is Director of Radiology, Holy Name Hospital, Teaneck, NJ, and
Associate Clinical Professor of Radiology, College of Physicians
and Surgeons, Columbia University, New York, NY.
Dr. Brunetti discloses a relationship with GE Healthcare,
Chalfont St. Giles, U.K., as a member of their PET Board of
Directors and also as a research grant recipient. She also
receives research grant support from Siemens Healthcare, Malvern,
Twenty-first century cancer therapies are increasingly employing
agents targeted to specific cellular processes. These agents are
best tailored to patient needs by adapting our diagnostic and
staging modalities to provide metabolic indications of disease
activity. Concurrent advances in both our understanding of the
molecular aberrations in cancer cells and our ability to image the
primary or secondary effects of these changes bring us closer to
the development of patient-centered treatment. One such cellular
factor is the over-expression of GLUT-1 transporters that
facilitates increased aerobic glycolysis, and consequently, uptake
F-fluorodeoxyglucose (FDG) by cancer cells. Functional positron
emission tomography (PET) with FDG and combined anatomic-functional
imaging with PET and computed tomography (PET-CT) have rapidly been
adopted as methods of diagnosis, staging and therapy monitoring in
a variety of cancers. This is due to the demonstrated improved
accuracy over conventional anatomic imaging methods.
In January, 2009, the Centers for Medicare & Medicaid
Services (CMS) published revised recommendations for PET coverage
based on review of two-and-a-half years of accumulated National
Oncologic PET Registry (NOPR) data. The decision regarding
breast-cancer coverage modifies previously covered indications of
initial staging, treatment monitoring and restaging to now cover
initial staging, excluding lymph node status, and imaging for
subsequent treatment decisions. The final decision was made in
April after a period of public comment that ended on February 6.
The CMS decision is in large part driven by financial factors and
concern regarding overuse and abuse of imaging modalities.
Ultimately, the value of any oncologic imaging procedure should be
viewed through the lens of both current and evolving therapies.
This is particularly true of breast cancer.
Breast cancer accounts for approximately one-third of cancers
diagnosed in women in the United States. It has become clear that
breast cancer is a heterogeneous disease with distinct molecular
subtypes-each associated with different clinical outcomes.
For the year 2008, the American Cancer Society estimated 184,450
new cases of breast cancer in the United States with 40,930 deaths
from the disease. The majority of breast cancers are sporadic, but
approximately 5% to 10% of breast cancers are hereditary and occur
in carriers of the BRCA1 and BRCA2 genetic mutations. Current
practice guidelines recommend pathologic assessment of the status
of both hormonal (estrogen receptor [ER] and progesterone receptor
[PR]) and human epidermal growth factor receptors (2[
]) at the time of diagnosis. These factors provide information that
contributes to staging, prognosis and therapy choice. The most
successful therapeutic chemotherapy regimens are therapies that
target these receptors. Patients who are negative for all three
factors, "triple-negative" breast cancer (ER-PR-
-, will have a worse prognosis as these tumors tend to be more
aggressive, are unresponsive to targeted therapy and must be
treated with conventional cytotoxic regimens.
Early diagnosis is still the most effective approach, and in
fact, U.S. mortality rates have dropped in the last decade. This is
a direct result of education, screen- ing programs and improved
imaging techniques such as digital mammography, aggressive use of
ultrasound and contrast-enhanced magnetic resonance imaging (MRI)
in addition to the increasing use of systemic adjuvant
Although published data do not support the use of FDG PET as a
first-line diagnostic tool for breast cancer, some comment is
justified regarding this topic. Detection of primary breast tumors
with whole-body PET is dependent on tumor size and histology. In
contrast to ductal carcinomas, lobular carcinomas are less glucose
avid and therefore are more likely to be false-negative on
whole-body FDG-PET imaging.
With respect to lesion size, sensitivity for detection of breast
tumors <1 cm is reported ≤25% whereas sensitivity increases to
91.9% in lesions with diameters between 1 and 2 cm (Figure 1).
Strategies have been suggested for improving the detection rate
on whole-body PET. These include dual-time-point imaging and prone
imaging. Based on the premise that cancer continues to accumulate
FDG while activity in normal or benign tissues declines with time,
Mavi et al. reported findings of dual-time-point FDG-PET imaging in
a prospective study of 152 patients with newly diagnosed breast
The study excluded cancers <3 mm. A limited PET scan of the
thorax was acquired 46 to 112 minutes after the whole-body
acquisition. Visual assessment and change in maximum standardized
uptake value (SUVmax) were recorded and compared to surgical
pathology. The authors reported sensitivities of 90.1% for invasive
cancers >10 mm, 82.7% for invasive lesions 4 to 10 mm, and 76.9%
for noninvasive breast cancers. Most lesions became more intense on
delayed scans. There were 6 tumors >10 mm that were false
negatives. These included 3 mixed ductal and lobular, 1 lobular, 1
mucinous, and 1 invasive ductal cancer.
Recently, Imbriaco et al. compared dual-time-point imaging of
breast lesions with dynamic breast MRI.
Forty-four patients with 55 lesions underwent dual-time-point
PET-CT in the prone position as well as breast MRI. Findings were
compared with surgical histopathology. The accuracy of MRI was 95%,
far greater than that achieved by PET-CT. However, the accuracy of
PET-CT increased from only 69% with single-time-point imaging to
84% with dual -time-point imaging. In spite of the issues relating
to the feasibility of performing dual-time-point imaging, these
findings support implementation of longer uptake periods following
FDG administration to optimize tumor-to-background activity. It is
also important to remember that incidental breast cancers may be
discovered on PET.
Due to the superficial location of breast tissue, additional
careful review of noncorrected images may improve lesion
perceptibility and facilitate discovery of unexpected primary
In an effort to improve MRI specificity, Moy et al. developed a
prototype positioning device that facilitates PET imaging of
patients in a prone position duplicating that of MRI and therefore
allowing computer fusion of PET and MRI images.
Forty-five lesions varying in size from 0.6 to 10 cm were imaged.
Fifteeen lesions were histologically proven to be cancer.
Sensitivity and specificity of MRI were 92% and 52%. Sensitivity
and specificity of MRI-PET fused images were 63% and 69%. The
positive predictive value for MRI alone was 69% but increased to
94% with PET-MRI fusion. Interestingly, in this small series
although the specificity of lesion detection was increased with
PET-MRI fusion, sensitivity was reduced. PET-MRI fusion allowed
synchronous acquisition of both modalities, combining the high
soft-tissue resolution and spectroscopy capability of MRI with the
in vivo molecular information provided by positron imaging and the
quantitative technology of both.
A particularly exciting avenue of research is the development of
18-F-labeled nanoparticles that can be detected by both in vivo PET
and MRI imaging.
Multiple centers are currently investigating PET-MRI fusion as a
new approach to oncologic imaging and future published data will
determine the feasibility and clinical utility of this approach.
Breast-cancer survival increases when diagnosed at very early
stages, and continued technologic advances that optimize resolution
and lesion detection bring us closer to achieving even better
survival rates. Ultimately, it may be dedicated positron emission
mammography scanners (PEM) that may provide significant gains in
diagnosis and molecular characterization of breast lesions. Current
PEM units have spatial resolution in the range of 1 to 2 mm and are
equipped with biopsy capabilities.
Potential applications include preoperative imaging for surgical
planning in patients who are either unable to undergo MRI or who
have confusing MRI scans due to hormonal influences. In addition,
PEM can establish a baseline to allow monitoring of
chemotherapeutic treatment response and detection of
Berg et al. reported a multicenter prospective trial of 94
consecutive patients with known breast cancer or suspicious breast
Findings of PEM were compared with histopathology. The sensitivity
and specificity for detection of cancer were 91% and 93% with
accuracy of 92%. Large-scale trials will be necessary to fully
explore the value of this focused technique.
A recent study of 208 patients presented by Schilling et al. at
RSNA in 2008 demonstrated similar index-lesion sensitivity for PEM
and MRI of 93%, compared to 69% for whole-body PET. PEM appeared to
have greater sensitivity for ductal carcinoma in situ (DCIS)
detection (93%) compared with breast MRI (83%, Figure 2). For the
detection of both ipsilateral and contralateral lesions, PEM
demonstrated better accuracy than MRI.
A large-scale 400-patient multicenter blinded study comparing MRI
and PEM is currently under analysis to further investigate the
value of this focused technique (personal communication: Kathy
Schilling, MD, Center for Breast Care, Boca Raton Community
Hospital, Boca Raton, FL).
There is minimal value in performing whole-body PET or PET-CT in
patients with early-stage disease in whom the likelihood of
metastatic disease is extremely low. The American Cancer Society
reports the 5-year-survival rate for patients diagnosed at stages 0
and I is 100%. Current practice guidelines recommend breast
conservation surgery followed by breast irradiation and hormonal
blockade. In this patient group, imaging guidance for establishment
of surgical margins and exclusion of multifocal disease is
critical. Although MRI has been the standard in this scenario, PEM
can also be utilized for presurgical planning to reduce the risk of
positive margins due to DCIS or satellite lesions in those patients
who are candidates for breast-conserving surgery.
For patients diagnosed with stage II disease, the 5-year
survival is 86% with further reduction in survival to 57% at stage
III and 20% at stage IV. These patients will frequently undergo
preoperative chemotherapy, lumpectomy or total mastectomy with
axillary lymph node dissection (ALND) followed by adjuvant
chemotherapy. Tumor size, axillary lymph node status and histologic
grade are 3 factors that determine prognosis in breast cancer.
Positive lymph nodes are defined as those with metastatic foci
>0.2 mm. Consequently, no currently available imaging modality
is sufficiently accurate for axillary node staging. Some authors
suggest, however, that when axillary nodes are demonstrated to be
positive on PET and PET-CT, the positive-predictive value is
sufficiently high to obviate the need for sentinel lymph node
biopsy in those patients who are ALND dissection candidates.
As false-positive findings in the axilla can be seen in
sarcoidosis, tuberculosis, rheumatoid arthritis and other
inflammatory conditions, obtaining an accurate and complete patient
history, along with careful evaluation of the size and biologic
activity of the primary lesion as well as the pattern of nodal
involvement is required before a confident diagnosis of
axillary-nodal metastasis can be made. (Figure 3)
In patients who present with locally invasive disease, i.e.,
stage IIB and greater, PET-CT performed as part of an initial
staging workup may alter therapy as a result of identification of
distant metastatic disease. Fuster et al. compared preoperative
PET-CT in patients with large (>3 cm) breast tumors with breast
MRI, chest CT, liver ultrasonography and bone scan.
The sensitivity and specificity of PET-CT in detecting distant
metastatic disease were 100% and 98%. For conventional imaging the
sensitivity and specificity were 60% and 83%. The findings on
PET-CT led to a change in staging in 42% of patients. Additional
data supporting the use of PET in initial staging is reported by
Cermik et al. in a prospective study of 271 patients with newly
diagnosed breast cancer.
Extra-axillary nodal involvement was detected in 22 patients and
distant metastatic disease in the absence of axillary metastasis
was discovered in 5 patients. In 9.2% of patients, the tumor node
metastasis (TNM) system stage was upgraded.
Heusner et al. have developed a single-session breast cancer
staging protocol utilizing whole-body PET-CT and prone PET-CT
The authors compared the integrated PET-CT protocol with the
diagnostic accuracy of a multimodality algorithm including MRI,
axillary ultrasound, SLNB, bone scan, chest radiography and
abdominal ultrasound for the initial staging of breast cancer in 40
patients. Findings relating to the primary tumor, ipsilateral
nodes, distant metastases, extra-axillary nodes and management
changes were evaluated. The sensitivity for detection of the
primary breast tumor was 100% for MRI and 95% for PET-CT. PET-CT
was more accurate in determining focality and correctly predicted
the pattern in 26 of 33 patients, whereas MRI was correct in 24 of
33. PET-CT detected 80% of ipsilateral nodes compared to 70%
discovered with clinical exam and ultrasound. In 3 patients PET-CT
identified extra-axillary nodes missed by conventional imaging and
correctly identified distant metastatic lesions in 10 patients,
while conventional imaging identified 7 of 10. PET-CT findings
resulted in therapeutic management change due to the detection of
distant metastases in 5 patients, and synchronous colon and lung
cancers in 2 patients.
The prognostic implications of the pattern of FDG uptake in
breast cancer are an intriguing research topic as the relationship
between FDG uptake and biologic behavior of breast cancer may
provide a method of risk stratification. The number of viable tumor
cells per volume, histologic subtype, tumor grade, microvessel
density and proliferative activity, as well as the expression of
GLUT-1 transporter and hexokinase I, all influence FDG uptake in
There is data to suggest that a poorer prognosis is associated with
higher tumor SUVmax.
An association exists between FDG accumulation and key cellular
factors that indicate cellular aggressiveness. Shimoda et al.
compared SUVmax and the immunohistochemcal and pathological factors
of 37 patients with breast carcinoma.
The authors found a strong correlation between FDG uptake and
mitotic counts; and the percentage of cells positive for the Ki-67
protein, which is a product of the
gene, and nuclear grade. Whereas standard prognostic indicators of
tumor size, histology, ER, PR and
over-expression did not. Recently, Basu et al. reported a 100%
sensitivity in detection of triple-negative [ER-/PR-/
] cancers utilizing dual-time-point FDG-PET imaging and higher
uptake of FDG in comparison to ER+/PR+/
Further investigation is needed to explore the clinical impact of
Bone marrow metastasis
Only 1% to 2% of patients present with radiographically evident
osseous metastases at the time of diagnosis.
Breast cancer is a systemic disease and micrometastatic disease in
the form of disseminated tumor cells (DTC) may be present in the
bone marrow of breast-cancer patients at the time of diagnosis and,
if present, is associated with a poorer distant metastasis-free
Interestingly, the presence of DTC in bone marrow did not correlate
with axillary lymph node (ALN) status in a series of 270
early-stage breast-cancer patients reported by Saha et al.
The frequency of bone marrow micrometastasis (BMM) in this series
was 9.6%. BMM were detected in 11.5% of patients with ALN
metastases and in 8.9% of patients with negative axillary lymph
nodes. The clinical impact of these studies has yet to be
established but may yield critical information regarding tumor
dormancy, progression and potential targets for novel drugs.
Skeletal metastases present a particular dilemma to the
oncologist as there has been no accurate method of monitoring
patients with bone-dominant breast cancer. It is well know that
osseous metastases in breast cancer can be osteoblastic, osteolytic
or mixed. Early published data indicated that FDG PET was less
sensitive than conventional bone scintigraphy in identification of
osteoblastic-osseous metastasis and demonstrated a higher
sensitivity in detection of lytic disease.
It is now evident that the presence of FDG uptake in bone lesions
of breast-cancer patients may be a valuable indicator of disease
activity. Several studies have reported a combination of
morphologic changes in bone metastases seen on CT and patterns of
uptake on FDG PET. Du et al. reviewed the findings on CT and FDG
PET of 25 patients who underwent pre- and posttreatment PET-CT.
Ninety-three percent of osteolytic and 81.8% of mixed osseous
metastases were FDG avid, while only 61% of osteoblastic lesions
demonstrated FDG uptake. Seventeen patients had metastatic lesions
detected only on FDG PET. After therapy, 80.5% of lytic lesions
became FDG negative and osteoblastic on CT, while 25% of
osteoblastic lesions became FDG negative. Twelve osteoblastic
lesions remained FDG positive and increased in size on CT. The
CT-negative lesions all became FDG negative, with 9 lesions
becoming osteoblastic on CT. The authors suggested that FDG uptake
is an indicator of cellular activity and CT morphologic changes are
variable. Tateishi et al. compared the SUVmax of bone lesions as an
indicator of response to therapy in a retrospective review of 102
patients with metastatic breast cancer.
Patients underwent FDG PET-CT scans prior to and approximately one
month after systemic chemotherapy. SUVmax, total lesion glycolysis
(TLG) and CT morphologic analysis were performed and compared with
medical record follow-up to assess outcome. The authors found that
after treatment an increase in CT attenuation with a decrease in
SUVmax was associated with response duration (RD) and that a
decrease of SUVmax of 8.5% or more was predictive of a long RD.
Similar results have been reported by Specht et al. in a
retrospective review of 405 patients.
The authors compared serial FDG-PET findings to clinical follow-up
and reported a twofold increase in the likelihood of disease
progression when FDG-positive bone lesions demonstrated no change
in FDG uptake posttherapy and a higher initial SUVmax was
predictive for a shorter time for skeletal disease progression.
Interpretation of FDG-PET bone findings can be challenging in the
absence of prior or baseline PET scans. In many cases, bone uptake
may be heterogeneous due to underlying degenerative changes or may
be increased as a result of chemotherapy. In these cases, it is
sometimes difficult to identify small or early foci of disease with
confidence (Figure 4).
Metastatic bone disease can also be imaged with
F-fluoride PET and PET-CT.
F-fluoride binds in hydroxyapatite at sites of bone remodeling in a
manner similar to
Tc-MDP bone scans, but at a rate that is twofold higher.
Both benign and malignant lesions may accumulate
F-fluoride so it is important to correlate findings with CT or MRI.
There are no studies that evaluate posttherapy up-take patterns of
F-fluoride. In view of the uptake mechanism of
F-fluoride, it may be that posttherapy scans might actually
demonstrate increased uptake as an index of response, paralleling
increased sclerosis that is evident on CT.
Breast cancer is a systemic illness and metastatic disease
occurs in approximately 25% to 40% of patients.
Despite advances in systemic therapies, metastatic breast cancer is
incurable. It is therefore critical to accurately identify the
presence and extent of disease so that appropriate therapy
decisions may be made at the time of diagnosis and in follow-up.
Guidelines of both the National Cancer Comprehensive Network (NCCN)
and the American Society of Clinical Oncology (ASCO) discourage the
use of FDG PET for surveillance of asymptomatic breast cancer
patients, relying instead on clinical indicators of disease. As was
noted in the previous discussion, the issue of osseous-metastatic
disease is complex and reliance on conventional bone scan alone may
not accurately define disease activity. Furthermore, metastatic
disease may be asymptomatic, and therefore, may be widespread
before becoming clinically apparent. Circulating serum tumor
markers such as cancer antigen (CA) 27.29 and CA 15-3 are used,
although their use is not encouraged by ASCO as a method of tumor
surveillance. Saad et al. compared the performance of CA 27.29 with
the findings of FDG PET-CT in patients with metastatic breast
cancer and found that CA 27.29 was a poor indicator of disease in
comparison to the findings of PET-CT.
For detection of locoregional recurrence and identification of
distant metastatic disease, FDG PET and PET-CT is superior to
conventional imaging alone.
Accurate identification of metastatic disease in internal mammary
lymph nodes is often difficult on CT. Detection of internal mammary
(IM) and mediastinal lymph node metastasis is improved with FDG
PET. Eubank et al. retrospectively reviewed the PET and CT scans of
73 breast cancer patients with thoracic metastases.
In 33 patients, biopsy confirmation was available. The sensitivity,
specificity and accuracy of PET in detection of IM metastases were
85%, 90%, and 88%, respectively. For CT, the sensitivity,
specificity and accuracy were 50%, 83% and 70% (Figure 5).
Detection of pulmonary and hepatic metastases is dependent on
lesion size and partial volume effects resulting from respiratory
motion. Dual -time-point PET-CT imaging improves hepatic lesion
detection by increasing tumor-to-background activity. Dirisamer et
al. reported a 90% sensitivity in diagnosis of liver metastasis on
delayed PET-CT vs. only 59% sensitivity on the initial scan.
This same author recently reported the findings of a series of 52
patients with suspected recurrent breast cancer imaged with
contrast-enhanced PET-CT. The findings of PET, CT and
contrast-enhanced PET-CT were compared. Verification of disease was
accomplished by biopsy or follow-up exams. All 3 modalities
identified 44 visceral metastatic lesions with the same accuracy.
Contrast-enhanced PET-CT and CT were more accurate in
identification of pulmonary lesions. The overall accuracy for all
metastatic foci was 77% for CT, 96% for PET and 98% for
In the near future, we will radically change our approach to
cancer management by:
- refining the resolving capability of our imaging
- developing process-targeted contrast agents and
radiopharmaceuticals, and by
- combining nanoparticle technology with our increasing
understanding of the cellular factors that govern transformation
of cells to malignant phenotypes.
With respect to breast cancer, it is possible that currently
accepted clinical staging and prognostic criteria will be modified
or completely replaced by a molecular and genetic patient-specific
tumor blueprint. This will likely be accomplished through a
multimodality approach of molecular typing with application of
patient-specific indicators of prognosis and risk for relapse,
combined with targeted therapies. Even after we have finally
attained that level of sophisticated biologic road mapping,
functional anatomic imaging with PETCT will remain a powerful tool
in therapy decision making.