Dr. Schilling is the Medical Director of Imaging & Intervention, Center for Breast Care, Boca Raton Community Hospital, Boca Raton, FL. Dr. Conti is an Associate Professor of Radiology, Division of Nuclear Medicine, and the Clinical Pharmacy and Biomedical Engineering Director, PET Imaging Science Center, Los Angeles, CA. Dr. Adler is the Medical Director, Adler Institute for Advanced Imaging, Jenkintown, PA. Dr. Tafra is the Medical Director, Anne Arundle Medical Center Breast Center, Annapolis, MD. Disclosures: Dr. Schilling and Dr. Tafra are site Principal Investigators on a multicenter trial sponsored by the National Institutes of Health (NIH) and Naviscan PET Systems (San Diego, CA). Dr. Adler has done some consulting work for Naviscan. Dr. Conti is a consultant on the Scientific Advisory Board of Naviscan.
Breast cancer is one of the most frequently diagnosed cancers in women, touching the lives of roughly 213,000 women in 2006.1 In
addition to invasive breast cancer, approximately 62,000 cases of in
situ breast cancer were projected to occur in 2006, with 85% of these
being ductal carcinoma in situ. Even with these increased numbers,
mortality is decreasing. Screening mammography has been the gold
standard for breast cancer surveillance for 3 decades and is credited
with decreasing mortality by 33%.2 Because mammography has
resulted in earlier detection of breast cancer, more patients today are
candidates for, and choose, breast-conserving surgery instead of
mastectomy. However, mammography is frequently inadequate as a planning
tool for lumpectomy. In addition, it has very limited value in women
with dense breasts. This may explain the ﬁnding that residual cancer can
be found in as many as 30% to 60% of patients after lumpectomy,
resulting in a second trip to the operating room.3
goal of molecular imaging is to preoperatively identify which patients
are best served by lumpectomy and deﬁne the margins for surgery by
identifying metabolic abnormalities in tissue, potentially decreasing
the number of second surgeries needed for resection of residual disease.
Any technology that could more precisely map the extent of both
invasive and noninvasive disease would lead to more precise surgery.
This article will review the history of molecular imaging in breast
cancer with a special emphasis on the use of the new technology positron
emission mamography (PEM), in pre- and postoperative breast cancer
Nuclear imaging of
breast cancer is not a new approach. Thallium 201 (Tl-201) was ﬁrst
shown to be an effective breast tumor-avid agent in 1978.4 Waxman et al5 later
compared Tl-201 with technetium (Tc)-99m sestamibi in 1993 and reported
that sestamibi had a higher sensitivity in detecting breast cancer. In
1994, Kao et al6 used Tc-99m sestamibi to examine palpable
breast masses. Of the 32 cases of breast cancer found, 27 were detected
by Tc-99m sestamibi, with a sensitivity of 84%, a speciﬁcity of 100%,
and an accuracy of 87%.6 This was a small but promising
result that prompted 2 large multicenter studies to evaluate
scintimammography in more than 2500 patients. These studies found a
sensitivity and speciﬁcity of scintimammography in the detection of
malignant breast tumors of approximately 85%.7,8 Further
analysis revealed that sensitivity fell signiﬁcantly with decreasing
tumor size. This was further investigated by Tofani et al,9 who
found that scintimammography had a sensitivity of only 48% for tumors
≤1 cm in size. It is important to note that all of these initial studies
were completed using conventional whole-body (WB) gamma cameras; during
this scanning, the patient is recumbent on an imaging table.
recently, it was thought that the sensitivity and speciﬁcity of
sestamibi imaging could be increased with the use of a small
ﬁeld-of-view (SFOV) gamma camera in which the detector is in close
proximity to breast tissue. Recent results using this type of camera
were reported by the Mayo clinic group.10 In this 100-patient
study, they found a detection sensitivity of 29% for tumors <5 mm,
86% for tumors between 6 and 10 mm, and 97% for tumors >11 mm in
diameter. The investigators thought that the technique may be an
important adjunct to mammography and that greater sensitivity might be
achieved with the optimization of collimation and the addition of a
second detector. This evolution of technology from WB imaging to SFOV or
organ-speciﬁc imaging in scintimammography was also seen with positron
emission tomography (PET), as described in the next section. The
characteristics of WB versus SFOV cameras for scintimammography and PET
are compared in Table 1.
Whole-body PET in breast cancer imaging
PET and PEM use the radiopharmaceutical 2-deoxy-2-[18F] ﬂuoro-D-glucose
(FDG), a positron-emitting analog of glucose, to detect metabolic
alterations within cells. This radiotracer takes advantage of the fact
that malignant cells express higher levels of the glucose transport
protein GLUT-1 and have increased glucose needs. Since 18F-FDG is taken
up like glucose but is not metabolized, it becomes metabolically trapped
within the cancer cell. The ﬁrst study to use WB PET imaging for breast
cancer was published in 1989.11 This study evaluated 17
patients with metastatic disease who had primary tumors >5 cm in
size. They reported that 14 (82%) of the tumors were detected with the
18F-FDG. The positive results of this study prompted Wahl et al12 in
1991 to evaluate the efﬁcacy of WB PET imaging for less advanced breast
cancer. They reported that FDG PET identiﬁed 10 of 10 primary breast
cancers >3 cm. Although the use of PET has been shown to be sensitive
and effective for the detection of advanced breast cancer and distant
metastatic disease in numerous studies,13,14 it is known to have limitations in detecting small, well-differentiated tumors and in-situ lesions.15 Summarizing
a number of studies, the detection rate of WB PET in primary breast
cancer has a sensitivity range of 80% to 100% and a speciﬁcity range of
75% to 100%, with an accuracy of 70% to 97%, a positive predictive value
(PPV) of 81% to 100%, and a negative predictive value (NPV) of 52% to
89%.12,16-21 As would be expected from prior study results,
the reports of the highest sensitivities for breast cancer detection
have been studies that included patients with large tumors.
A recent study by Mavi et al22 examined
the use of dual–time-point imaging as a way to increase sensitivity of
WB PET in primary breast cancer detection. In general, this approach
involves measuring the FDG uptake in a lesion at 2 separate times, such
as 60 and 120 minutes after tracer injection. Cancer cells typically
show continued FDG accumulation over this time interval, while normal or
nonmalignant cells typically do not. Mavi et al22 reported
detection sensitivities of 90.1% for lesions >10 mm (excluding 2
indeterminate cases), 82.7% for lesions 4 to 10 mm (excluding 1
indeterminate case), and 76.9% for ductal carcinoma in situ (DCIS)
(excluding 4 indeterminate cases). Thus, although the authors concluded
that dual–time-point imaging can improve the sensitivity and accuracy of
18F-FDG in assessing patients with primary breast cancer, there still
appears to be room for improvement. Finally, this approach does not
address the need for greater accuracy in presurgical planning.
PEM in breast cancer imaging
PEM is a new technology that is designed for the imaging of speciﬁc
small body parts where high-resolution detection of FDG uptake is
needed. An available dual-detector system (Naviscan PET Systems, Inc.,
San Diego, CA) consists of 2 ﬂat, high-resolution detector heads mounted
directly to compression paddles that can be rotated to optimize
imaging, such as in acquiring mediolateral oblique and craniocaudal
breast views. By lightly compressing the breast tissue during
acquisition, the image can be acquired in positions that are analogous
to those used in mammography, which allows for image coregistration and
comparison. The close proximity of the 13mm crystal detectors and
limited angle tomographic reconstruction results in an in-plane spatial
resolution of 1.5 mm full width at half maximum, compared with the 4.2
to 6.5-mm axial resolution found in commercially available WB PET
scanners. The difference in image resolution between WB PET imaging and
PEM can be seen in Figure 1. These images were acquired using a phantom
ﬁlled with ~100 uCi 18F-FDG imaged on the high-resolution PEM system
(standard 10-minute acquisition) and a WB PET scanner using a
“Brain-mode” 356 × 356 ﬁeld of view matrix, 10-minute acquisition
(Biograph PET scanner, Siemens Medical Solutions USA, Inc., Malven, PA).
It is important to remember that the spatial resolution in normal
breast tissue in the WB PET scanner would be negatively impacted by
recumbent imaging because of normal respiratory motion that was not
replicated in this phantom WB PET acquisition. Respiratory motion is not
an issue with PEM imaging, as the breast is immobilized (Table 1).
The results of the ﬁrst PEM pilot study in breast cancer, which used a 10-mm crystal, were published in 2005.23 Of
the 44 women with conﬁrmed breast cancers, 39 of the 44 primary index
tumors were seen. In addition, of the 19 patients who were undergoing
breast-conserving surgery, PEM correctly predicted 75% of patients with
positive margins and 100% with negative margins. Figure 2 provides an
example of a PEM image that highlights its utility in detecting
multicentric disease. Positron emission tomography also detected 4 of 5
histologically proven incidental breast cancers, 3 of which were not
seen by any other imaging modality. One such example case is shown in
Figure 3. The authors concluded that PEM showed promise in detecting
breast malignancies and assisted in planning breast-conserving surgery.
results of a second, larger multi-center study that examined the
performance efﬁcacy of the PEM in women with known breast cancer or
suspicious mammography ﬁndings were published in 2006.24 In
nondiabetic patients with proven breast cancer, PEM was found to have a
cancer detection sensitivity of 91%, speciﬁcity of 93%, NPV of 88%, and
an accuracy of 92%. Most importantly, PEM accurately identiﬁed 91% of
the cases of DCIS preoperatively. In this study, 36 of 73 biopsies (49%)
prompted by conventional imaging alone proved to be benign; however,
combining conventional imaging with PEM resulted in few false positives,
with a PPV of 95%. This ﬁnding highlights the advantage of combining
anatomic and metabolic characterization in cancer detection.
advantage of highly sensitive metabolic imaging is further highlighted
in a patient in whom DCIS was seen only with the PEM imaging but missed
with magnetic resonance imaging (MRI) and WB PET (Figure 4). This
patient was part of a PEM, MRI, WB PET trial being undertaken by
Schilling.25 Preliminary ﬁndings of this ongoing trial were presented at the Society of Nuclear Medicine meeting in June 200725 and
are summarized in Table 2. In addition to the benign ﬁndings listed,
pathologic analysis identiﬁed 39 distinct cancerous or in situ cancerous
lesions in the 28 study subjects. With a sensitivity of 92.3%, positron
emission mammography had the greatest sensitivity, while WB PET had a
sensitivity of only 39%. At the current interim analysis of this small
study, the results suggest that PEM is superior to WB PET and is at
least as sensitive as MRI in identifying malignant breast disease. In
addition, the author has found that the metabolic imaging provided by
PEM is helpful in premenopausal women being evaluated for breast cancer
because the lesion-to-back-ground FDG uptake ratio does not appear to be
affected by hormonal changes in the menstrual cycle. Like WB PET,
however, FDG is not recommended for use in pregnant women.
In an attempt to improve the detection sensitivity and speciﬁcity of PEM further, Adler et al26 investigated
the application of dual–time-point imaging using PEM in a pilot study
of 11 patients. They found a median increase in lesion-to-background
ratio of 36% (range 16% to 85%). This improved ratio appeared to be due
to a reduction in mean background FDG levels (Figure 5). Of interest was
the ﬁnding that 3 of 3 benign lesions showed a decrease in
lesion-to-background ratio at the second measurement. These results are
promising and suggest that delayed image comparison may prove helpful in
discriminating benign from malignant lesions. Additional, large-scale
studies will be needed to test this hypothesis.
PEM and WB PET/CT in surgical planning and breast cancer recurrence
ideal goal for any molecular imaging approach would be to provide a map
of the extent of both invasive and noninvasive disease to assist the
surgeon in undertaking more precise excision of involved breast tissue
and to more accurately monitor for recurrence. An advantage of the PEM
technology is that it uses mammographic positioning, which allows for
direct correlation of PEM images with mammography for both initial and
recurrence imaging (Figure 6). Positron emission mammography can also
provide a tomographic image that may further assist the surgeon in
determining the ideal approach to ensure negative margins. Another
molecular imaging goal would be to provide assistance in determining the
extent of disease (eg, lymph node involvement). While it is too early
to determine the sensitivity and speciﬁcity of the PEM technology for
this goal, some commercial sites are obtaining useful images of lymph
node involvement (Figure 7).
Approximately 16% to 30% of patients
with local-regional recurrence have been found to have metastatic
disease when evaluated with WB 27-30 In addition, 24% of patients with breast cancer recurrence locally will develop a site of distant disease within 18 months.29 Although
this highlights the importance of WB PET in the detection of metastatic
disease, an important question remains: whether the use of PEM imaging
for routine surveillance in women treated for breast cancer might allow
detection of local-regional recurrence at an earlier stage. The
corollary is, if detected earlier, could earlier therapy prevent or
decrease the incidence of cancer metastasis?
Whole-body PET has
been used to predict response to neoadjuvant chemotherapy in women with
advanced breast cancer. It has been shown to have a sensitivity range of
80% to 90% and a speciﬁcity range of 50% to 80% in predicting
pathological response (eg, the decrease in FDG uptake).31,32 The wide range of values reﬂects the differences in the deﬁnition of response among
different centers as well as the diminished sensitivity of WB PET in
smaller lesions. Although it appears that PET can frequently determine
an early response before other forms of imaging,33 the
question of whether PEM imaging will offer an even greater advantage in
the management of neoadjuvant chemotherapy patients will need to await
the results of a clinical trial.
New molecular imaging agents for PEM
the introduction of 18F-FDG in PET imaging has changed patient
management in a variety of cancers (including breast), the ultimate goal
in molecular imaging is to image the in vivo cancer biology of an
individual to allow therapy to be personalized. The introduction of new
positron-emitting imaging agents such as the cell proliferation markers
[F-18]-ﬂuoro-L-thymidine (FLT)34 and F-18 or C-11-2'-ﬂuoro-5-methyl-1-beta-d-arabinofuranosyluracil (FMAU),35 and [F-18]-ﬂuoromisonidazole,36 a
radiotracer marker for tumor hypoxia, offers new opportunities for
evaluating breast cancer and might help achieve this goal. In addition,
16a-[F-18]-ﬂuoroestradiol-17b (FES)37 ap-pears to be a
promising estradiol analog and provides an imaging approach to monitor
and predict clinical response to hormonal therapy in vivo. Positron
emission mammographic technology should be equally effective at imaging
the localization of these radiotracers, as it has been for 18F-FDG. The
current data would suggest that positron radiotracer development and
PET/PEM imaging technologies are in their infancy; however, combined,
they are bringing us closer to personalized cancer therapy.
authors would like to thank Ms. Mindy McKinstry of EPIC Imaging,
Portland, OR, for the axillary lymph node imaging and Judith E.
Kalinyak, MD, PhD, Medical Director, Naviscan PET Systems, Inc., for
providing assistance in preparing this manuscript.
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