, “Ultrasound-guided core biopsy”, “MR-guided core biopsy”, 
or “Surgical biopsy”), and with biopsy performed.  Disease-positive (D+) will be defined as a 
lesion recommended for biopsy with pathology of DCIS or invasive disease as reported on 
either the Needle Biopsy Pathology form or the Surgical Biopsy Pathology form.  PPV of biopsy 
for AB-MR will then be calculated as the ratio of disease-positive lesions to test-positive 
lesions, i.e. as the conditional probability P(D+/T+). 
 
 
 
 

 
 
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X. 
Demographics and Risk Score Summary 
Demographics and baseline characteristics will be summarized for the Enrolled Set and the Analysis Set, both 
overall and by randomization arm.  Data will be presented in side-by-side columns to allow for the assessment of 
any potential selection bias. 
 
Enrolled Set and Analysis Set (side-by-side) 
• 
Demographics 
- 
Age 
- 
Race 
- 
Ethnicity 
• 
Randomization arm 
• 
Breast density  
• 
Family history of breast cancer 
• 
Family history of ovarian cancer 
• 
Prior benign breast biopsies 
• 
Breast Cancer Screening Consortium (BCSC) 5-year and 10-year risk scores 3.       
(NOTE: BCSC scoring was not specified in the protocol, but will be added for completeness to help 
describe the study cohort). 
 
 
 
 

 
 
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XI. 
Statistical Analysis  
A. Statistical Analysis of the Primary Endpoint 
Refer to section IX for the definition of the invasive cancer detection rate.  The total number of invasive cancers 
detected, as well as the number of patients in whom invasive cancer was detected, will be reported for each 
modality.   
 
The invasive cancer detection rate at the patient-level, along with corresponding 95% confidence interval calculated 
using the Wilson method, will be reported for each modality.  A 95% confidence interval for the difference in 
invasive cancer detection rates will also be reported using the Wald interval with Bonett-Price Laplace adjustment 4.  
The comparison of the invasive cancer detection rate between DBT and AB-MR will be conducted using a two-
sided exact McNemar’s test to account for the paired design.   
 
B. Statistical Analysis of Secondary Endpoints 
Refer to section IX for the definition of these various screening metrics.     
 
The comparison of the sensitivity and specificity of AB-MR and DBT will be conducted at the patient-level using a 
two-sided exact McNemar’s test to account for the paired design, with 95% confidence intervals for the sensitivity 
and specificity of each modality calculated using the Wilson method. 
 
The comparison of PPV of biopsy between DBT and AB-MR will be reported at the patient-level.  Generalized 
estimating equation (GEE) regression will be used as suggested by Leisenring et al 5, with the p-value reported from 
the resulting score test.  The 95% confidence interval for PPV of biopsy for each modality will be derived from the 
GEE model using the appropriate estimable contrasts with robust standard error.   
 
The comparison of the additional imaging recommendation rate at the patient-level between AB-MR and DBT will 
use a two-sided exact McNemar’s test to account for the paired design, with 95% confidence interval for each 
modality calculated using the Wilson method.   
 
C. Statistical Analysis of Exploratory Endpoints 
Refer to section IX for the definition of these exploratory screening metrics.     
 
The overall cancer detection rate, will be estimated at the patient-level, with 95% confidence interval for each 
modality calculated using the Wilson method.  The comparison of the overall cancer detection rate between DBT 
and AB-MR will be conducted using a two-sided exact McNemar’s test to account for the paired design. 
 
The interval cancer rate, along with corresponding 95% confidence interval using the Wilson method, will be 
reported. 
 
The PPV of biopsy at the lesion-level will also be compared between DBT and AB-MR.  Again, generalized 
estimating equation (GEE) regression will be used as suggested by Leisenring et al 5, with the p-value reported from 
the resulting score test.  The 95% confidence interval for PPV of biopsy for each modality will be derived from the 
GEE model using the appropriate estimable contrasts with robust standard error.   
 
The local stage and histopathological and immuno-histochemical information of each detected cancer will be 
reported, along with appropriate summaries. 

 
 
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D. Adjustment for Multiplicity of Comparisons 
A post hoc, non-protocol-specified Bonferroni adjustment will be used to adjust for multiplicity of inference, 
including the primary endpoint and the four secondary endpoints, for a total of 5 comparisons, as follows:   
1. Comparison of invasive cancer detection rate (primary aim) 
2. Comparison of sensitivity (secondary aim) 
3. Comparison of specificity (secondary aim) 
4. Comparison of PPV of biopsy (secondary aim) 
5. Comparison of additional imaging recommendation rate (secondary aim) 
 
Accordingly, we will use an adjusted alpha level of 0.05/5=0.01 when reporting these 5 comparisons.  The analyses 
of exploratory endpoints will not be adjusted for multiplicity.  
 
 
 
 

 
 
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XII. 
References 
1.  Kuhl CK, Schrading S, Strobel K, Schild HH, Hilgers RD, Bieling HB. Abbreviated breast magnetic resonance 
imaging (MRI): first postcontrast subtracted images and maximum-intensity projection-a novel approach to breast 
cancer screening with MRI. J Clin Oncol. 2014; 32(22):2304-10. 
 
2.  Schrading S KC. MRI screening of women at average risk of breast cancer. J Clin Oncol. 2013; 31:(suppl 26; 
abstr 1). 
 
3.  Tice JA, Miglioretti DL, Li CS, Vachon CM, Gard CC, Kerlikowske K.  Breast density and benign breast 
disease: risk assessment to identify women at high risk of breast cancer. J Clin Oncol.  2015; 33(28):3137-43. 
 
4.  Fagerland MW, Lydersen S, Laake P.  Recommended tests and confidence intervals for paired binomial 
proportions.  Statist. Med. 2014; 33:2850-75. 
 
5.  Leisenring W, Alonzo T, Pepe MS. Comparisons of predictive values of binary medical diagnostic tests for 
paired designs. Biometrics. 2000; 56(2):345–51. 
 
 
 

 
 
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2.   Study Protocol 
 
 
Comparison of Abbreviated Breast MRI and Digital Breast 
Tomosynthesis in Breast Cancer Screening in Women 
with Dense Breasts 
STUDY CHAIR: 
Christopher Comstock, M.D. 
STUDY STATISTICIAN: 
Constantine Gatsonis, Ph.D. 
STUDY CO-CHAIR: 
Christiane Kuhl, M.D. 
STUDY CO-CHAIR: 
Gillian Newstead, M.D. 
STUDY EPIDEMIOLOGIST: 
Ilana Gareen, Ph.D. 
BREAST COMMITTEE CHAIR: 
Kathy Miller, M.D. 
BREAST COMMITTEE IMAGING CHAIR:  Christopher Comstock, M.D. 
Version Date:  February 26, 2018 
 
STUDY PARTICIPANTS 
 
ACTIVATION DATE 
 
 
September 2, 2016 
 
 
Addendum #1 – 2/17 
 
 
Addendum #2 – 5/17 
ALLIANCE / Alliance for Clinical Trials in 
Oncology 
 
Addendum #3 – 9/17 
NRG / NRG Oncology 
 
Addendum #4 
SWOG / SWOG  
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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Table of Contents 
Schema ......................................................................................................................... 20 
1. 
Introduction ........................................................................................................... 21 
1.1 
Rationale for Proposed Phase II Study ....................................................... 21 
1.2 
Current Breast Cancer Screening ............................................................... 21 
1.3 
Abbreviated breast MRI (AB-MR) ............................................................... 22 
1.4 
Patient-Reported Outcomes (PRO) ............................................................ 23 
1.5 
Significance of the Study ............................................................................ 24 
2. 
Objectives ............................................................................................................. 26 
2.1 
Primary Endpoints ...................................................................................... 26 
2.2 
Secondary Endpoints ................................................................................. 26 
3. 
Selection of Patients ............................................................................................. 27 
3.1 
Eligibility Criteria ......................................................................................... 27 
4. 
Randomization Procedures ................................................................................... 30 
4.1 
Registration Demographics ........................................................................ 33 
4.2 
Eligibility Verification ................................................................................... 34 
4.3 
Additional Requirements ............................................................................ 34 
4.4 
Instructions for Patients who Do Not Complete Imaging Tests ................... 36 
5. 
Imaging Administration .......................................................................................... 37 
5.1 
Imaging Schedule ....................................................................................... 37 
5.2 
Imaging ....................................................................................................... 38 
5.3 
Adverse Event Reporting Requirements .................................................... 40 
5.4 
Expected Adverse Events .......................................................................... 45 
5.5 
Supportive Care.......................................................................................... 46 
5.6 
Duration of Follow-up ................................................................................. 46 
6. 
Study Parameters ................................................................................................. 47 
7. 
Statistical Considerations ...................................................................................... 49 
7.1 
Overview .................................................................................................... 49 
7.2 
Primary Endpoint ........................................................................................ 49 
7.3 
Secondary Endpoints ................................................................................. 50 
7.4 
Gender and Ethnicity .................................................................................. 52 
7.5 
Study Monitoring ......................................................................................... 54 
8. 
Patient Reported Outcomes (PRO) and Quality of Life (QOL) Administration....... 55 
8.1 
PRO/QOL Assessment Schedule ............................................................... 55 
8.2 
PRO/QOL Data Collection Process ............................................................ 55 
8.3 
ECOG-ACRIN Systems for Easy Entry of Patient Reported Outcomes 
(EASEE-PRO) ............................................................................................ 56 

 
 
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9. 
Specimen Submissions ......................................................................................... 59 
9.1 
Tumor Tissue and Blood Submissions to ECOG-ACRIN Central 
Biorepository and Pathology Facility (CBPF) .............................................. 59 
9.2 
Tumor Tissue Submissions to Genomic Health Inc (GHI) .......................... 61 
9.3 
ECOG-ACRIN Sample Tracking System .................................................... 63 
9.4 
Sample Inventory Submission Guidelines .................................................. 64 
10. Laboratory Research Studies ................................................................................ 65 
10.1 Oncotype DX for DCIS Score Assay .......................................................... 65 
10.2 PAM50 Assessment ................................................................................... 66 
10.3 Lab Data Transfer Guidelines ..................................................................... 67 
11. Electronic Data Capture ........................................................................................ 68 
12. Patient Consent and Peer Judgment .................................................................... 68 
13. References ............................................................................................................ 68 
Appendix I   American Cancer Society Guidelines for Breast Screening with MRI as an 
Adjunct to mammography ..................................................................................... 71 
Appendix II  Pathology Submission Guidelines ............................................................. 72 
Appendix III  Patient Thank You Letter .......................................................................... 79 
Appendix IV  ECOG Performance Status ...................................................................... 80 
 
 
 

 
 
18 | P a g e  
 
STUDY CHAIR 
Christopher Comstock, M.D., 
Memorial Sloan-Kettering Cancer Center, 
300 E. 66th St RM 733 
New York, NY 10065 
Phone: (646) 888-4500 
Fax: (646) 888-4515 
Email: comstocc@mskcc.org 
 
 
 

 
 
19 | P a g e  
 
CANCER TRIALS SUPPORT UNIT (CTSU) CONTACT INFORMATION 
For regulatory requirements: 
For patient enrollments: 
For study data 
submission:  
Regulatory documentation must be 
submitted to the CTSU via the 
Regulatory Submission Portal. 
Regulatory Submission Portal: 
(Sign in at www.ctsu.org, and 
select the Regulatory Submission 
sub-tab under the Regulatory tab.) 
Institutions with patients waiting 
that are unable to use the Portal 
should alert the CTSU Regulatory 
Office immediately at 1-866-651-
2878 to receive further instruction 
and support. 
Contact the CTSU Regulatory Help 
Desk at 1-866-651-2878 for 
regulatory assistance. 
Please refer to the patient enrollment 
section of the protocol for instructions 
on using the Oncology Patient 
Enrollment Network (OPEN) which can 
be accessed at 
https://www.ctsu.org/OPEN_SYSTEM/ 
or https://OPEN.ctsu.org. 
Contact the CTSU Help Desk with any 
OPEN-related questions at 
ctsucontact@westat.com. 
Data collection for this 
study will be done 
exclusively through 
Medidata Rave.  Please 
see the data submission 
section of the protocol 
for further instructions.  
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific Web page of the CTSU Member Web site located at https://www.ctsu.org.  
Access to the CTSU members’ website is managed through the Cancer Therapy and Evaluation Program 
- Identity and Access Management (CTEP-IAM) registration system and requires user log on with CTEP-
IAM username and password.  
For clinical questions (i.e., patient eligibility or treatment-related) Contact the Study PI of the 
Coordinating Group. 
For non-clinical questions (i.e., unrelated to patient eligibility, treatment, or data submission) 
contact the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com. All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
The CTSU Web site is located at   https://www.ctsu.org 
 
Rev. 9/17 
Rev. 2/17 

 
 
20 | P a g e  
 
Women ages 40-75 with 
dense breasts already 
scheduled for routine 
screening DBT
R
A
N
D
O
M
I
Z
A
T
I
O
N
Arm A (DBT First)
Years 0 and 1 DBT followed by 
AB-MR. 
Year 0 PRO/QOL assessments 
to be completed approximately 2 
weeks after screenings.  
Accrual Goal= 1450
1.
Suspicious lesions detected on one or both of the modalities at the Year 0 or 1 time points will be biopsied as per local standard 
practice.
2.
Tissue collection and analysis for all cancers detected.
Arm B (AB-MR First)
Years 0 and 1 AB-MR followed 
by DBT. 
Year 0 PRO/QOL assessments 
to be completed approximately 2 
weeks after screenings.  
Return to routine mammographic 
screening and follow for 3 years
Schema 
 

 
 
21 | P a g e  
 
1. 
Introduction 
1.1 
Rationale for Proposed Phase II Study  
Due to breast density notification legislation in many states, standard of practice 
breast cancer screening for many women with dense breasts now includes 
annual mammographic screening supplemented by whole breast ultrasound. In 
addition to concerns over the added costs and potential overdiagnosis of this 
approach, whole breast ultrasound suffers from high unnecessary biopsy and 
short-term follow up rates with only a mild increase in sensitivity.1 The purpose 
of this study is to evaluate a low-cost abbreviated breast MRI (AB-MR) 
protocol as a supplemental screening method to mammographic screening 
in women with dense breasts. In addition, the study will assess the interval 
cancer rate and compare the types and biologies of cancers detected on 
mammography to those found on MRI. If AB-MR proves to detect significantly 
more high-grade cancers than mammography while reducing interval cancers, 
future studies may be indicated to evaluate AB-MR as a stand-alone screening 
modality to replace mammography.  
1.2 
Current Breast Cancer Screening 
Film mammography has been shown in multiple clinical trials to reduce mortality 
from breast cancer.2-4 Sixty-seven percent of women 40 and older in the U.S. 
reported having a mammogram within the past 2 years. However, screening 
mammography has remained relatively unchanged for over 50 years and has 
been criticized for high false positive rates and possible overdiagnosis.5,6The 
sensitivity of mammography is related to breast density. Although registry data 
has reported the sensitivity of digital mammography in women with dense 
breasts to be as high as 83.6%, with a specificity of 88.7%, a prospective 
multicenter trial reported the sensitivity to be as low as 38% with a specificity of 
97%.7-9 Digital breast tomosynthesis (DBT) is a newly FDA-approved 3-
dimensional mammographic technique that is rapidly becoming the standard in 
many practices. Early trials have shown that DBT increases breast cancer 
detection compared to standard full field digital mammography (FFDM) with 
fewer call-backs and false positive biopsy recommendations.10-13 In a recent 
study by Friedewald et al of 454,850 examinations, the use of DBT plus FFDM 
versus FFDM alone increased the cancer detection rate from 4.2/1000 to 
5.4/1000.13 Of the cancers detected on DBT, 75% were invasive and 25% were 
DCIS. 
Due to the shortcomings of mammographic screening, particularly in women with 
dense breasts, multiple states have enacted legislation mandating that the 
patient and referring physician be notified when the mammographic pattern of 
fibroglandular tissue (FGT) is dense, and that additional screening should be 
considered. It is estimated that more than 50% of women fall into the dense 
breast category, with 40% having heterogeneously dense breasts and 10% 
having extremely dense.14 These breast density notification laws have led to a 
proliferation of supplemental screening methods in women with dense breasts. 
Ultrasound has become the primary supplemental imaging modality to screen 
women with dense breasts that are at average and intermediate risk for breast 
cancer. Multiple studies have consistently shown that screening breast 
ultrasound will detect an additional 3 to 4 cancers occult on FFDM per 1000 

 
 
22 | P a g e  
 
women screened that are predominantly invasive carcinomas.1,15 Although DBT 
is slightly more sensitive than FFDM for breast cancer detection, the data 
suggests that screening breast ultrasound will detect additional 
mammographically occult cancers even in women having DBT. 
Therefore, the current standard screening practice for women with dense breasts 
is combined screening with annual DBT and whole breast screening ultrasound. 
However, screening breast ultrasound has a number of limitations including time, 
cost, and a low PPV of approximately 8%, leading to a significant number of 
unnecessary biopsies and a much higher rate of recommendation for short-term 
interval follow up.1,15-16 The combined cost of DBT ($290) with ultrasound ($390) 
and the additional call-backs, unnecessary biopsies, and short-term follow-up 
studies represent a significant economic burden on health care costs. 17 A recent 
study by Sprague et al estimated the cost per QALY gained by combined 
screening with mammography and ultrasound was $320,000.16 In addition, this 
approach likely contributes to overdiagnosis and overtreatment. 
1.3 
Abbreviated breast MRI (AB-MR) 
Breast MRI is the most sensitive breast cancer screening test. MRI detects a 
significant number of additional breast cancers in intermediate to high risk 
women with dense breasts who have had combined screening with FFDM and 
whole breast ultrasound.18,19 In the ACRIN 6666 trial, breast MRI was performed 
in 612 women who had undergone 3 negative annual screening rounds with 
FFDM and whole breast screening ultrasound.18 The additional cancer yield of 
screening MRI in these women was 14.7/1000. Biopsy was recommended in 
43/612 (7%) women, yielding malignancy in 8 (19%).Of the 8 cancers detected, 6 
(75%) were invasive and 2 (25%) were ductal carcinoma in situ (DCIS). 
MRI has also been shown to be more sensitive than WBUS in screening women 
at average to intermediate risk with dense breasts. In one study that included 427 
asymptomatic women at mild to moderately increased risk for breast cancer and 
dense breasts with a negative FFDM and WBUS, screening MRI resulted in an 
additional cancer yield of 18.2/1000.20 There were 7 invasive cancers (64%) and 
4 cases (36%) of DCIS. The invasive cancers detected were small T1, node 
negative cancers, and both the invasive cancers and DCIS were predominantly 
high-grade tumors—what is generally considered “biologically significant” 
disease. Ultrasound in the 11 patients diagnosed with breast cancer was 
negative. 
The sensitivity of breast MRI is also substantially higher than FFDM in women at 
average breast cancer risk. In one study that included 1387 women who 
underwent 1705 annual screening breast MRIs, the additional cancer yield of 
MRI in average risk women was 11/1000.21 A total of 18 cancers were detected, 
including 11 invasive cancers (61%) with a mean size of 11 mm and 7 cases 
(39%) of DCIS. Nine (82%) of the 11 invasive cancers and 6 (86%) of the 7 
cases of DCIS were either intermediate or high grade disease. The PPV of 
biopsy in this study was 33% (18/54), which is comparable to the accepted rate 
for mammography and significantly higher than that of ultrasound. 
Despite its high diagnostic accuracy among breast cancer screening tests, the 
cost of MRI has precluded its use as a screening test for all women with dense 
breasts. One alternative is AB-MR, which uses a scan time of less than 10 

 
 
23 | P a g e  
 
minutes (compared with 25-40 minute time for non-abbreviated breast MRI) and 
reduces its cost to one that is comparable to WBUS. Combined screening with 
DBT and AB-MR may be the best method to screen women with dense 
breasts. 
Early studies of screening MRI interpreting an abbreviated protocol have shown 
equivalent sensitivity to full MRI with only a slight decrease in specificity. 20, 22-24 
Kuhl et al compared the sensitivity and specificity of an abbreviated and full 
protocol, and reported a sensitivity of 100% and specificity 94% using the 
abbreviated protocol, which included only one pre- and one post-contrast 
acquisition and their derived images. Given the vastly superior sensitivity and 
specificity of MRI compared to whole-breast ultrasound (WBUS), AB-MR may be 
the optimal, cost-efficient supplemental screening modality to DBT in women with 
dense breasts. 
Screening AB-MR has the potential to detect many cancers that are missed on 
screening mammography and ultrasound, leading to earlier treatment and 
potentially reduced mortality. At the same time, AB-MR maintains a high positive 
predictive value (PPV) and preferentially selects for biologically significant 
tumors, thereby potentially reducing overdiagnosis and overtreatmentfigure 1,19,25. 
This proposed study will evaluate the additional invasive cancer yield of AB-MR 
to digital breast tomosynthesis (DBT) and the 1 year interval cancer rate. In 
addition, the study will provide an assessment of breast cancer incidence during 
a 3 year interval following AB-MR. Multihance will be used as the contrast 
agent. The high relaxivity of Multihance may improve sensitivity since the AB-
MR protocol includes only early phase post-contrast imaging. 
 
1.4 
Patient-Reported Outcomes (PRO)   
1.4.1 
Background and Rationale for QOL Study  
Consensus recommendations for high-quality decisions regarding the 
choice to participate in breast cancer screening need to ask for and 
incorporate patient values and preference. We plan to ask patients to 
provide information on their experiences with AB-MRI and DBT, as 
well as their willingness to return for each test, and their preference 
for examiner gender.  Information may be used to compare the tests, 

 
 
24 | P a g e  
 
as well as to determine how best to develop informed consent and 
patient education to enhance patient adherence. 
1.4.2 
QOL Study Design  
For a detailed description of the patient reported outcomes (PRO) 
data collection process, please refer to Section 8.3. In brief, the 
questionnaire will be administered to women approximately 2 weeks 
after the Year 0 (baseline) DBT and AB-MR to assess their 
aniticipated and actual pain/discomfort, fear/anxiety, and 
embarrassment before and during each test, as well as their 
willingness to repeat each test. 
1.4.3 
Rationale for Quality of Life Measure Selection  
We plan to use the Testing Morbidities Index (TMI) to evaluate short-
term test-related quality of life.  The TMI is a validated instrument that 
assesses seven attributes: pain or discomfort before and during 
testing, fear or anxiety before and during testing, embarrassment 
during testing, and physical and mental function after testing. The TMI 
measures short-term functional health on a preference-based or 
psychometric scale, and previous studies have shown early evidence 
of content, construct, and discriminative validity of the TMI. 26–29 The 
measure is unique because it was specifically designed to evaluate 
patient responses to diagnostic testing. 
1.5 
Significance of the Study 
Ongoing breast density notification legislation has led to a dramatic change in 
breast cancer screening practices nationally. A significant number of women with 
dense breasts are undergoing annual mammographic screening supplemented 
by WBUS. However, screening ultrasound has been shown to only minimally 
increase breast cancer detection, and interval cancer rates remain significantly 
high. In addition, due to the poor performance of screening ultrasound, the 
proliferation of its use has led to a dramatic increase in cost, unnecessary 
biopsies, and increases in short-term follow up studies. Breast MRI has the ability 
to detect as many as 150% more cancers compared to screening ultrasound 
while maintaining a high PPV and preferentially detecting biologically significant 
disease. AB-MR imaging is a new, fast, low cost method of performing breast 
MRI and has the potential to be a superior alternative to screening breast 
ultrasound. In addition, the detection of biologically significant tumors at a 
smaller size and earlier stage will lead to an overall reduction in surgical 
and adjuvant therapies and their associated morbidities. This study, 
comparing AB-MR to DBT and evaluating its value as a supplemental screening 
modality, represents an advanced imaging, high-impact, phase II trial with the 
potential to change the standard of care and improve clinical outcomes for breast 
cancer patients. The results of this study may change how intermediate risk 
women with dense breasts are screened for breast cancer. This study may also 
provide exploratory data on AB-MR as a potential standalone replacement to 
screening mammography which could be performed every 2-3 years rather than 
annually. Patients will be followed for three years after the AB-MR to compare 
the impact of AB-MR on the historical expected incident cancer rate of screening 
mammography. Compared to annual screening with mammography and 

 
 
25 | P a g e  
 
ultrasound, this approach could substantially reduce the false positives, costs, 
and overdiagnosis of biologically insignificant tumors associated with current 
breast cancer screening. 

 
 
26 | P a g e  
 
2. 
Objectives 
2.1 
Primary Endpoints 
2.1.1 
To compare the rates of detection of invasive cancers between 
the initial AB-MR and DBT. 
2.2 
Secondary Endpoints 
2.2.1 
To compare the positive predictive value (PPV) of biopsies, call 
back rates, and short-term follow up rates after AB-MR and DBT 
on both the initial and 1 year follow up studies. 
2.2.2 
To estimate and compare the sensitivity and specificity of AB-MR 
and DBT, using the 1 year follow up to define a reference 
standard. 
2.2.3 
To compare patient-reported short-term quality of life related to 
diagnostic testing with AB-MR and DBT using the Testing 
Morbidities Index. 
2.2.4 
To compare willingness to return for testing with AB-MRI vs DBT 
within the recommended screening interval and explore factors 
associated with willingness to return for screening. 
2.2.5 
To compare the tumor biologies of invasive cancers and DCIS 
detected on AB-MR and DBT.  
2.2.6 
To estimate the incident cancer rate during 3 years following the 
year-1 AB-MR/DBT when patients return to standard screening. 
 

 
 
27 | P a g e  
 
3. 
Selection of Patients 
Each of the criteria in the checklist that follows must be met in order for a patient to be 
considered eligible for this study. Use the checklist to confirm a patient’s eligibility. For 
each patient, this checklist must be photocopied, completed and maintained in the 
patient’s chart.  
In calculating days of tests and measurements, the day a test or measurement is 
done is considered Day 0. Therefore, if a test is done on a Monday, the Monday 
four weeks later would be considered Day 28.  
ECOG-ACRIN Patient No. ____________________________ 
Patient’s Initials (L, F, M) _______________________ 
Physician Signature and Date ___________________ 
NOTE: 
CTEP Policy does not allow for the issuance of waivers to any protocol 
specified criteria 
(http://ctep.cancer.gov/protocolDevelopment/policies_deviations.htm). 
Therefore, all eligibility criteria listed in Section 3 must be met, without 
exception. The registration of individuals who do not meet all criteria listed in 
Section 3 can result in the participant being censored from the analysis of the 
study, and the citation of a major protocol violation during an audit.  All 
questions regarding clarification of eligibility criteria must be directed to the 
Group's Executive Officer (EA.ExecOfficer@jimmy.harvard.edu) or the 
Group's Regulatory Officer (EA.RegOfficer@jimmy.harvard.edu). 
NOTE: 
Institutions may use the eligibility checklist as source documentation if it has 
been reviewed, signed, and dated prior to randomization by the treating 
physician. 
3.1 
Eligibility Criteria 
3.1.1 
Patients must be women ages 40 to 75 years and scheduled for 
routine screening DBT. 
3.1.2 
Women must not be pregnant or breast-feeding as gadolinium 
enhanced MRI and screening DBT are contra-indicated. 
All females of childbearing potential who are uncertain if they could be 
pregnant or may be pregnant or as per local site standard of practice 
in women undergoing DBT and MRI must have a blood test or urine 
study within 2 weeks prior to randomization to rule out pregnancy. 
A female of childbearing potential is any woman, regardless of sexual 
orientation or whether they have undergone tubal ligation, who meets 
the following criteria: 1) has not undergone a hysterectomy or bilateral 
oophorectomy; or 2) has not been naturally postmenopausal for at 
least 24 consecutive months (i.e., has had menses at any time in the 
preceding 24 consecutive months). 
3.1.3 
Women of childbearing potential must be strongly advised to use an 
accepted and effective method of contraception or to abstain from 
sexual intercourse for the following year until the Year 1 AB-MR and 
DBT studies are performed. 
Rev. 2/17 
Rev. 5/17 

 
 
28 | P a g e  
 
3.1.4 
Patient’s breast density must be known; patients must have 
mammographically dense breasts, ACR BI-RADS lexicon categories c 
or d (heterogeneous or extreme fibroglandular tissue) on their most-
recent prior screening. 
3.1.5 
Patient must be asymptomatic for breast disease and undergoing 
routine screening. 
3.1.6 
Patient must have no known breast cancer (DCIS or invasive cancer), 
not currently undergoing treatment for breast cancer, or planning 
surgery for a high risk lesion (ADH, ALH, LCIS, papilloma, radial 
scar). 
3.1.7 
Patient must not be taking chemoprevention for breast cancer. 
3.1.8 
Patient must not have undergone screening breast ultrasound within 
12 months prior to randomization 
3.1.9 
Patient must not have previously had a breast MRI. 
3.1.10 
Patient must not have previously had molecular breast imaging (MBI, 
MIBI) 
3.1.11 
Patient must agree to not undergo screening ultrasound (of breast) for 
the duration of the 1 year study period as screening ultrasound adds 
no benefit in women undergoing breast MRI   
3.1.12 
Patient must not be suspected of being at high-risk for breast cancer, 
as defined by the ACS breast MR screening recommendations 
(lifetime risk of ≥ 20-25%). See Appendix I.  
3.1.13 
Patient must be able to undergo breast MRI with contrast 
enhancement. Patients unable to undergo breast MRI with contrast 
enhancement for any reason are ineligible. 
3.1.13.1 
No history of untreatable claustrophobia; 
3.1.13.2 
No presence of non MR compatible metallic objects or 
metallic objects that, in the opinion of the radiologist, would 
make MRI a contraindication. 
3.1.13.3 
No history of sickle cell disease 
3.1.13.4 
No contraindication to intravenous contrast administration; 
3.1.13.5 
No known allergy-like reaction to gadolinium or moderate or 
severe allergic reactions to one or more allergens as 
defined by the American College of Radiology (ACR); 
patient may be eligible if willing to undergo pre-treatment as 
defined by the institution's policy and/or ACR guidance (see 
http://www.acr.org/quality-safety/resources/contrast-manual 
for reaction definition and premedication guidance); 
Rev. 9/17 

 
 
29 | P a g e  
 
3.1.13.6 
No known or suspected renal impairment. Requirements for 
GFR prior to MRI as determined by local site standard 
practice. 
3.1.13.7 
Weight less than or equal to the MRI table limit; 
3.1.13.8 
No women who have had prior contrast enhanced 
mammography (CESM or CEDM). 
3.1.13.9 
No women who have breast prosthetic implants (silicone or 
saline). 
 
 
 
 
 
Physician Signature 
 
Date 
OPTIONAL: 
This signature line is provided for use by institutions wishing to 
use the eligibility checklist as source documentation. 
 
 
Rev. 9/17 

 
 
30 | P a g e  
 
4. 
Randomization Procedures 
CTEP Registration Procedures 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) 
policy require all individuals contributing to NCI-sponsored trials to register and to renew 
their registration annually.  To register, all individuals must obtain a Cancer Therapy 
Evaluation Program (CTEP) Identity and Access Management (IAM) account 
(https://ctepcore.nci.nih.gov/iam).  In addition, persons with a registration type of 
Investigator (IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) (i.e., 
clinical site staff requiring write access to OPEN, RAVE, or TRIAD or acting as a 
primary site contact) must complete their annual registration using CTEP’s web-based 
Registration and Credential Repository (RCR) (https://ctepcore.nci.nih.gov/rcr). 
Documentation requirements per registration type are outlined in the table below. 
Documentation Required 
IVR 
NPIVR 
AP 
A 
FDA Form 1572 
 
 
 
 
Financial Disclosure Form 
 
 
 
 
NCI Biosketch (education, training, 
employment, license, and 
certification) 
 
 
 
 
HSP/GCP training 
 
 
 
 
Agent Shipment Form (if applicable) 
 
 
 
 
CV (optional) 
 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to 
access all CTEP and CTSU (Cancer Trials Support Unit) websites and applications.  In 
addition, IVRs and NPIVRs must list all clinical practice sites and IRBs covering their 
practice sites on the FDA Form 1572 in RCR to allow the following: 
• 
Added to a site roster 
• 
Assigned the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN 
• 
Act as the site-protocol PI on the IRB approval 
• 
Assigned the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL). 
Additional information can be found on the CTEP website at 
<https://ctep.cancer.gov/investigatorResources/default.htm>.For questions, please 
contact the RCR Help Desk by email at <RCRHelpDesk@nih.gov>. 
CTSU Registration Procedures 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
IRB Approval:   
Each investigator or group of investigators at a clinical site must obtain IRB approval for 
this protocol and submit IRB approval and supporting documentation to the CTSU 
Regulatory Office before they can be approved to enroll patients.  Assignment of site 
registration status in the CTSU Regulatory Support System (RSS) uses extensive data 
Rev. Add4 
Rev. 9/17 
Rev. 2/17 

 
 
31 | P a g e  
 
to make a determination of whether a site has fulfilled all regulatory criteria including but 
not limited to the following: 
• 
An active Federal Wide Assurance (FWA) number 
• 
An active roster affiliation with the Lead Network or a participating organization 
• 
A valid IRB approval 
• 
Compliance with all protocol specific requirements. 
In addition, the site-protocol Principal Investigator (PI) must meet the following criteria: 
• 
Active registration status 
• 
The IRB number of the site IRB of record listed on their Form FDA 1572 
• 
An active status on a participating roster at the registering site. 
Sites participating on the NCI CIRB initiative that are approved by the CIRB for this 
study are not required to submit IRB approval documentation to the CTSU Regulatory 
Office. For sites using the CIRB, IRB approval information is received from the CIRB 
and applied to the RSS in an automated process. Signatory Institutions must submit a 
Study Specific Worksheet for Local Context (SSW) to the CIRB via IRBManager to 
indicate their intent to open the study locally.  The CIRB’s approval of the SSW is then 
communicated to the CTSU Regulatory Office.  In order for the SSW approval to be 
processed, the Signatory Institution must inform the CTSU which CIRB-approved 
institutions aligned with the Signatory Institution are participating in the study. 
Downloading Site Registration Documents:  
Site registration forms may be downloaded from the EA1141 protocol page located on 
the CTSU members’ website. 
• 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
• 
Click on the Protocols tab in the upper left of your screen 
• 
Either enter the protocol # in the search field at the top of the protocol tree, or 
• 
Click on the By Lead Organization folder to expand 
• 
Click on the ECOG-ACRINlink to expand, then select trial protocol #EA1141 
• 
Click on LPO Documents, Click on the Site Registration Documents link 
Requirements For EA1141 Site Registration:  
• 
IRB approval (For sites not participating via the NCI CIRB; local IRB 
documentation, an IRB-signed CTSU IRB Certification Form, Protocol of Human 
Subjects Assurance Identification/IRB Certification/Declaration of Exemption Form, 
or combination is accepted) 
• 
MRI Qualification (through the ACR Imaging Core Laboratory) 
• ACR breast MRI accreditation.  
• AB-MR reader training certification. 
Submitting Regulatory Documents 

 
 
32 | P a g e  
 
Submit required forms and documents to the CTSU Regulatory Office, where they will 
be entered and tracked in the CTSU RSS. 
Regulatory Submission Portal: www.ctsu.org  (members’ area)  Regulatory Tab  
 Regulatory Submission 
When applicable, original documents should be mailed to: 
CTSU Regulatory Office 
1818 Market Street, Suite 1100 
Philadelphia, PA 19103 
Institutions with patients waiting that are unable to use the Portal should alert the CTSU 
Regulatory Office immediately at 1-866-651-2878 in order to receive further instruction 
and support. 
Required Protocol Specific Regulatory Documents 
1. Copy of IRB Informed Consent Document. 
NOTE:  
Any deletion or substantive modification of information concerning risks or 
alternative procedures contained in the sample informed consent 
document must be justified in writing by the investigator and approved by 
the IRB. 
2. A.  CTSU IRB Certification Form. 
 
Or 
B.  Signed HHS OMB No. 0990-0263 (replaces Form 310). 
 
Or 
 
C.  IRB Approval Letter 
NOTE:  
The above submissions must include the following details: 
• 
Indicate all sites approved for the protocol under an assurance number. 
• 
OHRP assurance number of reviewing IRB 
• 
OHRP IRB Registration Number of reviewing IRB 
• 
Full protocol title and number 
• 
Version Date 
• 
Type of review (full board vs. expedited) 
• 
Date of review. 
• 
Signature of IRB official 
Checking Your Site’s Registration Status: 
You can verify your site registration status on the members’ section of the CTSU 
website: 
• Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
• Click on the Regulatory tab at the top of your screen 
• Click on the Site Registration tab 
• Enter your 5-character CTEP Institution Code and click on Go 

 
 
33 | P a g e  
 
NOTE: 
The status given only reflects compliance with IRB documentation and 
institutional compliance with protocol-specific requirements as outlined by the 
Lead Network. It does not reflect compliance with protocol requirements for 
individuals participating on the protocol or the enrolling investigator’s status 
with the NCI or their affiliated networks. 
Patient Enrollment 
Patients must not start protocol trial procedures prior to randomization. 
Imaging should start within thirty (30) working days after randomization.  
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network 
(OPEN). OPEN is a web-based registration system available on a 24/7 basis. To access 
OPEN, the site user must have an active CTEP-IAM account (check at 
<https://ctepcore.nci.nih.gov/iam>) and a 'Registrar' role on either the LPO or 
participating organization roster. Registrars must hold a minimum of an AP registration 
type. 
All site staff will use OPEN to enroll patients to this study. It is integrated with the CTSU 
Enterprise System for regulatory and roster data and, upon enrollment, initializes the 
patient in the Rave database.  OPEN can be accessed at https://open.ctsu.org or from 
the OPEN tab on the CTSU members’ side of the website at https://www.ctsu.org. To 
assign an IVR or NPIVR as the treating, crediting, consenting, drug shipment (IVR only), 
or investigator receiving a transfer in OPEN, the IVR or NPIVR must list on their Form 
FDA 1572 in RCR the IRB number used on the site’s IRB approval. 
Prior to accessing OPEN, site staff should verify the following: 
• 
All eligibility criteria have been met within the protocol stated timeframes. 
• 
All patients have signed an appropriate consent form and HIPAA authorization form 
(if applicable). 
NOTE: 
The OPEN system will provide the site with a printable confirmation of 
registration and treatment information.   Please print this confirmation for your 
records. 
Further instructional information is provided on the OPEN tab of the CTSU members’ 
side of the CTSU website at https://www.ctsu.org or at https://open.ctsu.org.  For any 
additional questions contact the CTSU Help Desk at 1-888-823-5923 or 
ctsucontact@westat.com. 
4.1 
Registration Demographics 
The following information will be collected at registration: 
4.1.1 
Protocol Number  
4.1.2 
Investigator Identification  
4.1.2.1 
Institution and affiliate name 
4.1.2.2 
Investigator’s name 
4.1.3 
Patient Identification  
4.1.3.1 
Patient’s initials (first and last) 

 
 
34 | P a g e  
 
4.1.3.2 
Patient’s Hospital ID and/or Social Security number 
4.1.3.3 
Patient demographics 
• 
Gender 
• 
Birth date (mm/yyyy) 
• 
Race 
• 
Ethnicity 
• 
Nine-digit ZIP code 
• 
Method of payment 
• 
Country of residence 
4.2 
Eligibility Verification  
Patients must meet all of the eligibility requirements listed in Section 3. 
4.3 
Additional Requirements  
4.3.1 
Patients must provide a signed and dated, written informed consent 
form. 
NOTE: 
Copies of the consent are not collected by the ECOG-
ACRIN Operations Office – Boston. 
4.3.2 
Biological specimens are to be submitted as indicated in Section 10. 
4.3.3 
Patient Reported Outcomes (PROs) must be reported using the 
ECOG-ACRIN Systems for Easy Entry of Patient Reported Outcomes 
(EASEE-PRO). See Section 8.2 
4.3.4 
Clinical data collection for this study will be done exclusively through 
the Medidata Rave clinical data management system. Access to the 
trial in Rave is granted through the iMedidata application to all 
persons with the appropriate roles assigned in Regulatory Support 
System (RSS). To access Rave via iMedidata, the site user must 
have an active CTEP-IAM account  
(check at < https://ctepcore.nci.nih.gov/iam >) and the appropriate 
Rave role (Rave CRA, Read-Only, CRA (Lab Admin, SLA or Site 
Investigator) on either the LPO or participating organization roster at 
the enrolling site. To the hold Rave CRA role or CRA Lab Admin role, 
the user must hold a minimum of an AP registration type.  To hold the 
Rave Site Investigator role, the individual must be registered as an 
NPIVR or IVR.  Associates can hold read-only roles in Rave 
Upon initial site registration approval for the study in RSS, all persons 
with Rave roles assigned on the appropriate roster will be sent a study 
invitation e-mail from iMedidata. To accept the invitation, site users 
must log into the Select Login (https://login.imedidata.com/selectlogin) 
using their CTEP-IAM user name and password, and click on the 
“accept” link in the upper right-corner of the iMedidata page. Please 
note, site users will not be able to access the study in Rave until all 
required Medidata and study specific trainings are completed. 
Trainings will be in the form of electronic learnings (eLearnings), and 
can be accessed by clicking on the link in the upper right pane of the 
iMedidata screen. 
Rev. Add4 

 
 
35 | P a g e  
 
Users that have not previously activated their iMedidata/Rave account 
at the time of initial site registration approval for the study in RSS will 
also receive a separate invitation from iMedidata to activate their 
account. Account activation instructions are located on the CTSU 
website, Rave tab under the Rave resource materials (Medidata 
Account Activation and Study Invitation Acceptance). Additional 
information on iMedidata/Rave is available on the CTSU members’ 
website under the Rave tab at www.ctsu.org/RAVE/ or by contacting 
the CTSU Help Desk at 1-888-823-5923 or by e-mail at 
ctsucontact@westat.com. 
4.3.5 
Digital Imaging Data Submission Using TRIAD 
All on-study imaging studies, including additional spot views and 
ultrasounds, are to be submitted to the TRIAD database. 
TRIAD is ACR’s proprietary image exchange application that will be 
used as the sole method of data transfer to the ACR Clinical 
Research Center Core Laboratory for this trial. TRIAD can be installed 
on one or several computers of choice within the institutional “firewall” 
and on the institutional network; internet access is required. The 
TRIAD application can then be configured as a DICOM destination on 
either scanner(s) and/or PACS system for direct network transfer of 
study related images into the TRIAD directory. When properly 
configured, the TRIAD software de-identifies, encrypts, and performs 
a lossless compression of the images before they are transferred to 
the ACR Imaging Core Laboratory image archive in Philadelphia. 
4.3.5.1 
TRIAD Access Requirements 
Site radiology staff who will submit images through TRIAD 
will need to be registered with the Cancer Therapy 
Evaluation Program (CTEP) and have a valid and active 
CTEP Identity and Access Management (IAM) account. 
and be registered as an AP, NPIVR or IVR. Please refer to 
CTEP Registration Procedures of the protocol for 
instructions on how to request a CTEP-IAM account and 
complete registration in RCR. 
To submit images, the site user must be on the site’s 
affiliate rosters and be assigned the 'TRIAD site user' role 
on the CTSU roster. Users should contact the site’s CTSU 
Administrator or Data Administrator to request assignment 
of the TRIAD site user role. RAs are able to submit 
standard of care imaging through the same method. 
4.3.5.2 
TRIAD Installations 
When a user applies for a CTEP-IAM account with the 
proper user role, he/she will need to have the TRIAD 
application installed on his/her workstation to be able to 
submit images. TRIAD installation documentation can be 
found by following this link 
https://triadinstall.acr.org/triadclient/ 
Rev. Add4 
Rev. 2/17 
Rev. Add4 
Rev. 2/17 
Rev. 2/17 

 
 
36 | P a g e  
 
This process can be done in parallel to obtaining your 
CTEP-IAM account username and password. 
If you have any questions regarding this information, 
please send an e-mail to the TRIAD Support mailbox at 
TRIAD-Support@acr.org or call 703-390-9858 
4.4 
Instructions for Patients Who Do Not Complete Imaging Tests  
If neither of the baseline imaging tests are completed, no further data will be 
collected and the patient will be excluded from the study. If a patient completes 
only one of the baseline imaging tests, initial imaging data and 1 year follow-up 
data are still required to be collected and must be submitted through Medidata 
Rave according to the schedule in the EA1141 Forms Completion Guidelines. 
However, DBT and AB-MR screening at year 1 are not required, and no further 
follow-up data beyond 1 year will be collected. 
All other patients are required to collect and submit all requested data through 
Medidata Rave according to the schedule in the EA1141 Forms Completion 
Guidelines. 

 
 
37 | P a g e  
 
5. 
Imaging Administration 
5.1 
Imaging Schedule 
All patients will undergo both DBT and AB-MR within 30 days following 
randomization. The DBT and AB-MR will be performed on the same day and 
interpreted by two different radiologists, each blinded to the other modality.  
Although it is optimal to perform the DBT and AB-MR on the same day, sites may 
perform the DBT and AB-MR within 24 hours of each other as long as the 
radiologists remain blinded to the results of the other modality. Patients will be 
randomized to the order of which study is performed first. If DBT is the first test, 
any additional imaging (spot compression/magnification view and or ultrasound) 
recommended from the screening DBT views should be completed and a final 
recommendation recorded on the DBT imaging data forms by the interpreting 
radiologist prior to the AB-MR. If AB-MR is performed first, the results should be 
recorded on the AB-MR imaging data forms prior to DBT. No biopsy should be 
performed until both the DBT and AB-MR have been completed. All suspicious 
findings on either the DBT or AB-MR should be biopsied regardless of the 
recommendation of the other modality. If the same suspicious lesion is detected 
on both DBT and AB-MR, the interpreting radiologists will determine the best 
modality for biopsy guidance. High risk lesions, such as ADH and LCIS, on core 
biopsy will be managed as per local site standard practice. 
The specifications for performance and interpretative guidelines of the AB-MR and 
DBT will follow methods outlined below; 
• Breast density will be assessed by the radiologist interpreting the DBT, based 
on the standard BI-RADS classifications. 
• Recommendations for findings on DBT will be based on ACR guidelines. 
Recommendation for findings on AB-MR will be based on the Society of 
Breast MRI interpretative guidelines. 
• The interpreting radiologist may refer to mammograms or ultrasounds from 
previous years while interpreting the DBT or AB-MR. The radiologist must 
only be blinded to the other imaging study performed that same day as part of 
the study protocol. 
• Tissue collection and analysis for all cancer, including both invasive cancer 
and DCIS. 
• All women will undergo DBT and AB-MR at 1 year in the same order as the 
baseline DBT and AB-MR. The year 1 follow up imaging must be completed 
no less than 11 months from baseline imaging and no more than 13 months 
from baseline imaging  
• Patients will have follow-up contact through a follow-up visit, email, or phone 
call 6 months (+/- 1 month) after the year 0 imaging and immediately prior to 
the year 1 imaging. Patients diagnosed with breast cancer in the interval 
between the year 0 and year 1 imaging studies will have no subsequent follow 
up and will not undergo the year 1 study imaging. 
• Patients will be asked, but not required, to forgo WBUS during the study 
period as this may confound the data and as WBUS has already been shown in 
multiple trials to have no added benefit after negative breast MRI. 
Rev. 2/17 
Rev. 9/17 
Rev. Add4 

 
 
38 | P a g e  
 
5.1.1 
ARM A (DBT first) 
Patients randomized to Arm A of this study will undergo DBT followed 
by AB-MR. Although it is optimal to perform the DBT and AB-MR on 
the same day, sites may perform the DBT and AB-MR within 24 hours 
of each other as long as the radiologists remain blinded to the results 
of the other modality, and any work up needed from the DBT (spot 
compression/magnification views and or ultrasound) is completed 
prior to the AB-MR. 
5.1.2 
ARM B (AB-MR first) 
Patients randomized to Arm B of this study will undergo AB-MR 
followed by DBT. Although it is optimal to perform the DBT and AB-
MR on the same day, sites may perform the DBT and AB-MR within 
24 hours of each other as long as the radiologists remain blinded to 
the results of the other modality. 
5.2 
Imaging 
5.2.1 
Magnetic Resonance Imaging 
5.2.1.1 
Site Qualification  
Prior to patient enrollment, all participating scanners must 
be ACR Accredited for Breast MRI. 
All interpreting physicians must have completed the 
Society of Breast MRI for AB-MR interpretation training.  
5.2.1.2 
Magnetic Resonance Imaging (MRI) Procedures 
MRI will be performed within 30 days after patient 
randomization. The bilateral breast MRI should be 
acquired on a 1.5T or 3.0T MRI scanner with a dedicated 
breast radiofrequency coil. The patient should be scanned 
in prone position.  
AB-MR is defined as a breast MRI fulfilling the following 
requirements:  
Total scan time of less than 10 min (including localizer) 
A localization scan 
1 pre- and 1 post-contrast gradient echo (GRE) axial 
acquisition; The center of K-space should be between 60 
and 90 seconds post contrast administration. Fat 
suppression is recommended if it is usual site practice. 
In-plane resolution of 1 mm or less 
Slice thickness of 3 mm or less 
For advanced imaging sites, optional fast temporal 
scanning at 3 phases between 0-30 seconds after contrast 
injection as long as the center of K-space of the post-
contrast GRE remains between 60 and 90 seconds. 
Rev. 9/17 
Rev. 9/17 
Rev. 5/17 

 
 
39 | P a g e  
 
For sites approved to perform the optional advanced 
imaging, fast temporal scanning to include phases of 
approximately 3.5sec for 3T magnets and 7sec for 1.5T 
magnets starting with the contrast injection until 30 
seconds after completion of the contrast injection. Optional 
fast scanning may only be performed if the center of K-
space of the post-contrast GRE remains between 60 and 
90 seconds. 
Axial T2 weighted sequence with in-plane resolution 
matching the GRE sequences and 3 mm or less slice 
thickness 
Sequence 
Slice 
Thickness 
Gap 
Maximum In Plane Pixel Dimension 
for Phase and Frequency 
Axial GRE 
≤ 3 mm 
0 mm 
≤ 1 mm 
Contrast Medium: An intravenous catheter will be inserted 
in the arm or hand prior to the start of imaging. For the 
contrast-enhanced study following the T2-weighted, 
Multihance (no substitutions allowed) gadolinium contrast 
agent will be administered intravenously using a power 
injector at a dose of 0.1 mmol/kg body weight and rate of 2 
ml/second, followed by a 20 ml saline flush.  
MRI Findings: The Society of Breast MRI interpretation 
guidelines for AB-MR will be followed by the interpreting 
radiologist at each site. Site radiologist will use the study 
specific forms to document MRI results. Each breast MRI 
will be reported using the standard BIRADS guidelines 
5.2.2 
Digital Breast Tomosynthesis (DBT) Procedure:  
DBT will be performed within 30 days after patient randomization. 
DBT technique will be defined as per local site standard of care, which 
may include the following: tomosynthesis views in the CC or MLO 
views or both views with either a 2D full field digital mammogram or 
synthetic 2D views. 
DBT Findings: 
DBT interpretation will be performed by radiologists at each site using 
the standard of care American College of Radiology BI-RADS lexicon. 
Work-up of suspicious findings may include spot compression or 
magnification views, as well as targeted ultrasound. Each DBT will be 
reported using the standard BI-RADS guidelines. 
BI-RADS® 
Category 
Overall Final Assessment 
1 
Negative 
2 
Benign Finding(s) 
Rev. 2/17 

 
 
40 | P a g e  
 
3 
Probably Benign Finding – Short-Interval Follow-Up Suggested 
4 
Suspicious Abnormality – Biopsy Should Be Considered 
5 
Highly Suggestive of Malignancy – Appropriate Action Should Be Taken 
6 
Known Biopsy-Proven Malignancy – Appropriate Action Should Be Taken 
5.2.3 
Central Imaging Quality Control and Collection  
All breast imaging will be transferred and stored at the ACR Imaging 
Core Laboratory for quality control review. 
For this protocol, the following images will be collected and submitted 
to the ACR Core Laboratory via TRIAD: 
• All clinical imaging exams performed as part of standard of 
care; 
• AB-MR and DBT performed as part of study protocol 
• Any other imaging scans performed as part of the study, 
including ultrasounds and biopsy imaging. 
• Please refer to Section 4.3.5 for detailed TRIAD access and 
installation instructions. 
5.3 
Adverse Event Reporting Requirements 
5.3.1 
Purpose 
Adverse event (AE) data collection and reporting, which are 
required as part of every clinical trial, are done to ensure the 
safety of the patients enrolled, as well as those who will enroll in 
future studies using similar agents.  
• Routine reporting: Adverse events are reported in a routine 
manner at scheduled times during a trial using Medidata Rave.   
• Expedited reporting: In addition to routine reporting, certain 
adverse events must be reported in an expedited manner for 
timelier monitoring of patient safety and care. The following 
sections provide information and instructions regarding expedited 
adverse event reporting. 
5.3.2 
Terminology 
• Adverse Event (AE): Any untoward medical occurrence 
associated with the use of a drug/procedure in humans, whether or 
not considered drug/procedure related. Therefore, an AE can be 
ANY unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal product/procedure, whether or not 
considered related to the medicinal product. 

 
 
41 | P a g e  
 
• Attribution: An assessment of the relationship between the 
adverse event and the protocol treatment/procedures, using the 
following categories. 
ATTRIBUTION DESCRIPTION 
Unrelated 
The AE is clearly NOT related to 
treatment/procedures. 
Unlikely 
The AE is doubtfully related to 
treatment/procedures. 
Possible 
The AE may be related to 
treatment/procedures. 
Probable 
The AE is likely related to 
treatment/procedures. 
Definite 
The AE is clearly related to 
treatment/procedures. 
• 
CTCAE:  The NCI Common Terminology Criteria for Adverse 
Events provides a descriptive terminology that is to be utilized for 
AE reporting.  A grade (severity) is provided for each AE term.  
• Expectedness: Expected events are those that have been 
previously identified as resulting from administration of the 
agent/procedure. An adverse event is considered unexpected, for 
expedited reporting purposes, when either the type of event or the 
severity of the event is NOT listed in the protocol or drug package 
insert. 
5.3.3 
Reporting Procedure 
This study requires that expedited adverse event reporting use 
CTEP’s Adverse Event Reporting System (CTEP-AERS). The CTEP’s 
guidelines for CTEP-AERS can be found at http://ctep.cancer.gov.  A 
CTEP-AERS report must be submitted electronically to ECOG-ACRIN 
and the appropriate regulatory agencies via the CTEP-AERS Web-
based application located at http://ctep.cancer.gov. 
In the rare event when Internet connectivity is disrupted a 24-hour 
notification is to be made by telephone to  
• the AE Team at ECOG-ACRIN (617-632-3610) 
• the FDA (1-800-FDA-1088)  
An electronic report MUST be submitted immediately upon re-
establishment of internet connection. 
Supporting and follow up data: Any supporting or follow up 
documentation must be uploaded to the Supplemental Data Folder in 
Medidata Rave within 48-72 hours. In addition, supporting or follow up 
documentation must be faxed to the FDA (800-332-0178) in the same 
timeframe.  
CTEP Technical Help Desk: For any technical questions or system 
problems regarding the use of the CTEP-AERS application, please 

 
 
42 | P a g e  
 
contact the NCI Technical Help Desk at ncictephelp@ctep.nci.nih.gov 
or by phone at 1-888-283-7457. 
5.3.4 
Determination of Reporting Requirements 
Many factors determine the reporting requirements of each individual 
protocol, and which events are reportable in an expeditious manner, 
including:   
• the phase (0, 1, 2, or 3) of the trial  
• whether the patient has received an investigational or commercial 
agent or both 
• the Common Terminology Criteria for Adverse Events (CTCAE) 
grade 
• the relationship to the study treatment/procedures (attribution) 
• the expectedness of the adverse event 
Using these factors, the instructions and tables in the following 
sections have been customized for protocol EA1141and outline the 
specific expedited adverse event reporting requirements for study 
EA1141.   

 
 
43 | P a g e  
 
5.3.5 
Steps to determine if an event is to be reported in an expedited 
manner: 
 
Identify the type and grade of the event using 
CTCAE v5.0. 
Determine if the event is related to the protocol 
treatment/procedures (attribution). 
With this information, review the chart in 
Section 5.3.6 to determine if event is reportable 
via CTEP-AERS. 
Refer to footnote b in Section 
5.3.6 to determine if the event 
meets the protocol specific 
reporting requirements for this 
study. If so, report the event 
via CTEP-AERS. 
Is the event reportable? 
No 
Yes 
 
Report the event via CTEP-AERS 
Determine the expectedness of the event. An 
unexpected event is defined as one where the 
type of severity of the event is not listed in the 
investigator’s brochure, package insert or 
protocol. 
Rev. Add4 

 
 
44 | P a g e  
 
5.3.6 
Expedited Reporting Requirements for protocol EA1141 
Expedited reporting requirements for adverse events experienced by patients on protocol EA1141 
Attribution 
Grade 4 
Grade 5a 
ECOG-ACRIN and 
Protocol-Specific 
Requirements 
Unexpected 
Expected 
Unexpected 
Expected 
See footnote  
(b) for special 
requirements. 
Unrelated or Unlikely 
 
 
7 calendar 
days 
7 calendar 
days 
Possible,  
Probable,  
Definite 
7 calendar 
days 
 
7 calendar 
days 
7 calendar 
days 
7 Calendar Days: Indicates a full CTEP-AERS report is to be submitted within 7 calendar days of learning of the 
event. 
a 
A death occurring while on study or within 30 days of the last dose of treatment requires both routine and 
expedited reporting, regardless of causality.  Attribution to treatment or other cause must be provided. 
NOTE: A death due to progressive disease should be reported as a Grade 5 “Disease progression” under the 
System Organ Class (SOC) “General disorder and administration site conditions”.  Evidence that the 
death was a manifestation of underlying disease (e.g. radiological changes suggesting tumor growth 
or progression: clinical deterioration associated with a disease process) should be submitted. 
NOTE: Any death that occurs > 30 days after the last dose of treatment/procedures and is attributed 
possibly, probably, or definitely to the treatment/procedures must be reported within 7 
calendar days of learning of the event.   
b 
Protocol-specific expedited reporting requirements: The adverse events listed below also require expedited 
reporting for this trial: 
Serious Events:  Any event following treatment/procedures that results in persistent or significant 
disabilities/incapacities, congenital anomalies, or birth defects must be reported via CTEP-AERS within 7 
calendar days of learning of the event. For instructions on how to specifically report these events via CTEP-
AERS, please contact the AEMD Help Desk at aemd@tech-res.com or 301-897-7497. This will need to be 
discussed on a case-by-case basis.  
Kidney Adverse Events:  Any grade 4 kidney adverse event must be reported via CTEP-AERS within 7 
calendar days of learning of the event, regardless of attribution. 
Nephrogenic Systemic Fibrosis (NSF) or Nephrogenic Fibrosing Dermopathy (NFD):  Any occurrence of 
Nephrogenic Systemic Fibrosis (NSF) or Nephrogenic Fibrosing Dermopathy (NFD) must be reported via 
CTEP-AERS within 7 calendar days of learning of the event, regardless of attribution. 
5.3.7 
Other recipients of adverse event reports and supplemental data 
Adverse events determined to be reportable via CTEP-AERS must 
also be reported by the institution, according to the local policy and 
procedures, to the Institutional Review Board responsible for oversight 
of the patient. 
Rev. Add4 

 
 
45 | P a g e  
 
5.4 
Expected Adverse Events 
All toxicity grades below are described using the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0. 
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 website (http://ctep.cancer.gov). 
5.4.1 
MRI 
• Anxiety/stress; 
• Claustrophobia; 
• Discomfort; 
• Rare, but Serious: Injury associated with foreign bodies and the 
MR magnet; this is most likely to occur should the institution fail 
to ask or should a participant fail to inform the site of 
contraindications to MR use (e.g., presence of metallic or surgical 
implants or metal pieces in the body). 
5.4.2 
Contrast injection/IV Needle Placement 
• Hematoma at the injection site 
• Phlebitis; 
• Bleeding; 
• Infection; 
• Bruising; 
• Minor discomfort; 
• Headache; 
• Nausea; 
• Vomiting; 
• Hives; 
• Temporary low blood pressure; 
• Allergic-type reaction; 
• Rare, but Serious: Kidney impairment, details follow. 
Rare but severe adverse events occur in approximately 15/100,000 
persons administered intravenous gadolinium. There is a risk of death 
in 1/100,000 persons. 
Precautions should be exercised for patients with severely impaired 
renal function or hemolytic anemia. The very unlikely possibility of a 
reaction, including anaphylactic-like or cardiovascular reactions, 
should be considered, especially for patients with a known sensitivity 
to gadolinium or history of asthma. 
Nephrogenic Systemic Fibrosis (NSF) or Nephrogenic Fibrosing 
Dermopathy (NFD), kidney disorders, may occur in patients with 

 
 
46 | P a g e  
 
moderate to end-stage kidney disease (glomerular filtration rate < 30 
mL/min/1.73m2) and in patients with renal dysfunction due to the 
hepatorenal syndrome or in the perioperative liver transplantation 
period after they have had a MRI scan with gadolinium-based MR 
contrast agents. 
NSF causes fibrosis of the skin and connective tissues throughout the 
body. Patients develop skin thickening that may prevent bending and 
extending joints, resulting in decreased mobility of joints. NSF usually 
starts in the lower extremities. Fibrosis can also develop in the 
diaphragm, muscles in the thigh and lower abdomen, and lung 
vessels. 
Reference: FDA/Center for Drug Evaluation and Research. May 23, 
2007 Available at: 
http://www.fda.gov/cder/drug/infopage/gcca/qa_200705.htm.  
5.4.3 
DBT 
• Bruising 
• Skin abrasion 
5.5 
Supportive Care  
5.5.1 
All supportive measures consistent with optimal patient care will 
be given throughout the study. 
5.6 
Duration of Follow-up  
For this protocol, all patients will be monitored for breast cancer diagnosis for a 
total of 3 years following the year 1 AB-MR and DBT. Patients in follow-up are to 
be contacted through follow-up visits, emails, or phone calls every 6 months (+/- 
1 month) for 3 years after year 1 imaging to check to see if the patient was 
diagnosed with cancer. If neither of the baseline imaging tests are completed, 
the patient will be excluded from the study and no further data will be collected. If 
a patient completes only one of the baseline imaging tests, baseline data and 1 
year of follow-up data are still required to be collected and must be submitted 
through Medidata Rave according to the schedule in the EA1141 Forms 
Completion Guidelines. However, the year-1 DBT and AB-MR will not be 
performed and no further follow-up data beyond 1 year will be collected. All other 
patients are required to collect and submit all requested data through Medidata 
Rave according to the schedule in the EA1141 Forms Completion Guidelines. 
The 1 year patient follow-up should be performed immediately prior to the year 1 
imaging to confirm the patient has not been diagnosed with an interval breast 
cancer. 
If a patient is diagnosed with a primary cancer during the study period, no 
subsequent follow up or further study imaging will be performed. Pathology 
reports and site standard tests are required to be submitted upon the diagnosis 
of a primary cancer. Data are required to be collected and submitted through 
Medidata Rave according to the schedule in the EA1141 Forms Completion 
Guidelines for that visit. If a primary cancer is detected at Year 0, the PRO/QOL 
assessment is expected to be completed two weeks after the protocol 
scheduled screening and included in the final data collection. 
Rev. 9/17 
Rev. 2/17 

 
 
47 | P a g e  
 
6. 
Study Parameters 
 
Pre-Study 
Year 05,10 
6 Months Year 15,10 
Year 2-4 
Follow-up5,6,10 
Blood creatinine1 
 X1 
 
 
 X1 
 
Serum or Urine Pregnancy 
Test2 
 X2 
 X3 
 
 X3 
 
DBT 
 
 X9 
 
     X9, 13 
 
AB-MR8 
 
 X9 
 
     X9, 13 
 
PRO/QOL Questionnaires7 
 
 X7 
 
 
 
Participant Genetic and 
Medical History 
Questionnaire 
  X17 
 
 
 
 
Core Needle Biopsy11 
 
X 
 
X 
 
Patient Follow-up Contact 
 
 
  X14 
  X16 
  X15 
Tumor tissue from on study biopsies from consenting patients submitted per Section 9 
FFPE tumor tissue4 
 
 
X 
X 
Blood for banking from consenting patients submitted per Section 9 
Plasma, one (1) 10mL 
K2EDTA purple top tube12 
 
 
X 
 
Whole Blood, one (1) 10mL 
EDTA purple top tube12 
 
 
X 
 
1. If required by local site as standard of care. 
2. For women of childbearing potential suspected of being pregnant or unsure of their 
pregnancy status, or as per local site standard of practice in women undergoing DBT and 
MRI, a pre study pregnancy test must be done within 2 weeks prior to randomization. 
3. A pregnancy test must only be done prior to the year 0 and year 1 imaging studies in women 
suspected of being pregnant or unsure of their pregnancy status as per local site standard of 
practice. 
4. Submit from patients with newly detected cancers.  All submissions must be logged and 
tracked within the ECOG-ACRIN Sample Tracking System (STS). See Section 9. 
5. Copies of reports associated with any assessment of the tissue, including (but not limited to) 
pathology reports, OncotypeDx, and PAM50 are to be uploaded into Medidata RAVE. 
6. Every 6 months (+/- 1 month) for years 2-4. 
7. PRO/QOL Questionnaires will be timed to arrive approximately 2 weeks after the Year 0 
(baseline) screening tests (AB-MR and DBT) 
8. As outlined in Section 5.2.1, AB-MR is to be performed using Multihance (no substitutions 
allowed) gadolinium contrast agent.  
9. As outlined in section 5.1.1 and 5.1.2; patients randomized to Arm A of this study will 
undergo DBT followed by AB-MR, patients randomized to Arm B of this study will undergo 
AB-MR followed by DBT. 
10. For patients that are diagnosed with a primary cancer, no subsequent follow-up or further 
study imaging will be performed. Pathology reports and site standard tests are required to 
be submitted upon diagnosis of a primary cancer. Data are required to be collected and 
submitted through Medidata Rave according to the schedule in the EA1141 Forms 
Completion Guidelines for that visit. If a primary cancer is detected at Year 0, the 
Rev. Add4 
Rev. 9/17 
Rev. 2/17 

 
 
48 | P a g e  
 
PRO/QOL assessment is expected to be completed two weeks after the protocol scheduled 
screening and included in the final data collection. 
11. If a suspicious lesion is detected on one or both of the modalities at the baseline or one-
year post-baseline time points, a biopsy will be performed per local standard of care 
practices. 
12. Collect blood from consenting patients that are recommended for breast biopsy of 
suspicious lesions detected on the AB-MR or DBT at either year 0 or year 1. 
NOTE: Blood draw should occur prior to biopsy. 
13. The year 1 follow up imaging must be completed no less than 11 months from baseline 
imaging and no more than 13 months from baseline imaging. 
14. Patients are to be contacted via a follow-up visit, email, or phone call months (+/- 1 month) 
after year 0 imaging to see if the patient was diagnosed with cancer during the interval 
between year 0 and year 1 imaging. 
15. Patients in follow-up are to be contacted through follow-up visits, emails, or phone calls 
every 6 months (+/- 1 month) for 3 years after year 1 imaging to see if the patient was 
diagnosed with cancer. 
16. The 1 year patient follow-up contact should be performed immediately prior to the year 1 
imaging, via a follow-up visit, email, or phone call, to confirm the patient has not been 
diagnosed with an interval breast cancer. Patients diagnosed with breast cancer in the 
interval between the year 0 and year 1 imaging studies will have no subsequent follow up 
and will not undergo the year 1 study imaging. 
17. Participant data will be collected for the Participant Genetic and Medical History 
questionnaire. 
 

 
 
49 | P a g e  
 
7. 
Statistical Considerations  
7.1 
Overview 
This phase II trial is conducted to compare the rates of detection of invasive 
cancers by AB-MR and DBT. At baseline and at Year 1 post baseline, 
participants will undergo both tests on the same day and in randomized order. 
The randomization was added as a safeguard against potential bias that may 
result if one test systematically precedes the other in the course of the study.  
Per protocol, participants will be consented in advance of imaging, and both the 
AB-MR and DBT will be performed on the same day (or within a 24hr period) and 
interpreted independently by two different radiologists blinded to the results of the 
other modality. Although it is very unlikely that the interpreting radiologists will 
inadvertently access information from the independent reading of the other 
modality, the randomization is an additional assurance against such an 
eventuality. In addition, the randomization will help ensure that participants will 
be consented in advance of the imaging exams thus minimizing the potential of 
selection on the basis of imaging results. 
Participants will be followed for an additional period of 3 years. The length of 
three years of follow up was chosen as feasible and also based on the following 
heuristic. We hypothesize that AB-MR detects at least an additional 9 invasive 
cancers per thousand, equalling approximately 2 years of advanced detection 
compared to DBT. Thus the incident cancer rate of DBT should take 
approximately 2-3 years to return to the expected rate of 5/1000. 
DBT and AB-MR will be interpreted locally at the participating sites. The two 
modalities will be interpreted independently, and readers will be blinded to the 
results of the other modality. If DBT is the first test, any additional imaging (spot 
compression/magnification view and or ultrasound) recommended from the 
screening DBT views should be completed and a final recommendation recorded 
on the DBT imaging data forms by the interpreting radiologist prior to the AB-MR. 
If AB-MR is performed first, the results should be recorded on the AB-MR 
imaging data forms prior to DBT. No biopsies should be performed until the 
results of both the DBT and AB-MR have been independently recorded on their 
respective imaging data forms. All suspicious findings on either the DBT or AB-
MR should be biopsied regardless of the recommendation of the other modality.  
The recommendations and results of subsequent biopsies based on results from 
either modality will be recorded to determine the cancer yield, PPV, call back 
rate, and frequency of recommendations for short-term follow up for both DBT 
and AB-MR. 
The primary aim of the trial is to compare rates of detection for invasive cancer. 
Secondary aims evaluate and compare measures of diagnostic and predictive 
accuracy of the two modalities, measures of patient preference, molecular 
characteristics of cancers found, and incident breast cancer rate during the 3-
year follow up period.  
7.2 
Primary Endpoint  
The primary aim for this study is to compare the rate of detection of invasive 
cancers with AB-MR and DBT 
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50 | P a g e  
 
For each modality, the detection rate of invasive cancers is defined as the 
proportion of participants who had an invasive cancer detected by the modality 
and verified by pathology. Because of the paired design, the comparison of the 
invasive cancer detection rates will be made using McNemar’s test. 
Sample size considerations: We are not aware of previous studies comparing 
AB-MRI to DBT. Our choice of plausible values for the additional yield of AB-MRI 
at Year 0 was based on a recent comparative study of MRI to FFDM, which 
reported an additional yield of about 12/1000 invasive cancers in a population of 
women at average risk.20,21 We conservatively assumed that the difference in 
yield between AB-MR and DBT will be smaller and computed the sample size 
required to detect a difference as low as 9/1000. The following table presents 
computations of the required sample size to ensure power 90% using a two-
sided McNemar’s test of level 0.05 and for a range of values of the difference in 
detection rates and total rates of discordant pairs. Based on these computations 
we selected a sample size of 1363 cases with complete data from both tests and 
pathology. This sample size is needed to ensure power 90% for a difference in 
the rates of invasive cancer detection of 9/1000 when the discordant pair rate is 
in the middle of the range. Assuming that adequate information to evaluate the 
primary endpoint will not be available on up to 6% of cases, a sample size of 
1450 will provide power 90% to compare the diagnostic yield in invasive cancer 
of the two modalities. Women that complete either only the AB-MR or only the 
DBT and not both studies at Year 0 will not be included in the analysis. 
Power 
Sample size 
Difference in invasive cancer 
rates (ABMR –DBT) 
Proportion of 
discordant cases 
0.90 
1191 
0.009 
0.010 
0.90 
1363 
0.009 
0.011 
0.90 
1552 
0.009 
0.012 
0.90 
1057 
0.010 
0.011 
0.90 
1197 
0.010 
0.012 
0.90 
949 
0.011 
0.012 
 
7.3 
Secondary Endpoints  
a. To compare the positive predictive value (PPV) of biopsies, call back rates, 
and short-term follow up rates after AB-MR and DBT on both the initial and 1 
year follow up studies, 
Estimates of each quantity of interest will be derived separately for the 
baseline and the Year 1 screen. The year 1 screen is defined as imaging 
performed no less than 11 months from baseline screen and no more than 13 
months from baseline screen. For each screening occasion the estimates of 
call-back and short-term followup rates of the two modalities will be compared 
using McNemar’s test to account for the paired design. GEE regression 
modeling will be used in the comparison of PPVs.30 In addition, the change 
between baseline and Year 1 screen will be estimated separately for each 
modality. If a woman does not complete both the AB-MR and DBT on the 1 
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51 | P a g e  
 
year follow up study, they will be included for analysis of the primary endpoint 
but not of the secondary endpoints. 
b. To estimate and compare the sensitivity and specificity of AB-MR and DBT, 
using the 1 year follow up to define a reference standard. 
The analysis for this aim will use data from the baseline screen and 
subsequent 1-year followup. The year 1 follow up must be completed no less 
than 11 months from baseline screen and no more than 13 months from 
baseline screen. The sensitivities and specificities of the two modalities will 
be estimated using a reference standard comprising the information from any 
subsequent workup and the information from the 1-year followup. The 
information from the Year 1 screens will not be included in the reference 
standard. Estimates will be compared using McNemar’s test to account for 
the paired design. 
c. To compare patient-reported short-term quality of life related to diagnostic 
testing with of AB-MR and DBT using the Testing Morbidities Index.  
Separate TMI scores will be computed for each modality after the baseline 
screen. Scores will be compared using a nonparametric test that accounts for 
the pairing of scores by participant. 
d. To compare willingness to return for testing with AB-MRI vs DBT within the 
recommended screening interval and explore factors associated with 
willingness to return for screening. 
We will estimate the proportions of participants willing to return for screening 
with either test, AB-MRI only, DBT only, or not willing to return for either test. 
We will use polytomous logistic regression to examine factors associated with 
willingness to return, including screen result, cancer status, and demographic 
characteristics. 
e. To compare the tumor biologies of invasive cancers and DCIS detected on 
AB-MR and DBT;  
The analysis for this aim will be descriptive. Cancers detected during the 
study period will have tissue banked centrally that will undergo genetic 
profiling. For all invasive cancers detected during the study period, the 
NanoString PAM50 will be performed. The frequencies of cancer types 
determined by the NanoString analysis will be tabulated and compared. For 
DCIS, if the Oncotype-DCIS score was performed, the distributions of scores 
will be tabulated and compared. 
f. To estimate the incident cancer rate during 3 years following the year-1 AB-
MR/DBT when patients return to standard screening.  
Breast cancer incidence will be estimated over the 3 year followup period. 
Person-years will be measured from the beginning of the 3-year period, which 
will be at Year 1 post baseline.  

 
 
52 | P a g e  
 
7.4 
Gender and Ethnicity  
Using data from ACRIN 6652 (DMIST) and ACRIN 6666 we are making the 
following projections regarding gender and race enrollment for EA1141: Ethnic 
Category 
 
Gender 
Females 
Males 
Total 
Hispanic or Latino 
132 
0 
132 
Not Hispanic or Latino 
1318 
0 
1318 
Ethnic Category: Total of all subjects 
1450 
0 
1450 
 
Racial Category 
American Indian or Alaskan Native 
3 
0 
3 
Asian 
58 
0 
58 
Black or African American 
143 
0 
143 
Native Hawaiian or other Pacific Islander 
3 
0 
3 
White 
1236 
0 
1236 
More than one race 
7 
0 
7 
Racial Category: Total of all subjects 
1450 
0 
1450 
The accrual targets in individual cells are not large enough for definitive subgroup 
analyses. Therefore, overall accrual to the study will not be extended to meet 
individual subgroup accrual targets. 
However, since the AB-MR can be performed at any community site with 
standard breast MRI and as the study will cover the cost of the AB-MR, the trial 
should be equally accessible to all populations. Accrual of minorities will be 
monitored quarterly. Overall and individual site minority accrual rates will be 
closely monitored. Sites with low minority accrual rates will be contacted to 
determine their specific issues and help them target minority accrual. 
Rev. 2/17 

 
 
53 | P a g e  
 
Domestic Planned Accrual 
Racial Categories 
Not 
Hispanic 
or Latino: 
 
Female 
Not 
Hispanic 
or Latino: 
 
Male 
Hispanic or 
Latino: 
 
Female 
Hispanic 
or 
Latino: 
 
Male 
Total 
American 
Indian/Alaska Native 
3 
0 
0 
0 
3 
Asian 
55 
0 
0 
0 
55 
Native Hawaiian or 
Other Pacific Islander 
3 
0 
0 
0 
3 
Black or African 
American 
119 
0 
17 
0 
136 
White  
990 
0 
112 
0 
1102 
More Than One Race 
5 
0 
1 
0 
6 
Total 
1175 
0 
130 
0 
1305 
 
INTERNATIONAL (including Canadian participants) PLANNED 
ACCRUAL 
Racial Categories 
Not 
Hispanic 
or Latino: 
Female 
Not 
Hispanic 
or Latino: 
Male 
Hispanic or 
Latino: 
 
Female 
Hispanic 
or 
Latino: 
 
Male 
 
Total 
American 
Indian/Alaska Native 
0 
0 
0 
0 
0 
Asian 
3 
0 
0 
0 
3 
Native Hawaiian or 
Other Pacific Islander 
0 
0 
0 
0 
0 
Black or African 
American 
7 
0 
0 
0 
7 
White 
132 
0 
2 
0 
134 
More Than One Race 
1 
0 
0 
0 
1 
Total 
143 
0 
2 
0 
145 

 
 
54 | P a g e  
 
7.5 
Study Monitoring 
This study will be monitored by the ECOG-ACRIN Data Safety Monitoring 
Committee (DSMC). The DSMC meets twice each year. For each meeting, all 
monitored studies are reviewed for safety and progress toward completion. When 
appropriate, the DSMC will also review interim analyses of outcome data. Copies 
of the toxicity reports prepared for the DSMC meetings are included in the study 
reports prepared for the ECOG-ACRIN group meeting (except that for double 
blind studies, the DSMC may review unblinded toxicity data, while only pooled or 
blinded data will be made public). These group meeting reports are made 
available to the local investigators, who may provide them to their IRBs. Only the 
study statistician and the DSMC members will have access to interim analyses of 
outcome data. Prior to completion of this study, any use of outcome data will 
require approval of the DSMC. Any DSMC recommendations for changes to this 
study will be circulated to the local investigators in the form of addenda to this 
protocol document. A complete copy of the ECOG-ACRIN DSMC Policy can be 
obtained from the ECOG-ACRIN Coordinating Center. 
 

 
 
55 | P a g e  
 
8. 
Patient Reported Outcomes (PRO) and Quality of Life (QOL) 
Administration 
8.1 
PRO/QOL Assessment Schedule 
Patients will be asked to complete forms approximately 2 weeks after the Year 0 
(baseline) screen. 
Questionnaires will be timed to arrive approximately 2 weeks after the Year 0 
(baseline) screening tests (AB-MR and DBT). We have chosen two weeks with 
the hope that it will be recent enough for participants to recall their experience, 
but distant enough that patients will have been notified of their results prior to 
completing questionnaires. This survey will ask participants about fear/anxiety, 
pain/discomfort, embarrassment, difficulties with daily activities experienced with 
each test, as well as their willingness to undergo each test again, and their 
preference for male or female technologists. 
 
8.2 
PRO/QOL Data Collection Process  
Patients will be recruited at the time of randomization into the patient reported 
outcomes portion of the study. At the time of randomization at the sites, patients 
will complete a Participant Contact Information Form. The form collects 
information used to maintain contact with the participant over the course of the 
trial, including name, address, phone number, and e-mail (if available). 
This form is retained in the study participant’s chart at the site and is not 
submitted to the ECOG-ACRIN master database. The completed form is faxed to 
the central ECOG-ACRIN Outcomes and Economic Assessment Unit (OEAU) 
located at Brown University so that the participants can be contacted for the 
Patient Reported Outcomes (PRO) portion of the study.  The contact information 
is stored in a dedicated SQL database and IS NOT linked to the master ECOG-
ACRIN database. The OEAU RA will not have access to the main ECOG-ACRIN 
database that contains screening results.  
8.2.1 
On the Participant Contact Information Form, patients will be asked to 
express a preference for on-line or paper administration of patient 
reported outcome (PRO) forms. Patients may choose to complete 
questionnaires using a web-based application (see Section 8.3 for a 
description) or by mail.  Administration of questionnaires, both web-
based and paper will be coordinated by the OEAU. Administration of 
the questionnaires will be triggered based on completion of study 
milestones marked by submission of forms in RAVE. 
Patients will be prompted to complete web-based forms via an email 
prompt. These emails will include a link to the web site for 
questionnaire completion. Questionnaires will be completed on-line 
using a unique patient account. The web site will reference a study-
specific toll-free phone number that patients can use to reach the 
OEAU staff should they have questions or need assistance. All data 
will be stored on a secure server. If patients do not complete the web 
questionnaire within 10 working days of the date of the e-mail, a 
second email will be sent, which will ask the patient to confirm that the 
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56 | P a g e  
 
patient has been able to access the questionnaire on the web. If 
patients have still not responded within 20 working days of the original 
e-mail, the OEAU Research Associate will attempt to telephone the 
patient and administer the questionnaire by telephone. If 
questionnaires are telephone-administered, they will be marked as 
such in the data base. 
8.2.2 
Mailed questionnaire completion  
Mailed questionnaire packets will include a letter introducing the study 
and include a study-specific toll-free phone number that patients can 
use to reach the OEAU staff should they have questions or need 
assistance, questionnaires, and pre-addressed, stamped envelopes 
for return mailing to the OEAU.  If patients do not complete the paper 
questionnaire within 10 working days of the date of the mailing, the 
OEAU RA will attempt to telephone the patient.  If the patient has not 
received the paper questionnaires, additional questionnaires will be 
sent after confirming the correct mailing address.  If the questionnaire 
is available to the patient, the OEAU RA will urge the study patient to 
complete and return the questionnaire. If patients have still not 
responded within 20 working days of the original mailing, the OEAU 
will attempt to telephone the patient and telephone administer the 
questionnaire. If questionnaires are telephone-administered, they will 
be marked as such in the data base.   
8.3 
ECOG-ACRIN Systems for Easy Entry of Patient Reported Outcomes 
(EASEE-PRO)  
8.3.1 
A secure environment for control of user records, information, 
and transactions (SECURIT). 
Provides a secure – limited access point for entering data into the 
restricted secure Personally Identifiable Information (PII) Database, 
for management of user data, creating user accounts, and reporting. 
The SECURIT web management interface requires the secure 
hypertext transfer protocol (HTTPS) to ensure encryption of 
transmitted data. 
8.3.1.1 
PII database: is a dedicated secure limited access 
database, used to store protected PII. 
8.3.1.1.1 
Secure: All communications to the PII 
database through SECURIT are encrypted. 
The database resides behind a firewall and 
cannot be reach from outside the OEAU.   
8.3.1.1.2 
Limited access: this database is restricted 
not only by username and password but is 
also restricted to specified internal OEAU 
computers by IP address, so that only 
authorized users logging in at the OEAU 
from pre-specified computers may 
access/enter PII.  At no time is outside 
access allowed to this database. 

 
 
57 | P a g e  
 
8.3.1.1.3 
Protected restricted PII (eg., SSN) are 
encrypted at the time of data entry and 
double data entered for verification.  All 
users regardless of their security level are 
blinded to this protected data, and it cannot 
be decrypted without the encryption key, 
housed in a safe, in a location separate 
from the OEAU.  This type of data is 
generally collected for long term follow-up 
where it may be needed to be decrypted for 
select patients in order to search registries 
like the national death index to determine 
survival status of lost participants.  In these 
instances, with appropriate approvals, the 
Database Administrator will decrypt this 
data in accordance with the approved 
retrieval specification. 
8.3.1.2 
User records: This functionality allows OEAU 
personnel, using specific computers within the OEAU, 
to create user records, enter user information into the 
PII database, and establish user web accounts in the 
separate user database. Allows the management of 
users and their data, including the ability to update a 
participants preferred contact method, address, and 
participation status (eg., no longer wishes to be 
contacted with respect to the PRO component of the 
study). 
8.3.1.3 
Information: This functionality allows the OEAU to 
record all participant contact, document any changes 
to the participant, and make any important notes 
related to the participant. 
8.3.1.4 
Transactions: SECURIT provides a reporting and 
monitoring interface to the PRO database, which is 
used to store non-PII patient reported survey 
responses.  
8.3.1.4.1 
Allows OEAU to monitor per patient form 
completion status using the tracking 
management facility.  This facility reports on 
what data is currently expected from 
participants, CRAs, and the OEAU 
interviewers. 
8.3.1.4.2 
Aggregate reporting: this series of reports 
allows the OEAU to monitor the distribution 
of patients over data completion methods 
and form completion methods (both overall 
and by site). 
8.3.2 
Database utility and control environment (PRO-DUCE).  

 
 
58 | P a g e  
 
This utility interfaces with the main clinical database containing 
CRF/trigger data (Medidata RAVE), monitors the clinical database for 
events (eg., participant registrations, scheduled procedures, and other 
triggers) and establishes event scheduling. The system sets up email 
reminders to CRAs, participants [and SMS text message reminders, 
when applicable to the study], and OEAU personnel to ensure timely 
completion of surveys. 
8.3.3 
Web entry systems (PROWESs).  
A website where participants complete online surveys. 
8.3.3.1 
PROWESs provides a front facing web portal for 
participants to complete questionnaires and have 
those results stored in the PRO database. 
8.3.3.2 
Secure site using HTTPS and requiring a username 
and password login. 
8.3.3.3 
On login, user is presented with brief instructions; 
including the approximate time for completion, number 
of questions to be completed in this session, and any 
important information regarding this survey (including 
help and contact information) 
8.3.3.4 
PROWESs is a one-way interface, data cannot be 
returned from the PRO-database to the user. 
8.3.4 
Valet Interface and data entry system (PROVIDES). 
8.3.4.1 
The PROVIDE system is a web interface that allows 
site CRAs and OEAU RAs to act as a valet and enter 
a participants responses to a survey into the PRO 
database. This allows Site CRAs to enter forms 
completed by the patient on site and allows the OEAU 
staff to enter participants responses acquired via 
phone, mail and fax competed surveys. 
8.3.4.2 
Secure site using HTTPS and requiring a username 
and password login. 
8.3.4.3 
Which forms can be entered is restricted by 
username, site affiliation, and role; thus, Sites RAs 
can only enter surveys predesignated as on-site data 
collection surveys and only for their own patients. 
8.3.4.4 
On login, user is presented with brief instructions; is 
requested to select the protocol, case number, 
timepoint and verify the case ID by providing the 
participant birthdate. 
8.3.4.5 
PROVIDES is a one-way interface, data cannot be 
returned from the PRO database to the user. 

 
 
59 | P a g e  
 
9. 
Specimen Submissions 
Tumor tissue samples are requested to be submitted from study patients who have 
cancers (DCIS and invasive) detected and have consented to allow the submission of 
the tissue for research. Samples should only be submitted after clinical management of 
the patient has been determined from the tumor tissue. Tumor tissue samples should be 
submitted from all cancers unless there is inadequate material for submission. 
Blood samples are requested to be submitted from study patients that are recommended for 
breast biopsy of suspicious lesions detected on the AB-MR or DBT at either year 0 or year 1 and 
have consented to allow the submission of blood for future research for discovery/validation of 
potential circulating biomarkers that could be used to risk stratify patients in the future. 
All specimens must be labeled with the ECOG-ACRIN protocol number (EA1141), the patient’s 
initials and ECOG-ACRIN patient sequence number, and if applicable, the GHI requisition 
number/barcode from the kit, the collection date, and the type of sample. For pathology 
materials, it is strongly recommended that full patient names be provided. 
All specimens must be logged and tracked via the ECOG-ACRIN Sample Tracking 
System (STS) Web Application (Section 9.3) and submitted with an STS generated 
shipping manifest. 
NOTE: 
If tumor tissue is submitted to Genomic Health, Inc (GHI) for Oncotype 
assessments, it is requested that the patient’s participation is noted on the 
Oncotype Requisition Form and that the submission be logged into STS.  
This will assist in communications between ECOG-ACRIN and GHI regarding 
the proper routing and use of the residuals after completion of the assay. 
If tumor tissue is not available for submission, please indicate this in STS. 
NOTE: 
From all patients with tumors detected, copies of the pathology report and 
other standard of care assessments performed on the tumor tissue samples 
are to be submitted in RAVE. This is required and not impacted by the 
patient’s consent for submission of the tissue for research. 
Guidelines for pathologists are provided in Appendix II. 
9.1 
Tumor Tissue and Blood Submissions to ECOG-ACRIN Central 
Biorepository and Pathology Facility (CBPF) 
Tumor tissue and blood are to be submitted from patients who answer ‘Yes’ to 
‘My samples and related information may be kept in a Biobank for use in future 
health research.’ 
9.1.1 
Tumor Tissue Submissions 
For invasive cancers detected and biopsied during the study period 
(and all patients from whom only slides were submitted to GHI for the 
OncotypeDX DCIS assessment), formalin fixed paraffin-embedded 
tumor tissue samples are requested to be submitted for the laboratory 
research studies defined in Section 10 and for future research studies. 
Rev. 2/17 
Rev. 2/17 
Rev. 2/17 

 
 
60 | P a g e  
 
9.1.1.1 
Submission requirements: 
Forms 
The relevant pathology and surgical reports must 
accompany all tissue submissions: 
• 
Copy of the diagnostic or surgical Pathology Report 
• 
Other Immunologic and cytologic reports 
• 
STS generated shipping manifest for all submitted tissue. 
Tumor tissue submissions: 
Representative formalin fixed paraffin embedded (FFPE) 
tumor tissue blocks. 
NOTE: 
If blocks are unavailable for submission, cores 
and slides are to be submitted. All cores and 
slides must be adequately labeled, with slides 
numbered sequentially in the order cut. 
Alternative submission requirement: 
• 
One (1) H&E slide 
• 
Twenty (20) 4-5 µm unstained air-dried plus 
slides 
• 
Two (2) 4 mm cores 
9.1.2 
Blood Submissions 
Blood samples are requested to be submitted for future research 
studies from patients that are recommended for breast biopsy of 
suspicious lesions detected on the AB-MR or DBT at either year 0 or 
year 1. 
NOTE: 
Blood draw should occur prior to biopsy. 
9.1.2.1 
Plasma 
• Draw 10mL of peripheral blood into one (1) plastic 
K2EDTA purple top tube 
• Immediately invert tube 10 times 
• Centrifuge within 30 minutes of draw at room 
temperatire at 1500g for 20 minutes in a swing bucket 
or fifteen (15) minutes for a fixed angle centrifuge 
• Aliquot plasma into four (4) cryovials 
• Replace the cap on the purple top tube 
• Freeze cryovials and residual cells at –70ºC. Batch ship 
quarterly overnight on dry ice. If specimens cannot be 
stored at –70ºC, store at –20ºC and ship on dry ice 
within one (1) week of collection. 
9.1.2.2 
Whole Blood 
• Draw 10mL of whole blood into one (1) plastic EDTA 
purple top tube 
• Immediately invert 10 times 
Rev. 2/17 
Rev. Add4 
Rev. 2/17 
Rev. 2/17 

 
 
61 | P a g e  
 
• Freeze at –70ºC 
• Batch ship quarterly overnight on dry ice. If specimens 
cannot be stored at –70ºC, store at –20ºC and ship on 
dry ice within one (1) week of collection. 
9.1.3 
Shipping Procedures: 
The pathology materials are to be submitted within one month of 
performance of the procedure. Tissue samples are to be shipped at 
ambient (use a cool pack in warm weather). 
Frozen blood samples must be shipped overnight on dry ice Monday-
Thursday only, do not ship the day before the weekend or holiday. 
Shipping manifest form generated from the ECOG-ACRIN STS must 
accompany the tissue and blood samples. 
Access to the shipping account for shipments to the ECOG-ACRIN 
CBPF at MD Anderson can only be obtained by logging into 
fedex.com with an account issued by the ECOG-ACRIN CBPF. For 
security reasons, the account number will no longer be given out in 
protocols, over the phone, or via email. If your site needs to have an 
account created, please contact the ECOG-ACRIN CBPF by email at 
eacbpf@mdanderson.org 
Ship to: 
ECOG-ACRIN Central Biorepository and Pathology Facility 
MD Anderson Cancer Center 
Department of Pathology, Unit 085 
Tissue Qualification Laboratory for ECOG-ACRIN, Room G1.3586 
1515 Holcombe Blvd 
Houston, TX 77030 
Phone: Toll Free 1-844-744-2420 (713-745-4440 Local or 
International Sites) 
Fax: 713-563-6506 
Email: eacbpf@mdanderson.org 
9.2 
Tumor Tissue Submissions to Genomic Health Inc (GHI) 
This section outlines the submission of tumor tissue for the OncotypeDX DCIS 
Score Assay. 
For DCIS cancers detected and biopsied during the study period, formalin fixed 
paraffin-embedded tumor tissue samples are requested to be submitted for the 
laboratory research studies defined in Section 10.1. 
9.2.1 
Ordering the OncotypeDX Specimen Kit 
Contact Genomic Health Customer Service (866-662-6897) and 
request the “Oncotype Specimen Kit”. 
The kit will be shipped overnight and will contain instructions, a 
shipping kit (includes cryotubes and slide cassette), a mailer, and a 
requisition form containing barcode labels to place on the submitted 
materials. One Oncotype Specimen Kit and Requisition Form should 
be completed per patient. 
Rev. 2/17 
Rev.2/16 

 
 
62 | P a g e  
 
DO NOT MIX BARCODE LABELS BETWEEN PATIENTS. 
9.2.2 
Tumor Tissue and Form Submissions 
Tumor tissue submissions to GHI must be logged into the ECOG-
ACRIN Sample Tracking System (STS). Participating sites will 
correspond directly with GHI, not via STS. The CBPF will log receipt 
of materials from GHI into the STS. Receipt logging will not occur in 
real time. For more information on the STS, see Section 9.4. 
• Submit the following utilizing the kit and forms provided by GHI: 
• Completed requisition form and STS manifest (see Appendix II for 
insuctions on how to complete the requisition form, please note the 
STUDY NAME/CODE must be filled out as: ‘01-194-IIS-
EA1141.’ 
• DCIS Tumor Tissue Block (place barcode label on back of 
cassette). 
OR 
• Fifteen (15) 5 µm serial unstained slides, oriented similarly and air 
dried. Label each slide with barcode and number in the order they 
were cut. 
NOTE: 
Proper sterile sectioning technique MUST be followed. 
Failure to follow sterile technique can affect testing and 
delay results. If sterile technique cannot be followed, 
submission of a tumor block is strongly recommended. 
If only slides are submitted, additional materials are to 
be submitted to the CBPF per Section 9.1. 
NOTE: 
Pathology reports are to be FAXed to the ECOG-
ACRIN CBPF. Label with EA1141, ECOG-ACRIN 
patient sequence number, and the GHI requisition 
number. 
9.2.3 
Notification of Results 
Genomic Health will notify the institution of the DCIS Score (DS) via 
the mechanism selected on the OncotypeDX Requisition Form within 
14 days of receipt of the tissue by Genomic Health. If you do not 
receive a report within 14 days, contact GHI Customer Service at 
(866) 662-6897. Genomic Health will not distribute reports directly to 
the ECOG-ACRIN Operations Office – Boston. 
The institution must upload a redacted copy of the first page of the 
“OncotypeDX Patient Report” (labeled with protocol number EA141, 
patient initials, and ECOG-ACRIN patient sequence number) to the 
‘DCIS Score’ eCRF in Medidata Rave. 
9.2.4 
Central Laboratory: Specimen Processing and Routing 
Specimens submitted will be processed to maximize their utility for 
current and future research projects and may include, but not limited 
to, extraction of plasma, serum, DNA and RNA. Invasive tumor 
Rev. 2/17 

 
 
63 | P a g e  
 
specimens will be routed for the research studies outlined in Section 
10. If tumor tissue is submitted to Genomic Health, Inc and the 
patient’s participation in this trial is noted on the Oncotype requisition 
form, residuals will be forwarded to the CBPF to be used in future 
research. 
Specimens from patients who consented to allow their specimens to 
be used for future approved research studies will be retained in an 
ECOG-ACRIN-designated central repository. For this trial, specimens 
will be retained at the ECOG-ACRIN Central Biorepository and 
Pathology Facility. Residual specimens from any laboratory research 
studies, including the DCIS Score Assay by Genomic Health, will also 
be returned to the ECOG-ACRIN CBPF for possible use in future 
approved research studies. Specimens will be de – identified prior to 
distribution for any approved research projects. 
If future use is denied or withdrawn by the patient, the specimens will 
be removed from consideration for use in any future study. Pathology 
materials may be retained for documentation purposes or returned to 
the site. All other specimens will be destroyed per guidelines of the 
respective repository. 
9.3 
ECOG-ACRIN Sample Tracking System 
It is required (barring special circumstances) that all samples submitted on this 
trial be entered and tracked using the ECOG-ACRIN Sample Tracking System 
(STS). As of June 2007, the software will allow the use of either 1) an ECOG-
ACRIN user-name and password previously assigned (for those already using 
STS), or 2) a CTSU username and password. 
When you are ready to log the collection and/or shipment of the samples 
required for this study, please access the Sample Tracking System software by 
clicking https://webapps.ecog.org/Tst.  
Important: Please note that the STS software creates pop-up windows, so you 
will need to enable pop-ups within your web browser while using the software.  A 
user manual and interactive demo are available by clicking this link: 
http://www.ecog.org/general/stsinfo.html. Please take a moment to familiarize 
yourself with the software prior to using the system. 
An STS generated shipping manifest must be generated and shipped with all 
sample submissions. 
Please direct your questions or comments pertaining to the STS to ecog-
acrin.tst@jimmy.harvard.edu. 
If the STS is unavailable, the Generic Specimen Submission Form (#2981) is to 
be used as a substitute for the STS shipping manifest. The completed form is to 
be faxed to the receiving laboratory the day the samples are shipped. Indicate 
the appropriate Lab on the submission form: 
• ECOG-ACRIN CBPF 
• Genomic Health, Inc 

 
 
64 | P a g e  
 
Retroactively enter all sample collection and shipping information when STS is 
available. 
Note that GHI will not indicate receipt within STS. 
9.4 
Sample Inventory Submission Guidelines  
Inventories of all samples submitted will be tracked via the ECOG-ACRIN STS 
and receipt and usability verified by the receiving laboratory. Inventories of 
samples forwarded and utilized for approved laboratory research studies will be 
submitted by the laboratory to the ECOG-ACRIN Operations Office - Boston on a 
monthly basis in an electronic format defined by the ECOG-ACRIN Operations 
Office - Boston. 

 
 
65 | P a g e  
 
10. 
Laboratory Research Studies 
For patients diagnosed with invasive cancer, tissues will be sent to the CBPF as 
outlined in Section 9.1, and the PAM50 assessment will be performed as a research 
test. PAM50 results will not be returned to the site. 
If the site submits tissues for the Oncotype DX Breast Cancer Assay, performed by 
Genomic Health, Inc. (GHI) and the patient’s participation in EA1141 is reported to GHI, 
GHI will distribute test results and tissue residuals to ECOG-ACRIN for use in future 
research. Results will be returned to sites per GHI standard procedures. 
10.1 
Oncotype DX for DCIS Score Assay  
This assessment is performed by Genomic Health, Inc.  
The Oncotype DX® Breast Cancer Assay analyzes RNA derived from fixed 
paraffin-embedded tissue using RT-PCR. The quantitative RT-PCR assay is 
capable of quantifying up to 400 genes from small RNA fragments (50–250 bp) 
extracted from three 10-micron FPET sections.  The assay machine measures 
mRNA abundance by recording real-time fluorescence and time to a certain 
amplification threshold.  The assay (Oncotype DX Breast Cancer Assay, 
Genomic Health, Redwood, CA; http://www.genomichealth.com/oncotype) is 
performed within 10-14 days.  
Using manually microdissected DCIS tissue the Oncotype DX® Breast Cancer 
Assay is run which includes all 21 genes from the Recurrence Score. The DCIS 
Score result is generated from 12 of the 21 Recurrence Score, these genes 
specific to the calculation of the DCIS Score result, and they include 7 cancer-
related and 5 reference genes (Table 1).  This subset of genes were selected for 
inclusion in the DCIS Score algorithm because they are strongly prognostic and 
predict local recurrence risk regardless of tamoxifen use.  
Table 1: Genomic Health DCIS Score Algorithm (Oncotype DX) 
Group 
Genes 
Proliferation 
Ki67, STK15, survivin, cyclin B1, MYB2 
Hormone Receptor 
PR 
Reference 
Beta-actin, GDPDH, RPLPO, GUS, TFRC 
GSTM-1 
GSTM-1 
The DCIS Score result is evaluated both as a continuous variable (from 0 to 100) 
and as a categorical variable (based on 3 prespecified risk groups: low, 
intermediate and high). The DCIS Score™ result quantifies the risk of any local 
recurrence, as well as the risk of an invasive local recurrence.35 

 
 
66 | P a g e  
 
 
*HR=hazard ratio. 
Table 2. Genomic DCIS Score, Results from Validation Study35 
Recurrence Score 
(1–100) 
Risk group 
No. (%) 
10-year risk of any local 
breast event (95% C.I.) 
10-year risk of an invasive local 
breast event (95% C.I.) 
< 39 
Low 
230 (70%) 
10.6% (6.9, 16.2) 
3.7% (1.8, 7.7) 
39 –54 
Intermediate 
53 (16%) 
26.7% (16.2, 41.9) 
12.3% (5.1, 27.8) 
> 54 
High 
44 (13%) 
25.9% (14.8, 43.1) 
19.2% (9.5, 36.4) 
10.2 
PAM50 Assessment  
This assessment will be directed by Brian Leyland-Jones, MD.  
The PAM50 assay will be performed on tumor tissue submitted from all patients 
diagnosed with invasive breast cancer.  The assessments will be performed 
retrospectively at the end of the trial.  Results will not be returned to the site or 
patient. 
PAM50 Background 
In 2009, a 50-gene set (PAM50) was proposed for standardizing subtype 
classification. The PAM50 Breast Cancer Intrinsic Classifier is the clinical 
manifestation of this gene set using a digital gene expression assay on the 
NanoString nCounter Dx Analysis System that has been validated on formalin-
fixed, paraffin-embedded tissues. Multivariable analyses using the PAM50 
subtypes and other clinical data (e.g., node status, grade, ER-status) show that 
the PAM50 is an independent predictor of survival in breast cancer. The PAM50 
test provides additional information about the tumor biology and quantitative data 
on biomarkers already used for treatment decisions. Along with a categorical 
classification of breast cancer subtype, the clinical PAM50 test also determines a 
quantitative value for proliferation.  The PAM50 gene set testing will be 
performed using an Investigational Use Only (IUO) PAM50 Assay on the 
nCounter Dx Analysis System produced by NanoString Technologies.  The IUO 

 
 
67 | P a g e  
 
PAM50 assay uses the same reagents, procedures and algorithm as the 
Prosigna Gene Expression Assay, which have all been analytically validated and 
cleared for use by the FDA as a prognostic test in ER+ breast cancer patients 
who are treated with endocrine therapy alone. In this study, it is anticipated that 
only a small number of invasive cancers will be detected in premenopausal 
women; although the PAM50 is not FDA approved for premenopausal women, 
evidence suggests the PAM50 scoring is also predictive in this group of women 
as well.31-33 
Assay Description 
Used together, the PAM50 and nCounter Dx Analysis System are a nucleic acid 
hybridization, visualization and image analysis system based upon coded probes 
designed to detect the messenger RNA transcribed from 58 genes. The test input 
is purified RNA from FFPE breast tumor specimens. The PAM50 assay uses 
gene-specific probe-pairs that hybridize directly to the mRNA transcripts in 
solution. The nCounter Dx Analysis System delivers direct, multiplexed 
measurements of gene expression through digital readouts of the relative 
abundance of the mRNA transcripts. 
Specifications are included to control for sample quality, RNA quality, and 
process quality. The PAM50 assay utilizes prototypical expression profiles 
(centroids) which are associated with and define each of the four intrinsic 
subtypes of breast cancer. Patients are categorized into one of the four subtypes 
based upon how close their gene expression pattern is to each of the centroids 
(Luminal A, Luminal B, Her2-Enriched, and Basal-Like). 
Specimens and Processing: 
Formalin-fixed paraffin-embedded (FFPE) tumor tissue block from the residual 
disease on the definitive surgical specimen will be collected and submitted to the 
CBPF.  Tissue specimens and an H&E stain will be routed to the Leyland-Jones 
Laboratory.  The tissue will be evaluated for tumor area and cellularity, 
processed, and the tumor areas will be transposed to unstained slides. Tissue 
will be macrodissected and RNA will be extracted with a manual kit and 
subjected to PAM50 analysis, as described above. 
10.3 Lab Data Transfer Guidelines 
The data collected on the above mentioned laboratory research study will be 
submitted electronically using a secure data transfer to the ECOG-ACRIN 
Operations Office – Boston by the investigating laboratories on a quarterly basis 
or per joint agreement between ECOG-ACRIN and the investigator. 

 
 
68 | P a g e  
 
11. 
Electronic Data Capture 
Please refer to the EA1141 Forms Completion Guidelines for the forms submission 
schedule. Clinical data collection will be performed exclusively in Medidata Rave.  
Imaging studies are to be submitted via TRIAD 
Quality of Life study data are to be submitted via Medidata Rave 
This study will be monitored by the Clinical Data Update System (CDUS) version 3.0. 
Cumulative CDUS data will be submitted quarterly from the ECOG-ACRIN Operations 
Office – Boston to CTEP by electronic means. 
12. 
Patient Consent and Peer Judgment 
Current FDA, NCI, state, federal and institutional regulations concerning informed 
consent will be followed. 
13. 
References 
3. 
Berg WA, Blume JD, Cormack JB, et al. Combined screening with ultrasound and 
mammography vs mammography alone in women at elevated risk of breast cancer. 
JAMA. 2008;299(18):2151-63. 
4. 
Fletcher SW, Elmore JG. Clinical practice. Mammographic screening for breast cancer. N 
Engl J Med. 2003;348(17):1672-80. 
5. 
Humphrey LL, Helfand M, Chan BK, Woolf SH. Breast cancer screening: a summary of the 
evidence for the U.S. Preventive Services Task Force. Ann Intern Med. 2002;137(5 Part 
1):347-60. 
6. 
Medicine Io. Saving Women's lives: integration and innovation: a framework for 
progress in early detection and diagnosis of breast cancer. 2005. 
7. 
Welch HG, Passow HJ. Quantifying the benefits and harms of screening mammography. 
JAMA internal medicine. 2014;174(3):448-54. 
8. 
Berlin L. Point: Mammography, breast cancer, and overdiagnosis: the truth versus the 
whole truth versus nothing but the truth. J Am Coll Radiol. 2014;11(7):642-7. 
9. 
Carney PA, Miglioretti DL, Yankaskas BC, et al. Individual and combined effects of age, 
breast density, and hormone replacement therapy use on the accuracy of screening 
mammography. Ann Intern Med. 2003;138(3):168-75. 
10. 
Kerlikowske K, Grady D, Barclay J, Sickles EA, Ernster V. Effect of age, breast density, and 
family history on the sensitivity of first screening mammography. JAMA. 1996;276(1):33-
8. 
11. 
Pisano ED, Gatsonis C, Hendrick E, et al. Diagnostic performance of digital versus film 
mammography for breast-cancer screening. N Engl J Med. 2005;353(17):1773-83. 
12. 
Ciatto S, Houssami N, Bernardi D, et al. Integration of 3D digital mammography with 
tomosynthesis for population breast-cancer screening (STORM): a prospective 
comparison study. Lancet Oncol. 2013;14(7):583-9. 

 
 
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13. 
Skaane P, Bandos AI, Gullien R, et al. Prospective trial comparing full-field digital 
mammography (FFDM) versus combined FFDM and tomosynthesis in a population-
based screening programme using independent double reading with arbitration. Eur 
Radiol. 2013;23(8):2061-71. 
14. 
Skaane P, Bandos AI, Gullien R, et al. Comparison of digital mammography alone and 
digital mammography plus tomosynthesis in a population-based screening program. 
Radiology. 2013;267(1):47-56. 
15. 
Friedewald SM, Rafferty EA, Rose SL, et al. Breast cancer screening using tomosynthesis 
in combination with digital mammography. JAMA. 2014;311(24):2499-507. 
16. 
Price ER, Hargreaves J, Lipson JA, et al. The California breast density information group: 
a collaborative response to the issues of breast density, breast cancer risk, and breast 
density notification legislation. Radiology. 2013;269(3):887-92. 
17. 
Hooley RJ, Greenberg KL, Stackhouse RM, Geisel JL, Butler RS, Philpotts LE. Screening US 
in patients with mammographically dense breasts: initial experience with Connecticut 
Public Act 09-41. Radiology. 2012;265(1):59-69. 
18. 
Sprague BL, Stout NK, Schechter C, et al. Benefits, harms, and cost-effectiveness of 
supplemental ultrasonography screening for women with dense breasts. Ann Intern 
Med. 2015;162(3):157-66. 
19. 
New Choice Health Care Market Place.  http://www.newchoicehealth.com/Directory. 
20. 
Berg WA, Zhang Z, Lehrer D, et al. Detection of breast cancer with addition of annual 
screening ultrasound or a single screening MRI to mammography in women with 
elevated breast cancer risk. JAMA. 2012;307(13):1394-404. 
21. 
Kuhl C, Weigel S, Schrading S, et al. Prospective multicenter cohort study to refine 
management recommendations for women at elevated familial risk of breast cancer: 
the EVA trial. J Clin Oncol. 2010;28(9):1450-7. 
22. 
Kuhl CK, Schrading S, Strobel K, Schild HH, Hilgers RD, Bieling HB. Abbreviated breast 
magnetic resonance imaging (MRI): first postcontrast subtracted images and maximum-
intensity projection-a novel approach to breast cancer screening with MRI. J Clin Oncol. 
2014;32(22):2304-10. 
23. 
Schrading S KC. MRI screening of women at average risk of breast cancer. J Clin Oncol. 
2013;31:(suppl 26; abstr 1). 
24. 
Mango VL, Morris EA, David Dershaw D, et al. Abbreviated protocol for breast MRI: are 
multiple sequences needed for cancer detection? European journal of radiology. 
2015;84(1):65-70. 
25. 
Melsaether A GY, Seuss S, Heacock L, Moy L. Abbreviated MRI (AB-MR) of the Breast – 
Do We Need a Second Post-Contrast Scan? Oral presentation, RSNA, Chicago 2015. 
Abbreviated MRI (AB-MR) of the Breast – Do We Need a Second Post-Contrast Scan? 
Oral presentation, RSNA, Chicago 2015. 
26. 
Heacock L MA, Pysarenko KM, Toth H, Moy L. Sensitivity of an Abridged Breast MRI 
Protocol to Detect Biologically Significant Breast Cancers. Oral presentation, RSNA, 
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27. 
Sung JS, Stamler S, Brooks J et al. Breast Cancers Detected on High Risk Screening MRI 
and Mammography: Method of Detection Reflects Tumor Histopathology. Radiology. 
2016 Sep;280(3):716-22. doi: 10.1148/radiol.2016151419. PMID: 27097237 
28. 
Swan JS, Kong CY, Hur C, Halpern EF, Itauma O, Williams O, Motazedi T, Lee JM. 
Comparing morbidities of testing with a new index: screening colonoscopy versus core-
needle breast biopsy. J Am Coll Radiol. 2015 Mar;12(3):295-301. doi: 
10.1016/j.jacr.2014.08.014. Epub 2014 Oct 13. PubMed PMID: 25441485. 
29. 
Humphrey KL, Lee JM, Donelan K, Kong CY, Williams O, Itauma O, Halpern EF, Gerade BJ, 
Rafferty EA, Swan JS. Percutaneous breast biopsy: effect on short-term quality of life. 
Radiology. 2014 Feb;270(2):362-8. doi: 10.1148/radiol.13130865. Epub 2013 Nov 11. 
PubMed PMID: 24471385; PubMed Central PMCID: PMC4228748. 
30. 
Swan JS, Hur C, Lee P, Motazedi T, Donelan K. Responsiveness of the testing morbidities 
index in colonoscopy. Value Health. 2013 Sep-Oct;16(6):1046-53. doi: 
10.1016/j.jval.2013.07.008. PubMed PMID: 24041354. 
31. 
Swan JS, Kong CY, Lee JM, Itauma O, Halpern EF, Lee PA, Vavinskiy S, Williams O, Zoltick 
ES, Donelan K. Patient and societal value functions for the testing morbidities index. 
Med Decis Making. 2013 Aug;33(6):819-38. doi: 10.1177/0272989X13487605. Epub 
2013 May 20. PubMed PMID: 23689044; PubMed Central PMCID: PMC3817009. 
32. 
Leisenring W, Alonzo T, Pepe MS. Comparisons of predictive values of binary medical 
diagnostic tests for paired designs. Biometrics. 2000;56(2):345–351. 
33. 
Chia SK, Bramwell VH, Tu D, et al. A 50-gene intrinsic subtype classifier for prognosis and 
prediction of benefit from adjuvant tamoxifen. Clin Cancer Res. 2012;18(16):4465-72. 
34. 
Fan C, Oh DS, Wessels L, et al. Concordance among gene-expression-based predictors 
for breast cancer. N Engl J Med. 2006;355(6):560-9. 
35. 
Liu S, Chapman JA, Burnell MJ, et al. Prognostic and predictive investigation of PAM50 
intrinsic subtypes in the NCIC CTG MA.21 phase III chemotherapy trial. Breast Cancer 
Res Treat. 2015;149(2):439-48. 
 
 

 
 
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Appendix I  
 
American Cancer Society Guidelines for Breast Screening with MRI as 
an Adjunct to mammography 
1. BRCA mutation 
2. First-degree relative of BRCA carrier, but untested 
3. Lifetime risk ∼20–25% or greater, as defined by BRCAPRO or other models that are largely 
dependent on family history 
4. Recommend Annual MRI Screening (Based on Expert Consensus Opinion) 
5. Radiation to chest between age 10 and 30 years 
6. Li-Fraumeni syndrome and first-degree relatives 
7. Cowden and Bannayan-Riley-Ruvalcaba syndromes and first-degree relatives 
8. Insufficient Evidence to Recommend for or Against MRI Screening 
• 
Lifetime risk 15–20%, as defined by BRCAPRO or other models that are largely 
dependent on family history 
• 
Lobular carcinoma in situ (LCIS) or atypical lobular hyperplasia (ALH) 
• 
Atypical ductal hyperplasia (ADH) 
• 
Heterogeneously or extremely dense breast on mammography 
• 
Women with a personal history of breast cancer, including ductal carcinoma in 
situ (DCIS) 
Rev. Add4 

 
 
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Appendix II 
 
Pathology Submission Guidelines 
The following items are included in Appendix II: 
1. Guidelines for Submission of Pathology Materials  
(instructional sheet for Clinical Research Associates [CRAs]) 
2. Instructional memo to submitting pathologists 
3. ECOG-ACRIN Generic Specimen Submission Form (#2981) 
 
Rev. 2/17 

 
 
73 | P a g e  
 
Guidelines for Submission of Pathology Materials 
1. Tumor Tissue Submissions to Genomic Health from Patients with DCIS 
Contact Genomic Health Customer Service (866-662-6897) and request the 
“Oncotype Specimen Kit.” 
One Oncotype Specimen Kit and Requisition Form should be completed per patient. 
DO NOT MIX BARCODE LABELS BETWEEN PATIENTS. 
• 
Tumor Tissue Block (place barcode label on back of cassette) 
OR 
Fifteen (15) 5 µm serial unstained slides, oriented similarly and air dried. Label each 
slide with barcode and number in the order they were cut. 
NOTE: 
Proper sterile sectioning technique MUST be followed. Failure to follow sterile 
technique can affect testing and delay results. If sterile technique cannot be 
followed, submission of a tumor tissue block is strongly recommended. 
• 
Shipping Manifest Form from Sample Tracking System (STS) 
• 
Completed Oncotype DX Requisition Form 
This form is to be completed on-line or written as instructed in the kit except for the 
following fields: 
• 
“STUDY NAME/CODE” enter the protocol number 01-194-IIS-EA1141 and the 
ECOG-ACRIN EA1141 patient sequence number assigned at randomization. 
• 
BILLING INFORMATION (section V): Please leave blank. 
• 
ADDITIONAL PHYSICIAN (section III): Enter the contact information of the 
institutional CRA coordinating the EA1141 study. 
• 
BLOCK RETURN” information (section VI). After testing, all residual block 
material will be forwarded by Genomic Health to the ECOG-ACRIN CBPF. 
• 
BLOCK RETURN CONTACT = ECOG-ACRIN Central Biorepository and 
Pathology Facility 
• 
BLOCK RETURN PHONE NUMBER = (844) 744-2420 
2. Tumor Tissue Submissions to CBPF from Patients with Invasive Cancer (and 
all patients from whom only slides were submitted to GHI for the OncotypeDX 
DCIS assessment) 
1. Adequate patient identifying information must be included with every 
submission. It is strongly recommended that full patient names be provided. 
The information will be used only to identify patient materials, and will 
expedite any required communications with the institution (including site 
pathologists). 
2. Pathology materials: 
Representative tumor tissue (DCIS or invasive) is submitted after all local 
assessments required for patient care are complete and are requested to be 
submitted within 30 days of the procedure. 

 
 
74 | P a g e  
 
Forms 
The relevant pathology and surgical reports must accompany all tissue submissions: 
• 
Copy of the diagnostic or surgical Pathology Report 
• 
Other Immunologic and cytologic reports 
• 
STS generated shipping manifest for all submitted tissue. 
Tumor tissue submissions: 
Representative formalin fixed paraffin embedded (FFPE) tumor tissue blocks. 
NOTE: 
If blocks are unavailable for submission, cores and slides are to be submitted.  
All cores and slides must be adequately labeled, with slides numbered 
sequentially in the order cut.  Alternative submission requirement:  
• 
One (1) H&E slide 
• 
Twenty (20) 4-5 µm unstained air-dried plus slides 
• 
Two (2) 4 mm cores 
NOTE: 
Since blocks are being used for laboratory studies, in some cases the blocks 
may be depleted and therefore may not be available for return. 
Keep a copy of the STS- Shipping Manifest or Submission Form for your records. 
Double-check that ALL required forms, reports and pathology samples are included in the 
package to the CRA.  
The CRA will Mail pathology materials to: 
ECOG-ACRIN Central Biorepository and Pathology Facility 
MD Anderson Cancer Center  
Department of Pathology, Unit 085 
Tissue Qualification Laboratory for ECOG-ACRIN, Room G1.3586 
1515 Holcombe Blvd 
Houston, TX 77030 
Phone: Toll Free 1-844-744-2420 (713-745-4440 Local or International Sites)  
Fax: 713-563-6506 
Email: eacbpf@mdanderson.org 
If you have any questions concerning the above instructions or if you anticipate any 
problems in meeting the pathology material submission deadline of one month, contact 
the Pathology Coordinator at the ECOG-ACRIN Central Biorepository and Pathology 
Facility. 
 

 
 
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MEMORANDUM 
TO:  
__________________________________________________ 
 
(Submitting Pathologist) 
FROM: 
Stanley Hamilton, M.D., Chair 
 
ECOG-ACRIN Laboratory Science and Pathology Committee 
DATE:  
____________________________________ 
SUBJECT: 
Submission of Pathology Materials for EA1141: Comparison of 
Abbreviated Breast MRI and Digital Breast Tomosynthesis in 
Breast Cancer Screening in Women with Dense Breasts 
 
The patient named on the attached request has been entered onto an ECOG-ACRIN 
protocol by _____________________________ (ECOG-ACRIN Investigator). This 
protocol requires the submission of, as appropriate, tumor tissue specimens (DCIS or 
invasive) for laboratory research studies. 
Keep a copy of the submission for your records and return any relevant completed 
forms, the surgical pathology report(s), the slides and/or blocks and any other required 
material (see List of Required Material) to the Clinical Research Associate (CRA). The 
CRA will forward all required pathology material to the ECOG-ACRIN Central 
Biorepository and Pathology Facility (CBPF) and Genomic Health as appropriate. 
Pathology materials submitted for this study will be retained at the ECOG-ACRIN 
Central Repository for future studies per patient consent.  Paraffin blocks will be 
returned upon request for purposes of patient management. 
Please note: Since blocks are being used for laboratory studies, in some cases the 
material may be depleted, and, therefore, the block may not be returned. 
If you have any questions regarding this request, please contact Genomic Health 
Customer Service (650-556-9300) or the Central Biorepository and Pathology Facility at 
(1-844-744-2420 (713-745-4440 Local or International Sites) or email: 
eacbpf@mdanderson.org 
The ECOG-ACRIN CRA at your institution is: 
Name: _____________________________________  
Address: ___________________________________  
Phone: ____________________________________  
Thank you. 

 
 
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ECOG-ACRIN Generic Specimen Submission Form  
Form No. 2981v3 
Page 1 of 1 
Institution Instructions: This form is to be completed and submitted with all specimens ONLY if the Sample Tracking System (STS) is not available. Use one form per patient, per time- 
point. All specimens shipped to the laboratory must be listed on this form. Enter all dates as MM/DD/YY. Keep a copy for your files. Retroactively log all specimens into STS once the 
system is available. Contact the receiving lab to inform them of shipments that will be sent with this form. 
Protocol Number    
 
Patient ID     
 
Patient Initials   Last  
 First     
 
Date Shipped    
 
Courier     
 Courier Tracking Number   
 
Shipped To (Laboratory Name)   
 
Date CRA will log into STS    
 
FORMS AND REPORTS: Include all forms and reports as directed per protocol, e.g., pathology, cytogenetics, flow cytometry, patient consult, etc. 
Required fields for all samples 
Additional fields for tissue submissions 
Completed by  
Receiving Lab 
Protocol Specified Timepoint: 
Sample Type  
(fluid or fresh tissue, 
include collection tube type) 
Quantity 
Collection  
Date and Time 24 HR 
Surgical or  
Sample ID 
Anatomic  
Site 
Disease Status  
(e.g., primary, mets, 
normal) 
Stain or Fixative 
Lab ID 
 
Fields to be completed if requested per protocol. Refer to the protocol-specific sample submissions for additional fields that may be required. 
Leukemia/Myeloma 
Studies: 
Diagnosis 
Intended Treatment Trial 
Peripheral WBC Count (x1000) 
Peripheral Blasts % 
Lymphocytes % 
 
 
 
 
Study Drug 
Information: 
Therapy Drug Name 
Date Drug Administered 
Start Time 24 HR 
Stop Time 24HR 
 
 
 
 
Caloric Intake: 
Date of Last Caloric Intake 
Time of Last Caloric Intake 24HR 
 

 
 
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CRA Name   
 
CRA Phone   
 
CRA Email   
 
Comments 
 
9/12/14 

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

 
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Appendix IV 
 
ECOG Performance Status 
PS 0 
Fully active, able to carry on all pre-disease performance without 
restriction 
PS 1 
Restricted in physically strenuous activity but ambulatory and able to 
carry out work of a light or sedentary nature e.g., light house work, office 
work. 
PS 2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours. 
PS 3 
Capable of only limited self-care, confined to bed or chair more than 50% 
of waking hours. 
PS 4 
Completely disabled. Cannot carry on any self-care. Totally confined to 
bed or chair. 
 
Rev. Add4