A Study to Evaluate the Accuracy of a Breast Cancer Locator (BCL) in Patients With Palpable Cancers
Phase: NA
Conditions: Breast Cancer
Sponsor: Dartmouth-Hitchcock Medical Center

 
Version  12.4.15 
 
1
 
 
 
 
 
 
 
 
 
D15120  
 
A Study to Evaluate the Accuracy of a  
Breast Cancer Locator in Patients with Palpable Cancers  
 
 
 
Principal Investigator: 
Richard J. Barth Jr., MD 
 
Co-investigators: 
Christina Angeles, MD 
Kari Rosenkranz, MD 
 
Consultants: 
Venkat Krishnaswamy, PhD 
Keith Paulsen, PhD 
Tim Rooney, MD 
Tor Tosteson, PhD 
Wendy Wells, MD 
 
 
 
 
 
 
 
 
 
 
 
 
 
Comprehensive Breast Program, Norris Cotton Cancer Center 
Radiobiology and Bioengineering Research Program, Thayer School of Engineering 
 
Dartmouth-Hitchcock Medical Center 

 
Version  12.4.15 
 
2
 
 
 
ABBREVIATIONS 
 
3D 
three-dimensional 
BCL 
Breast Cancer Locator 
BCS 
breast conserving surgery 
CCRC 
Clinical Cancer Review Committee at the Norris Cotton Cancer Center 
CPHS 
The Committee for the Protection of Human Subjects at Dartmouth 
College 
DCIS 
ductal carcinoma in situ 
DHMC 
Dartmouth-Hitchcock Medical Center 
DSMAC 
Data Safety Monitoring and Accrual Committee 
FDA 
U.S. Food and Drug Administration 
GCP 
Good Clinical Practice 
IRB 
institutional review board 
LED 
light-emitting diode 
MRI 
magnetic resonance imaging 
NCCC 
Norris Cotton Cancer Center 
NCI 
National Cancer Institute (U.S.) 
OR 
operating room 
SAE(e) 
serious adverse event(s) 
UADE(s) 
unanticipated adverse device effect(s) 
US 
ultrasound 
 

 
Version  12.4.15 
 
3
 
Section 1.  INTRODUCTION 
 
Approximately 75% of the 240,000 women diagnosed with breast cancer annually in the US 
choose breast conserving surgery (BCS) (1). The goal of BCS is to resect the tumor with a 
surrounding margin of tissue free of cancer while simultaneously preserving the overall shape 
and appearance of the breast. With advances in breast cancer screening techniques, many 
women now have malignant tumors detected before they become clinically palpable. For non-
palpable lesions, localization of the tumor prior to surgery is needed. The standard technique 
for such patients is wire localization, in which a wire is pre-operatively placed near the tumor 
under mammographic, ultrasonic, or MRI guidance. 
Wire localization suffers from several limitations. It adds another procedure prior to 
surgery, complicating and lengthening the process. It can be uncomfortable for the patient.  Its 
biggest limitation is  inaccuracy. Wire localization requires the surgeon to estimate the three 
dimensional (3D) position of the cancer from 2 dimensional mammography images. Wire 
localized excision results in positive margins approximately 30% of the time (2,3). These cases 
require additional surgery to remove the remaining cancer, which is both costly and 
emotionally difficult for patients. If 30% of the estimated 150,000 BCS cases per year in the US 
require re-excision, at a cost per re-excision of $11,000, the annual expense of re-excisions in 
the US is approximately $500,000,000.  
Alternatives to wire localization have been tested. Intraoperative ultrasound has been 
shown to be superior to wire localization (4-5). Unfortunately, most ductal carcinoma in situ 
(DCIS) and some invasive cancers that are mammographically visible are not evident on 
ultrasound.  
Magnetic resonance imaging of the breast has been shown to be more sensitive than 
ultrasound or mammography for the detection of cancer (6). Breast cancer size, as determined 
by histopathology, is also more accurately defined by MRI than by mammography or US (7-9). 
Several groups have shown that the superior tumor visualization resulting from preoperative 
prone MRI results in changes in the operative plan in 20-25% of cases (10-12). Despite this 
evidence, the use of MRI has not been demonstrated to produce better short-term outcomes: 
the prospective randomized COMICE trial failed to demonstrate a decrease in the positive 

 
Version  12.4.15 
 
4
margin rate and need for re-excision with the use of pre-operative prone MRI (13). The 
COMICE study authors recognized that the inability of prone MRI to result in decreased 
positive margin rates might be due to the way the imaging data is presented to the surgeon, 
stating that “techniques to ensure surgical precision is at an optimum need further 
examination” (13). The shape of the breast during prone MR imaging (with the breast pendant 
in a bilateral imaging coil) is radically different from the supine, arm-extended position in the 
operating room.  
Supine MRI more accurately replicates the surgical position. Indeed, a study by 
Sakakibara, et al. (14) randomized patients with small foci of DCIS to undergo wire localized or 
supine MRI guided BCS and found the positive margin rate and resected tissue volume were 
lower in patients undergoing supine MRI guided excision. A more recent non-randomized 
study of patients with larger foci of DCIS by these same investigators has also been reported 
(15). 
We recently developed a method of MRI-guided BCS that incorporates preoperative 
supine MRI to define tumor extent and uses an intraoperative optical scan to adjust the MRI 
image to the exact breast position in the OR (16). This localization technique provides the 
surgeon with three dimensional views and measurements of tumor shape and position within 
the breast as it appears during surgery. When combined with intraoperative tracking 
technology, we showed in a pilot study of 18 patients that this approach enabled us to localize 
breast cancer as accurately as by palpation (16). We are currently funded by the NCI via an 
R21 grant and are actively accruing patients to a randomized clinical trial (D0928) which 
compares supine MRI/optical scanning/intra-operative tracking localization to wire localization 
for patients with non-palpable breast cancer.   
Although our supine MRI/ optical scanning/ intra-operative tracker technology is 
accurate, it has some limitations that may limit its widespread utilization. The software that 
modifies the MRI image into the intra-operative acquired scanned image is complicated and 
currently requires the surgeon have intra-operative technical assistance. The current system 
only generates an outline of the tumor on the breast surface, but does not provide any 
guidance for the surgeon when operating inside the breast.   
We have now invented a device, the Breast Cancer Locator (BCL) which overcomes 
these limitations. BCL uses 3D printing to create a bra-like plastic form that matches the breast 

 
Version  12.4.15 
 
5
surface when the patient is in the supine MRI (and surgical) position. This locator can be 
constructed pre-operatively, sterilized and provided to the surgeon at the time of procedure. 
The outline of the breast cancer on the breast surface at the point where the cancer is closest 
to the skin is built into the locator, so that the surgeon can simply apply the locator to the 
patient’s breast and trace the tumor outline on the skin. The locator also contains 5 cylinders 
which project outward from its surface. A needle will be placed in each cylinder. The depth and 
angle that the needle passes into the breast is controlled by the angle and length of the 
cylinder. The surgeon will inject a small amount of blue dye at each site, creating a 1 cm 
diameter blue spot in the breast parenchyma. The spots will be made 1 cm away from the 
medial, lateral, cranial, and caudal tumor edges as defined by the supine MRI. A fifth cylinder 
will allow the surgeon to place a needle and make an injection of blue dye 1 cm superficial to 
the tumor. After the blue dye is injected, a hook wire will be deployed through this needle into 
the MRI defined center of the tumor. When the BCL is removed, the hook wire will remain, 
indicating the direction from the skin surface, through the blue spot superficial to the tumor, to 
the center of the tumor. With these landmarks established, the surgeon will then be free to 
move the patient on the OR table (e.g., place the arm out to the side, rotate the patient to one 
side or the other) to facilitate surgery.  
When the breast is marked by the BCL, the surgeon will then have the standard wire 
localizing the cancer which they are used to. This wire will be placed at least as accurately as it 
is currently being placed by Radiologists (who are relying on spot mammographic, US or MRI 
images to try to localize the cancer or the clip left behind at the time of initial biopsy (which 
might not have deployed at the center of the cancer)). When placed by the BCL the wire will 
give surgeons directional information from the skin at the incision site towards the center of the 
cancer. When wires are placed pre-operatively by Radiologists the wire is commonly placed by 
Radiologists such that it enters the skin far away from the site of the incision. The surgeon will 
now also have additional information to guide the cancer excision. The projected edges of the 
often irregularly shaped breast tumor will appear on the surface of the breast. The surgeon will 
also now have landmarks inside the breast to ensure that the desired amount of tissue around 
the tumor is removed. 
We propose to test the accuracy of the BCL in patients who have palpable tumors, so 
that the guidance provided by the BCL is not necessary for the surgeon to resect the cancer 

 
Version  12.4.15 
 
6
accurately. If the BCL places the ink spots with perfect accuracy and the surgeon perfectly 
accurately follows the spots to do the excision, the margins may still be positive when the 
tumor histologically extends past its edges as defined by MRI. To estimate how often this may 
happen, we reviewed data on 27 patients from our pilot study of the supine MRI/optical 
scan/tracker system on patients with palpable cancers (16) and data from our current study of 
this system on patients with non-palpable cancers. The MRI diameter was larger than the 
pathologic diameter in 13 cases; the median overestimate in diameter was 4 mm. The MRI 
diameter was smaller than the pathologic diameter in 14 cases; the median underestimate was 
5 mm. The pathologic tumor diameter was more than 2 cm greater than the MRI diameter in 
only 1 case (4%). Upon review of the literature, Boetes et al. evaluated 60 breast cancers; in 
only 1 patient was the pathologic tumor diameter greater than 2 cm larger than the diameter on 
MRI (8). In another study, 2 of 68 pts had pathologic diameters more than 2 cm greater than 
the diameter on MRI (7).  Thus, if one were to excise 1 cm on each side of the MRI defined 
tumor, one would expect the histologic margin to be positive because of the inability of MRI to 
detect tumor in roughly 5% of patients.  
In this study, we will enroll women with palpable cancers to assess the accuracy of the 
BCL and concomitant procedure as a vehicle to optimize and validate the approach in surgical 
cases where the new device will not substantially alter or modify the standard-of-care 
procedure before initiating an evaluative trial of the BCL in non-palpable breast cancer cases. 
Taking this path towards clinical evaluation also does not interrupt or otherwise compete for 
patients with our ongoing R21-funded clinical study D0928, which enrolls patient with non-
palpable cancers. 
 
 
Section 2.  OBJECTIVES 
 
We propose to test whether the Breast Cancer Locator (BCL) accurately defines the 
edges of the cancer. Twenty patients with palpable invasive breast cancer will undergo pre-
operative supine MRI, creation of a BCL, and breast surgery using the BCL as an adjunct to 
palpation-guided tumor resection.  Patients will also have the tumor position on their skin 
localized with the supine MR/optical scan/tracker method. 

 
Version  12.4.15 
 
7
 
The primary objective is to measure the distance from the center of the spots made by the BCL 
to the cancer edges. 
  
Our secondary objectives are to determine: 
1. the pathologic final margin (distance from the tumor to the specimen edge). 
2. the difference between the medial, lateral, cranial and caudal tumor edges as defined 
by the BCL and the supine MR/optical scan/tracker system. 
3. lumpectomy specimen volumes. 
 
 
Section 3.  ELIGIBILITY CRITERIA 
 
1. Age > 18 years 
2. Histologic diagnosis of palpable invasive breast cancer or ductal carcinoma in situ 
3. Patient desire to undergo breast surgery 
4. Ability to voluntarily provide informed consent to participate prior to any study-related 
assessments/procedures being conducted 
5. The cancer enhances on breast MRI imaging. 
 
Exclusion Criteria 
 
1. Absolute contraindication to MRI, including presence of implanted electrical device 
(pacemaker or neurostimulator), aneurysm clip, or metallic foreign body in or near eyes 
2. Severe claustrophobia 
3. Contraindication to use of gadolinium-based intravenous contrast, including life- 
threatening allergy or compromised renal function (creatinine > 2.0) 
4. History of median sternotomy 
5. Pregnancy.  Patient attestation that they are not pregnant will be acceptable as per 
standard policy for MRIs at DHMC.  
 

 
Version  12.4.15 
 
8
An eligibility worksheet will be completed for each patient prior to enrollment and will be signed 
and dated by the surgeon investigator. 
 
 
Section 4.  TREATMENT PLAN 
 
Patients with a percutaneous core biopsy demonstrating invasive carcinoma or ductal 
carcinoma in situ will undergo contrast-enhanced bilateral breast MRI in the prone position, 
which is the current clinical standard at Dartmouth. At the time of surgical consultation, patients 
with palpable invasive breast cancer or DCIS who desire breast surgery will be invited to be a 
part of the study.  Prior to surgery, these patients will undergo a contrast-enhanced supine MRI 
and an optical scan of the breast while in the same position during the MRI using the GO!Scan 
3D optical scanner (Creaform, Levis, Québec, Canada). The study Radiologist will outline the 
tumor edges on the supine MRI. These supine MRI images will be used to create a Breast 
Cancer Locator (BCL) using 3D printing. The printed product will include a surface which will fit 
over the breast, with a cut-out for the nipple and a 5 mm opening located 4 cm directly vertical 
from the nipple (which will allow the surgeon to be sure the locator is positioned accurately on 
the breast). The BCL will also contain a cut-out for the surgeon to draw the tumor image on the 
breast surface, and 5 cylinders to guide needle injections of dye to define the cancer edges. It 
will also contain the printed surface of the tumor, which will be connected to the surface of the 
tumor locator by a removable cylinder, and will enable the surgeon to have a visual model of 
the cancer in the breast. The BCL will be sterilized using standard microwave techniques for 
use in the Operating Room (OR).   
 
In the OR, the patient will undergo general anesthesia. The patient’s arm will be placed 
out to the side in the surgical position. The GO!Scan 3D optical scanner  will be used to scan 
an image of the breast. The tumor location defined by the supine MRI images will be 
transposed into the optically scanned image with software we are using in our current trial 
(D0928) and displayed for the surgeon. Using a tracker, the surgeon will mark the medial, 
lateral, cranial and caudal edges of the tumor on the breast skin.  
The patient will then be prepped and draped. The patient’s arm, attached to an arm 
board, will be moved parallel to the OR table, so that it is in the approximate position as when 
the supine MRI was performed. The BCL will be positioned on the breast, using the nipple and 

 
Version  12.4.15 
 
9
a point drawn 4 cm directly vertical from the nipple to ensure accurate positioning, and will be 
secured in place.  The outline of the cancer on the breast surface will be drawn by the 
surgeon. Four injections of 0.02 ml of methylene blue dye (Methylene Blue Injection, 1% 
Akorn, Inc Lake Forest, IL)  will be made by the surgeon using a 21 gauge needle of 
appropriate length to create spots to delineate the cranial, caudal, medial and lateral tumor 
margins. An additional methylene blue dye injection will be made to delineate the superficial 
margin. The fifth needle port will then be partly detached so that a second needle can be 
placed through this port into the MRI defined center of the cancer and a hook wire will be 
placed inside this needle and deployed in the center of the tumor. The BCL will then be 
removed and the distances from the medial, lateral, cranial and caudal edges as determined 
by the BCL will be compared to the edge locations determined by the optical scan/tracker 
method.   
The surgeon will then perform either a breast conserving tumor resection or a 
mastectomy. The objective of the breast conserving resection will be to remove approximately 
1 cm of normal feeling breast tissue around all of the palpable tumor edges as per standard-of-
care. For breast conserving resections, the specimen volume will be determined by water 
displacement and specimen scanning using the GO!Scan. The location of the 4 horizontal blue 
dye spots in the specimen will be identified by the surgeon with black silk sutures; the location 
of the superficial blue dye spot will be marked with a white VICRYL suture. The specimen 
surfaces will be inked with 6 different colors, as per standard Dartmouth protocol. Specimen 
mammograms will be obtained and then the specimen will be sent to Pathology.  
Mastectomy specimens will be sent to Pathology and inked with blue ink on the 
superficial surface and black ink on the deep surface. The surgeon will then perform a breast 
conserving resection on the mastectomy specimen in Pathology. The goal of this procedure 
will be to remove approximately 1 cm of normal tissue around the tumor and to identify the 
blue dye spots and place marking sutures in the same way that they will be placed on breast 
conserving resection specimens. The specimen volume will be determined, margins will be 
inked with 6 colors and a specimen mammogram will be obtained. 
In Pathology, the specimen will be cut along the horizontal plane defined by the black 
silk sutures. The pathologist will place black-inked pins through the middle of the blue dye 
spots. A photo will be taken of the tissue slice showing the tumor in the middle with the 4 blue 

 
Version  12.4.15 
 
10
dye spots with pins in place. When tissue sections are cut, the black ink from the pins will 
appear on the sections, allowing the pathologist to measure the distance from the pin to the 
tumor. An additional cut will be made to include the white vicryl suture, in a plane 
perpendicular to the one defined by the black silk sutures. A black inked pin will be placed 
through the middle of this superficial blue spot, a photo will be taken of the tumor and this pin, 
and a section will be cut so the pathologist can measure the distance from this pin to the 
tumor.  
Margins for invasive cancers will be considered positive if cancer cells are present at 
any of the edges of the specimen slices.  Margins will be considered positive for DCIS if there 
are tumor cells < 1 mm from the edge.  The distance to the nearest margin will be determined 
in all cases.  
   
 
Section 5.  POTENTIAL TOXICITY 
 
Supine MRIs are administered according to standard-of-care practice for prone breast 
MRI and represent no more additional risk than would be experienced by women receiving 
these exams as part of their (non-research) breast care.  The risk of contrast enhanced MRI is 
very low, reflecting the minute risk of life-threatening allergy and development of nephrogenic 
sclerosis related to gadolinium-based intravenous contrast.  Patients deemed to be at higher 
risk for gadolinium-induced nephrogenic sclerosis because of compromised renal function will 
not be eligible for participation.  Patients who experience a significant allergic reaction to 
gadolinium-based intravenous contrast at the time of their clinical prone MRI will also be 
considered ineligible for study participation. 
 
Optical scans will be performed using a GO!Scan 3D optical scanner (Creaform, Levis, 
Québec, Canada). This scanner is able to scan the entire breast in 1 minute. It uses white light 
(LED) to form the image, like a flashlight. No anticipated risks are associated with the use of 
this scanner.   
 
Participants will be undergoing surgical excision of their breast cancer regardless of 
their participation in this study. The risks of surgery include a low chance of bleeding or 
infection. We are performing this study on patients with palpable cancers because the surgeon 
does not need imaging information to excise palpable cancers: the extent of surgery is guided 

 
Version  12.4.15 
 
11
by the edges of the tumor mass palpated at the time of surgery. Therefore, even if the Breast 
Cancer Locator is inaccurate, no negative consequences will be experienced by the patient. 
Methylene blue dye is approved for use in humans and has minimal toxicity (17-21). It 
has been used for many years for routine identification of sentinel nodes in breast cancer 
patients.  Transient blue staining of the skin may be seen with injections close to the skin.  
Potential serious adverse effects are very rare and include one case of skin necrosis with 
intradermal injection and 2 case reports of possible anaphylactic reactions.  
 
5.1 Reporting Requirements for Unanticipated Adverse Device Effects (UADEs) 
 
Adverse events and unanticipated problems will be reported to The Dartmouth Committee for 
the 
Protection 
of 
Human 
Subjects 
(CPHS) 
as 
per 
their 
statement 
found 
at 
http://www.dartmouth.edu/~cphs/docs/aedsmmemo.pdf using their CPHS – UPIRSO, SAE, 
UADE Reporting Form found at http://www.dartmouth.edu/~cphs/tosubmit/forms/. UADEs 
should be reported as soon as possible, but no later than 10 working days after the 
investigator learns of the effect.   
 
Adverse effects to be reported to the CPHS are: any adverse experience, defined as any 
untoward or unfavorable medical occurrence in a human subject, including any abnormal sign 
(for example, abnormal physical exam or laboratory finding), symptom, or disease, temporally 
associated with the subject’s participation in research, whether or not considered related to the 
subject’s participation in the research), that is considered: 
• 
Serious: Death; a life-threatening adverse drug experience; inpatient hospitalization or 
prolongation of existing hospitalization; a persistent or significant disability or incapacity; 
or a congenital anomaly or birth defect; and 
• 
Unexpected:  Any adverse experience, the specificity or severity of which is not 
consistent with the current investigator brochure or consent form; and 
• 
Possibly related:  There is a reasonable possibility that the incident, experience, or 
outcome may have been associated with the procedures involved in the research; and 
• 
is experienced by a participant in a trial open at a site subject to review by the CPHS.  
 

 
Version  12.4.15 
 
12
The following definitions will be used to assess causality: 
• 
No: 
The clinical adverse event is definitely unrelated to study procedures  (e.g., does 
not follow a reasonable temporal sequence from study procedure, present prior to 
procedure, etc.) 
• 
Unlikely: 
The study procedures do not have any reasonable association with the 
observed experience; however, relationship cannot be definitely excluded. 
• 
Possibly: 
The connection with study procedures appears feasible, but cannot be 
excluded with certainty (e.g., follows a reasonable temporal sequence from procedure, 
but may also be related to other known factors). 
• 
Probably: 
The clinical experience appears related to the study procedures with a 
high degree of certainty (e.g., follows a reasonable temporal sequence from procedure  
and abates upon termination of the procedure, cannot be reasonably explained by 
known characteristics of the patient’s clinical state or other modes of therapy 
administered to the patient, etc.) 
 
An unanticipated problem involving risks to subjects or others is defined as any incident, 
experience, or outcome that meets each of the following criteria: 
• 
Unanticipated in terms of nature, severity, or frequency given: (a) the research 
procedures that are described in the protocol-related documents, such as the IRB-
approved research protocol and consent document; and (b) the characteristics of the 
subject population being studied; and 
• 
Possibly related to participation in the research means there is a reasonable possibility 
that the incident, experience, or outcome may have been associated with research 
participation; and 
• 
The problem suggests that the research places subjects or others at a greater risk of 
harm (including physical, psychological, emotional, economic, legal, or social harms) 
than was previously known or recognized. 
 
 
Copies of each report and documentation of IRB notification and receipt will be kept in the 
Clinical Investigator’s study file. 
 

 
Version  12.4.15 
 
13
 
Section 6.  DEVICE FORMULATION AND PREPARATION 
 
Supine MRI images will be obtained on a Phillips 3T MRI scanner using two circular 
Philips SENSE Flex-M coils (2-element phased array receive-only coils) prior to and following 
an intravenous gadolinium–based contrast agent. Prior to scanning, 8 fiducial markers will be 
placed on the skin in standardized locations. A pre-injection T1 weighted ultrafast gradient 
echo sequence will be used to define the breast volume and tissue structures. A post-injection 
T1-weighted turbo gradient-echo volume acquisition with fat saturation will be used to 
determine tumor location and shape.  
Supine MRI images will be used to create a Breast Cancer Locator using 3-dimensional 
printing. The printed product will include a surface that will fit on the breast, a cut-out for the 
nipple and for a spot 4 cm directly vertical from the nipple (to ensure that the BCL is positioned 
accurately on the breast surface), a cut-out for the surgeon to draw the tumor image on the 
breast surface, and 5 cylinders to guide needle injections of dye to define the cancer edges. A 
needle will be placed in each cylinder. The depth and angle that the needle passes into the 
breast is controlled by the angle and length of the cylinder. Needles will be 21 gauge in 
diameter and of sufficient length. A syringe will be included which will allow accurate injection 
of 0.02 ml of methylene blue dye. The surgeon will inject the blue dye at each site, creating a 1 
cm diameter blue spot in the breast parenchyma. The spots will be made 1 cm away from the 
medial, lateral, cranial and caudal tumor edges as defined by the supine MRI. All of these 
spots will be in the same cross-sectional plane. This plane will be perpendicular to a line 
formed from the center of the tumor to surface of the skin at the location where the tumor is 
closest to the skin. The fifth cylinder will allow the surgeon to inject methylene blue dye 1 cm 
superficial to the tumor and will allow a second needle to be placed from the skin into the MRI 
defined center of the tumor.  
The BCL will also contain the printed surface of the tumor, colored differently, which will 
be connected to the surface of the tumor locator by a removable cylinder. This form will enable 
the surgeon to have a visual model of the cancer in the breast.  
Each BCL will undergo quality assurance testing prior to use. Defined length and bore 
needles will be placed into each of the cylinders and the distance from the tip of the needle to 
the tumor will be measured. A BCL will only be used if this distance is within 2 mm of the 

 
Version  12.4.15 
 
14
expected distance as calculated by the MRI model. In the case of irregularly shaped tumors 
this distance may be greater than 1 cm. The tumor locator will be sterilized using standard 
microwave techniques for use in the OR.   
 
 
 
Sections 7 and 8.  Clinical ENDPOINTS AND STATISTICAL ANALYSIS 
 
 
Our primary objective is to determine the accuracy of the Breast Cancer Locator (BCL). 
The primary outcome measure is the distance measured by Pathology from the tumor edge to 
the center of the ink spots, as marked by the black inked pins. Five (5) measurements will be 
made per patient. The BCL will be considered accurate if all 5 measurements are > 0 cm from 
the tumor edge.  
As discussed in the Introduction, we expect that in approximately 5% of patients the 
pathologically determined tumor diameter will be at least 2 cm greater than the MRI defined 
diameter; thus even if a 1 cm margin around the MRI defined tumor edge was excised, a 
positive margin (a distance of zero or less) would be expected in 5% of patients. We will 
evaluate the accuracy of the BCL after the first 10 patients. If the BCL is accurate in < 80% of 
patients, we will make modifications in the locator and test an additional 10 patients. If it 
remains inaccurate, additional modifications may be made and additional patients may be 
accrued to this study up to a maximum of 50 patients. If the measurements are accurate in 
80% of patients or more of the patients in a test cohort of ten patients, we will accrue an 
additional 10 patients to confirm the finding. Once the accuracy is determined to be > 80% in 
20 patients we will terminate accrual.  
The modifications we make in the BCL will be based on a thorough review of each case 
that was inaccurate. We will review every step in the process, including the definition of the 
cancer edges by Radiology, the quality assurance testing of the manufactured BCL (Section 6, 
P. 13), the pin placement in the ink spots and edge measurement by Pathology, and whether 
the cases represent unusual cancers where the pathologic extent of the tumors exceeds the 
extent visible on MRI (e.g., Infiltrating lobular cancer). We may discover an unforeseen design 
flaw in the methodology or product manufacture that will only become evident once we start to 
use it. 

 
Version  12.4.15 
 
15
Annually at Dartmouth we care for approximately 300 patients with invasive ductal 
cancer and 100 patients with DCIS.  Approximately 2/3 of these patients (266) will undergo 
breast conserving surgery.  Approximately 1/4 of these patients will have palpable tumors (67).  
We anticipate that it will be possible to accrue one half (33) of these patients per year.  Thus, 
we expect that it will take 8 months to complete accrual of 20 patients. 
We plan to use the accuracy information from this trial to support a larger multi-
institutional or randomized study of the use of the Breast Cancer Locator in patients with non-
palpable breast cancer. We anticipate that the main outcome measure of the next, larger trial, 
like our current trial of the supine imaging/optical scan and intra-operative tracker system 
(D0928, phase II), will be the positive margin rate. 
Secondary endpoints will be analyzed as follows. One secondary outcome measure will 
be the positive margin rate as defined by standard pathologic evaluation of the entire 
specimen. Our senior breast Pathologist, Dr. Wendy Wells, has performed a detailed analysis 
of the surgical margins for patients who had a core biopsy which was positive for cancer or 
DCIS and then underwent partial mastectomy at Dartmouth in the year 2005.  A total of 125 
patients with invasive ductal carcinoma were identified: 31 (25%) had positive margins.  
Twenty six of 53 patients undergoing partial mastectomy for DCIS had positive margins (45%).  
Overall, 57/178 patients (32%) had positive margins.  A two-thirds decrease in the positive 
margin rate (i.e., from 32% to 11% or less) would be clinically meaningful.  
Another secondary outcome measure, the distances between the specimen edges as 
determined by the Breast Cancer Locator and by the supine MRI/optical scan/ tracker system, 
will be measured and descriptive statistics will be employed. We will conclude that the two 
methods of depicting the tumor edges on the breast skin surface are equivalent if the mean 
distances between the edges are < 5 mm. 
We also wish to minimize the excision of normal breast tissue around the cancer. 
Lumpectomy specimen volumes will be measured and descriptive statistics employed. 
Measured specimen volumes will be compared to theoretical ideal specimen volumes 
generated by calculating the volume of the tumor specimen with 1 cm added to all of its 
surfaces based on the supine MRI.   
Relevant data will be saved in Velos electronic case report forms.   
 

 
Version  12.4.15 
 
16
Section 9. SAFETY AND DATA MONITORING 
 
This study will be monitored by the Data Safety Monitoring and Accrual Committee 
(DSMAC) of the Norris Cotton Cancer Center.  The Committee meets quarterly to review 
accrual rates and information for studies that have accrued participants.  The Clinical Cancer 
Review Committee (CCRC) determines the frequency of DSMAC review. The DSMAC has the 
authority to suspend or to recommend termination to the CCRC of all research activities that 
fall within its jurisdiction.  In the event that a study is suspended or terminated, that information 
will be forwarded to the CPHS (Dartmouth IRB) office. 
 
 
Section 10. ON-SITE MONITORING 
 
Clinical research monitoring for regulatory compliance and data integrity will be 
conducted according to the NCI-approved NCCC Data and Safety Monitoring Plan.  Internal 
monitoring is conducted by appropriately trained staff of the NCCC Office of Clinical Research 
and Dartmouth-Hitchcock Medical Center Clinical Trials Office (CTO( who are not involved in 
the study.  This monitoring will include periodic assessment of the regulatory compliance, data 
quality, and study integrity.  Study records will be reviewed and directly compared to source 
documents and the conduct of the study will be discussed with the investigator. Monitors may 
request access to all regulatory documents, source documents, CRFs, and other study 
documentation for on-site inspection.  Direct access to these documents is guaranteed by the 
investigator, who must provide support at all times for these activities. 
 
Participation as an investigator in this study implies acceptance of potential inspection 
by government regulatory authorities and applicable Dartmouth research compliance and 
quality assurance offices. The investigator will permit study protocol related audits and 
inspections by the Dartmouth CPHS, government regulatory bodies, and the Dartmouth 
compliance and quality assurance groups of all study related documents (e.g., source 
documents, regulatory documents, data collection instruments, study data.). The investigator 
will ensure the capability for inspections of applicable study-related facilities (e.g., diagnostic 
laboratory). 

 
Version  12.4.15 
 
17
Section 11. RECORD RETENTION 
 
 
Following closure of the study, the investigator will maintain all site study records In a 
safe and secure location.  The records are maintained to allow easy and timely retrieval when 
needed (e.g., audit or inspection) and, whenever feasible, to allow any subsequent review of 
data in conjunction with assessment of the facility, supporting systems, and staff.  Upon 
completion of study analysis, research information is stored in Dartmouth College Records 
Management off-site storage located at 6218 Etna Road, Hanover, NH.  Documents are 
shredded on site after 50 years of storage. 
 
Electronic case report forms, participant, and study information will be kept in the Velos 
eResearch password-protected database (or equivalent) indefinitely. 
 
 
Section 12.  HUMAN SUBJECTS 
 
 
The patients for this study will be accrued from the population treated at the Dartmouth-
Hitchcock Medical Center.  All patients will sign an informed consent, which describes the 
treatment to be performed and discusses the risks and benefits of participation in the study. 
 
Patients must give a statement of informed consent.  The informed consent must meet 
the requirements of the FDA (21 CFR 50.25 Elements of Informed Consent) and the 
Committee for the Protection of Human Subjects at Dartmouth College, the Dartmouth-
Hitchcock Medical Center IRB.  Before initiating a trial, the investigator will have written and 
dated approval from the CPHS for the trial protocol, amendment(s), written informed consent 
form, consent form updates, subject recruitment procedures (e.g., advertisements) and written 
information to be provided to subjects.  The investigators, or a person designated by the 
investigators, will explain the benefits and risks of participation in the study to each subject 
(and impartial witness when applicable) and obtain written informed consent prior to the 
subject entering the study (i.e., before initiation of non-routine tests and administration of study 
drug).  The final form must be agreed to by the CPHS and must contain all elements in the 
sample form, in language readily understood by the subject.  Each subject’s original consent 
form, signed and dated by the subject and by the person who conducted the informed consent 

 
Version  12.4.15 
 
18
discussion, will be retained by the investigator.  In addition, a copy of the informed consent will 
be given to the subject. 
 
Risk/Benefit analysis:  
Risks associated with this study include the risks of an additional MRI and all 
participants have potential confidentiality risks.  Even if the Breast Cancer Locator is highly 
inaccurate, this will pose no additional risk to the patient because the surgeon is going to plan 
their resection by taking a suitable margin (approximately 1 cm) of normal feeling breast tissue 
all around the palpable edges of the tumor. Methylene blue dye is approved for use in humans 
and has been used for many years to identify sentinel nodes in breast cancer patients. 
Methylene blue is considered to be the safest blue dye to use for sentinel node identification 
and has minimal toxicity. Patients may experience a transient blue discoloration of the skin. 
Potential serious adverse effects are very rare: one case of skin necrosis with intradermal 
injection has been observed and two cases of possible anaphylaxis have been reported (18-
21). The risk of an additional MRI is negligible and reflects the minute risk of life-threatening 
allergy and development of nephrogenic sclerosis related to gadolinium-based intravenous 
contrast.  Patients deemed to be at higher risk for gadolinium-induced nephrogenic sclerosis 
because of compromised renal function will not be eligible for participation.  Patients who 
experience a significant allergic reaction to gadolinium-based intravenous contrast at the time 
of their clinical prone MRI will also be considered ineligible for study participation.  
Risk of breach of confidentiality of the medical records of participants will be minimized.  
Subject identity is numerically coded and is not available to research investigators or otherwise 
stored on the databases maintained by the researchers to archive the clinical encounters 
accrued as part of the studies conducted under this protocol.  In this regard, all conventional 
clinical image data is de-identified prior to its use for analysis.  Databases which are used to 
store subject-sensitive information, even though completely de-identified as stored, are 
password-protected and encrypted during file/data transfers from viewing terminals.  As further 
safe-guard, the Data Safety Monitoring and Accrual Committee of the Norris Cotton Cancer 
Center will oversee the conduct of the trial. 
The importance of the knowledge to be gained and the ultimate potential for benefit for 
future patients if this new technology is effective far outweighs the nominal risks experienced 

 
Version  12.4.15 
 
19
by the women who participate in this clinical study.  
Pregnant women will be excluded due to the potential risk of gadolinium to the fetus.  
Women with child-bearing potential are eligible for enrollment into the study.  The risks 
of participating in the imaging sessions for these women are no greater than for any other 
participant.  Risks associated with breast surgery vis-à-vis child-bearing potential are outlined 
as part of standard of care.  Thus, any woman of child-bearing years enrolled in this protocol 
would already understand (and have accepted) the surgical risks to her fertility.  
Only women will be enrolled in the study because breast cancer is predominantly a 
female disease.  The imaging apparatus is design to accommodate the size and shape 
variations associated with the adult female breast.  While a very small proportion of breast 
cancer appears in males, the imaging systems are not designed to image the male breast.  All 
racial and ethnic categories will be recruited commensurate with the racial/ethnic composition 
of the DHMC patient catchment area. 
Patients will be considered “on study” and will be monitored for adverse events by the 
operating surgeon from the time of registration until 2 weeks after surgery.  
 
 
Section 13. OBLIGATIONS OF INVESTIGATORS 
 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of Helsinki. 
The Principal Investigator is responsible for personally overseeing the treatment of all study 
patients. The Principal Investigator must assure that all study site personnel, including sub-
investigators and other study staff members, adhere to the study protocol and all 
FDA/GCP/NCI regulations and guidelines regarding clinical trials both during and after study 
completion. 
The Principal Investigator at each institution or site will be responsible for assuring that 
all the required data will be collected and entered onto the Case Report Forms. Periodically, 
monitoring visits will be conducted and the Principal Investigator will provide access to his/her 
original records to permit verification of proper entry of data. At the completion of the study, all 

 
Version  12.4.15 
 
20
case report forms will be reviewed by the Principal Investigator and will require his/her final 
signature to verify the accuracy of the data. 
 
Section 14.  REFERENCES 
 
1. 
Veronesi U, Boyle P, Goldhirsch A, and Viale G. Breast Cancer. Lancet 2005;365:1727-
1741. 
2. 
Kaufman CS, Delbecq R, and Jacobson L. Excising the Reexcision: Stereotactic Core-
Needle Biopsy Decreases Need for Reexcision of Breast Cancer. World Journal of 
Surgery 1998;22:1023-1028. 
3. 
Cangiarella J, Gross J, Symmans WF, et al. The Incidence of Positive Margins with 
Breast Conserving Therapy Following Mammotome Biopsy for Microcalcification. J Surg 
Onc 2000;74:263-266. 
4. 
Harlow SP, Krag DN, Ames SE, and Weaver DL. Intraoperative Ultrasound Localization 
to Guide Surgical Excision of Nonpalpable Breast Carcinoma. Journal of the American 
College of Surgeons 1999;189:241-246. 
5. 
Rahusen F, Bremers A, Fabry H, et al. Ultrasound-guided Lumpectomy of Nonpalpable 
Breast Cancer Versus Wire-guided Resection: A Randomized Clinical Trial. Ann Surg 
Onc 2002;9:994-998. 
6. 
Berg WA, Gutierrez L, NessAiver MS, et al. Diagnostic Accuracy of Mammography, 
Clinical Examination, US, and MR Imaging in Preoperative Assessment of Breast 
Cancer. Radiology 2004;233:830-849. 
7.  
Kristoffersen Wiberg M, Aspelin P, Sylvan M, Bone B. Comparison of lesion size 
estimated by dynamic MR imaging, mammography and histopathology in breast 
neoplasms. Eur Radio 2003; 13:1207-12. 
8.  
Boetes C, Mus R, Holland R et al. Breast tumors: comparative accuracy of MR imaging 
relative to mammography and US for demonstrating extent. Radiology 1995; 197:743-7. 
9. 
Davis P, Staiger M, Harris K et al. Breast cancer measurements with MRI, 
ultrasonography and mammography. Breast Cancer Res 1996; 37:1-9. 
10. 
Bedrosian I, Mick R, Orel SG, et al. Changes in the surgical management of patients 
with breast carcinoma based on preoperative magnetic resonance imaging. Cancer 
2003;98:468-473. 
11. 
Houssami N, Ciatto S, Macaskill P, et al. Accuracy and surgical impact of magnetic 
resonance imaging in breast cancer staging: Systematic review and meta-analysis in 
detection of multifocal and multicentric cancer. J Clin Onc 2008;26:3248-3258. 
12. 
Schell AM, Rosenkranz K, and Lewis PJ. Role of Breast MRI in the Preoperative 
Evaluation of Patients with Newly Diagnosed Breast Cancer. Amer J. Roentgenology 
2009;192:1438-1444. 

 
Version  12.4.15 
 
21
13. 
Turnbull L, Brown S, Harvey I, et al. Comparative effectiveness of MRI in breast cancer 
(COMICE) trial: a randomised controlled trial. Lancet 2010;375:563-571. 
14. 
Sakakibara M, Nagashima T, Sangai T, et al. Breast-conserving Surgery using 
Projection and Reproduction Techniques of Surgical-position Breast MRI in Patients 
with Ductal Carcinoma in situ of the Breast. J Am Coll Surg 2008;207:62-68. 
15.  
Sakakibara M, Yokomizu J, Shima N et al. MRI guided quadrantectomy in patients with 
DCIS detected pre-operatively by mammographic calcifications. JACS 2014; 219: 295-
302. 
16. 
Pallone M, Poplack S, Avutu H, Paulsen K and Barth R. Supine Breast MRI and 3D 
optical scanning: a novel approach to improve tumor localization for breast conserving 
surgery. Ann Surg Onc 2014; 21: 2203-2208. 
17.  
Czarnecki D, Feider H, Splittgerber G. Toluidine blue dye as a breast localization 
marker. Amer J. Roentgenology 1989; 153: 261-3. 
18.  
Bezu C, Coutant C, Salengro A et al. Anaphylactic response to blue dye during sentinel 
lymph node biopsy. Surgical Oncology 2011; 20: e55-59. 
19.  
Reyes F, Noelck M, Valentino C et al. Complications of methylene blue dye in breast 
surgery: case reports and review of the literature. J. Cancer 2011; 2: 20-5. 
20.  
Golshan M, Nakhlis F. Can methylene blue only be used in sentinel lymph node biopsy 
for breast cancer? The Breast Journal 2006; 12: 428-30.  
21. 
Ramin S, Azar F, Malihe H. Methylene blue as the safest blue dye for sentinel node 
mapping: emphasis on anaphylaxis reaction. Acta Oncologica 2011; 50: 729-31.