Cumali Aktolun • Muammer Urhan • Umut Elboga
Breast cancer, the second leading cause of cancer-related death in women throughout the world, is often curable when the disease is local and diagnosed at an early stage.1 Mammographic screening programs allow for diagnosis at an early stage resulting in increased detection of low-risk cancers, premalignant lesions, and ductal carcinoma in situ (DCIS).
Breast cancer is a histopathologically, genetically, and clinically heterogeneous malignancy. The most common histopathologic types include invasive ductal carcinoma, invasive lobular carcinoma, and DCIS. Based on the molecular and genetic features, many subtypes of these major histologic types of breast cancer have been described.
Imaging is still the key technology for screening, initial diagnosis, and evaluation of the disease extent. Mammography that uses ionizing radiation to image breast tissue is the most commonly used screening method for early breast cancer detection which has been effective in reducing breast cancer mortality in certain populations. It relies on differentiation of the normal breast from abnormal by delineating patterns of density differences and calcification in the breast tissue that may be the sole evidence for malignancy. The examination is performed by compressing the breast firmly between two plates to spread overlapping tissues and reduce the amount of radiation exposure. For routine purposes, mammographic images are usually taken in both mediolateral oblique and craniocaudal projections that include breast tissue from the nipple to the pectoral muscle. Its limitations include low specificity and false-negative results especially in women with radiographically dense breasts and breast implants. The sensitivity of mammography is lower in women with radiographically dense breasts and a significant percentage of young women (depending on age, race, and ethnicity) have dense breast tissue.2,3
Breast radiation absorbed dose (mean glandular dose) associated with standard two-view mammography is about 3.91 mGy for digital mammography and 4.98 mGy for screen-film mammography.4 The radiation risk associated with mammography is acceptable for diagnostic purposes, but the radiation dose absorbed by the breasts during multiple mammographic screening procedures throughout the years has been a continuous topic of debate both in the medical community and the general public.
One of the major criteria for abnormality detected on mammography is calcification that may also be seen in many benign conditions resulting in high false-positive rate and low specificity. Almost two-thirds of abnormal findings detected on mammography are benign. Hence, in current clinical practice, women with abnormal mammographic findings must undergo additional diagnostic procedures including ultrasonography, magnetic resonance imaging (MRI), and/or tissue sampling (fine-needle aspiration, core biopsy or excisional biopsy). Although mammography is the gold standard procedure for breast cancer screening, its low specificity often leads to a large number of unnecessary interventions performed to evaluate suspicious mammographic breast lesions.5,6
Supplemental screening with breast MRI is recommended in women with selected high- and intermediate-risk factors while screening with breast ultrasonography is an option for women in these risk groups who cannot undergo breast MRI.
MRI may have an additional role in the diagnostic work-up as it is quite sensitive especially detecting multifocal/multicentric tumor foci in the breast as small as 2 to 3 mm in diameter. In addition to diagnostic evaluation in women and preoperative planning for some patients with known breast cancer, breast MRI may be used to evaluate the lesions obscured by breast implants, assessing palpable masses following surgery or radiation therapy, occult breast cancer in patients with axillary nodal metastasis detected by mammography or ultrasonography. In addition to its use as a diagnostic tool, MRI is more sensitive than screening mammography in selected patients. It can be used as a screening test for women with a high risk of breast cancer who are BRCA 1/2 mutation carriers, or have a strong family history of breast cancer, or other genetic syndromes such as Li-Fraumeni or Cowden disease.7 Although rare, serious side effects associated with commonly used MR contrast agents including nephrogenic systemic fibrosis are a source of concern.8 In addition, MRI is more expensive than any other morphologic imaging modality. Its specificity ranges from 37% to 97%, as contrast-enhancing foci can also be frequently seen in healthy breasts. Women who are screened with MRI thus have more negative surgical biopsies.
Ultrasonography is useful for diagnostic evaluation of palpable or suspicious lesions detected on mammography rather than serving as a primary screening modality. Unlike mammography, its use in breast cancer screening and diagnosis is complementary. Although it is widely used, its indications vary greatly from one site to another. Nevertheless, the number of unnecessary biopsies decreased significantly with the advent of the newest transducer technology and the use of ultrasonography in combination with mammography.
Radionuclide imaging techniques using tumor-seeking agents with penetrating γ-rays are not affected by dense breast tissue and breast implants. They have the potential of confirming or excluding the presence of malignant tissue in a given lesion detected by mammography. Currently, biopsy is routinely performed on a breast lesion before any surgical procedure is planned. Any diagnostic test including radionuclide imaging would thus be helpful in avoiding unnecessary biopsies.
RADIONUCLIDE IMAGING OF THE PRIMARY TUMOR AT INITIAL DIAGNOSIS
Starting from the late 1980s, many tumor-seeking radiopharmaceuticals have been used in the efforts to detect primary breast cancer. In addition, thanks to the advances in imaging technology, breast imaging methods that had been unknown before have been developed using these radiopharmaceuticals labeled with γ-emitters and positron emitters (Table 11.1).
Breast Scintigraphy Using Gamma Camera Imaging
Breast scintigraphy, also known as scintimammography, is a diagnostic imaging method that utilizes tumor-seeking radiopharmaceuticals to detect the primary tumors of the breast. A large number of radiopharmaceuticals have been used for breast scintigraphy, but technetium-99m methoxyisobutylisonitrile (99mTc-sestamibi, also known as 99mTc-MIBI) is the most widely used radiopharmaceutical for this purpose. 99mTc-MIBI is avidly taken up by many malignant tumors9 and is currently the radiopharmaceutical of choice for breast scintigraphy.
RADIONUCLIDE IMAGING METHODS IN BREAST CANCER
99mTc-MIBI was originally used to evaluate myocardial perfusion. Aktolun et al.9 were the first to show that 99mTc-MIBI can be used to detect the primary tumor in patients with breast cancer. It has the advantages of 99mTc which offers low radiation burden and high photon flux suitable for gamma camera imaging. MIBI is a positively charged lipophilic molecule that accumulates in the negatively charged mitochondria in rapidly proliferating tumor cells.10The mechanism of accumulation in the tumor is multifactorial and does not depend on the presence of architectural distortion or local or diffuse density variation in the breast. There is a positive correlation between energy demand and increased mitochondrial activity of tumor cells.
The amount of 99mTc-MIBI activity used for breast scintigraphy was originally defined as 10 mCi,9 but activities as high as 25 mCi have been reported in studies published subsequently.11 Most of the dosimetric studies performed for comparison of breast scintigraphy with mammography were based on the figures obtained from the radiation absorbed dose after the injection of these high amounts of 99mTc-MIBI which unnecessarily placed this technique in a less favorable position compared to mammography. In recent studies, however, the amount of activity has been reduced to 8 to 10 mCi.12 It should be noted that, with the current strategies using 99mTc-MIBI activities greater than 10 mCi, breast scintigraphy is not indicated for breast cancer screening because of the high glandular and whole-body radiation dose. 99mTc-MIBI breast imaging should not be considered as an alternative to biopsy.
The time necessary to complete the imaging session can be as long as 40 minutes. This is another challenge in competition with mammography in diagnostic setting. In their recent study comparing the diagnostic performance of molecular breast imaging (MBI) performed with standard 10-minute-per-view acquisitions and half-time 5-minute-per-view acquisitions, with and without wide beam reconstruction processing, Hruska et al.13 focused on reducing the time needed for imaging and reported comparable results with 10-minute- and 5-minute-per-view MBI, resulting in substantial agreement in the final assessment. In an era when more efforts are focused on reducing the injected 99mTc-MIBI activity for a more favorable radiation dose to the breast and the whole-body, reducing imaging time unavoidably requires injection of a higher activity which is less likely to gain acceptance clinically.
The interval between injection of radiopharmaceutical and imaging has been a topic of investigation in some studies.14 In a standard protocol, 10 to 15 mCi of 99mTc-MIBI is injected into the arm opposite the breast with the suspected lesion. Both breasts should be imaged for the purpose of comparison during interpretation. One hour after intravenous injection of 99mTc-MIBI, patients are positioned supine with the arms raised up to allow evaluation of the axilla and the breast. Some departments prefer starting the acquisition as early as 5 minutes after injection and perform imaging as late as 90 minutes after injection.14,15
In their original study, Aktolun et al.9 preferred supine planar and single photon emission tomography (SPECT) imaging, but prone technique for patient positioning has gained wider acceptance throughout the world.11 Most authors suggested placing the patients in prone position using a table with a cutout to fit the breast. Breasts are placed as close as possible to the detector to increase the sensitivity and lesion detectability. Two lateral breast images are obtained for 10 minutes (Fig. 11.1). A supine image is also recommended to cover the axillae. If patients cannot be positioned in the prone position, an anterior supine view with the arms up is obtained to evaluate two breasts and axillary region simultaneously.
SPECT may provide additional information about primary breast cancer and the axilla.16,17 For SPECT imaging, the patient is usually positioned in the supine position to obtain sufficient counts for high-resolution images. All images must be meticulously reviewed, particularly in patients with fibroglandular changes as false-positive findings may be seen.
The sensitivity of scintimammography is higher for palpable breast tumors than nonpalpable lesions because of the limited resolution of gamma camera technology.18 In patients with a relatively high number of fibrocystic lesions, false-positive findings may be obtained whereas in patients with small malignant lesions faint or no activity (false-negative) may be seen.
Breast Scintigraphy Using Dedicated Breast Imaging Devices
Breast scintigraphy as described above can be performed using a general purpose gamma camera that is available in all Nuclear Medicine departments, but the ability of these devices to detect small tumors is limited. The breasts are about 15 cm away from the collimator and the region of interest may be up to 25 cm away from the collimator. In addition, only the lateral and anterior/posterior views can be acquired with general purpose cameras. Side-by-side correlation with the standard craniocaudal and mediolateral oblique views acquired in routine mammography are almost impossible to obtain. Dedicated breast imaging devices overcome these problems by reducing the size of the detector and integrating it with a breast compression device. The breast is pressed against the collimator/detector face while the patient is imaged in a seated position.
FIGURE 11.1. Breast scintigraphy performed using a general purpose gamma camera. Invasive ductal carcinoma (red arrow) in a woman with dense breast parenchyma and a metastatic lymph node in the right axilla (blue arrow) seen on mammography (A).99mTc-MIBI uptake by the primary tumor was seen on both projections in prone and right anterior oblique positions (B, C; red arrow), whereas metastatic lymph node in the axilla was more apparent only in right anterior oblique position (C; blue arrow). Note that according to color scala, body part over a certain count rate was seen as a white region (B; thick red arrow).
Dedicated imaging devices with small field of view (FOV) and higher resolution have revealed more favorable results than previously obtained.19 These devices produce images of the breast parenchyma in the same projections comparable to mammography (Fig. 11.2). The axillae are not included in these images which may result in missing important findings. With this technology, breast scintigraphy has evolved to MBI and breast-specific gamma imaging (BSGI).
MBI is performed through a matched, solid-state cadmium zinc telluride (CZT) detector in a dual-head configuration in which each CZT detectors are used as individual pixel elements. By contrast, BSGI uses a single detector head with pixelated sodium iodide scintillator technology and an array of position-sensitive photomultiplier tubes. Hurska et al. developed a semiconductor-based gamma camera system to detect malignant breast lesions <2 cm and labeled this technique MBI.12 The sensitivity and specificity of 99mTc-MIBI imaging with this device increased compared to conventional breast scintigraphy imaging. Using this technique, malignant breast lesions <1 cm were detected with 86% sensitivity.
Brem et al.20 used a breast-specific gamma camera to evaluate 94 women considered at high risk of breast cancer despite normal mammographic findings. They reported 100% sensitivity and 85% specificity for BSGI.
FIGURE 11.2. A patient referred for BSGI imaging due to suspicious microcalcification in the left breast. In the left craniocaudal and left medial lateral images, a well-defined focus of increased 99mTc-MIBI activity is identified (red arrows). The final diagnosis made through core biopsy and lumpectomy was moderately differentiated invasive carcinoma, 1.5 cm in size. (Images courtesy of Stanley J. Goldsmith, MD, The New York Presbyterian Hospital, Weill Cornell Medical Center, NY, USA.)
A recent study compared the results of semiquantitative BSGI with an uptake ratio cutoff of 1.5 to breast ultrasonography and mammography and found that BSGI with visual and semiquantitative analyses had a significantly higher specificity than BSGI with visual analysis alone, mammography, and ultrasound (all, p < 0.01).21 Small breast lesions still pose a problem as they may have a ratio less than the designated threshold because of the volume averaging.
Sensitivity of BSGI compared to that of traditional gamma camera breast scintigraphy methods improved from 85% to 92% for lesions >1 cm and from 47% to 67% for lesions <1 cm.22 A more recent study reported 96.4% and 59.5% sensitivity and specificity, respectively, for BSGI.23
A recent retrospective study reviewing 1,480 BSGI studies demonstrated that in comparison with breast MRI, BSGI is a cost-effective and accurate imaging modality for the evaluation of tumors in patients with dense breast tissue.24 BSGI had a sensitivity of 92%, specificity of 73%, positive predictive value (PPV) of 78%, and negative predictive value (NPV) of 90%. The corresponding figures for breast MRI were 89%, 54%, 67%, and 83%. The accuracy of BSGI was higher, at 82%, versus MRI, at 72%, while the cost was almost one-fourth of the breast MRI cost ($850 versus $3381).
Rechtman et al. has recently confirmed that BCGI is not affected by dense breast tissue.25 By studying the performance of BCGI in women with dense breast (BI-RADS density 3 and BI-RADS density 4) in comparison to that in women with nondense breast. They found no significant difference in BSGI breast cancer detection and parenchymal breast density and concluded that BSGI has high sensitivity for the detection of breast cancer in women with dense and nondense breasts (sensitivity 95.8% and 95.1%, respectively). In conclusion, BSGI is an effective adjunct imaging modality in women with both dense and nondense breasts.
In terms of its influence on surgical management of patients with breast cancer, BSGI changed surgical management to mastectomy in a substantial proportion of patients believed to be eligible for breast conserving surgery following standard imaging.26 Its influence on surgical management was comparable to breast MRI.
In a retrospective review of BSGI, mammography and breast ultrasonography in 121 patients with 153 breast lesions, Kim et al.27 reported the overall sensitivity and specificity of BSGI as 92.2% and 89.3%, whereas these values were 53.6% and 94.7% and 91.5% and 53.3%, for mammography and breast ultrasonography, respectively (p < 0.0001 and p < 0.0004). In breast lesions ≤1 cm, the sensitivity and specificity of BSGI were 80.6% and 91.5%, which were different from mammography and breast ultrasonography, respectively (p < 0.0001 and p < 0.0003).
In patients with DCIS, BSGI performed slightly better than mammography; the sensitivity was 93.9% for BSGI and 90.9% for mammography whereas the combined use of mammography and scintigraphy achieved 100% sensitivity.28
In a study assessing the ability of MIBI to predict early response to neoadjuvant chemotherapy, Mitchell et al.29 found that the changes in tumor-to-background (T/B) ratio on MBI images at 3 to 5 weeks following initiation of neoadjuvant chemotherapy were accurate at predicting the presence or absence of residual disease after neoadjuvant chemotherapy completion. Diagnostic performance of BSGI in the assessment of residual tumor after neoadjuvant chemotherapy has also been studied in 122 breast cancer patients.30 Excluding luminal and/or HER2 subtypes, the diagnostic performance of BSGI was comparable to MRI but more accurate than MRI in the assessment of residual tumor extent. Both modalities underestimated the tumor size in luminal and/or HER2 subtypes, most probably because of the low cellularity in these entities.
Rhodes investigated the performance of BSGI, mammography, and the combination of the two modalities in 936 asymptomatic women with heterogeneously or extremely dense breasts on prior mammogram, as well as additional risk factors including BRCA mutations and personal history of breast cancer.31 Overall sensitivity was 82% for BSGI, 27% for mammography, and 91% for both combined. The specificity was surprisingly high: 93% for BSGI, 91% for mammography, and 85% for both. The number of breast cancers diagnosed per the number of biopsies performed was 28% for BSGI and 18% for mammography.
These results suggest that radionuclide breast imaging has a clinical role as a second-line diagnostic tool to be used after mammography in the evaluation of patients in whom the sensitivity of mammography is low because of the density of the breast parenchyma. Detection of small-sized tumors is still a serious problem associated with all breast scintigraphy techniques as tumor detection is not dependent on tumor type, but rather on tumor size. Sensitivity is the lowest for tumors less than 5 mm in diameter.
BSGI and MBI have been suggested for a variety of clinical applications in practice guidelines.32–34 Despite the fact that 99mTc-MIBI was suggested for breast imaging as early as 1992,9 none of these breast imaging techniques have yet gained clinical acceptance as a routine procedure because of the low sensitivity, especially in small lesions, and high radiation burden associated with these techniques. Developing a breast dedicated SPECT and SPECT/CT and using new 99mTc-labeled molecular probes may increase the sensitivity and specificity of this technique overcoming current efficacy problems. Decreasing the amount of injected radioactivity is essential to decrease the radiation burden to the breast and the entire body.
A major disadvantage of radionuclide breast imaging is that all body organs are irradiated because of circulating radionuclide while fibroglandular breast tissue is the only radiosensitive tissue exposed to ionizing radiation in mammography.35 Although the use of BSGI or MBI has been proposed for women at high risk of breast cancer, there is controversy and speculation over whether some women, such as those with BRCA mutations, have higher radiosensitivity.36,37 The risk associated with ionizing radiation from imaging studies is greater for women at high risk of breast cancer, whether or not they are more radiosensitive, because they generally start screening at a younger age and therefore have a longer postradiation experience.
18F-Fluorodeoxyglucose Positron Emission Tomography (18F-FDG PET/CT) Imaging
18F-FDG is taken up by primary and metastatic breast tumor cells in proportion to the rate of glucose metabolism. Positron emission tomography detecting 18F-FDG uptake has been investigated for the detection of primary breast tumors at the initial diagnosis, but it has been studied more widely to detect recurrent and metastatic breast cancer as well as to assess the response to antitumor therapy (Fig. 11.3).38,39
At initial diagnosis, the histology and the size of the tumor play the most important role in 18F-FDG uptake. Cumulative experience showed that the diagnostic performance of 18F-FDG PET imaging in primary tumors less than 1 cm is not as good as that in larger tumors as a consequence of volume averaging. 18F-FDG PET has poor sensitivity in noninvasive breast tumors but invasive breast cancers including infiltrating ductal and infiltrating lobular carcinomas show high 18F-FDG uptake. Infiltrating ductal carcinoma has even more avid uptake of 18F-FDG and hence higher sensitivity than infiltrating lobular carcinoma, possibly because of multiple biologic variants including glucose transport-1 expression, hexokinase I activity, tumor microvessel density, amount of necrosis, number of lymphocytes, tumor cell density, and mitotic activity index.40
A study comparing prone 18F-FDG PET and MR breast scans in 31 patients who underwent MR and 18F-FDG PET scanning showed that the PPV increased from 77% in MR alone to 98% when fused with 18F-FDG PET, and the specificity rose from 53% to 97% (p < 0.05). The false-negative rate on 18F-FDG PET alone was 26.7%, and after fusion with breast MR, this figure was reduced to 9%.41
FIGURE 11.3. Metabolic flare demonstrated in a 28-year-old female with metastatic breast carcinoma. Findings at presentation were axillary lymphadenopathy and a 1.1-cm solid lesion in the left breast. Diagnosis of invasive ductal breast carcinoma was made with true-cut biopsy. There were only a few foci of bone marrow invasion in the lumbar vertebrae (blue arrows) and multiple hypermetabolic lymph nodes (thick red arrow) as well as the primary tumor in the left breast (thin red arrow) seen on the first 18F-FDG PET/CT MIP whole-body image (A). The patient was treated with chemotherapy and then referred for a repeat 18F-FDG PET/CT to assess the response to treatment (B). Despite the decrease in the metabolic activity of the axillary lymph nodes (SUVmax 15.9 versus 7.9) additional lesions in the skeleton (blue arrows) and a hypermetabolic lymph node in the mediastinal area (green arrow) appeared on 18F-FDG PET/CT performed after six cycles of chemotherapy (B). Initial interpretation was “disease progression.” The oncologist in charge of the patient disagreed with the diagnosis as the lump in the axilla decreased in size on palpation and blood CA 15–3 levels dropped significantly (from 307 ng/dL to 101 ng/dL). The final decision was that the metastatic lesions not seen on the initial 18F FDG PET/CT scan became visible on the second 18F PET/CT scan as the uptake in the axillary lymph nodes decreased in response to chemotherapy (metabolic flare?).
Despite the high sensitivity and specificity in these breast tumors, because of its insufficient spatial resolution resulting in failure to detect early-stage breast cancers, 18F-FDG PET/CT has not gained universal acceptance and is not approved to determine extent of disease at the time of initial diagnosis of primary breast cancer. It has a potential clinical role in the diagnostic work-up of selected cases including patients with dense breasts and breast implants. The motivation to exploit this avid F18 F-FDG uptake and to overcome the difficulties associated with general purpose PET/CT scanners has led to more focused efforts using dedicated small FOV PET imaging systems with higher resolution that are designed solely for breast imaging.
18F-FDG Positron Emission Mammography
Thompson et al.42 first proposed a prototype PEM device in 1994, and the first clinical 18F-FDG PEM study appeared as early as 1996.43 Doshi et al.44 created a breast imaging system consisting of two 15- × 15-cm2 arrays of 3- × 3- × 20-mm3 cerium-doped, lutetium oxyorthosilicate detector elements coupled with arrays of position-sensitive photomultiplier tubes. After several versions of small FOV systems, positron emission mammography (PEM) with a full breast size scanner that utilizes two sets of linearly scanning planar detectors has become commercially available. A typical PEM system consists of at least one pair of planar scintillation detectors in coincidence. The breast is placed between these detectors to permit either limited angle or full three-dimensional (3D) tomographic reconstruction if data are acquired from multiple angles.
Initial clinical trials using PEM reported sensitivity in the range of 80% to 86% in depicting primary breast cancer in patients with palpable or nonpalpable but highly suspicious mammographic lesions.45–49 With the recent developments in technology, new versions of PEM have revealed considerably higher detection rates (96%).50–52
The efficiency of PEM scanner is about 10 times higher than regular PET systems, especially in small tumors.51,52 Considering that intraductal cancer represents more than 30% of reported cancers and is the breast cancer with the highest probability of achieving surgical cure, it is likely that the use of PEM would complement anatomic imaging modalities in the areas of surgical planning, monitoring high risk patients and choosing patients for minimally invasive therapy. Clinical trials with a full breast PEM device showed high clinical accuracy in characterizing lesions identified as suspicious on the basis of conventional imaging or physical examination (sensitivity 93%, specificity 83%), with high sensitivity preserved (91%) for intraductal cancers.47 A subsequent study in patients with biopsy-confirmed breast cancer with a median size of 22 mm reported 89% sensitivity of PEM in the detection of malignancy.48 In this study, the PEM scan also revealed an additional, mammographically occult, DCIS lesion measuring 2 to 3 mm in width.48
In a multicenter trial, PEM imaging demonstrated 90% sensitivity and 86% specificity in detecting breast malignancy in 94 patients who were either undergoing a breast biopsy or were recently diagnosed with breast cancer.49PEM results were correlated with histopathology for 92 lesions in 77 women with 48 malignant lesions, of which 42 are index lesions, 3 ipsilateral lesions, and 3 contralateral malignant lesions. Of these 48 cancers, 16 (33%) were clinically evident; 11 (23%) were DCIS, and 37 (77%) were invasive (30 ductal, 4 lobular, and 3 mixed; median size 21 mm). PEM depicted 10 of 11 (91%) DCIS and 33 of 37 (89%) invasive cancers. Overall, the sensitivity of PEM was for detecting cancer was 90%, specificity 86%, PPV 88%, NPV 88%, accuracy 88%, and area under the receiver-operating characteristic curve 0.918. In three patients, cancer foci were identified only on PEM, significantly changing patient management.49 Excluding eight diabetic subjects and eight subjects whose lesions were characterized as clearly benign with conventional imaging, PEM sensitivity was 91%, specificity 93%, PPV 95%, NPV 88%, accuracy 92%, and area under the receiver-operating characteristic curve 0.949 when interpreted with mammographic and clinical findings. It was concluded that 18F-FDG PEM had high diagnostic accuracy for breast lesions, including DCIS.49
The sensitivity of PEM was investigated in relation to pathologically confirmed tumor size.51 A total of 113 breast lesions from 101 patients were included in the analysis. The patients underwent 18F-FDG PEM and whole-body PET/computed tomography (CT) before surgical resection, and images were analyzed visually and quantitatively using the tumor-to-normal-tissue uptake ratio (TNR). Tumors were classified into four groups based on size using pathologic results. The sensitivity of PEM and PET/CT were compared in the overall subjects and in each group. By visual analysis, PEM showed significantly higher sensitivity than PET/CT (95% versus 87%; p = 0.004), which was more remarkable in the groups with small tumor. By quantitative analysis, the TNR of PEM was significantly higher than that of PET/CT in the small tumor groups whereas no difference was found in the overall group. With a cutoff TNR of 2.5, PEM showed significantly higher sensitivity than PET/CT in the overall and small-tumor groups. In conclusion, PEM had higher sensitivity for tumor detection than PET/CT, particularly in small tumors. Based on these findings, the authors of this study suggested that PEM can be used for diagnosis and characterization of small lesions as a supplementary imaging modality for PET/CT.51
Schilling et al.52 compared in 208 women the performance characteristics of PEM with breast MRI as a presurgical imaging and planning option for index and ipsilateral lesions in patients with newly diagnosed, biopsy-proven breast cancer. Of these patients, 26.4%, 7.1%, and 64.2% were pre-, peri-, and postmenopausal, respectively; and 48.4% had extremely or heterogeneously dense breast tissue, whereas 33.5% had a history of hormone replacement therapy (HRT). Each patient underwent MRI, PEM, and whole-body positron emission tomography (WBPET) within 10 days. A direct comparison between PEM, PET, and MRI showed that the sensitivity of PEM was 93% for known index lesions and 85% for unsuspected additional lesions.52 The sensitivity values for PEM were significantly higher than those of PET and comparable to those of MRI, whereas PEM also had higher specificity than MRI for the detection of unsuspected lesions (74% versus 48%). Furthermore, in this study, PEM successfully depicted invasive tumors measuring as small as 3 mm, and exhibited 100% and 85.7% sensitivity for T1a (>1 mm but ≤5 mm) and T1b (>5 mm but ≤10 mm) IDC lesions, respectively.52 In addition, the authors reported that breast density, hormone replacement therapy, and menopausal status did not interfere with lesion detection with PEM. These factors are known to affect the glandular tissue of the breast and make interpretation of classic imaging modalities (mammography and MRI) challenging as far as cancer detection is concerned. Thus, with its ability to overcome certain limitations of MRI, PEM using 18F-FDG has been proposed as an appropriate alternative to MRI in the presurgical management of breast cancer patients.52
A recent study comparing detection rates of additional ipsilateral lesions using either PEM or MRI reported comparable sensitivity for each moduality, but, higher specificity for PEM.53 Furthermore, increased cancer detection was reported when PEM and MRI were combined compared to MRI alone. These findings indicate an additional potential role for PEM in presurgical planning, as it can provide an accurate estimation of tumor size and focality. As a result, the extent of the disease can be more precisely defined, and unnecessary additional biopsies in women with newly diagnosed breast cancer could be avoided. Contrary to these initial encouraging results, in a recent study, however, PEM has been found to be less sensitive than MRI in identifying contralateral malignancies in women with newly diagnosed breast cancer.54
Despite its obvious advantages, a few limitations apply for PEM scans. First, the specificity of a PEM scan can be attenuated because of high 18F-FDG uptake in other medical or physiologic phenomena.55 Benign breast lesions, such as fibroadenomas in the rapid growth phase and acute or chronic inflammatory processes (e.g., fat necrosis) are known to result in increased focal 18F-FDG uptake56; however, these conditions can often be differentiated from malignancy by conventional imaging.
During a PEM scan, proper positioning of the breast is essential because noninclusion of the malignancy in the FOV can result in false-negative results. Interpretation of PEM scans can also be challenging, especially in lesions that are in close proximity to the chest wall, as well as in larger breasts.
Increased breast density has also been reported to result in significantly higher 18F-FDG uptake57; however, no confirmatory study has addressed this issue with PEM.52 Finally, a few cases of lobular carcinomas (known to be a source of false-negative results on both PET and MRI because of their decreased vascularity and metabolic activity) are not visualized with PEM.49 Thus, a negative PEM scan should not exclude the use of further investigation for the lesions that appear suspicious either clinically or on conventional imaging.
Integration of Computed Tomography with Positron Emission Mammography. Raylman et al. proposed a model integrating the PEM–tomography imager and biopsy system (called PEM–PET) that utilizes large area (15 × 20 cm2) rotating detectors to produce tomographic images of radiotracer concentration by the lesion in the breast. They reported that reconstructed transaxial and axial spatial resolutions of that scanner are less than 2 mm and the PEM–PET scanner also enables image-guided biopsy of suspicious lesions in the breast.55,58 Their proof of concept study in five patients showed that the PEM/PET system which has a resolution of about 2 mm in all three dimensions is capable of producing good quality breast-PET images compared standard methods and identifying some lesions not visible in standard mammograms.58
The diagnostic efficacy of another integrated 18F-FDG PET/CT mammography (mammo-PET/CT) was compared in a 2013 study with conventional torso PET/CT (supine-PET/CT) and MR-mammography for the initial assessment of breast cancer in 40 patients.59 Each patient underwent supine-PET/CT, mammo-PET/CT, and MR-mammography. The size of the tumor, the distance between the tumor and the chest wall, and the tumor and the skin, volume of axillary fossa, and number of metastatic axillary lymph nodes between supine-PET/CT and mammo-PET/CT were noted. The difference of focality of primary breast tumor and tumor size in mammo-PET/CT and MR-mammography was also compared. Their results revelead that significant differences were found in the tumour size (supine-PET/CT: 1.3 ± 0.6 cm, mammo-PET/CT: 1.5 ± 0.6 cm, p < 0.001), tumor to thoracic wall distance (supine-PET/CT: 2.2 ± 0.9 cm, mammo-PET/CT: 2.2 ± 2.1 cm, p < 0.001), and tumor to skin distance (supine-PET/CT: 2.1 ± 0.8 cm, mammo-PET/CT: 2.1 ± 1.4 cm, p < 0.001).66 The volume of axillary fossa was significantly wider in mammo-PET/CT than supine-PET/CT (21.7 ± 8.7 cm versus 23.4 ± 10.4 cm, p = 0.03), and mammo-PET/CT provided more correct definition of the T-stage of the primary tumor than did supine-PET/CT (72.5% versus 67.5%) while there was no significant difference in the number of metastatic axillary lymph nodes detected by both modalities. Compared with MR-mammography, mammo-PET/CT provided more correct classification of the focality of lesion than did MR-mammography (95% versus 90%). In the T-stage, 72.5% of patients with mammo-PET/CT and 70% of patients with MR-mammography showed correspondence with histologic results.59 They concluded that mammo-PET/CT provided more correct definition of the T-stage and evaluation of axillary fossa might also be delineated more clearly than with supine PET/CT, and the mammo-PET/CT indicates similar accuracy with MR-mammography for the determination of T-stage of primary breast tumor and more correct than MR-mammography for defining focality of lesion.
Using more specific tumor-seeking radiopharmaceuticals and advances in imaging technology including integrating breast dedicated positron emission tomography with MR may help this technique to gain acceptance in breast cancer imaging in future.
RADIONUCLIDE IMAGING FOR THE EVALUATION OF AXILLARY INVOLVEMENT
Locoregional staging includes axillary and internal mammary lymph node evaluation. Axillary lymph node status is a major prognostic factor for determining the survival in patients with newly diagnosed breast cancer. Internal mammary lymph nodes are not commonly included in routine staging. Axillary involvement is found in 10% to 30% of patients with T1 (<2 cm) tumors, in 45% for T2 tumors (2.1 to 3 cm) and 55% to 70% for larger tumors (> 3 cm).60
Axillary involvement is revealed by physical examination in less than 50% of patients and usually not identified by mammography. CT and MRI have a limited role in detecting metastatic lymph nodes harboring breast cancer as the specificity of morphologic imaging is relatively low. In addition to its ability to detect the primary tumor, breast scintigraphy using 99mTc MIBI performed in supine position using general purpose gamma cameras, especially with the addition of SPECT and SPECT/CT, is potentially useful in the detection of metastasis in the axillary lymph nodes (Fig. 11.1). The sensitivity of breast scintigraphy using general purpose gamma cameras is low in the detection of metastatic axillary lymph nodes, and 20% of the patients with metastatic involvement would be missed.61 Breast dedicated imaging devices have currently no role in the evaluation of the axilla.
In studies reported up to 1998, the sensitivity of breast scintigraphy to detect axillary lymph node metastases is 77% and the specificity 89%.61,62 A recent meta-analysis reviewed 45 studies and reported an average sensitivity of 83% and specificity of 85%.63 Scintigraphy is still not accurate enough to replace axillary lymph node biopsy or surgical nodal dissection.
Comparative studies showed that SPECT significantly improves the sensitivity and accuracy of breast scintigraphy to detect axillary lymph node involvement compared to planar imaging, especially when lymph nodes are nonpalpable and small in size.64,65 In selected cases, SPECT in combination with radio-guided sentinel lymph node (SLN) biopsy could provide additional information.64 The NPV of breast scintigraphy increases with SPECT imaging; however, false-negative results might be seen because of the small size of lymph nodes and/or to partial or micrometastatic involvement.64 The performance of SPECT imaging can be improved by using a pinhole collimator (pinhole SPECT).65 This procedure reveals more lymph nodes in the axillary region and thus provides important prognostic information even in series with nonpalpable lymph node metastases.64 Furthermore, although SPECT was highly accurate and had a good NPV, only pinhole SPECT provided information on the number of involved nodes and the correct patient classification for prognostic purposes.65
Radionuclide Localization of Occult Lesions
Fifteen percent to 20% of occult breast lesions are malignant and frequently are detected in asymptomatic women with mammographic screening programs.66 The occult lesion should be marked before breast-conserving surgery which is currently the surgical technique of choice. In some centers, those lesions are removed by placing a marker (Kopans wire) with the aid of ultrasonography; however, the wire may be misleading as it can be displaced during surgery. Furthermore, migration or rupture of the wire may lead to pneumothorax although this risk is small when the procedure was performed by an experienced team.67 The procedure is associated with significant discomfort to the patients and may even cause injuries to the surgical team and pathologists.66
The widespread use of radio- and ultrasound-guided biopsies for nonpalpable breast lesions has resulted in the increased demand for accurate preoperative localization of lesions and axillary lymph node assessment.67,68Radionuclide occult lesion localization (ROLL) is still considered a significant innovation.68–70 Thus, in the last decade, radionuclide-guided excision of breast tumors has gained acceptance throughout the world.69,70 It is a practical technique for the localization and resection of nonpalpable breast lesions, but requires experienced nuclear medicine staff. ROLL is performed after injecting a small activity of 99mTc-labeled macroaggregated albumin (MAA) (∼10 MBq) into the breast tissue adjacent to the lesion under the guidance of ultrasonography or stereotactic mammography. Using a hand-held gamma probe, the surgeon can remove the suspected “hot” lesion with a reduced excision volume, better cosmetic results and a higher percentage of tumor-free margins.71,72
Radio-guided sentinel lymph node (SLN) biopsy and radio-guided occult lesion localization can be performed in combination (SNOLL) for either infiltrating cancers or high-grade intraductal atypia.73,74 The combined procedures gained further acceptance because of their higher diagnostic accuracy in addition to excelling in assessment of surgical margins compared to the hook-wire technique. The SNOLL procedure allows real-time verification of resecting the tumor lesion and the SLNs. The absence of radioactivity in the surgical bed after excision confirms the excision of the tumor. The success of the resection can be further confirmed by demonstrating the high count rate in the resected material. With stereotactic ROLL, duration of surgery is shortened by executing SLNB first, then resecting the primary lesion.75
Sentinel Lymph Node Biopsy. SLN biopsy is a minimally invasive procedure performed for the investigation of potential nodal involvement.76 Its principle is based on the assumption that metastatic invasion starts from the tumor site in an orderly progression. According to this principle, the nodal basin is free of malignancy if the SLN is not involved. Patients with SLN metastasis undergo lymph node dissection. Compared to diagnostic axillary lymph node dissection, complications are reduced with the SLN biopsy.77 The current standard of axillary lymph node staging in early-stage breast cancer is SLN biopsy. In the Axillary Lymphatic Mapping Against Nodal Axillary Clearance (ALMANAC) trial, more than 1,000 patients were randomized to undergo either axillary lymphadenectomy or sentinel node biopsy.78 Lymphedema was present in 13% of the axillary lymphadenectomy group and in 5% of the sentinel node group 12 months after surgery.
Many centers use sentinel node biopsy only in patients with a unifocal tumor smaller than 3 cm, whereas others have extended the application to patients with large T2 or T3 (>5 cm) tumors, multifocal/multicentric carcinomas or to patients who have received neoadjuvant chemotherapy.79 Currently, the sentinel node biopsy procedure is recognized as the standard procedure for stages I and II.80,81 In these stages, this approach has a positive node rate similar to those observed after lymphadenectomy. There is no significant difference in the success rate of sentinel node biopsy according to clinical tumor size or clinical nodal status.
Sentinel Lymph Node Mapping
A radiotracer, blue dye, or combination of both is used for sentinel node imaging to identify the lymph node. Radiopharmaceuticals used for SLN imaging are colloids labeled with 99mTc (Table 11.2). These radiocolloids allow sentinel node visualization with a gamma camera before surgery as well as intraoperative detection with a hand-held gamma probe. Controversies exist with regard to the selection of agents, the size of the particles of the radiocolloids, the optimal route for injection, time to scintigraphy and intraoperative detection, and whether or not extra-axillary lymph nodes should also be considered.82
Dyes. Blue dyes will color lymph nodes blue as they pass slowly through the lymphatics. Isosulfan blue is most frequently used in the United States whereas Patent blue V is used frequently in Europe. Data from three major studies (ALMANAC trial; the National Surgical Adjuvant Breast and Bowel Project [NSABP] B-32 trial; the American College of Surgeons Oncology Group [ACOSOG] Z0010 trial) showed that the overall risk of allergic reaction is close to 1% for both dyes, with an approximately 0.1% risk of severe reactions.78,80,81,83 Despite a risk of allergic reactions to blue dye, most teams favor the combination of radiocolloid and Blue dye for mapping procedure.
COLLOIDS USED FOR SENTINEL LYMPH NODE IMAGING AND DETECTION IN BREAST CANCER
Colloids. The choice of tracer is often guided by local availability (Table 11.2). 99mTc-labeled colloids of human serum albumin are often used in Europe whereas 99mTc-sulfur colloid is used in the United States and 99mTc-antimony trisulfide in Australia.
Size of Colloid. Several studies have been conducted investigating the effect of colloid size. Smaller particles are believed to be better taken up by lymphatic channels and accumulate better in SLNs while reducing the amount of radioactivity at the injection site. This reduction of the radioactivity at the injection site makes the SLN identification easier because it decreases the “shine through” effect. On the other hand, proponents of larger particles believe that smaller particles may migrate so rapidly and diffusely into the secondary regional lymph nodes that identification of SLNs becomes difficult. Mariani et al.84 suggest that 99mTc-labeled colloids with most of the particles in the 100- to 200-nm size range are best for sentinel node biopsy in breast cancer. Linehan et al.85 retrospectively compared unfiltered sulfur colloid with filtered sulfur colloid and demonstrated that unfiltered sulfur colloid was superior to filtered colloids in SLN localization.
By contrast, Lloyd et al.86 evaluated the SLN identification rate with filtered versus unfiltered radionuclide and found no difference between filtered and unfiltered colloids. De Cicco et al.87 studied 382 breast cancer patients with three different size ranges of radiolabeled colloids and concluded that SLN identification was most accurate with large-sized (2- to 1-μm) radiolabeled colloids. Small-sized (200- to 400-nm) particles were however found to be superior to regular-sized (400- to 1,000-nm) particles in the intraoperative identification.88 The mean radioactive counts of the hottest nodes of the small-sized tin radiocolloid were significantly higher than those of the regular-sized tin radiocolloid.88 This increased uptake of radiocolloid made intraoperative SLN identification with a hand-held gamma probe accurate and easy to perform.
Injection Methods. The optimal injection approach has been the subject of active debate in recent years (Table 11.3). Peritumoral injection was the first injection method proposed for lymphatic mapping in breast cancer and has proved to be very effective for this purpose.89 Different injection techniques have been advocated. These injection techniques can be classified into two categories: deep injection and superficial injection. Deep injection techniques, also referred as subcutaneous injection or parenchymal injection include peritumoral (PT), subtumoral (ST) and intratumoral (IT) injection techniques. Superficial injection techniques, also referred as epidermal (ED) or dermal injection include intradermal (ID), subdermal (SD), periareolar (PA) and subareolar (SA) injection techniques.90
Generally, satisfactory results of SLN detection have been reported for all of the different injection sites. In most cases, the SLNs detected by deep or superficial injections are the same.91–93 Multiple studies support the notion that the location of the injection does not significantly affect the identification of SLN. It appears that there is preferred drainage to the same few axillary SLNs for most of the breast tissues and its overlying skin. Thus, accurate identification of these nodes is not affected by the injection location.92,94,95 However, others argue that the superficial method including intradermal or PA/SA injections has the highest detection rate for SLN.
INJECTION TECHNIQUES FOR SENTINEL LYMPH NODE IMAGING AND DETECTION
Many studies have shown equivalent rates for detection of SLN, whereas a few have shown that PA and SA injections are slightly better than PT injection, with one study96 showing a relatively large difference between superficial and deep injections. Blue dye injection was used more often with PT injection, probably because a larger injection volume is feasible with deep injection. As stated above, blue dye injection has a slightly lower rate for detection of SLN which may partially explain why PT injection has lower detection rate than SA/PA injection. Noguchi et al.91 recently reanalyzed multiple studies and found that the use of radiotracers results in a higher SLN identification rate than the use of blue dyes, regardless of the injection method (PT or SA/PA).
So far, only two randomized prospective clinical trials have been published,97,98 and the results are inconclusive. Povoski et al. compared the outcomes following injection by different routes (including intradermal, intraparenchymal, and SA) of 99mTc sulfur colloid in 400 patients with breast cancer. The intradermal injection route demonstrated a significantly better SLN identification rate and less time to first localization on preoperative lymphoscintigraphy. The intraoperative identification of SLN for intradermal, intraparenchymal, and SA injections were 100%, 90%, and 95%, respectively, with decreased time to harvest the first SLN during surgery, and with greater radiotracer uptake in the SLN.113 However, these findings were not confirmed by other prospective randomized multicenter study, which revealed a similar intraoperative SLN detection rate for PA injection as compared with PT injection (99.11% in both cases).98
Other factors should be considered when deciding on the injection technique. One major advantage of superficial injection is that it is easy to perform and results in less interference with scintigraphic imaging. In addition, there is no need for ultrasound guidance for the injection, even with nonpalpable breast cancer. Intradermal or subdermal injection is more painful. The addition of pH-balanced 1% lidocaine to the radiocolloid solution has been reported to improve patient comfort without compromising SLN identification.99 Deep injection may be difficult to perform if the tumor is nonpalpable, and ultrasound guidance may be needed. Important advantages of deep injection are the improved detection of extra-axillary nodes (as discussed below) and the possibility of a larger injection volume. For tumors in the upper outer quadrant, radiotracer injection may cause shine-through activity which interferes with detection of SLN on preoperative scintigraphy.
Although both deep and superficial injection approaches are valid techniques and are complementary, the combination of both injection techniques (either PT and SA/PA injections107 or SD/PT injection100) may improve detection accuracy and decrease the false-negative rate. It is recommended that at least some of the radiocolloid or dye be injected via the PT route to avoid missing those SLNs not located in the ipsilateral axilla.90 In addition, there is good agreement that injection of a combination of radiotracer and blue dye using both superficial and deep injections enhances detection of SLN.90,91 This is also supported by a recent study on the breast lymphatic anatomy, which showed that in some cases there exists alternative lymphatic drainage in the breast, although the majority of the superficial lymph vessels of the breast drain to only one sentinel node.101
Since PT injection with radiotracer provides additional information about the internal mammary nodes (IMNs), the best combination is likely PA/SA injection with blue dye plus PT injection with radiotracer. It should be noted that if IMN or other extra-axillary nodes need to be detected, or if the patient has had prior breast surgery or biopsy, deep injection with radiotracer and preoperative scintigraphic imaging should be performed.
Preoperative Scintigraphic Imaging and Intraoperative Gamma Probe Detection
The combination of preoperative scintigraphic mapping with intraoperative probe detection is a widely used protocol for identifying SLN in patients with breast cancer. In most cases, after injection of 99mTc colloid, scintigraphic images of the neck and chest are acquired to evaluate the distribution of radiotracer in the patient. The skin overlying each detected radioactive focus is marked to indicate the location of the possible SLN. The images and marks on the skin provide the surgeon with a map of the distribution of the radiotracer. Preoperative scintigraphic imaging results in more efficient intraoperative searches for all SLNs and more SLNs removed.102 It is especially helpful if a node of interest is located close to an injection site or if the uptake in a node of interest is only slightly greater than that of neighboring tissue. In addition, if extra-axillary SLNs need to be explored (e.g., to evaluate the status of IMN, or in patients with prior breast surgery), then preoperative scintigraphic imaging is crucial.
The timing of preoperative scintigraphy is determined by the particle size of the radiotracer. For commonly used radiocolloids, the movement of radiotracer within lymphatic channels is rapid, with SLNs frequently seen at 15 minutes, and the vast majority of SLNs identified by 90 minutes. The location and number of nodes detected scintigraphically in patients with breast cancer are not affected by imaging time after injection of 99mTc nanocolloid or sulfur colloid, that is, whether the imaging was performed early (15 minutes to 4 hours after radionuclide injection) or delayed (18 to 24 hours after radionuclide injection).103–105 For intraoperative gamma probe detection, surgery can be done up to 16 to 18 hours after injection with radiocolloids of 200 to 1,000 nm.106 For smaller-sized radiocolloids, reinjection of radiotracer may be needed just before surgery.107
Intraoperative gamma probes detect more SLNs than preoperative scintigraphy.108,109 Even in lymphoscintigraphy-negative patients, SLNs can often be detected intraoperatively by gamma probing.108,109 It has been suggested that the addition of intraoperative imaging may enhance the potential of node detection, but this is still under investigation, and needs to be confirmed in larger series of patients.
SPECT/CT. There are limited data on the use of hybrid SPECT/CT in lymphatic mapping in patients with breast cancer. It has been shown that SPECT/CT can detect additional nodes not visualized on planar images and is especially useful in visualization of SLNs outside the axilla or nodes close to the injection site.110 However, the current approach with combined injection of markers, preoperative planar scintigraphic imaging, and intraoperative probing has proven very successful with SLN detection rates over 95%, so the need for SPECT/CT imaging will be limited.
Nucleic Acid Amplification: Some molecular methods have been used previously for sentinel node diagnosis but have shown lack of reproducibility, longer time for the intraoperative assessment, and inability to study the whole lymph node. A new molecular method has been developed recently, based on a one-step nucleic acid amplification (OSNA) method. This procedure is in the phase of validation in some centers, while some others routinely apply this method.102
In one multicenter study, the false-negative rate of scintigraphic SLN detection was 17.7% if only one node was resected, 10% if 2, 6.9% if 3, 5.5% if 4, and 1% if 5 or more.99 These results should not imply removal of multiple nodes, but all identified hot or blue nodes should be resected. Careful palpation by the surgeon of the operative field is also required to identify any suggestive large, hard, nonblue, and nonradioactive nodes.99
The American Society of Clinical Oncology Guideline emphasized that a multidisciplinary team should aim at a sentinel node identification rate of 85% with a false-negative rate of 5% or less to abandon axillary dissection.111False-negative cases may result from massive involvement of the real sentinel node, a circumstance that interferes with the uptake of both radiocolloid and dye and lymph flow that goes to a node other than the true sentinel node.111,112
Interpreting Images. Major criteria to identify lymph nodes as sentinel nodes are the visualization of lymphatic ducts, the time of appearance, the lymph node basin, and the intensity of lymph node uptake. Following these criteria visualized radioactive lymph nodes may be classified as follows111: (i) Definitively sentinel nodes: This category involves all lymph nodes draining from the site of the primary tumor through an own lymphatic vessel, or a single radioactive lymph node in a lymph node basin. (ii) Highly probable sentinel nodes: This category includes lymph nodes appearing between the injection site and a first draining node, or nodes with increasing uptake appearing in other lymph node stations. (iii) Less probable sentinel nodes: All higher echelon nodes may be included in this category.
The use of these categories to characterize radioactive lymph nodes is also helpful for clinical decision making.111–113 Lymph nodes of the first two categories (definitively sentinel node or highly probable sentinel node) are the nodes recognized by the nuclear physician and that must be removed at the operation room by the surgeon. Less probable sentinel nodes may sometimes be removed depending on the degree of remaining radioactivity measured by the gamma probe during the control of the surgical field.111–113
18F-FDG PET/CT in the Evaluation of Axillary, Internal Mammary, and Mediastinal Lymph Node Metastases
The degree of apparent 18F-FDG uptake in breast cancer varies with size of the tumor focus, at least in part because of volume averaging. This can result in low sensitivity of 18F-FDG PET imaging particularly in the detection of small breast carcinomas, locoregional micrometastases, and nonenlarged tumor-infiltrated lymph nodes. Axillary or mediastinal lymph node metastases are one of the most important prognostic factors for survival in patients with breast cancer. There was no efficient and reliable noninvasive imaging modality to assess axillary lymph node metastasis until the introduction of 18F-FDG PET imaging into clinical practice of breast cancer.114 Surgical dissection had, therefore, been the sole modality to confirm or exclude the presence of metastatic involvement of the axilla. The utility of 18F-FDG PET imaging as a noninvasive method was therefore investigated in the evaluation of axillary involvement as early as 1991.39 Initial studies using PET systems revealed low sensitivity, especially in metastatic tumor deposits less than 1 cm.39,114,115 Introduction of PET systems integrated with an anatomical imaging system (CT or MRI) have significantly improved the diagnostic performance of PET for the assessment of axillary lymph nodes. Compared to conventional imaging modalities, functional imaging with 18F-FDG PET/CT is more sensitive to detect axillary lymph node metastases resulting in significant changes in patient management (Fig. 11.3).116–118 Recent studies, however, noted that the sensitivity of 18F-FDG PET/CT in the assessment of axillary nodes is lower than initially reported, likely because of the increased detection rate of micrometastases in the axilla in up to 45% of the patients studied using the newest immunohistochemical staining methods.119–121 In recent studies, the sensitivity of 18F-FDG PET/CT has been reported to be between 20% and 43% for axillary lymph node staging in primary breast cancer.122–124
Furthermore, false-positive results with 18F-FDG PET are seen because physiologic 18F-FDG uptake is observed in inflammatory sites which make distinguishing metastatic lymph nodes from reactive lymph nodes difficult.125Dual time-point imaging may be of clinical value for lesion detectability and differentiating inflammatory lesions from malignant lesions.126–128 In a study by Choi et al.,129 the sensitivity and specificity of dual time-point 18F-FDG PET to detect ALN metastasis were reported to be 60.3% and 84.7%, respectively. Numerous past reports showed that the sensitivity of 18F-FDG PET/CT for ALN metastasis detection was lower in T1 breast carcinomas compared to T2 or T3 tumors.130–132 Despite these advances and superiority to morphologic imaging modalities, currently, 18F-FDG PET is not sensitive enough to detect small metastasis in axillary lymph node. Further refinements in technology and radiopharmaceuticals to increase specificity and sensitivity are necessary in order for 18F-FDG PET/CT imaging to be accepted as a reliable clinical tool for axillary lymph node staging in breast cancer patients.
RADIONUCLIDE IMAGING FOR DISTANT METASTASIS
18F-FDG PET/CT in the Diagnostic Work-Up of Distant Metastases
18F-FDG PET/CT with its whole-body imaging feature is superior to conventional imaging modalities to localize distant metastatic tumor.133 Whole-body 18F-FDG PET/CT imaging detects not only the primary breast tumor and axillary lymph node metastases, but also skeletal and visceral metastases (Figs. 11.3 and 11.4).134–136 By contrast, distant breast cancer metastases are generally characterized by significantly increased metabolic activity compared to normal breast tissue. 18F-FDG PET/CT with significant metabolic information is often more sensitive than conventional imaging for the detection of distant metastases, particularly in the recurrent setting. The reported rates of sensitivity and specificity of 18F-FDG PET for the detection of distant metastases range from 80% to 100% and 50% to 97%, respectively.136 Mahner et al.137 reported the sensitivity and specificity of 18F-FDG PET 87% and 83%, respectively, whereas the corresponding figures for combined conventional imaging modalities were 43% and 98%. 18F-FDG PET detected more metastatic lesions than other imaging modalities including CT.
Groheux et al.138 also reported that 18F-FDG PET/CT detected unexpected metastasis changing the clinical stage in 52% of patients. They also found that 18F-FDG PET/CT is particularly more accurate and efficient in the detection of distant metastasis in inflammatory locally advanced breast cancer (LABC) than noninflammatory LABC. The additional sensitivity of 18F-FDG PET/CT for regional nodes and distant disease may be particularly important in staging for LABC.
FIGURE 11.4. Multiple foci of distant metastases in the liver (green arrow) and the skeleton (some of them designated with blue arrow) in a 64-year-old woman (A:18F-FDG PET MIP image; B: Transaxial PET; C: transaxial CT; D: PET/CT fusion). On the second 18F-FDG PET/CT performed after six cycles of chemotherapy, lesions in the liver have significantly disappeared, but the tracer uptake in the skeleton has become more prominent (E:18F-FDG PET MIP image).
Some patients with LABC quickly develop distant metastases despite appropriate therapy. The detection of distant metastases in the patients with LABC is therefore crucial to determine treatment options. 18F-FDG PET imaging has been found to be superior to conventional imaging modalities including CT in the detection of internal mammary and mediastinal nodal involvement which were not visible on conventional imaging modalities.139–142 Based on these reports, it is evident that 18F-FDG PET/CT can improve staging and alter therapeutic options in patients with LABC and locoregional recurrence. In addition to confirming distant metastatic disease, 18F-FDG PET/CT reveals more metastatic sites and has an impact on management for a major change in treatment in patients with recurrent breast cancer.143
18F-FDG PET/CT and 18F-Fluoride PET/CT Imaging in Bone Metastases
PET imaging offers the opportunity for functional evaluation of bone lesions or the local skeletal response to metastasis (Fig. 11.3). In the context of skeletal relapse, although 18F-FDG PET outperforms the bone scan for detection of predominantly lytic bone disease, its use to evaluate sclerotic bone metastasis remains controversial.144–146 In recent publications, it has been reported that both lytic and sclerotic bone lesions are identified as well or better than a 99mTc-MDP bone scan using combined 18F-FDG PET/CT.146–148
18F-fluoride is a highly sensitive bone-seeking PET tracer used to detect skeletal abnormalities. It has a high and rapid uptake in the bone with rapid blood clearance, producing a high bone-to-background ratio in a short time. Uptake of 18F-fluoride is an indicator of blood flow and bone remodeling. The uptake mechanism of 18F-fluoride is similar to that of 99mTc-MDP with better pharmacokinetic characteristics including faster blood clearance and two-fold higher uptake in bone. These pharmacokinetic superiorities combined with the 3D sectioning ability of PET scanner, 18F-fluoride PET imaging is an attractive alternative to 99mTc-MDP. The tracer preferentially accumulates at skeletal metastatic sites reflecting increased local blood flow, osteoblastic activity, and bone mineralization. Thus, in contrast to other tracers, 18F-fluoride images the osseous response to a metastatic focus rather than the tumor itself. High uptake in comparison with normal bone has been demonstrated in both lytic and sclerotic breast cancer metastases suggesting that even in predominantly lytic disease 18F-fluoride is able to usefully report an accompanying osteoblastic reaction.148–150 The diagnostic role of 18F-fluoride PET for skeletal staging is supported by data from a number of primary cancers including breast cancer, and prospective comparison with the conventional bone scan has demonstrated superior diagnostic accuracy for both individual lesions and whole-patient comparisons in metastatic breast cancer.150,151
Initial results proved 18F-fluoride PET imaging to be highly accurate in demonstrating a very early bone reaction when small bone marrow metastases were present. This allows accurate detection of breast cancer bone metastases and results in significant effect on clinical management, compared with the effect on management with conventional bone scan.150 In skeletal metastases arising from a variety of primary cancers, the diagnostic specificity for both lytic and blastic bone diseases has been improved by combined functional and morphologic evaluation using 18F-fluoride PET/CT.152,153
Damle et al.154 compared the role of 18F-fluoride PET/CT, 18F-FDG PET/CT, and 99mTc-MDP bone scans in the detection of bone metastases in patients with breast (72 patients), lung, and prostate carcinomas. The sensitivity and NPV of 18F-fluoride PET/CT was 100% in all three malignancies, whereas that of 18F-FDG PET/CT was 73% and 80% in breast cancer, 79% and 73% in lung cancer, and 72 and 65% in prostate cancer. Specificity and PPV of 18F-FDG PET/CT were 100% in lung and prostate cancers and 97% and 96% in breast cancer. Compared to the 99mTc-MDP bone scan, all parameters were superior for 18F-fluoride PET/CT in prostate and breast cancer but sensitivity and NPV were equal in lung cancer. 99mTc-MDP bone scan had superior sensitivity and NPV compared to 18F-FDG PET/CT but had low specificity and PPV.
18F-fluoride PET imaging also provides an opportunity to image therapy response with high sensitivity and a rational mechanism for quantitative measurement that may provide a clinically useful method to assess changes in bone turnover as a result of therapy.155
Whole-Body Bone Scan in the Diagnostic Work-Up of Bone Metastases of Breast Cancer
Bones are the most common site of breast cancer metastases either before the initial diagnosis or at any stage during the clinical course.144,156–158 Whole-body bone scans are used as a metastatic survey tool in most patients with breast cancer (Fig. 11.5). Techentium-99m methylene diphosphonate (99mTc-MDP) is the most commonly used radiotracer for whole-body bone scanning. 99mTc-MDP bone scintigraphy images the osteoblastic response to bone destruction by tumor cells. Unlike cross-sectional imaging, radionuclide bone scans permit evaluation of the entire skeleton. Despite the high frequency of false-positive uptake in benign lesions with increased bone turnover, such as fracture or degenerative changes, bone scintigraphy has high diagnostic sensitivity (87% to 88%).159 In experienced hands, with suitable correlative imaging protocols, bone scintigraphy can also have good specificity particularly when supplemented with SPECT or SPECT/CT. However, malignant skeletal involvement in relapsed breast cancer may result in lytic, blastic, or mixed lesions and full evaluation typically requires additional morphologic tools to guide clinical management using plain radiographs, CT, and MRI, depending on lesion location and clinical context. Although this multimodality approach is effective in establishing fracture risk or confirming spinal cord compression, its ability to differentiate between active and inactive diseases in those receiving treatment remains problematic.160
FIGURE 11.5. Most bone metastases in primary breast cancers are mixed (lytic and sclerotic) type, but, in a subgroup of patients, they are only sclerotic. A: A photopenic lesion (red arrow) was clearly seen in the right lateral margin of the sternum on whole-body bone scintigraphy in a 59-year-old patient with breast cancer. This patient had undergone right radical mastectomy 4 years earlier because of invasive breast carcinoma (2.9-cm tumor). The lesion is lytic (red arrow) on CT scan (B).
Radionuclide bone scans can be affected by antineoplastic therapy. An initial increase in osteoblastic activity in responding lesions can mimic disease progression on serial bone scans. This is known as the “flare response” in which known lesions appear more active and previously undetectable lesions become visible.161 There is a time lag of up to 6 months from the start of therapy before reliable assessment of response to therapy using bone scan. This complexity of assessment has resulted in skeletal disease being generally regarded as nonmeasurable. Detailed correlation with plain films or CT may improve the ability to differentiate between responders and nonresponders.162
ASSESSMENT OF RESPONSE TO ANTINEOPLASTIC THERAPY
18F-FDG PET/CT in Monitoring the Response to Treatment
The concept of using 18F-FDG PET to predict a therapeutic response is based on early changes in tumor glucose utilization and the close correlation of changes in 18F-FDG uptake with the effectiveness of treatment.163,164 There are several potential clinical applications for the PET-based prediction of a response to treatment with primary chemotherapy. First, metabolic imaging could identify breast cancer with low tumor metabolic activity before treatment; patients with such tumors might be more suitable candidates for surgery or hormone therapy (Figs. 11.3 and 11.4). Second, patients for whom PET predicts a poor response after the first cycle of chemotherapy could be switched to alternative therapies earlier.
At least two sequential 18F-FDG PET scans are currently necessary to predict a treatment response; one is obtained before treatment to serve as a baseline, and the other is obtained after the initiation of chemotherapy; for example, after the first or second cycle. Some studies confirmed a more pronounced decrease in 18F-FDG uptake in patients showing a histopathologic response than in nonresponders.165–167
In an early study by Smith et al.,165 30 breast cancer patients received eight cycles of primary chemotherapy. The mean reduction in 18F-FDG uptake after the first cycle was significantly higher in lesions with a partial, complete macroscopic or complete microscopic response than in nonresponding lesions. Dose Schwarz et al.166 evaluated the use of sequential 18F-FDG PET to predict response after the first and second cycles of standardized chemotherapy for metastatic breast cancer. Among a series of 17 metastatic lesions responded, all responders were correctly identified after the first cycle of primary chemotherapy by a decrease in the SUV of greater than 72% compared with the baseline.166 In a more recent report, 64 breast cancer patients underwent 18F-FDG PET after the first, second, and third cycles of chemotherapy.167 Relative changes in tumor 18F-FDG uptake were superior to alterations in tumor size to monitor treatment response. A decrease in 18F-FDG uptake of 40% predicted a histopathologic response with an accuracy of 77% after the first cycle of chemotherapy and 87% after the second cycle.167
McDermott et al.168 investigated whether there is an optimal method to define tumor volume and an optimal imaging time to predict pathologic response in patients with large or locally advanced breast cancers during anthracycline-based chemotherapy. They found that 18F-FDG PET is efficient to predict the pathologic response of most primary breast tumors throughout the duration of a neoadjuvant chemotherapy regimen. This technique, however, was ineffective for tumors with low image contrast on pretherapy PET scans. A positive correlation was also found between the histopathologic response and the level of 18F-FDG uptake after the first and second cycles of chemotherapy but no defined SUV threshold was clearly superior for the optimal separation of responders and nonresponders during chemotherapy.
In a prospective multicenter trial in which 272 18F-FDG PET scans were performed in 104 patients, it was confirmed that the greater the reduction in tumor metabolic activity early in the course of therapy, the more likely the patient would achieve a histopathologic response.169 In patients who showed a histopathologic response, the SUV decreased by 50.5% ± 18.4% (mean ± SD) after the first cycle of primary chemotherapy; in comparison, the SUV decreased by 36.5% ± 20.9% in nonresponders. Patients who did not show a histopathologic response were identified with an NPV of 89.5% after the first cycle of therapy when a relative decrease in the SUV of less than 45% was used as a cutoff. The NPV after the second cycle of therapy was 88.9% when the cutoff was a 55% decrease in the SUV. A metabolic response after one cycle of therapy predicted outcomes in patients regardless of whether they continued to receive a combination of epirubicin and paclitaxel or received a planned switch to epirubicin followed by paclitaxel. A high NPV is essential for clinical decision making to ensure the continuation of treatment in all patients potentially responding to therapy.169 An important observation from this study is that 18F-FDG PET identified patients with low tumor metabolic activity before treatment as not achieving histopathologic response. Twenty-four of 104 breast carcinomas (23%) had a baseline SUV of less than 3, and none responded to chemotherapy. These tumors were more likely to be well differentiated and estrogen receptor (ER) positive. These findings suggest that breast cancers with low metabolic activity identified by 18F-FDG PET before treatment are not likely to respond to primary chemotherapy. Therefore, for patients with such tumors, it is possible that initial management should be different; for example, if the tumor is operable, the patient should undergo surgery immediately or perhaps should have primary hormonal therapy.
The main rationale for primary chemotherapy is to test chemosensitivity, allowing for subsequent changes in the chemotherapy regimen, with the aim of designing a more individualized treatment plan. In the trials in which early changes in primary chemotherapy were implemented, the clinical response was used to guide treatment decisions.170–172 It is still unclear which patients would benefit most from an early change in treatment, such as a switch to a noncross-resistant or second-line chemotherapy regimen because there was no advantage to a change for most nonresponders. Nevertheless, patients showing a clinical response to primary chemotherapy benefited from either the addition of a noncross-resistant chemotherapeutic agent (such as a taxane) or prolonged treatment.172,173 For the establishment of therapy modifications based on response assessments during chemotherapy, a tool more suitable than the clinical response is desirable. Metabolic 18F-FDG PET criteria could serve as a method for this purpose and thus provide a clinically useful surrogate endpoint.
There are significant differences between the goals of primary systemic therapy of newly diagnosed breast cancer and the goals of treatment of metastatic disease. Generally, a few chemotherapeutic regimens are used for primary systemic therapy but many palliative treatment options are available for metastatic disease. Histopathology is used as a surrogate endpoint for the validation of primary chemotherapy, but in most of the patients there are no tissue specimens available from metastatic breast cancer for the evaluation of a response.
Only a few studies have reported on the clinical utility of sequential 18F-FDG PET in patients with metastatic disease. In a study by Gennari et al.,174 a rapid decrease in tumor glucose metabolism was observed after the first cycle of therapy in 6 of 9 responding patients but there was no substantial decrease in nonresponding patients. Specht et al.175 retrospectively reviewed 28 patients who underwent serial 18F-FDG PET during systemic therapy for bone-dominant metastatic breast cancer. The treatments were varied including endocrine therapy, chemotherapy, biologic therapy, and bisphosphonates. Smaller relative decreases in the SUV were associated with a shorter time to progression. A patient with no change in the SUV was twice as likely to progress as a patient with a 42% median decrease in the SUV.175
Dose Schwarz et al.176 confirmed previous observations on the predictive value of early changes in glucose metabolism in metastatic breast cancer. Compared with the baseline PET data, the 18F-FDG uptake in responding metastatic lesions decreased to 72% ± 21% after the first cycle of chemotherapy and to 54% ± 16% after the second cycle. By contrast, the 18F-FDG uptake in metastases not responding to chemotherapy declined only to 94% ± 19% after the first cycle of chemotherapy and to 79% ± 9% after the second cycle. 18F-FDG PET correctly predicted the responses in all patients after the first cycle of chemotherapy and was more accurate than conventional imaging procedures after the third cycle of chemotherapy. As discussed earlier, patients would potentially benefit most from the early identification of ineffective treatments, particularly in cases of metastatic breast cancer, because various alternative treatment options are available. In addition, patients could be spared the toxicity of ineffective treatments.176 In patients with metastatic breast cancer, sequential 18F-FDG PET allowed prediction of response to treatment after the first cycle of chemotherapy. The use of 18F-FDG PET as a surrogate endpoint for monitoring therapy response has the potential of offering improved patient care by individualizing treatment and avoiding ineffective chemotherapy.
The pattern of changes in glucose metabolism depends on the type of therapeutic agent. For example, a transient increase in glucose metabolism followed by a decrease in 18F-FDG uptake has been observed for tumors responding to hormone therapy with tamoxifen. Mortimer et al.177 investigated in 40 patients with biopsy-proved advanced ER-positive breast cancer whether 18F-FDG PET and the estrogen analog 16-α-[18F-]fluoroestradiol-17-β (FES), performed before and after treatment with tamoxifen, could be used to detect hormone-induced changes in tumor metabolism (Fig. 11.3) and changes in levels of ER.
The same group of investigators confirmed their initial findings in 51 postmenopausal women with advanced ER-positive breast cancer using 18F-FES PET and 18F-FDG PET at baseline and repeat 18F-FDG PET after 30 mg estradiol, and found that baseline tumor 18F-FES uptake and metabolic flare after an estradiol challenge were both predictive of responsiveness to endocrine therapy in ER positive breast cancer.178
The critical issue in the use of 18F-FDG PET to monitor and predict a response to treatment in the setting of metastatic disease is the accurate identification of ineffective treatment. For example, if a threshold of a 20% decrease in the SUV after the first cycle of therapy is used to identify ineffective therapy, then serial 18F-FDG PET will not identify all nonresponding patients because some tumors might exhibit an initial decrease at or just below this level in 18F-FDG uptake.
The current use of 18F-FDG PET to monitor treatment in breast cancer varies among institutions as well as different practices in various countries. Generally, baseline 18F-FDG PET before systemic therapy provides an accurate assessment of the extent of disease, and 18F-FDG PET approximately 6 weeks after the completion of therapy accurately reflects the response to treatment. Despite recently published highly encouraging results,131,179,180 prediction of the therapeutic response by 18F-FDG PET after the first or second cycle of therapy as well as early changes to alternative therapies in patients not showing a metabolic response have not yet universally accepted and approved.
Novel Agents for Radionuclide Imaging in Breast Cancer
Molecular characterization of cellular activities in the tumor microenvironment with novel agents offers new opportunities for the diagnosis and treatment of breast cancer. Measurement of key tumor parameters is possible through molecular imaging that provides valuable information on prognosis, optimal therapeutic strategies, and response to treatment. Using a variety of probes to study different molecular targets, information obtained from molecular images can also provide anatomic localization of tumor foci.
Recent efforts have focused on developing new PET imaging tracers to provide specific information on the molecular activities in the tumor microenvironment including hormone receptor expression, tumor cell proliferation, membrane phospholipid synthesis, angiogenesis, apoptosis, and hypoxia. Information obtained from imaging studies can help developing targeted anticancer drugs by identifying patients likely to benefit from such treatment by showing the expression of a relevant receptor or protein. Loss of the cells that previously displayed these targets documents efficacy of treatment and indicates the merits of continuation of therapy. Clearly, modulation of the imaging target could reflect either extermination of the relevant cells or development of resistance through loss of protein expression. Combined assessment using multiple imaging probes is likely to lead to more precise assessment of tumor biology and more accurate prognostic stratification. Once the target and an appropriate probe are determined, molecular therapeutic agents labeled with a radionuclide emitting α- or β-particles can be developed for molecular targeted radionuclide therapy.
Hormone Receptor Imaging
Endocrine therapy targeting steroid receptors is still the most effective form of systemic therapy in breast cancer. Hormone receptor expression can vary between primary tumor and its recurrent disease in 30% or more of the cases.181–184 Targeting hormone receptors in breast cancer tissue provides new perspective in the diagnostic work-up of these cancers. Investigation of hormone receptors using either radiolabeled analogs or antagonists reveals new information on the biologic behavior of these receptors. This information can be exploited for several clinical purposes including assessment of response to hormone therapy as well as providing a basis for developing new antireceptor drugs. Two major hormone receptors, estrogen and progesterone receptors (PRs), have been targeted so far, and promising results have been reported but the number of human studies and the number of subjects in these studies have been limited.
Estrogen Receptor Imaging. 16-α-[18F]-fluoro-17-β-estradiol (FES) is a radiolabeled estrogen analog. Its uptake reflects the functional status of tumor ER in breast cancer.182–184 Whole-body imaging of ER expression with 18F-FES PET can be a valuable diagnostic modality when the standard work-up is inconclusive.185–189 Dehdashti et al. found interesting correlations between the therapeutic response to endocrine treatment and 18F-FES uptake: Patients who were responding to tamoxifen treatment showed higher initial 18F-FES uptake than nonresponders (and also “metabolic flare” phenomenon with 18F-FDG tracers after the initiation of the therapy).177,186,190,191 Linden et al.192found similar results after 6 months of hormonal treatment (i.e., tamoxifen), but the connection between 18F-FES uptake and response to treatment was higher in patients with luminal A molecular subtype (only ER-positive) tumors than with luminar B (both human epidermal growth factor receptor 2 [HER2] and ER positive) ones. With tamoxifen and fulvestran treatment, the eventually detected decline of 18F-FES caused by the treatment was higher than the treatment-related decline because of estrogen-depleting aromatase-inhibitor therapies.193 Despite these promising initial results, clinical confirmation of the diagnostic efficacy is still necessary.
Progesterone Receptor Imaging. The presence of the PR is associated with increased likelihood of hormone responsiveness whereas PR-negative tumors are less likely to respond to therapy. This suggests that the presence of PR is essential for an adequate therapeutic response. Furthermore, this relationship between ER and PR suggests that the estrogen response pathway may not be functional in these tumors.
21-[18F]-fluoro-16-α-ethyl-19-norprogesterone (FENP) and 4-[18F]-fluoropropyl-tanaproget (FPTP) have been developed to characterize the PR status of breast cancer patients.194 Clinical studies with18F-FENP were not successful because of high and rapid metabolism of this tracer but new agents, such as 18F-FPTP, may overcome these difficulties.195,196 Tanaproget is a nonsteroidal progestin, binding with high specificity and sensitivity to PRs; thus it is a potentially useful agent for PET imaging. Zhou et al.197 investigated this agent in in vitro and in vivo studies. Their initial results indicated that the use of 18F-FPTP is feasible for PR imaging.198 Moreover, Dehdashti et al.199 also studied the uptake of 21-18F-fluoro-16α,17α-[(R)-(1’-α-furylmethylidene)dioxy]-19-norpregn-4-ene-3,20-dione (FFNP) and obtained promising results confirming safety and sensitivity to assess PR status of women with newly diagnosed breast cancer.
Insulin-like growth factor receptor imaging. Type 1 insulin-like growth factor receptor (IGF-1R) is a transmembrane tyrosine kinase receptor which plays an important role in signaling cell survival and proliferation. Preliminary studies showed that IGF-1R–targeted therapy in breast cancer can be potentially monitored by radionuclide imaging of IGF-1R expression.188,189
Human Epidermal Growth Factor Receptor 2 Imaging
HER2 is a protein involved in tumor cell survival, proliferation, maturation, metastasis, and angiogenesis, and has antiapoptotic effects. Overexpression of HER2, the result of the HER2 gene amplification, is present in 25% to 30% of breast cancer patients.200,201 The expression of HER2 is regulated by signaling through ERs. Trastuzumab is a recombinant IgG1 monoclonal antibody targeting the extracellular domain of HER2. It is widely used clinically in patients with HER2 overexpressing breast cancer. Trastuzumab is cardiotoxic and expensive and therefore should be restricted to HER2-positive breast cancers only. HER2 tumor expression can vary during treatment and can differ in metastatic lesions within a patient.202–205 Methods that are able to assess the HER2 status noninvasively would be helpful for decision making within antineoplastic therapy protocols. HER2 testing using radionuclide imaging can potentially be helpful to assess noninvasively the HER2 status in vivo.
Currently available HER2-targeted ligands include full-length monoclonal antibodies, Fab fragments, F(ab)2 fragments, diabodies, minibodies, affibodies, scFv-Fc, and peptides. Full-length HER2 monoclonal antibodies have been labeled with iodine-131 (131I), indium-111 (111In), and 99mTc for HER2 SPECT imaging, and iodine-124 (124I), yttrium-86 (86Y), bromine-76 (76Br) and zirconium-89 (89Zr) for HER2 PET imaging. The smaller HER2-targeting antibody fragments, proteins, and peptides were also labeled with 131I, 111In, and 99mTc for HER2 SPECT imaging and with 18F, gallium-68 (68Ga), copper-64 (64Cu), 124I, and 76Br for HER2 PET.206
Perik et al.207 performed 111In-labeled trastuzumab planar scintigraphy and SPECT in 15 HER2-positive metastatic breast cancer patients. Forty five percent of single tumor lesions were shown and new tumor lesions seen on PET imaging using Zr-89 trastuzumab.208 Preliminary data showed excellent tumor uptake and successful detection of HER2-positive breast cancer metastases noninvasively. HER2 PET imaging may also be useful for the evaluation of HER2 downregulating therapies including heat shock protein 90 (HSP 90) inhibitors.209 Despite encouraging results, no definitive conclusion on the clinical role of HER2 imaging has been made to date.
Tumor Cell Proliferation Imaging
18F-FDG is a highly sensitive agent to study increased glucose metabolism and detection of viable tumor tissues in the body. To measure the exact proliferation of tumors, more specific tracers are also under investigation. Some special tracer molecules are currently available to study therapeutic response and tumor proliferation by measuring the rate of the cell membrane synthesis or increased amino acid and nucleic acid utilization.
Radionuclide Imaging of Amino Acid Metabolism. The initial model for these molecules was carbon-11 (C-11) methionine,210 an essential amino acid molecule used by every cell of the human body, especially enhanced protein synthesis in tumor cells. C-11 methionine is incorporated into newly synthesized proteins, paving way to image the increased protein metabolism of cancers. Its uptake correlates with tumor proliferation in patients with breast cancer. This can be exploited in the assessment of therapeutic response. Initial reports have demonstrated changes in amino acid metabolism after anti-neoplastic therapy using C-11 methionine PET imaging to assess the response to therapy.211,212
In association with glutamine and glutamate metabolism of the tumors, the cystine/glutamate exchanger (xCtransporter, xCT) is also a potential target for radiotracer imaging. Koglin et al.213 found excellent tumor visualization and high tumor-to-background ratios using (4S)-4-(3-[18F]fluoropropyl)-L-glutamate (BAY 94–9392, also named 18F-FSPG) in preclinical tumor models. Baek et al.214 successfully studied 18F-FSPG in the detection of breast tumors. The number of patients (n = 5), however, is small, limiting the value of these results. 18F-FSPG has also been evaluated to quantify glutathione-based drug resistance and oxidative stress-induced signaling pathways in which system xCT plays an important role by exchanging and transporting cysteine to the cell.214
Radionuclide Imaging of DNA Synthesis. Radiolabeled pyrimidine analogs such as carbon-11 (C-11) thymidine and 18F-fluoro-deoxy-L-thymidine (18F FLT) have been used to study DNA synthesis, cellular proliferation rate, and enhanced nucleic acid utilization in tumor cells. Because of the limited availability of C-11, thymidine PET imaging using C-11 has not attracted significant interest. 18F-FLT PET imaging, however, was found to be suitable for the visualization of breast cancers and assessment of the early response after chemotherapy.215,216 18F-FLT uptake was seen in 8 out of 10 primary breast tumors and some large axillary lymph node metastases but small axillary lymph node metastases were not detected.216 In another report, slightly better results were seen in 12 patients where 13 out of 14 primary breast tumors and 7 out of 8 axillary lymph node metastases could be detected.217 Pio et al.218showed that 18F-FLT PET imaging was a reliable imaging method to assess early response after one cycle of chemotherapy. They also found that 18F-FLT imaging correlates with long-term efficacy of antineoplastic therapy by showing correlation with the late changes of tumor markers. Lubberink et al.219 compared the effectiveness of tumor-to-whole blood ratio (TBR) measurements with the semiquantitative SUV results in locally advanced breast cancer patients treated with neoadjuvant chemotherapy.
18F-FDG and 18F-FLT PET imaging for the assessment of tumor response to chemotherapy were compared in 14 patients with primary or metastatic breast cancer.218 A strong correlation was found between the percentage decrease in 18F-FLT tumor uptake 2 weeks after initiation of chemotherapy and late size changes as determined by CT scan. No correlation was found between 18F-FDG uptake changes over the first 2 weeks and late size measurements.218 Similar results were obtained when 18F-FLT PET was performed 1 week after initiation of chemotherapy.219 These results suggest that 18F-FLT PET may be useful to predict response to therapy in breast cancer patients but further investigations are needed to validate the clinical utility in larger groups of patients.
Phospholipid Synthesis Imaging. C-11 choline PET imaging has been investigated in breast cancer to detect clinically aggressive tumor phenotypes in patients with ER-positive breast cancer; the tumor-to-background ratio was high and the choline uptake correlated well with tumor grade.220 These results were confirmed by Kenny et al.221 who showed that tumor response to trastuzumab therapy could be early assessed by C-11 choline PET imaging only after 1 month following antineoplastic treatment.
Contractor et al.222 also found significant correlation between tumor proliferation and choline uptake on PET scans. C-11 choline uptake was also correlated with the proliferation measured by 18F-fluoro-thymidine PET. Tateishi et al.223 also examined the correlation between FDG uptake and C-11 choline uptake in breast cancer patients. Although C-11 choline showed higher specificity for the detection of aggressive disease, both FDG and choline had similar uptake profile.223
Angiogenesis is the physiologic process of new blood vessel formation which is the key index for tumor growth. It should therefore be a potential target for PET imaging.
VEGF-receptor. VEGF is an important downstream protein produced as a result of multiple processes including hypoxia, activation of growth factor receptors (EGFR, HER2), and intracellular proteins (HIF-1a, mTOR etc.). Radiolabeled anti-VEGF and Fab fragments were studied with the aim of antiangiogenesis imaging. Imaging of VEGF using specific tracers is of great interest to select patients who could benefit from VEGF-targeted therapies, and to assess the response to new treatment regimes. Several radiolabeled probes including anti-VEGF antibodies and Fab fragments have been investigated for the development of VEGF imaging probes.224 In metastatic breast cancer, the addition of bevacizumab, a humanized monoclonal antibody which neutralizes all isoforms of VEGF-A, to paclitaxel leads to an increased response rate and increased progression-free survival.225
Increased vascularization is present in all preinvasive lesions, ductal as well as lobular, and increases with lesion severity. Also, immunohistochemically determined VEGF expression in normal glandular structures is lower than malignant lesions, with the highest levels found in ductal lesions.226 The presence of high VEGF levels in the extracellular matrix can increase the tumor uptake and may well make detection of small lesions possible. More efforts are needed to assess the usefulness of radionuclide imaging of VEGF probes in the management of breast cancer.
Integrin Imaging. Integrins are transmembrane receptors which are important in the cell-to-cell interactions. It was shown that αυβ3 integrin is strongly related to tumor angiogenesis, and it is overexpressed on both endothelial and tumor cells in breast cancer. Integrin imaging originally based on the use of arginine–glycine–aspartic acid (RGD)-based radioligands. McParland et al.227 tested first the [18F]-fluciclatide, also named [18F]-AH111585 (AH111585 is a cyclic peptide containing RGD motif that binds directly to integrin receptors such as αυβ3 with high affinity) in healthy volunteers to assess the safety and biodistribution of integrin tracers. They found that [18F]-AH111585 is a safe PET tracer with a dosimetry profile comparable to other common 18F-PET tracers. High 18F-galacto-arginine–glycine–aspartic acid (18F-galacto) RGD uptake was found in lesions of squamous cell cancer of the head and neck, melanoma, breast cancer, osteosarcoma, and soft tissue sarcoma with a significant correlation of αυβ3 integrin expression.228 Beer et al.229 examined the tumor uptake of αυβ3-selective PET tracer 18F-galacto RGD in 16 patients with primary tumors (primary tumor in 12 and metastatic breast cancer in 4 patients), and found that all primary tumors and metastases were clearly identified. 18F-galacto RGD PET represents a combination of tracer binding to activated endothelial cells and tumor cells expressing variable levels of αυβ3 integrin.229
There are two principle methods of cell death in tumor cells; immediate cell death (necrosis) or programmed delayed cell death (apoptosis). Cell division and cell destruction are in balance in the majority of tumors; but in some tumors, failure of cell destruction can occur leading to cell immortality and growth of the cancer. Most effective cancer treatments including radiation therapy and chemotherapy involve the induction of apoptosis. Once this process has started, it is irreversible and cell death in about 10 days is inevitable.230
Annexin imaging. During apoptosis, there is blebbing of the affected cell wall surface and reversal of some components of the cell membrane. This results in some antigens such as membrane-associated phosphatidylserine (PS) being exposed to annexin V, a naturally occurring human protein. Annexin V binds avidly to PS which is normally found only on the inner leaflet of the cell membrane double layer. PS is actively transported to the outer layer as an early event in apoptosis and becomes available for annexin binding. Annexin also gains access to PS as a result of the membrane fragmentation associated with necrosis.
Annexin V has been labeled with both single photon and positron emitting radionuclides. Initial studies showed that programmed cell death caused by radiation and chemotherapy using 99mTc EC-annexin could be quantified in vitro and in vivo.231 It was demonstrated in an animal model that 18F-annexin-V PET imaging accurately measures the internal levels of apoptosis noninvasively with high image contrast between healthy and dying tissues within 1 hour after injection of 18F-annexin V.232 Its potential role in breast cancer management has not yet been fully discovered.
There are two types of tumor hypoxia; chronic and acute.233 Chronic (diffusion-limited) hypoxia is defined as cells exposed to low-oxygen levels for longer than 24 hours, which frequently occurs in poorly vascularized regions. Acute (perfusion-limited) hypoxia involves transient exposure of cells to hypoxia, ranging from minutes up to 24 hours. This typically involves cells located near capillaries exhibiting transitory interruptions in blood flow (e.g., as a result of functional changes in vascular stability). Tumors with high hypoxic volumes tend to have a poor prognosis as they are associated with an aggressive phenotype and increased risk of metastasis,234 and often respond poorly to radiotherapy and/or chemotherapy.235 Approximately 25% to 40% of all invasive breast cancers contain hypoxic regions.236,237 Preclinical studies have reported correlation between 18F-FDG uptake and tumor hypoxia detected with pimonidazole or 18F-fluoromisonidazole (18F-FMISO), a PET tracer designed to identify hypoxic cells. Initial clinical studies have confirmed the correlation between FDG and FMISO retention.238–241 In a recent study, 18F-FMISO PET/CT showed that tumor-to-background ratio at 4 hours ≥1.2 is an optimal cutoff that highly suggests resistance to hormonal therapy.242
99mTc-sestamibi breast scintigraphy and 18F-FDG PET imaging are two main radionuclide methods widely investigated in the diagnostic work-up of primary breast cancer. Recent technical refinements including the development of small FOV imaging devices (MBI, BSGI, PEM) have improved the diagnostic performance of gamma cameras and PET scanners. Low specificity, failure to detect small lesions, and high radiation burden are three main problems associated with current techniques of radionuclide imaging of primary tumor in patients with breast cancer. The role of radionuclide imaging in the evaluation of primary tumor is emerging, but its actual indications have not yet determined yet. It is most likely that these methods will have a clinical role in patients with dense breast tissue, fibrocystic changes, and inconclusive findings from anatomical imaging modalities.
The sensitivity of current 18F-FDG PET imaging techniques in axillary staging is not reliable enough to depend on because of nonspecific uptake in benign lymph nodes and possibility of missing small nodes with metastasis in breast cancer. 18F-FDG PET/CT is superior to conventional imaging modalities in the evaluation of distant metastases. Its superiority is also evident in the investigation of bone metastases, especially when 18F-fluoride is preferred while the nonspecific uptake in benign bone changes continues to be a challenge when 18F-fluoride is used. The most important role of PET imaging is to monitor the response to antineoplastic therapy using either 18F-FDG or newest novel agents.
Integrated efforts should focus on determining the role of both single photon and positron imaging methods in the diagnostic evaluation of primary tumor of breast cancer. To secure a place in clinical setting, reducing the imaging time and the amount of radioactivity is essential for all emerging radionuclide techniques proposed for the detection of primary tumor in breast cancer. The breast imaging technology will likely undergo significant refinement. Breast dedicated SPECT/CT for gamma imaging and PET/MR for positron imaging are likely the two techniques to be exploited in future for the detection of primary tumor in patients with breast cancer. Clinical experience in human subjects is needed for the new tumor-seeking novel agents that have the potential of studying tumor microenvironment at molecular level.
Further increase in the diagnostic performance PET/CT imaging will help these radionuclide techniques in gaining a firm place in diagnostic armamentarium of staging and monitoring the response to therapy. Novel agents documenting molecular functions of tumor cells at subcellular level will likely gain clinical acceptance in early detection of nonresponders decreasing the cost of management of breast cancer and achieving the ultimate goal of individualized treatment in these patients.
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