Supine MRI in Breast Cancer Patients Undergoing Upfront Surgery or Receiving Neoadjuvant Therapy
Phase: NA
Conditions: Breast Cancer
Sponsor: Dana-Farber Cancer Institute

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cover Page for ClinicalTrials.gov 
 
• Protocol title: SUPINE MRI IN BREAST CANCER 
PATIENTS RECEIVING UPFRONT SURGERY OR 
NEOADJUVANT THERAPY 
 
• NCT #: NCT02956473 
 
• Protocol Version Date: 11/08/2022 

NCI Protocol #: 
N/A 
 
DF/HCC Protocol #: 16-277 
 
TITLE: Supine MRI in Breast Cancer Patients Receiving Upfront Surgery or 
Neoadjuvant Therapy 
 
Coordinating Center: 
Dana-Farber/Brigham and Women’s Cancer Center 
Brigham and Women’s Hospital 
75 Francis Street 
Boston, MA 02115 
 
*Principal Investigator (PI): 
Tari King, MD 
Department of Surgery 
Dana-Farber/Brigham and Women’s Cancer Center 
75 Francis Street 
Boston, MA 02115 
Ph: 617-632-3891 
Fax: 617-582-9969 
Email: Tking7@partners.org 
 
 
*Other Investigators: 
 
Eva Gombos, MD 
Department of Radiology 
Brigham and Women’s Hospital 
75 Francis Street 
Boston, MA 02115 
Ph: (617) 732-6269 
Email: egombos@partners.org 
 
Jennifer Bellon, MD 
Department of Radiation Oncology 
Brigham and Women’s Hospital 
75 Francis Street 
Boston, MA 02115 
Phone: 617-632-3591 
Jbellon@partners.org 
 
Julia Wong, MD 
Department of Radiation Oncology 
Brigham and Women’s Hospital 
75 Francis Street 
 
 
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Boston, MA 02115 
Phone: 617-632-3591 
Email: Jwong@partners.org 
 
 
 
Jayender Jagadeesan, PHD 
Department of Radiology 
Brigham and Women’s Hospital 
75 Francis Street 
Boston, MA 02115 
P: (617) 794-3251 
Email: jjagadeesan@partners.org 
 
 
 
 
 
Statistician: 
Study Coordinator and Data Manager: 
Wei Wang, PhD. 
Stephen (Dan) DeSantis 
Brigham and Women’s Hospital 
Dana Farber Cancer Institute 
Statistics Department 
 Breast Oncology 
221 Longwood Ave, Room 438M 
450 Brookline Ave 
Boston, MA 02115 
 Boston, MA 02215 
P: 617-525-6708 
P: (617) 632-5597 
F: 617-732-4013 
F: (617) 632-3550 
Email: wwang4@partners.org 
Email: sdesantis1@partners.org 
 
 
Study Exempt from IND Requirements per 21 CFR 312.2(b). 
 
Protocol Type / Version # / Version Date: Version #4, 11/08/2022 
Original, Version #1, 5/25/2016 

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STUDY SCHEMA 
Selection, Enrollment and Imaging: 
Newly diagnosed breast cancer (stage I, II, III non-inflammatory) planning upfront surgery or 
neoadjuvant therapy (NAT) 
 
 
Patient informed consent obtained 
Eligibility confirmed 
Patient registered 
Pre-surgery or Pre-NAT MRI performed in routine prone position and investigational supine 
position 
 
Extent of disease/ lesions seen on MRI compared with other standard imaging modalities 
including mammogram and ultrasound 
 
If additional suspicious findings seen only on MRI a second-look US and/or addition 
mammographic views with or without biopsy will be performed using prone and supine MRI 
sequences for guidance 
Radiologist completes brief survey regarding usefulness of supine MRI for second-look US +/- 
biopsy (if applicable) 
 
Patient proceeds with upfront surgery or NAT: 
 
 
 
If receives NAT, post-NAT imaging obtained to include +/-mammogram, +/- US, + breast 
MRI prone+supine 
 
Surgery: 
 
 
Per surgeon/radiologist preference, tumor localization (with wire or radio-seed) performed by 
radiologist prior to surgery 
 

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Radiologist completes brief survey regarding usefulness of supine MRI for localization 
Breast surgery performed and specimen sent to pathology 
 
 
Lumpectomy 
Mastectomy 
Surgeon completes brief survey regarding 
usefulness of supine MRI for surgical planning 
after completion of the operation 
 
Follow-up and Final Pathology Results 
 
 
Obtain final tumor volume, tumor size on pathology: compare to pre-operative imaging 
estimates of tumor size and volume 
Negative margins on pathology 
Negative margins on 
Positive Margin 
patients with pathological 
pathology with residual 
on pathology 
complete response (pCR) 
tumor (no pCR) 
 
 
No further surgery 
May consider reoperation 
Strongly consider 
reoperation 
 
 
Postoperative radiation therapy (if applicable) 
Radiation oncologist survey 

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TABLE OF CONTENTS 
1.1 
Study Design and Hypotheses 
7 
1.2 
Primary Objectives 
8 
1.3 
Secondary Objectives 
8 
2. 
BACKGROUND 
9 
2.1 
Study Disease and Rationale 
9 
2.2 
Correlative Studies Background 
12 
3. 
PARTICIPANT SELECTION 
12 
3.1 
Inclusion Criteria 
12 
3.2 
Exclusion Criteria 
13 
3.3 
Inclusion of Women and Minorities 
13 
4. 
REGISTRATION PROCEDURES 
13 
4.1 
General Guidelines for DF/HCC Institutions 
13 
4.2 
Registration Process for DF/HCC Institutions 
13 
4.3 
General Guidelines for Other Investigative Sites 
14 
4.4 
Registration Process for Other Investigative Sites 
14 
5. 
TREATMENT AND IMAGING PLAN 
14 
5.1 
Treatment Plan 
14 
5.2 
Description of Intervention/Intervention Regimen 
15 
5.3 
Post-Surgery: Adjuvant Radiation Therapy 
17 
Patients who require adjuvant radiation therapy postoperatively will be referred to radiation 
oncologists at the DFCI. If the patient chooses to pursue their radiation treatment with DFCI 
clinicians (patients are offered a choice as to where to complete their radiation treatment), then 
the radiation oncologist will be provided with all imaging, including supine MRI images 
acquired pre-surgery for treatment planning purposes. These images will be utilized for 
planning of the radiation treatment plan. Following completion of the initial radiation 
treatment plan, the attending treating radiation oncologists will be asked to complete a brief 
survey to assess their perceived usefulness of the supine MRI data for treatment planning 
purposes. 
17 
5.4 
Duration of Follow Up 
17 
5.5 
Criteria for Taking a Participant Off-Study 
17 
6. 
Expected toxicities, Adverse Events, and Dosing delays/Dose Modifications 
18 
6.1 
Adverse Event Characteristics 
19 
6.2 
For Expedited Adverse Event Reporting 
19 
6.3 
Expedited Reporting to Hospital Risk Management 
19 

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6.4 
Routine Adverse Event Reporting 
20 
7. 
STUDY CALENDAR 
20 
8. 
DATA REPORTING / REGULATORY REQUIREMENTS 
21 
8.1 
Data Reporting 
21 
8.2 
Data Safety Monitoring 
21 
8.3 
Multicenter Guidelines 
21 
8.4 
Collaborative Agreements Language 
21 
9. 
STATISTICAL CONSIDERATIONS 
21 
9.1 
Study Design/Endpoints 
22 
9.2 
Sample Size, Accrual Rate and Study Duration 
22 
9.3 
Stratification Factors 
23 
9.4 
Interim Monitoring Plan 
23 
9.5 
Analysis of Primary Endpoints 
23 
9.6 
Analysis of Secondary Endpoints 
24 
9.7 
Reporting and Exclusions 
24 
10. 
PUBLICATION PLAN 
25 
REFERENCES 
26 

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OBJECTIVES 
 
1.1 
Study Design and Hypotheses 
This study is designed as a prospective Phase II trial aimed to determine the value of supine 
breast MRI for women newly diagnosed with stage I-III non-inflammatory breast cancer 
undergoing upfront surgery or neoadjuvant therapy (NAT). 
 
We hypothesize that breast MRI with supine sequences will provide advanced image-based 
characteristics for (1) radiological procedures (2) surgical operations and (3) adjuvant radiation 
delivery, and further hypothesize that these images will allow for superior characterization and 
localization of breast lesions as compared to traditional imaging studies (mammography, 
ultrasound, prone MRI). This will be measured by a combination of qualitative (clinician surveys 
of supine MRI usefulness for radiologic and surgical procedures and for radiation 
treatment/delivery) and quantitative measures (correlation in residual tumor size estimation with 
the gold standard method, success rate of US-guided lesion identification and/or biopsy 
performed with supine MRI guidance, and rate of re-excisions for breast conserving surgical 
operations when supine MRI used for surgical planning). 
 
More specifically, we hypothesize that: 
(1) Supine breast MRI will provide an accurate assessment of residual breast tumor size 
(2) Supine breast MRI will be superior to other imaging modalities in estimation of final tumor 
size as determined on post-operative pathology (gold standard). 
(3) Supine MRI will help radiologists identify suspected satellite lesions and/or additional 
suspicious findings during the second look ultrasound procedure. Tissue sampling under 
sonographic-guidance is more cost effective and patient centric for the patient compared to 
biopsy under MRI-guidance; therefore, the correlation of MRI findings with ultrasound findings 
is an important patient-centered endpoint. 
(4) Supine breast MRI will improve surgical planning efforts for breast conserving surgery by 
providing surgeons with more accurate information regarding the tumor’s location within the 
breast in the supine position, which will translate into reduced re-excision rates associated with 
this procedure. 
(5) Supine breast MRI will improve adjuvant radiation therapy planning efforts following breast 
surgery by providing radiation oncologists with more accurate imaging information of the patient 
in the supine position, allowing for potentially improved radiation delivery 
 
A total of 74 patients will be recruited to participate in this study. Enrolled patients will under go 
upfront surgery or receive a NAT regimen at the discretion of the treatment team. All patients 
will have their breast tumor evaluated with standard imaging to include mammography, 2D 
and/or 3D, ultrasound, prone contrast-enhanced MRI and investigational supine contrast- 
enhanced MRI sequence pre-surgery. For patients planning for NAT, we will also attempt to 
obtain a prone contrast-enhanced MRI and investigational supine contrast-enhanced MRI 
sequence pre-NAT; however if a patient presents with an outside pre NAT MRI this will not be 
repeated. The tumor’s position on all imaging modalities will be registered, and tumor location 
between supine and prone MRI sequences will be determined. Investigational supine MRI 
images will be provided to radiologists and surgeons for purposes of performing additional 
imaging interventions, if they are deemed necessary by the treatment team, and for surgical 

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planning. Estimates of tumor size pre-operatively as identified by each imaging modality will be 
compared to final pathology, allowing the correlation of each imaging modality for estimating 
residual tumor size with the gold standard method (pathology). 
 
For patients undergoing BCT, the prone and supine MRI images will be registered in the image- 
processing software, 3D Slicer, and the segmented tumor models will be overlaid on the images. 
Screenshots showing the displacement of the tumor from the prone to the supine images will be 
provided to the surgeon to plan the tumor resection. Following completion of the operation a 
survey of the breast surgeon will be administered to determine their perceived usefulness of the 
supine imaging for surgical planning. Volume of excised tissue, rates of positive margins, and 
the need for reoperation, will be recorded, and these measures (using supine MRI imaging) will 
be compared to historical data to determine the impact of supine MRI imaging on surgical 
outcomes. 
 
Patients requiring postoperative radiation therapy will be referred to radiation oncology post- 
operatively. Supine MRI images obtained prior to surgery will be provided to the radiation 
oncologists for breast treatment planning. A survey will then be administered to the attending 
treating radiation oncologist to assess the usefulness of supine MRI for treatment planning. 
 
1.2 
Primary Objectives 
 
The primary objectives are: 
 
1) Determine the Pearson correlation between pre-operative prone and supine MRI for 
estimating tumor size as compared to the gold standard of pathologic evaluation of the surgical 
specimen. 
2) To compare the Pearson correlation between pre-surgical standard imaging (mammography, 
ultrasound, prone MRI) and the gold standard of pathologic evaluation of the surgical specimen 
and the Pearson correlation between pre-surgical supine MRI and gold standard of pathologic 
evaluation of the surgical specimen for the evaluation of tumor size. 
 
3) To explore the potential changes occurring in tumor-associated properties/dimensions 
between the prone and supine imaging position and to determine the correlation of tumor 
location and geometry on pre-surgical supine MRI with prone MRI. Tumor location will be 
assessed in terms of distance from nipple, chest wall, and skin. Tumor geometry will be assessed 
on multiple properties including volume, surface area, diameter, spherocity, and compactness. 
Patients with both pre-NAT and pre-surgical MRI will also be evaluated for the pre-NAT 
prone/supine MRI and pre-surgical prone/supine MRI comparison. 
 
 
1.3 
Secondary Objectives 
Secondary objectives for this trial are listed below. 
 
1. To assess the value of supine MRI for radiologists performing second look US examinations/ 
biopsies following identification of new lesions on MRI, and performing preoperative lesion 
localization using supine MRI guidance. Value will be assessed by both qualitative (survey of 

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radiologists on perceived usefulness of supine MRI for imaging localization/procedures*) and 
quantitative measures (success rate of second-look ultrasound lesion localizations and procedures 
utilizing supine MRI guidance). Procedures include lesion biopsy and pre-surgical lesion 
localization performed by radiologist. 
2. To explore the perceived benefit of pre-surgical supine MRI for surgical planning as measured 
by the collective results of a survey of surgeons performing BCS in our study patient population. 
3. To explore the effect of supine MRI on influencing BCS outcomes by determining the percent 
of patients requiring re-excisions or having a pathologic positive margins when supine 
MR imaging is performed and available for surgical planning purposes. 
4. To explore the perceived benefit of pre-surgical supine MRI for adjuvant radiation breast 
treatment planning as measured by the collective results of a survey of radiation oncologists 
treating patients in our study population post-operatively. 
 
2. BACKGROUND 
2.1 
Study Disease and Rationale 
Breast cancer affects millions of women worldwide and is the second most common cancer in 
the world [1]. Over 249,00 new cases of breast cancer are estimated to be diagnosed in 2016 in 
the United States alone, with breast-cancer specific morality rates predicted to exceed 40,000 
[2]. Treatment for breast cancer has evolved in recent decades following an improved 
understanding of the biology of the disease, and contemporary breast cancer care now mandates 
a multidisciplinary, multimodal approach for optimal outcomes. Surgery, radiation, and systemic 
therapy (including endocrine, biologic, and chemotherapeutic agents) are key modalities utilized 
in the ongoing treatment algorithm for breast cancer patients. For early stage disease, breast 
conservation therapy or ‘BCT’ (consisting of lumpectomy or ‘breast conserving surgery’ (BCS) 
followed by post-operative radiation therapy) has become a mainstay of treatment following 
demonstration of its equivalence to mastectomy in terms of long term survival in at least six 
modern prospective randomized trials [3-8]. 
 
BCT has enabled less invasive surgical treatment for breast cancer without compromising 
survival, however it currently is limited in its application to well-selected candidates. Although 
size is not an absolute contraindication to BCT, a very large tumor size relative to breast volume 
is considered a relative contraindication [9]. MRI is routinely utilized to determine extent of 
disease at diagnosis and to determine candidacy for upfront surgery in patients who are desirous 
of BCT. For women with large and locally advanced breast cancers, breast conserving surgery 
only became a surgical option following the inclusion of neoadjuvant therapy (NAT) into 
contemporary cancer treatment algorithms. NAT has demonstrated efficacy in shrinking breast 
tumors preoperatively, enabling some patients to become BCT candidates who otherwise would 
not have qualified [10-14]. Numerous studies have established equivalence of BCT after NAT 
compared to BCT with post-surgical systemic adjuvant therapy with respect to both survival and 
local recurrence rates [13, 15-17]. By utilizing modern era therapy, over 50% of patients with 
certain breast cancer subtypes (including triple negative and HER2+) treated with NAT are 
expected to achieve a pathological complete response (pCR) following NAT administration, 
which is associated with improved long-term prognosis [18, 19]. 
 
 
In the upfront surgery setting, the use of Breast MRI has been shown to compliment traditional 

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imaging modalities (MMG/US) for determining extent of disease; however there remains a 
problem with over-estimation of lesion size. This combined with the frequency of identification 
of second lesions which require biopsy (and are often not visible on MMG/US) has been shown 
to correlate with increased use of mastectomy, with patients often deferring biopsy altogether. 
Whether or not supine MRI can improve upon correlation with tumor size in the upfront surgery 
setting and whether or not supine MRI can lead to improved identification of second lesions 
requiring biopsy has not been tested. 
 
In the NAT setting, breast MRI has demonstrated higher accuracy over physical examination, 
mammography, and targeted breast ultrasound in the evaluation of tumor response to NAT and 
prediction of amount of residual disease. [12, 20-28]. The correlation of residual tumor size 
following NAT and histopathology in patients who underwent prone MRI before BCS has been 
reported to be approximately r=0.7 (Bhattacharyya et al (r=0.71), Rosen et al (r=0.75), 
Martincich et al (r=0.72), Segara et al (r=0.75)[12, 27-29]. For patients who require NAT for 
downstaging to BCT, repeating the MRI after NAT (pre-surgery) is standard for surgical 
treatment planning. In practice, it is uncommon to exclusively rely on a single imaging modality 
for breast cancer evaluation, and newly diagnosed breast cancer patients routinely have 
diagnostic mammography and ultrasound imaging as well. In patients undergoing NAT, these 
images are also repeated after NAT (pre-surgery) for surgical treatment planning. 
 
One of the challenges inherent with the current breast MRI design is that the images are obtained 
with the patient in the prone position. Tumors are displayed to both radiologists and surgeons in 
relation to their position in the prone breast, however both ultrasound and surgery are performed 
on the supine breast. The changes in breast position- especially for patients with large or pliable 
breasts- can significantly displace breast tumors, making it difficult for radiologists to correlate 
MRI and sonographic findings, and for surgeons to localize tumors intraoperatively[33, 34]. 
 
Limitations of other modalities are numerous. For example, NAT can induce unpredictable 
fibrous changes that can reduce the reliability of clinical examination. Certain breast cancer 
subtypes, such as lobular carcinoma for example, are difficult to visualize mammographically 
and can increase in firmness after NAT, causing an initially occult lesion to become more 
clinically palpable with treatment[30]. Assessment of tumor size on exam and with 
mammography can be undermined by the infiltrative nature of locally advanced breast cancers, 
especially in the setting of dense breast tissue [25, 26, 31]. Suspicious microcalcifications 
initially noted on mammogram may persist, become coarser, or occasionally increase on 
mammograms after NAT. Peintinger et al demonstrated that a combination of mammogram and 
ultrasound could provide moderate agreement in predicting residual tumor size after NAT; 
however, the correlation and agreement with pathologic residual tumor size was underestimated 
for lobular carcinoma and overestimated for poorly differentiated tumors [32]. Yeh et al also 
demonstrated similar findings when comparing agreement regarding the rate of response 
between clinical examination, mammography, sonography, and MRI with pathology as the 
reference standard, with agreement rates of 19%, 26%, 35%, and 71%, respectively [26]. 
Although MRI was noted to be the superior modality in this study, it was not without its own 
limitations; MRI was felt to both underestimate and overestimate residual tumor measurements, 
leaving clinicians with an ongoing need for an improved way to monitor the response to and the 
disease remaining after NAT regimens. 

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Breast imaging, most commonly breast CT, is used post-operatively for patients requiring 
adjuvant radiation therapy, in order to identify radiation delivery regimens that will accurately 
and completely target the desired tissue while minimizing the effect on surrounding structures 
such as the heart and lungs. Treatment plans are designed on a patient-by-patient basis, and are 
influenced by a range of factors including breast density, lumpectomy cavity volume, and use of 
adjuvant chemotherapy, which can delay radiation treatment and contribute to cavity contraction 
making cavity identification more challenging [35, 36]. Multiple studies have demonstrated 
limitations in single-modality treatment planning with significant inter-observer variability in 
delineation of tumor cavities, and multi-modality imaging using a combination of MRI and CT 
has been suggested as a way of improving target volume definition in patients with difficult to 
visualize cavities [35, 37-39]. Jacobson et al, for example, found that acquisition of a non- 
contrast supine MRI during treatment planning sessions provided more detailed visual 
information than CT in the post-lumpectomy breast, and suggested that the combination of 
images could improve delineation of target cavities [35]. Nevertheless, debate remains about the 
ultimate utility of MRI for breast treatment radiation planning, and additional studies evaluating 
the potential benefits are warranted [39-42]. 
 
A secondary objective of a Phase I Clinical Trial we recently completed at our institution 
evaluating the feasibility of intraoperative breast MRI was to better characterize the positional 
change that occurs between the prone and supine imaged breast [30, 33, 34]. Our results, 
presented in 2015 at the Society of Breast Imaging Annual Meeting and at the New England 
Surgical Society Annual Meeting, showed that substantial tumor displacement occurs when the 
breast changes from the prone to the supine position, with an average tumor displacement of over 
6cm [43, 44]. Additionally, we found substantial tumor deformation occurring between 
positions, with an average change in the measured volume of 23.8%, surface area of 6.5%, 
compactness of 16.2% and maximum 3D diameter of 7.1% (mean change from prone to supine 
imaging (as a percentage of the prone metrics) [34, 43]. This was unanticipated, as breast cancers 
have been shown to be more stiff than surrounding breast parenchyma (Krouskop et al showed 
stiffness of normal fat, normal glandular tissue, and invasive ductal carcinomas to be 20 kPa, 57 
kPa, and 490 kPa, respectively) and thus deformation was suspected to be negligible [43, 45]. 
These deformations and displacements were visually represented on ‘composite’ MRI images, 
which simultaneously displayed a tumor’s location/shape using “3D tumor models” in both the 
prone and supine position (tumors were registered, and prone and supine MRI were overlaid), 
enabling surgeons and radiologists alike to visually identify each tumor’s location/size/shape in 
both orientations. Briefly, this was achieved by rigidly registering breast tumors on both post- 
contrast MRI series on thoracic cavities using the Mutual Information criterion, following initial 
alignment of the pulmonary veins [46-48]. 3D tumor models were then created in 3D Slicer by 
segmenting the tumors on the supine and prone MRIs using semi-automatic threshold-based 
algorithms on the subtracted images computed from the first post- and pre-contrast volumes, 
which were then further registered using Iterative Closest Point registration [48]. These tumor 
models, and their associated prone and MRI scans, were overlaid to generate the composite 
models presented to surgeons prior to surgery. Anecdotally, we found that these composite 
images were viewed as useful by both radiologists and surgeons alike, in assisting with tumor 
localization and with surgical planning. Based on these results, our institution adopted a policy 

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that allows for selective performance of supine MRI sequences in addition to prone MRI 
sequences for patients undergoing breast MRI earlier this year. 
 
Contrast-enhanced breast MRI is a useful imaging tool however it is not indicated for all patients 
with breast cancer. Although it has high sensitivity and moderate specificity for detecting breast 
carcinoma, it is associated with false positive findings and prospective and retrospective studies 
have failed to show that routine prone preoperative MRI is beneficial in improving BCT 
outcomes in terms of re-excision, local recurrence, or overall survival rates yet its use 
persists.[49-55] Further although post NAT is associated with the highest correlation between 
residual tumor size and pathologic size; it’s use in this setting has also not been demonstrated to 
improve BCT outcomes. This study will evaluate the role of obtaining supine breast MRI in 
addition to prone breast MRI in patients undergoing upfront surgery or receiving NAT. We 
hypothesize that having supine sequences in addition to prone sequences available for review by 
breast surgeons and radiologists that this will 1) improve surgical conceptualization of breast 
tumors in the supine position and thus improve surgical planning, 2) influence outcomes 
including positive margin/reoperation rates following breast conserving surgery, 3) aid 
radiologists in identifying tumors on targeted ultrasound, and 4) improve the direct comparison 
of tumors at MRI and ultrasound. 
 
2.2 
Correlative Studies Background 
Not applicable 
 
3. PARTICIPANT SELECTION 
3.1 
Inclusion Criteria 
3.1.1 Participants must be female 
3.1.2 Participants must have a pre-operative standard mammogram with or without ultrasound. 
These may be performed at outside institutions but must be reviewed at BWH/DFCI. 
3.1.3 Participants must have biopsy confirmed and clinical stage I, stage II, or stage III non- 
inflammatory breast carcinoma. If biopsy was done at an outside hospital, pathology will 
be reviewed at (BWH, BWFH) 
3.1.4 Patient must meet standard MRI guidelines and be able and willing to undergo MRI 
3.1.5 Participants must be candidates for definitive local therapy with breast conserving 
therapy or deemed as potential candidates following NAT (this takes into account tumor 
to breast size ratio appropriate for BCT, and the ability to undergo standard radiation 
therapy post-operatively). 
3.1.6 Study participants will be restricted to those aged ≥18. 
3.1.7 Ability to understand and the willingness to sign a written informed consent document. 

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3.2 
Exclusion Criteria 
3.2.1 Participants with a known BRCA 1 or 2 mutation. 
3.2.2 Participants with a known Li-Fraumeni or Cowden’s Disease. 
3.2.3 Participants with prior mantle radiation. 
3.2.4 Participants with inflammatory breast cancer or multi-centric disease 
3.2.5 Participants who are pregnant. 
3.2.6 Participants who are already enrolled in a conflicting investigational trial 
3.2.7 Participants with known active collagen vascular disease. 
3.2.8 Participants with prior history of ipsilateral breast carcinoma treated with BCS and 
radiation therapy. 
3.2.9 Patients who have biopsy confirmed multi-centric disease not eligible for BCS. 
3.2.10 Participants who are unable to undergo MRI because of documented contra-indications 
for contrast-enhanced MRI, including but not limited to renal failure 
3.2.11 Participants who exceed the weight limit for the operative surgical table, 350 lbs or who 
will not fit into the 60 cm diameter bore of the MRI scanner. 
 
3.3 
Inclusion of Women and Minorities 
3.3.1 Inclusion of Women and Minorities: Only women are involved in this 
study. Men are not at likely as women to have breast cancer and are not likely 
candidates for breast conserving surgery, and are not eligible for this trial. 
Approximately 10% of the target enrollment is Hispanic or African American, 
which is reflective of the demographics of a patient population who present 
serially and are evaluated for breast cancer in our practice. 
 
3.3.2 
 Inclusion of Children: Breast cancer is rare in children and children would 
not likely be candidates for neoadjuvant therapy and are excluded from this 
study. 
 
 
4. REGISTRATION PROCEDURES 
4.1 
GENERAL GUIDELINES FOR DF/HCC INSTITUTIONS 
Institutions will register eligible participants in the Clinical Trials Management System (CTMS) 
OnCore. Registrations must occur prior to the initiation of protocol therapy. Any participant not 
registered to the protocol before protocol therapy begins will be considered ineligible and 
registration will be denied. 
 
An investigator will confirm eligibility criteria and a member of the study team will complete the 
protocol-specific eligibility checklist. 
 
Following registration, participants may begin protocol therapy. Issues that would cause 
treatment delays should be discussed with the Overall Principal Investigator (PI). If a participant 
does not receive protocol therapy following registration, the participant’s registration on the 
study must be canceled. Registration cancellations must be made in OnCore as soon as possible. 
 
4.2 
Registration Process for DF/HCC Institutions 
DF/HCC Standard Operating Procedure for Human Subject Research Titled Subject Protocol 

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Registration (SOP #: REGIST-101) must be followed. 
 
4.3 
General Guidelines for Other Investigative Sites 
Not applicable 
 
4.4 
Registration Process for Other Investigative Sites 
Not applicable 
 
5. TREATMENT AND IMAGING PLAN 
 
5.1 
Treatment Plan 
Enrolled patients are those who have newly diagnosed Stage I, II, or III non-inflammatory breast 
cancer undergoing upfront surgery or NAT, with inclusion and exclusion criteria in Section 3. 
For this study, the treatment will include performance of an investigational supine MRI, in 
addition to standard prone MRI, mammography, and ultrasound, performed at one of our 
participating sites in the pre-surgical setting. Imaging will be performed on an outpatient basis, 
as is standard for breast cancer patient management. For patients receiving NAT, as is described 
in Section 5.2.1, pre NAT MRI will be attempted. If additional lesions/extent of disease is 
suggested on investigational MRI, additional imaging evaluation with mammography and/or 
ultrasound may be performed (refer to Section 5.2.1 below). In cases in which additional 
imaging evaluation with/without biopsy is required following MRI exams, attending breast 
radiologists will complete a short survey on their perceived usefulness of the supine MRI in 
lesion localization and/or lesion biopsy. Histopathology will be correlated to radiographic lesion 
findings in cases in which biopsy are performed. 
 
Patients deemed candidates for BCS with upfront surgery will proceed to surgery using the 
supine and prone imaging studies for surgical planning. Patients who will be receiving NAT per 
their clinical treating team. Post NAT (pre-surgical) imaging will be obtained at the completion 
of NAT (refer to Section 5.2.2). These imaging studies will then be reviewed by the treating 
radiologist and surgeon, and will be utilized for surgical planning. Surgery will be either standard 
BCT or mastectomy (with appropriate nodal intervention including sentinel lymph node biopsy 
and/or axillary dissection), as deemed appropriate by the treating surgeon. No investigational or 
commercial agents, or devices will be used or administered during the operation with the intent 
to treat the participants’ breast cancer. When BCT is performed, standard cavity shave margins 
will be taken (as per institutional guidelines). At the conclusion of the operation, the surgical 
specimen will be sent for histopathology. If the final pathology indicates that there are positive 
margins amendable to resection, the patient will be scheduled to undergo re-excision and/or 
mastectomy in the standard operating room. At the discretion of the treating surgeon, additional 
re-excisions may be performed for close margins not meeting the definition of a true positive 
margin. Following completion of each BCT operation, the attending surgeon will be asked to 
complete a brief survey to assess their perceived usefulness of the supine MRI data in surgical 
planning/lesion localization. 
 
This protocol will include the standard imaging sequences to image the patient in the prone 
position and identify the extent of the disease. In addition, a single post-contrast MRI VIBE 
sequence of the breast with the patient in the supine position will be obtained. The prone and 

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supine MRI images will be registered in the image-processing software, 3D Slicer, and the 
segmented tumor models will be overlaid on the images. Screenshots showing the displacement 
of the tumor from the prone to the supine images will be provided to the surgeon to plan the 
tumor resection. The supine post-contrast sequences will be used to estimate the tumor position 
with respect to fixed landmarks such as the nipple, skin and chest wall. If there are additional 
findings seen initially on MRI, the supine sequence will help to localize the findings during 
second look ultrasound. 
 
For patients who received NAT, post-NAT pre-operative breast MRI with supine sequence will 
be obtained. If tumor was visible pre-NAT on the other imaging modalities such as 
mammogram, 2D and/or 3D ultrasound they will also be performed at post-NAT. These images 
will be used to determine if preoperative lesion localization is necessary using either radioactive 
seed or wire placement; if required, these images will be utilized by the breast imaging service 
preoperatively for lesion localization procedure per standard practice and the radiologist will be 
surveyed post-localization regarding usefulness of supine MRI for lesion localization procedure. 
Supine MRI will be provided in addition to standard imaging modality images for patients 
ultimately eligible for breast conserving surgery for preoperative surgical planning and for 
intraoperative tumor resection. 
 
Patients enrolled to participate in this study will receive standard of care with breast conserving 
therapy or mastectomy for local therapy. Detailed risks and benefits of participating in the study 
will be reviewed with patients prior to obtaining consent, and all questions will be answered. 
After general endotracheal anesthesia is induced, the standard operation will be performed by a 
breast surgical oncologist, including a lumpectomy or mastectomy, with or without sentinel node 
biopsy and/or possible axillary dissection. The surgical specimen will be sent for standard 
histopathology. Final specimens will include the original lumpectomy specimen, any nodal tissue 
(sentinel node(s) versus axillary dissection components if nodal procedure was performed), and 
shave margins/targeted re-excisions. These samples will be sent for analysis by pathology. 
 
 
5.2 
Description of Intervention/Intervention Regimen 

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5.2.1 Pre-Surgical Evaluation 
Patients with biopsy-proven breast cancer deemed eligible for this study (refer to 
inclusion/exclusion criteria, Section 3) will be identified during surgical consultation at a 
participating institution. A signed, written consent form will be obtained before any study- 
specific assessments are initiated. Each participant will undergo a history and physical 
examination, and will be required to have a diagnostic mammogram with or without ultrasound 
reviewed at Brigham and Women’s Hospital (BWH) or Dana Farber Cancer Institute (DFCI). 
Patients who are eligible and give written consent to participate will then be scheduled to receive 
a prone and supine contrast-enhanced MRI. Patients who have already had a breast MRI at an 
outside institution, for their present cancer, and who will receive NAT, will not be required to 
undergo an additional pre-NAT MRI. All patients (upfront surgery and NAT patients) will be 
required to have a pre-surgical prone and supine MRI. Prone MRI will consist of the standard 
imaging sequences as identified by institutional guidelines to image the patient’s breast(s) in the 
prone position and identify the extent of the disease. An FDA-approved gadolinium-based MRI 
contrast agent, as per standard of care, will be administered in order to acquire images that will 
be used to identify the lesion. The dosage will be consistent with institutional safety guidelines. 
See Section 6 below for further information regarding MRI contrast agent. 
 
In addition, a single post-contrast MRI VIBE (volumetric interpolated breath-hold examination) 
sequence of the breast with the patient in the supine position will be obtained. Prior to obtaining 
this MRI, a second dose of gadolinium MRI contrast agent may be given at the discretion of the 
radiologist, with dose calculated by the radiologist per institutional policy, to ensure adequacy of 
supine MRI images. The supine post-contrast sequences will be used to estimate the tumor 
position with respect to fixed landmarks such as the nipple, skin and chest wall. If MRI identifies 
additional disease not initially seen on other imaging exams, repeat ultrasound and/or 
mammogram with additional views will be performed (‘second look’ exams) to attempt to 
identify these lesions on an additional imaging modality. Biopsy of newly identified suspicious 
lesions will be executed with MRI, ultrasound, or stereotactic guidance at the discretion of the 
treatment team, and histopathologic-radiographic correlation will be performed. 
 
5.2.2 Post-NAT Evaluation 
For patients undergoing NAT, repeat evaluation with imaging studies will be performed at the 
conclusion of NAT treatment,. Imaging will include dedicated pre-surgical breast MRI in both 
prone and supine positions, as well as ultrasound and mammography as deemed necessary by the 
treatment team. Imaging protocols utilized for post-NAT evaluation will be per institutional 
standards and will be consistent with those utilized for pre-NAT evaluation. 
 
These imaging studies will then be reviewed by the treating radiologist and surgeon, and 
determination will be made if a radiographic complete response (rCR) has occurred. Quality of 
the supine MRI sequence will be determined by the attending radiologists, and at this time if the 
quality is deemed unacceptable for interpretation, the image will not be utilized in residual tumor 
calculations. If rCR has not occurred, estimated sizes and volumes of the remnant tumor will be 
made using each imaging modality by the treating radiologist and recorded in standard format. If 
additional disease is uncovered at this time, it will also be recorded. Using the information 
obtained from the totality of imaging studies, the surgeon will determine whether or not the 
patient is eligible to proceed with BCT or mastectomy. 

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5.2.3 Surgery 
Surgery will be either BCT or mastectomy (with appropriate nodal intervention including 
sentinel lymph node biopsy and/or axillary dissection), as deemed appropriate by the treating 
surgeon and according to current guidelines. Informed consent as per institutional standards will 
be obtained from the patient prior to surgery and all risks and benefits of surgical intervention 
and alternative options (no surgery) will be reviewed with the patient. When BCT is performed, 
standard cavity shave margins will be taken (as per institutional guidelines). At the conclusion of 
the operation, the surgical specimen will be sent for histopathology. Following completion of 
each BCT operation, the attending surgeon will be asked to complete a brief survey to assess 
their perceived usefulness of the supine MRI data in surgical planning/lesion localization. 
 
5.2.4 Post-Surgery: Histopathogy Assessment 
Lymph node specimens (if taken during surgery) will be evaluated by histopathological analysis 
along with the breast specimen (lumpectomy or mastectomy) at the conclusion of surgery. If the 
final pathology indicates that there are positive margins amendable to resection, the patient will 
be scheduled to undergo re-excision and/or mastectomy in the standard operating room. At the 
discretion of the treating surgeon, additional re-excisions may be performed for close margins 
not meeting the definition of a true positive margin. 
 
5.3 
Post-Surgery: Adjuvant Radiation Therapy 
Patients who require adjuvant radiation therapy postoperatively will be referred to radiation 
oncologists at the DFCI. If the patient chooses to pursue their radiation treatment with DFCI 
clinicians (patients are offered a choice as to where to complete their radiation treatment), then 
the radiation oncologist will be provided with all imaging, including supine MRI images 
acquired pre-surgery for treatment planning purposes. These images will be utilized for planning 
of the radiation treatment plan. Following completion of the initial radiation treatment plan, the 
attending treating radiation oncologists will be asked to complete a brief survey to assess their 
perceived usefulness of the supine MRI data for treatment planning purposes. 
 
5.4 
Duration of Follow Up 
All patients will have a post-surgical visit at their surgical institution (BWH or BWFH). 
Participants will be followed until their first post-surgical visit after the completion of surgical 
therapy. 
 
5.5 
Criteria for Taking a Participant Off-Study 
If the patient is enrolled in the study, and they are unable to undergo supine MRI for any reason, 
or during the course of the supine MRI they are unable to complete the supine MRI series, they 
will discontinue participation in the study at that time. Those patients who, following enrollment 
in the trial, do not proceed to receive a pre-surgical MRI, or who do not receive surgery at one of 
our institutions, will be removed from the study. 
 
Participants will also be removed from study when any of the following criteria apply: 
● Lost to follow-up 
● Withdrawal of consent for data submission 
● Death 

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The reason for taking a participant off study, and the date the participant was removed, must be 
documented in the case report form (CRF). 
 
For Centralized Subject Registrations, the research team submits a completed Off Treatment/Off 
Study form to ODQ when a participant comes off study. This form can be found on the ODQ 
website or obtained from the ODQ registration staff. 
 
For Decentralized Subject Registrations, the research team updates the relevant Off 
Treatment/Off Study information in OnCore. 
 
 
6. EXPECTED TOXICITIES, ADVERSE EVENTS, AND DOSING DELAYS/DOSE MODIFICATIONS 
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial. There are no 
interventional agents (drugs or devices) being investigated as part of this protocol, and therefore 
there are no associated adverse events such as toxicities that would commonly be anticipated in 
these scenarios. There are also therefore are no protocol-specific dose delays or modifications 
unique to this study to report. 
 
This protocol will utilize gadolinium contrast-enhanced MRI imaging, which is a standard FDA- 
approved imaging agent, and expected toxicities are therefore included and described here. The 
use of gadolinium contrast has been associated with relatively minimal risk compared to other 
contrast agents; however, some contrast-related reactions have been identified [56, 57]. IV- 
administered gadolinium contrast has been associated with renal failure and allergic reactions. 
Both of these events are identified as potential adverse events, and patients will be informed of 
the risk of such adverse events. Patients that have a known contrast allergy will be excluded from 
participating in this study. There is approximately 0.07% risk of an allergic reaction with IV 
contrast according to a retrospective review of 78,353 cases of IV-gadolinium injections 
published in 2007, with a more recent study reporting an overall adverse effect rate of 0.0404% 
among 158,439 administrations, within the 0.0003-1.2% range reported in other studies [56, 57]. 
If an allergic reaction does occur, the procedure will be aborted and supportive care, including 
maintaining airway and administration of steroids and epinephrine, will be initiated. This will be 
reported appropriately as an adverse event. Patients will be screened to ensure they are MRI- 
eligible and those who are not for any reason, including but not limited to renal failure, will be 
excluded from participating in this study. 
 
In our protocol, two MRI sequences will be obtained. Of these two sequences, prone and supine, 
the prone sequence is standard and the supine MRI is investigational. Additional adverse events 
applicable to this study will therefore be related to performance of supine MRI sequences. All 
patients undergoing supine MRI will already be receiving a prone MRI. To perform supine MRI, 
patients will be subjected to physical maneuvering required to position them and their breast(s) 
in the supine position to obtain the imaging series. It is possible that an adverse event may occur 
during this maneuvering. These events would be unanticipated, and would be reported according 
to institution guidelines. An additional smaller dose of gadolinium-based contrast agent may be 
administered prior to supine MRI, which would result in patients receiving higher contrast doses 

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than routine breast MRI examination. The risk for nephrotoxicity and nephrogenic systemic 
fibrosis is infinitesimally small in patients with normal renal function, however, and the dose and 
concentration that each patient receives will be calculated such that FDA guidelines for contrast 
agents are met and such that there will be no significant increased risk of nephrotoxicity 
compared to that with routine breast MRI with contrast. The additional dose of contrast may, 
however, slightly increase the risk of gadolinium-based contrast retention. Recent studies have 
shown that gadolinium-based contrast may persist long after administration (primarily in the 
brains of patients who are subjected to four or more contrast-based MRI scans), even in patients 
with normal renal function. The significance of this retention, however, remains uncertain, as it 
is currently unknown if these gadolinium deposits are harmful or could lead to adverse health 
effects. 
6.1 
Adverse Event Characteristics 
● CTCAE term (AE description) and grade: The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 will be utilized for AE reporting. All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.0. A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
● For expedited reporting purposes only: 
- 
AEs for the agent(s) that are listed above should be reported only if the adverse event 
varies in nature, intensity or frequency from the expected toxicity information which 
is provided. 
 
● Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
6.2 
For Expedited Adverse Event Reporting 
6.2.1 Investigators must report to the Overall PI any serious adverse event (SAE) that occurs 
after the intervention, or within 30 days of the intervention, on the local institutional SAE 
form. 
 
6.2.2 DF/HCC Expedited Reporting Guidelines 
Investigative sites within DF/HCC will report AEs directly to the DFCI Office for 
Human Research Studies (OHRS) per the DFCI IRB reporting policy. 
 
 
6.3 
Expedited Reporting to Hospital Risk Management 
Participating investigators will report to their local Risk Management office any participant 
safety reports or sentinel events that require reporting according to institutional policy. 

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6.4 
Routine Adverse Event Reporting 
Not Applicable 
 
 
7. STUDY CALENDAR 
Assessment 
Prior to upfront 
surgery or NAT 
treatment 
(within 3 months 
of registration) 
Post-NAT 
Evaluation 
Surgery 
Post-operatively (within 
six weeks after surgery) 
History and 
Breast Exam 
X 
X 
X 
Vital Signs 
X 
X 
Conventional 
Mammogram 
with or without 
US 
X 
X 
Staging biopsy 
X 
Informed 
Consent 
X 
Prone MRI 
X 
X 
Supine MRI 
X 
X 
Second look 
Ultrasound / 
Mammography 
with/without 
biopsy* 
X* 
Radiologist 
Surveys 
X‡ 
X‡ 
X‡ 
Surgery 
X 
Surgeon 
Survey s 
X 
Pathology 
Review 
X 
Radiation 
Oncologist 
Survey 
X† 
*Second look ultrasound and/or biopsy will only be performed if deemed necessary by the 
treating team in scenarios in cases in which additional lesions are newly identified during MRI 
evaluation (this is an ‘optional’ and not ‘mandatory’ portion of the study) 
‡ Radiologist surveys will be completed after second-look US performance (pre/post NAT) 
and/or at time of breast biopsies (pre/post NAT) and/or at time of lesion localization (day of 
surgery) when supine MRI information is used. 
†Only in cases of patients who are referred for postoperative radiation therapy and have a 
treatment plan made by DFCI radiation oncologists. 

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8. DATA REPORTING / REGULATORY REQUIREMENTS 
Adverse event information and instructions for AE reporting can be found in Section 6 (Adverse 
Events: List and Reporting Requirements). 
 
8.1 
Data Reporting 
 
8.1.1 Method 
The trial is collecting limited data variables. The study team will collect, manage, and 
perform quality checks on the data for this study. The study will utilize a case report form 
collected after patients complete all study procedures and up to 30 days after their study 
completion. Surveys from providers will be collected at the completion of a patient’s on 
study procedures. Data will be collected and shared with an outside collaborator for 
analysis. The data will not be identifiable. 
 
 
8.1.2 Responsibility for Data Submission 
Investigative sites within DF/HCC are responsible for submitting data forms to the 
Overall PI within 30 days of a patient coming off study. 
 
 
8.2 
Data Safety Monitoring 
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity 
and accrual data from this study. The committee is composed of clinical specialists with 
experience in oncology and who have no direct relationship with the study. Information that 
raises any questions about participant safety will be addressed with the Overall PI and study 
team. 
 
The DSMC will review each protocol up to four times a year or more often if required to review 
toxicity and accrual data. Information to be provided to the committee may include: up-to-date 
participant accrual; all grade 2 or higher unexpected adverse events that have been reported; 
summary of all deaths occurring with 30 days of intervention for Phase I or II protocols; any 
response information; audit results, and a summary provided by the study team. Other 
information (e.g. scans, laboratory values) will be provided upon request. 
 
 
8.3 
Multicenter Guidelines 
Not applicable 
 
8.4 
Collaborative Agreements Language 
Not applicable 
 
 
9. STATISTICAL CONSIDERATIONS 
This is a phase II study aimed at evaluating the ability of breast MRI (prone and supine) to 
accurately estimate breast tumor size (in term of correlation with gold standard size on post- 
operative pathology analysis). This study is also designed to compare correlation between supine 

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breast MRI with existing imaging modalities at estimating tumor size. Finally, this study is 
designed to characterize the changes occurring in breast tumor-associated properties/dimensions 
between the prone and supine imaging position and to determine the correlation of tumor 
location and geometry on pre-surgical supine MRI and prone MRI.  A total of 80 patients will 
be recruited to participate in this study. 
 
9.1 
Study Design/Endpoints 
The primary objective of the study is to determine the usefulness of pre-surgical prone and 
supine MRI for estimating tumor size (as compared to tumor size on post-operative pathology, 
which is the existing gold standard). This will be evaluated using correlation coefficients 
between estimated tumor size on prone MRI and estimated tumor size on post-operative 
pathology. 
 
9.2 
Sample Size, Accrual Rate and Study Duration 
For the primary outcome, with 73 eligible patients we will have 90% power to detect a 
correlation coefficient between pre-surgical prone or supine MRI and tumor size of 0.85 from 
0.70 with a two-sided one sample z-test at alpha=0.05 level. 
 
With 73 eligible patients, we will also have more than 80% power to detect a difference in 
correlation from 0.85 between the supine MRI and the pathology tumor size and 0.70 between 
the standard imaging and the pathology tumor size with a two-sided two sample z-test at 
alpha=0.05 level, assuming the correlation between the supine MRI and the standard imaging is 
0.70. 
 
Assuming the dropout rate will be 10%, we will plan to accrue a total of 80 patients. With an 
anticipated enrollment of 5 patients per month, accrual should be completed in approximately 16 
months. 
 
The below table “Accrual Targets” reflects the accrual targets anticipated for this study. As noted 
in detail in Section 3.3, men are not likely candidates for breast conserving surgery, and are not 
eligible for this trial. Approximately 10% of the target enrollment will be Hispanic or African 
American. 

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Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
8 
+ 
0 
= 
8 
Not Hispanic or Latino 
72 
+ 
0 
= 
72 
Ethnic Category: Total of all subjects 
80 
(A1) 
+ 
0 
(B1) 
= 
80 
(C1) 
Racial Category 
American Indian or Alaskan Native 
1 
+ 
0 
= 
1 
Asian 
4 
+ 
0 
= 
4 
Black or African American 
12 
+ 
0 
= 
12 
Native Hawaiian or other Pacific Islander 
0 
+ 
0 
= 
White 
63 
+ 
0 
= 
63 
Racial Category: Total of all subjects 
80 
(A2) 
+ 
0 
(B2) 
= 
80 
(C2) 
(A1 = A2) 
(B1 = B2) 
(C1 = C2) 
9.3 
Stratification Factors 
Not applicable 
 
9.4 
Interim Monitoring Plan 
Not applicable 
 
9.5 
Analysis of Primary Endpoints 
There are three primary objectives of this study, each with unique endpoints. 
 
The first is to evaluate the correlation between prone breast MRI and pathologic measurement in 
estimating tumor size, and the correlation between supine breast MRI and pathologic results. A 
95% confidence interval will also be calculated for each correlation coefficient. One sample z- 
test will be conducted to compare whether these correlation coefficients are different from 0.6. 
 
The second is to compare the correlation between supine breast MRI and pathologic 
measurement for estimation of tumor size, and the correlation between existing breast imaging 
modalities and pathologic tumor size. Similarly, correlation coefficient will be calculated 
between supine MRI and the pathologic results and between existing breast imaging modalities 
and the pathologic tumor size. Two-sample z-test for comparing correlated correlation 
coefficients will be conducted to compare whether these two correlation coefficients are equal. 
 
The third is to characterize the changes occurring in breast tumor-associated properties/ 
dimensions between the prone and supine imaging position for all patients with pre-surgical 
MRIs. We will also determine the correlation of tumor location and geometry on pre-NAT and 
post-NAT (pre-surgical) supine MRI with prone MRI among the subgroup of patients with pre 
and post NAT imaging. As described in Section 2.1, in our prior work comparing prone to supine 
MRI, we utilized image processing software that enabled us to generate tumor models and 
specifically calculate differences in the metrics computed from the segmented tumor label maps 
on supine and prone MRI. As a first order statistics, we plan to examine differences in the shape 

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and size of the tumor on supine and prone MRI. Further, we hope to correlate these difference 
metrics with variables including but not limited to breast size (measured on the axial slice 
through the nipple) and location (inner/outer, upper/lower). Correlation coefficients will be 
calculated for parameters related to tumor shape and size between supine and prone MRI, and 
one sample t-test (or non- parametric Wilcoxon test) will be used to test whether the difference in 
shape and size parameters between these two measurements are significantly different from 0. A 
regression model will be used to check whether these differences are correlated to breast size and 
location, age and other clinical characteristics. 
 
9.6 
Analysis of Secondary Endpoints 
There are four secondary objectives for this study. Descriptive statistics will be used for these 
objectives. 
 
The first is to assess the value of supine MRI for radiologists performing second look US 
examinations/ biopsies following identification of new lesions on MRI, and performing 
preoperative lesion localization using supine MRI guidance. This value will be assessed by both 
qualitative (survey of radiologists on perceived usefulness of supine MRI for imaging 
localization/procedures*) and quantitative measures (success rate of second-look ultrasound 
lesion localizations and procedures utilizing supine MRI guidance). Procedures include lesion 
biopsy and pre-surgical lesion localization performed by radiologist. 
A frequency table will be calculated for the survey questions and the success rate of second-look 
biopsies and/or localizations. 
 
The second is to assess the perceived benefit of supine MRI for surgical planning as measured by 
the collective results of a survey of surgeons performing BCT in our study patient population. A 
frequency table will again be calculated for the survey responses. 
 
The third is to explore the effect of supine MRI on influencing BCS outcomes by determining 
the percent of patients requiring re-excisions or having pathologic positive margins when supine 
MR imaging is performed and available for surgical planning purposes. This will be an 
exploratory endpoint. 
 
The fourth and final secondary endpoint is to assess the perceived value of supine MRI for 
adjuvant radiation breast treatment planning as measured by the collective results of a survey of 
radiation oncologists treating patients in our study population post-operatively. Again, a 
frequency table will be calculated for the survey responses. 
 
9.7 
Reporting and Exclusions 
 
1. Patients who are not evaluable for tumor evaluation by MRI as a result of MRI-related 
problems (ie degree of contrast washout for supine MRI prevents MRI interpretation as deemed 
by attending radiologist) will not be included in the primary analysis. 
 
2. Patients who do not have surgical treatment at our institution will not be included in the 
primary analysis. 

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9.7.1 Evaluation of Toxicity 
Not applicable 
 
10. PUBLICATION PLAN 
Results of this study should be made public within 24 months of reaching the end of the study. 
The end of the study is the time point at which the last data items are to be reported, or after the 
outcome data are sufficiently mature for analysis, as defined in Section 9.2. If a report is planned 
to be published in a peer-reviewed journal, then that initial release may be an abstract that meets 
the requirements of the International Committee of Medical Journal Editors. We anticipate that a 
full report of the outcomes should be made public no later than three (3) years after the end of 
the study. 

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