Trial Information

A Comparison of the Diagnostic Accuracy of Adjunctive Digital Breast Tomosynthesis Versus Adjunctive Contrast Enhanced Breast Magnetic Resonance Imaging in the Preoperative Assessment of Breast Cancer

STUDY OVERVIEW

Subjects are enrolled within 4 weeks of the date of diagnosis of biopsy proven ductal
carcinoma in-situ (DCIS) or Invasive Breast Cancer. Approximately 50 subjects will be
enrolled. In addition to Dartmouth-Hitchcock Medical Center's (DHMC)current standard imaging
practice, i.e. bilateral mammography with or without sonography and bilateral CEMRI, all
subjects will undergo bilateral DBT within four weeks of CEMRI and prior to surgical
treatment. Usual clinical practice, i.e. interpretation of current standard imaging
(Mammography, Sonography and CEMRI), and clinical assessment based on physical exam as well,
as discussion with the patient and breast surgeon of record, will dictate local treatment,
i.e. surgical excision only, breast conservation therapy (BCT) or mastectomy.

Any routine diagnostic examinations completed as part of the subject's standard of care
imaging will be read and interpreted as part of the patient's standard of care. There will
be no delays in reading or interpretation of the routine care images.

Blinded reads of the DBT and CEMRI images will be conducted, with the patient's mammography
+/- sonography available for reference. The interpreting radiologists ("readers") will
evaluate tumor size and extent of disease, along with the presence or absence of
multi-focality or contralateral disease. The two imaging paradigms will be compared in the
estimation of breast cancer extent using the gold-standard histologic result.

DBT mammography may provide new or different information about the index lesion than
standard imaging, but this will not alter clinical management. However, if DBT detects an
additional abnormality separate from the index lesion either in the ipsilateral or
contralateral breast, it will be evaluated further with standard imaging technology (e.g.
diagnostic mammography and or sonography) targeted to this site to assess the level of
suspicion for malignancy and potential need for biopsy.

PROCEDURES

Tomosynthesis Acquisition

Study participants shown to have DCIS or invasive breast cancer by fine needle aspiration
cytology and/or core needle biopsy, and who have signed informed consent, will undergo a
bilateral DBT mammogram within 4 weeks of CEMRI (prior to surgical treatment). The DBT
mammogram includes a 2D acquisition and a 3D acquisition, under the same compression in both
the standard craniocaudal (CC) and mediolateral (MLO) projections. In the rare instance that
the index malignancy is not included on a view due to a chest wall location, a single repeat
view of the involved (i.e. cancerous) breast will be performed in an attempt to image the
malignancy on the combined DBT mammogram. For each view, the subject will be positioned and
compressed as for standard mammographic imaging. The patient will remain under compression
for no more than 15 seconds. During the compression, a 3D dataset (about a 4 second
exposure) and a 2D dataset (about a 2 second exposure) will be acquired. Once the subject is
positioned and compressed, the technologist will activate the motion of the x-ray tube to
move to the starting position of -7.5 degrees. The technologist will then start the
tomosynthesis 3D acquisition, which is completed at +7.5 degrees (an arc of 15 degrees). The
x-ray tube then by design moves back to the center and automatically acquires the 2D
dataset. At the conclusion of image acquisition, the compression is automatically released.

A Radiologic Technologist registered for radiography and mammography will perform the
tomosynthesis study. The technologist performing the DBT exam has been trained in the use
and operation of the DBT imaging system.

Device Description

A DBT system similar to the commercially available product ('Selenia Dimensions', Hologic,
Inc., Danbury CT) will be used for the data collection. The 'Selenia Dimensions' 2D/3D
digital mammography system has been approved by the FDA for screening and diagnostic breast
imaging.

The breast tomosynthesis system is a digital mammography system (Hologic, Inc, Danbury, CT)
that is capable of producing standard two-dimensional images and a three-dimensional
tomosynthesis mammogram. The 2D and 3D tomographic datasets are acquired under the same
compression. The breast tomosynthesis system employs a tungsten target anode with
interchangeable rhodium, silver, and aluminum x-ray filters. The filtration material is
chosen based on breast thickness and exam protocol and, along with the tungsten target,
minimizes x-ray dose while maximizing image content. The three-dimensional tomosynthesis
x-ray imaging technology involves acquiring images of a stationary compressed breast, at
multiple angles during a short-scan. The individual images are then reconstructed into a
series of thin high-resolution slices that are displayed individually or in a dynamic cine
mode. When in combination mode, the system acquires both the 3D dataset and then the 2D
standard mammographic image. The dose for a single combination 2D/3D acquisition for the
"average breast" i.e. compressed breast thickness of 4.5 cm, 50% fat, 50% glandular
composition is approximately 2.45 mGy, less than the FDA limit for a single mammogram image
(3 mGy) for the same breast thickness and composition.

The DBT system will only be used for subjects who have signed the Informed Consent.

Quality Control

The Hologic Tomosynthesis Digital Mammography System (DBT) will be checked by a qualified
medical physicist prior to any testing or imaging of subjects to assure the system is
operating correctly with optimum image quality. A Study Technologist will review images,
obtain phantom images and check system operation on a periodic basis to assure that optimum
image quality is maintained. The quality control procedures described in the systems'
operator manuals will be used throughout the trial. If there is any noticeable degradation
in image quality, a Hologic engineer will be called immediately to recalibrate or repair the
system.

CEMRI

Each subject will undergo bilateral CEMRI as part of usual clinical practice, not because of
their participation in the study. Subjects who are unable to undergo contrast enhanced MRI
due to contraindications to MRI or gadolinium based intravenous contrast are not eligible
for study enrollment.

Image Interpretation

The DBT images will be evaluated by a Mammography Quality Standards Act certified
radiologist. There will be two readers for each subject: one reader will interpret DBT
(blinded to results of CEMRI), while the second reader will interpret CEMRI (blinded to
results of DBT). Each reader interprets the adjunct exam (i.e. DBT or CEMRI) unblinded to
conventional imaging (i.e. mammography +/- sonography) and completes the appropriate rating
instrument.

Size Determination

Study Readers will estimate the maximal in plane diameter in at least two imaging planes of
the index malignant lesion. For DBT, maximal diameters should be measured in the CC and MLO
projections. For CEMRI, maximal diameters should be measured in axial and sagittal
projections. Readers will also report on and diagram the location of additional lesions that
are not considered definitely benign.

Histological Interpretation

The specimen (lumpectomy or mastectomy) is sequentially sectioned into 5 mm slices and the
number of slices is recorded in the gross description. Targeted sections are taken of both
lumpectomies and mastectomies by sampling lesions identified by imaging (per usual clinical
protocol). Such lesions are submitted as appropriate along with 1-2 sections of a
surrounding cuff of normal appearing parenchyma in each appropriate direction. The distance
between multiple lesions is measured, and in such cases a single section of intervening
tissue is submitted for histologic examination. Incidental lesions identified on gross exam
are sampled as appropriate. The histopathologic specimen is viewed by a pathologist with
3-20 years of experience in breast pathology. Invasive disease is graded according to the
Nottingham Bloom Scarff Richardson system. DCIS is graded according to a modified Van Nuys
system, including the nuclear grade, the presence or absence of necrosis, and the pattern of
growth. The number of consecutive slides containing DCIS will be multiplied by the
approximate thickness of each tissue section (5mm) in order to determine the histopathologic
size.

Tumor size will be determined by gross examination of the pathology specimen when visible on
gross examination. Tumor size estimate in this case will reflect an aggregate of invasive
and non-invasive, i.e. DCIS, components.

If no gross lesion is seen, the measurement of tumor size will be determined by the
microscopic measurement of the lesion. Since the 2 components are intermingled, the size
reported represents an aggregate size.

In addition to the gross exam measurement, if a lesion is substantially composed of DCIS,
(i.e. extensive intraductal component present) by microscopic examination, we will specify
the size of both the invasive component (by microscopic exam) as well as a measurement of
the DCIS component (by microscopic exam) and provide an aggregate size of both invasive and
DCIS components).

In cases of invasive cancer with an extensive component of DCIS treated with mastectomy or a
very wide local excision, standard pathologic sampling of the lesion may not allow for
accurate microscopic size estimate of the lesion. In these select cases the pathologist
will indicate the type of growth pattern of the DCIS component as either "mass-like" or "non
mass-like".