Breast Cancer DOI 10.1007/s12282-015-0613-z
SPECIAL FEATURE
The way to the next generation molecular diagnostics
Molecular imaging using PET for breast cancer Hiroaki Kurihara1 • Chikako Shimizu2 • Yasuji Miyakita3 • Masayuki Yoshida4 Akinobu Hamada5 • Yousuke Kanayama6 • Kan Yonemori2 • Jun Hashimoto2 • Hitomi Tani1 • Makoto Kodaira2 • Mayu Yunokawa2 • Harukaze Yamamoto2 • Yasuyoshi Watanabe6 • Yasuhiro Fujiwara2 • Kenji Tamura2
•
Received: 26 February 2015 / Accepted: 16 April 2015 Ó The Japanese Breast Cancer Society 2015
Abstract Molecular imaging can visualize the biological processes at the molecular and cellular levels in vivo using certain tracers for specific molecular targets. Molecular imaging of breast cancer can be performed with various imaging modalities, however, positron emission tomography (PET) is a sensitive and non-invasive molecular imaging technology and this review will focus on PET molecular imaging of breast cancer, such as FDG-PET, FLT-PET, hormone receptor PET, and anti-HER2 PET. Keywords Breast cancer PET Molecular imaging Molecular target therapy HER2
Introduction Molecular imaging is defined by the Society of Nuclear Medicine as the visualization, characterization, and measurement of biological processes at the molecular and & Hiroaki Kurihara [email protected] 1
Department of Diagnostic Radiology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
2
Department of Breast and Medical Oncology, National Cancer Center Hospital, Tokyo, Japan
3
Department of Neurosurgery, National Cancer Center Hospital, Tokyo, Japan
4
Department of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan
5
Department of Clinical Pharmacology Group for Translational Research Support Core, National Cancer Center Research Institute, Tokyo, Japan
6
RIKEN Center for Molecular Imaging Science, Kobe, Hyogo, Japan
cellular levels in humans and other living systems [1]. The imaging of specific molecular targets that are associated with cancer will facilitate earlier diagnosis and better management of cancer patients. Molecular imaging of breast cancer can be performed with various imaging modalities, such as magnetic resonance imaging (MRI) using a contrast agent [2–6], positron emission tomography (PET) using a positron-emitting radionuclide [7–9], single photon emission computed tomography (SPECT) using a gamma-emitting radionuclide [10–12], optical imaging using a fluorescent dye [13, 14], or contrastenhanced ultrasound (US) [15, 16]. PET is a highly sensitive and non-invasive molecular imaging technology that has become an indispensable tool in cancer research, clinical trials, and medical practice. This review will focus on the use of PET molecular imaging of breast cancer. PET imaging using 18F-fluorodeoxyglucose (FDG) enables physicians to see where a tumor is located in the body. Using certain radiolabeled tracers, PET imaging is also expected to visualize the expression and activity of particular molecules, cells, and biological processes that influence the behavior of tumors and/or their responsiveness to therapeutic drugs [7–9, 17, 18]. To date, various tracers have been discovered and developed. Recent advances in molecular/cell biology have enabled the design of specific tracers to image molecular targets non-invasively using PET [19]. Here, we highlight recent advances in molecular imaging with PET for breast cancer. We begin with an overview of tracers and targets for molecular PET imaging of breast cancer. Next, we will focus on FDG-PET imaging, FLTPET imaging, hormone receptor PET imaging, and HER2 PET imaging. We will also describe other targets used for PET imaging of breast cancer briefly.
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Tracers for and targets of breast cancer used in molecular PET imaging PET molecular imaging is based on the detection of radiolabeled tumor-specific tracers. Radioisotopes used for PET imaging (e.g., 18F, 11C, 15O, 13N, 64Cu, 124I, 89Zr) emit positrons. For molecular PET imaging of breast cancer, several tracers targeting certain tumor characteristics have been developed (Table 1). To target general phenomena, a certain tracer can be used to visualize either cellular glucose metabolism or DNA synthesis, processes that are both increased in tumor cells compared to normal cells [8, 17]. Most breast cancers express hormone receptors on the surface of tumor cells that provide targets of interest for imaging in these subsets of patients [24]. Moreover, other receptors present at the tumor cell membrane such as human epidermal growth factor receptor 2 (HER2), epidermal growth factor receptor (EGFR), insulinlike growth factor-1 receptor (IGF-1R), and plateletderived growth factor receptor b (PDGFR-b) may also be of interest for imaging. In addition, tumor cells secrete Table 1 Molecular targets/tumor characteristics and PET tracers for breast cancer Target/tumor characteristics
PET tracer
References
Glucose metabolism
FDG
[25–33]
DNA synthesis
FLT
[34–36]
ER
FES
[24, 41– 46]
18
[68]
18
[69]
18
[70]
18
[71]
F-fluorotamoxifen
PR
F-FMNP F-FENP F-FPTP
89
[58, 61]
64
[59, 60]
64
[72]
89
[74]
11
[75]
IGF-1R
89
[76]
VEGFR
64
[77]
89
[78]
64
[79]
18
[80]
HER2
Zr-labeled trastuzumab Cu-labeled trastuzumab
EGFR
Cu-labeled trastuzumab fragment 89 Zr-labeled cetuximab Zr-panitumumab C-PD153035 Zr-labeled R1507 Cu-DOTA-VEGF Zr-bevacizumab
Integrin
Cu-DOTA-RGD F-galacto-RGD
[73]
FDG 18F-fluorodeoxyglucose, FLT 18F-fluorothymidine, ER estrogen receptor, FES 16a-18F-fluoro-17b-estradiol, PR progesterone receptor, 18F-FMNP 21-18F-fluoro-16-a-methyl-19-norprogesterone, 18FFENP 21-18F-Fluoro-16a-ethyl-norprogesterone, 18F-FPTP 4-18Ffluoropropyl-tanaproget, HER2 human epidermal growth factor receptor 2, EGFR epidermal growth factor receptor, IGF-1R type 1 insulin-like growth factor receptor, VEGFR vascular endothelial growth factor receptor, RGD arginine–glycine–aspartic acid peptide
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growth factors, such as vascular endothelial growth factor (VEGF) and transforming growth factor b (TGF-b) that could be tracer target candidates. Targets that are involved in hypoxia and angiogenesis such as VEGF-receptors, aVb3 integrin, fibronectin, and endostatin could also be used as tracer targets since both of these processes are important to tumor growth.
FDG-PET imaging The best studied and most widely used PET tracer for clinical purposes is FDG [25]. FDG-PET visualizes glucose metabolism, which is often increased in tumor cells compared to normal cells. Uptake by the tumor can usually be detected with a PET scanner 45–90 min after FDG injection (Fig. 1). The limited anatomical information obtained from FDG-PET alone has been improved by integrated PET/CT or a PET/MR scanner that provides fusion images of PET with CT or MRI [26–28]. FDG-PET has been found to be helpful for primary tumor detection and diagnosis, staging of locoregional and distant metastases, and in monitoring response to therapy. In a pre-operative setting, high FDG uptake by tumors was observed, particularly in ductal carcinomas [29]. FDG uptake itself, however, is not tumor specific, and it can be difficult to distinguish between malignant and benign breast cells. Moreover, falsepositive results can occur when activated inflammatory cells such as granulocytes and macrophages exist [30]. For early detection and diagnosis of breast cancer, the ability to detect non-palpable, small malignancies less than 1 cm in diameter is desirable; however, whole body FDG-PET has not been extensively used for this purpose because the spatial resolution of previous-generation clinical PET cameras is limited [8, 31]. High-resolution, high-sensitivity positron emission mammography (PEM) has been developed for detection and diagnosis of early-stage breast cancer (Fig. 2). PEM using FDG can detect primary breast cancer lesions as small as 3 mm in diameter [32, 33]. Its clinical utility for screening or as an adjunct to mammography has to be demonstrated by future studies.
FLT-PET imaging The pyrimidine analogue PET tracer 18F-fluoro-L-thymidine (FLT) has been developed to image increased cellular DNA synthesis. FLT-PET imaging shows normal physiological uptake in liver, bone marrow and the urinary tract (Fig. 3). In breast cancer patients, small studies have been reported. In a group of 12 breast cancer patients, FLT uptake was seen in 92 % of primary breast tumors and 87 % of axillary lymph node metastases [34]. Another
Breast Cancer Fig. 1 Typical images of whole body FDG-PET/CT showing breast cancer. Both Maximumintensity projection (MIP) image (a) and PET/CT fusion image (b) showed nodular lesion of 1.5 cm in diameter in lt breast of a 64-year-old woman. Following core needle biopsy revealed invasive ductal carcinoma
study compared FDG and FLT for monitoring and predicting tumor response to chemotherapy in 14 patients with primary or metastatic breast cancer. This study showed a strong correlation between the percentage decrease in FLT uptake within the tumor 2 weeks after initiating chemotherapy and the reduction in tumor size measured by CT at a later interval (average, 3.3 months). No correlation was found between FDG uptake changes over the first 2 weeks and these response measurements [35]. Based on these results, FLT-PET may help predict patient response to therapy [36].
Hormone receptor PET imaging Up to 70 % of breast cancer patients show tumors positive for hormone receptors. The majority of them are positive for estrogen receptor (ER) and more than 95 % of tumors positive for progesterone receptor (PR) are also ER-positive. Immunohistochemical determination of ER and PR expression at the time of primary diagnosis is a part of standard care. Anti-hormonal treatment strategies are based on hormone receptor expression, which is predictive of response to such treatment. Hormone receptor expression, however, can vary between primary and recurrent tumors in approximately 30 % of cases [37, 38]. The other study demonstrated that the discordance between the ER status of the primary tumor and the distant metastases was 41 % for bone marrow metastases, and 44 % for liver metastases [39]. In addition, anti-hormonal treatment induces ER loss in a number of patients with acquired hormonal resistance [40]. Thus, monitoring hormone receptor expression in
primary tumor and metastatic sites throughout the course of the disease might help a physician determine if anti-hormonal treatment should be used during the different phases of treatment. To monitor hormone receptor status in a noninvasive and repeated fashion, the PET tracer 16a-18Ffluoro-17b-estradiol (FES) was developed as a receptor ligand for ER [24]. Several studies using FES-PET have been performed in breast cancer patients and revealed the correlation of FES tumor uptake with immunohistochemical ER tumor density [41–44]. These studies suggested a potential role for FES-PET in assessing ER status, especially in patients with multiple tumors or tumors that are difficult to perform a biopsy on. Comparing the tumor uptakes of FES and FDG, as well as ER status among 43 patients showed an 88 % overall agreement between FES uptake and ER status. In contrast, there was no observed correlation either between FDG uptake and ER status or between FES and FDG uptake [41]. In 47 patients with immunohistochemically ER-positive tumors, FES-PET was performed at baseline either prior to or shortly after the initiation of anti-hormonal therapy. FES uptake by tumors at baseline was subsequently compared with the response determined by a combination of clinical assessment and modified RECIST criteria 6 months after the therapy. In patients with low FES uptake by tumor lesions at baseline (n = 15), no response was shown. In a group comprising 32 patients with a high FES tumor uptake at baseline, 34 % of the patients responded to anti-hormonal therapy [45, 46]. Therefore, FES-PET could not be recommended as a routine imaging technique for the workup of a breast cancer patient. It could, however, be useful for predicting response to anti-hormonal therapy.
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Breast Cancer Fig. 2 Typical images of PEM showing breast cancer. a Mediolateral oblique (MLO) view of PEM; b cranio-caudal (CC) views of PEM; c MIP image of whole body PET/CT. Within lt breast of a 73-year-old woman, PEM images could visualize a lesion of 7 mm in diameter that whole-body PET/ CT scanner could hardly detect. Courtesy of Dr. Masami Kawamoto, Yuai-Clinic, Yokohama, Japan
HER2 PET imaging HER2, which is overexpressed in 25–30 % of breast cancer patients is involved in tumor cell survival, proliferation, maturation, metastasis, and angiogenesis [47, 48]. Trastuzumab, a humanized monoclonal antibody against HER2 is widely used and targeting HER2 with trastuzumab is a well-established therapeutic strategy for HER2-positive breast cancer [49–53]. HER2 expression is routinely determined using immunohistochemistry (IHC) or fluorescence in situ hybridization [54], however, technical problems can arise when lesions cannot be easily accessed by core needle biopsy [55]. In addition, HER2 expression can vary during the course of the disease [56] and even between tumor lesions in the same patient [57]. To overcome these problems, a novel non-invasive technique such as HER2 PET imaging is required to determine HER2 expression. So far, full-length HER2 monoclonal antibodies have been labeled with 124I, 86Y, 76Br, 89Zr, and 64Cu for HER2 PET imaging [58, 59]. The smaller HER2 targeting antibody fragments, proteins, and peptides have been labeled with 18F, 68Ga, 64Cu, 124I, and 76Br for HER2 PET imaging [58]. With use of 64Cu-trastuzumab PET imaging technique, for example, primary tumor lesions larger than 2 cm in diameter and metastatic brain lesions larger than 1 cm in diameter could be visualized [59, 60]. The typical 64Cu-DOTA-trastuzumab PET images within HER2-positive breast cancer patients are shown in Fig. 4. In human subjects, an autoradiogram of a frozen section prepared from the removed tumor specimen revealed high accumulation in the area where HER2-positive cells were
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Fig. 3 Normal uptake of FLT-PET/CT. An MIP image of whole body FLT-PET/CT in a 64-year-old woman. FLT has been developed to visualize the activity of DNA synthesis that is increased in tumor cells compared to normal cells. Physiological high uptakes of FLT were also shown in normal organs of liver, bone marrow and the urinary tract
seen by IHC (Fig. 5), confirming the HER2 specificity of Cu-DOTA-trastuzumab PET imaging. Another HER2 PET imaging technique, 89Zrtrastuzumab PET imaging, also have succeeded to visualize
64
Breast Cancer Fig. 4 64Cu-DOTAtrastuzumab PET images of HER2-positive breast cancer and metastatic brain lesion. a Primary lesion of HER2positive breast cancer in a 69-year-old woman was visualized by whole body PET/ CT with use of 64Cu-DOTAtrastuzumab. Compared to the normal breast tissue, higher uptake was found within the tumor. Upper panel axial PET/ CT fusion image; lower panel magnified PET/CT fusion image (94). b Metastatic brain lesion in a 54-year-old woman having HER2-positive breast cancer was also visualized by 64CuDOTA-trastuzumab PET/CT (upper panel). A significant uptake was found in the areas corresponding to the brain metastatic lesion that was detected by MRI (lower panel)
HER2 positive tumor in a human. Due to the relatively longer half-life of Zr-89, 89Zn-trastuzumab provides clearer images; however, it induces higher radiation exposure [61]. In contrast, the shorter half-life of 64Cu induces lower radiation exposure but provides images with non-specific activity in the blood [59, 62]. Recently, several novel HER2 inhibitors have been developed and approved, including lapatinib, pertuzumab, and trastuzumab emtansine (T-DM1). Monitoring changes in HER2 expression at tumor sites may help physicians to determine which kind of HER2 inhibitors should be used during the different phases of treatment or if other nonHER2 inhibitors should be used instead. Preclinical results with HER2 imaging are abundant and promising; however, clinical data are still limited. The findings with clinical HER2 PET imaging may support the further development and exploration of the potential of this technique.
Other targets for PET imaging of breast cancer Triple-negative breast cancer, a type of breast cancer that is immunohistochemically negative for ER, PR, and HER2, typically has a poor prognosis [63–65]. Much research is
ongoing to identify the biological processes and targets that drive the behaviors of triple-negative breast cancer. Molecular imaging of these targets may aid target identification, drug development, and in predicting and evaluating response to therapy. For example, EGFR overexpression is seen in 57 % of triple-negative breast cancers. Several tracers have been developed for EGFR imaging, including radiolabeled EGFR tyrosine kinase inhibitors, epidermal growth factor, and EGFR antibodies [66]. The EGFR-directed monoclonal antibody cetuximab has been successfully radiolabeled with 64Cu at our institute [67].
Future direction of molecular imaging with PET Molecular imaging of breast cancer is not commonly used in daily clinical practice; however, its applications are expected and promised for improving breast cancer management. We have reported results made with sensitive PET molecular imaging techniques but these techniques still have limitations, including feasible capacity and spatial resolution, which impede early tumor detection. The resolutions of PEM and the latest generation of PET/CT
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Breast Cancer Fig. 5 HER2 specificity of 64 Cu-DOTA-trastuzumab. a HER2-positive breast cancer in a 55-year-old woman; b metastatic brain tumor in a 61-year-old woman having HER2-positive breast cancer. Frozen section specimens removed from the lesions showing high uptake on 64CuDOTA-trastuzumab PET/CT images (upper panels) were used for IHC (middle panels) and autoradiogram (lower panels). High accumulations of autoradiogram (red arrows) were observed in the area where HER2-positive cells (black arrows) were seen by IHC, confirming the HER2 specificity of 64Cu-DOTA-trastuzumab PET imaging in human subjects
and PET/MR scanners have improved and may lead to improved anatomical interpretation of the images. In addition to the innovations in imaging modalities, the indirect combination of PET imaging and other novel modalities such as optical imaging could serve other purposes. The molecular target and its tracer for the novel modality still have to be validated for clinical use. In a combined setting, more sensitive PET imaging can be used for the target and tracer validation. Thus, molecular imaging with PET could prove to be a powerful tool for novel tracer discovery and development. Another potential application of molecular PET imaging could lie in clinical trials. In combination with pharmacokinetic and pharmacodynamic studies, molecular imaging studies in a clinical trial would provide a more powerful approach to explore appropriate ways of using molecularly targeted drugs. Moreover, during preclinical phase or phase 0 trials, molecular imaging with
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PET can provide proof of concept and further the development of new therapeutic agents. Acknowledgments The authors thank Dr. Masami Kawamoto for providing appropriate PEM images. The authors thank Mr. Takayuki Namma and the staff of Sumitomo Heavy Industries for supporting 64 Cu-DOTA-trastuzumab/cetuximab production, and Mr. Akira Hirayama and the staff of GE Healthcare for optimizing PET/CT scan. We also thank Ms. Riako Onoe for secretarial support during this study. Conflict of interest of interest.
The authors declare that they have no conflict
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SPECIAL FEATURE
The way to the next generation molecular diagnostics
Molecular imaging using PET for breast cancer Hiroaki Kurihara1 • Chikako Shimizu2 • Yasuji Miyakita3 • Masayuki Yoshida4 Akinobu Hamada5 • Yousuke Kanayama6 • Kan Yonemori2 • Jun Hashimoto2 • Hitomi Tani1 • Makoto Kodaira2 • Mayu Yunokawa2 • Harukaze Yamamoto2 • Yasuyoshi Watanabe6 • Yasuhiro Fujiwara2 • Kenji Tamura2
•
Received: 26 February 2015 / Accepted: 16 April 2015 Ó The Japanese Breast Cancer Society 2015
Abstract Molecular imaging can visualize the biological processes at the molecular and cellular levels in vivo using certain tracers for specific molecular targets. Molecular imaging of breast cancer can be performed with various imaging modalities, however, positron emission tomography (PET) is a sensitive and non-invasive molecular imaging technology and this review will focus on PET molecular imaging of breast cancer, such as FDG-PET, FLT-PET, hormone receptor PET, and anti-HER2 PET. Keywords Breast cancer PET Molecular imaging Molecular target therapy HER2
Introduction Molecular imaging is defined by the Society of Nuclear Medicine as the visualization, characterization, and measurement of biological processes at the molecular and & Hiroaki Kurihara [email protected] 1
Department of Diagnostic Radiology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
2
Department of Breast and Medical Oncology, National Cancer Center Hospital, Tokyo, Japan
3
Department of Neurosurgery, National Cancer Center Hospital, Tokyo, Japan
4
Department of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan
5
Department of Clinical Pharmacology Group for Translational Research Support Core, National Cancer Center Research Institute, Tokyo, Japan
6
RIKEN Center for Molecular Imaging Science, Kobe, Hyogo, Japan
cellular levels in humans and other living systems [1]. The imaging of specific molecular targets that are associated with cancer will facilitate earlier diagnosis and better management of cancer patients. Molecular imaging of breast cancer can be performed with various imaging modalities, such as magnetic resonance imaging (MRI) using a contrast agent [2–6], positron emission tomography (PET) using a positron-emitting radionuclide [7–9], single photon emission computed tomography (SPECT) using a gamma-emitting radionuclide [10–12], optical imaging using a fluorescent dye [13, 14], or contrastenhanced ultrasound (US) [15, 16]. PET is a highly sensitive and non-invasive molecular imaging technology that has become an indispensable tool in cancer research, clinical trials, and medical practice. This review will focus on the use of PET molecular imaging of breast cancer. PET imaging using 18F-fluorodeoxyglucose (FDG) enables physicians to see where a tumor is located in the body. Using certain radiolabeled tracers, PET imaging is also expected to visualize the expression and activity of particular molecules, cells, and biological processes that influence the behavior of tumors and/or their responsiveness to therapeutic drugs [7–9, 17, 18]. To date, various tracers have been discovered and developed. Recent advances in molecular/cell biology have enabled the design of specific tracers to image molecular targets non-invasively using PET [19]. Here, we highlight recent advances in molecular imaging with PET for breast cancer. We begin with an overview of tracers and targets for molecular PET imaging of breast cancer. Next, we will focus on FDG-PET imaging, FLTPET imaging, hormone receptor PET imaging, and HER2 PET imaging. We will also describe other targets used for PET imaging of breast cancer briefly.
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Breast Cancer
Tracers for and targets of breast cancer used in molecular PET imaging PET molecular imaging is based on the detection of radiolabeled tumor-specific tracers. Radioisotopes used for PET imaging (e.g., 18F, 11C, 15O, 13N, 64Cu, 124I, 89Zr) emit positrons. For molecular PET imaging of breast cancer, several tracers targeting certain tumor characteristics have been developed (Table 1). To target general phenomena, a certain tracer can be used to visualize either cellular glucose metabolism or DNA synthesis, processes that are both increased in tumor cells compared to normal cells [8, 17]. Most breast cancers express hormone receptors on the surface of tumor cells that provide targets of interest for imaging in these subsets of patients [24]. Moreover, other receptors present at the tumor cell membrane such as human epidermal growth factor receptor 2 (HER2), epidermal growth factor receptor (EGFR), insulinlike growth factor-1 receptor (IGF-1R), and plateletderived growth factor receptor b (PDGFR-b) may also be of interest for imaging. In addition, tumor cells secrete Table 1 Molecular targets/tumor characteristics and PET tracers for breast cancer Target/tumor characteristics
PET tracer
References
Glucose metabolism
FDG
[25–33]
DNA synthesis
FLT
[34–36]
ER
FES
[24, 41– 46]
18
[68]
18
[69]
18
[70]
18
[71]
F-fluorotamoxifen
PR
F-FMNP F-FENP F-FPTP
89
[58, 61]
64
[59, 60]
64
[72]
89
[74]
11
[75]
IGF-1R
89
[76]
VEGFR
64
[77]
89
[78]
64
[79]
18
[80]
HER2
Zr-labeled trastuzumab Cu-labeled trastuzumab
EGFR
Cu-labeled trastuzumab fragment 89 Zr-labeled cetuximab Zr-panitumumab C-PD153035 Zr-labeled R1507 Cu-DOTA-VEGF Zr-bevacizumab
Integrin
Cu-DOTA-RGD F-galacto-RGD
[73]
FDG 18F-fluorodeoxyglucose, FLT 18F-fluorothymidine, ER estrogen receptor, FES 16a-18F-fluoro-17b-estradiol, PR progesterone receptor, 18F-FMNP 21-18F-fluoro-16-a-methyl-19-norprogesterone, 18FFENP 21-18F-Fluoro-16a-ethyl-norprogesterone, 18F-FPTP 4-18Ffluoropropyl-tanaproget, HER2 human epidermal growth factor receptor 2, EGFR epidermal growth factor receptor, IGF-1R type 1 insulin-like growth factor receptor, VEGFR vascular endothelial growth factor receptor, RGD arginine–glycine–aspartic acid peptide
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growth factors, such as vascular endothelial growth factor (VEGF) and transforming growth factor b (TGF-b) that could be tracer target candidates. Targets that are involved in hypoxia and angiogenesis such as VEGF-receptors, aVb3 integrin, fibronectin, and endostatin could also be used as tracer targets since both of these processes are important to tumor growth.
FDG-PET imaging The best studied and most widely used PET tracer for clinical purposes is FDG [25]. FDG-PET visualizes glucose metabolism, which is often increased in tumor cells compared to normal cells. Uptake by the tumor can usually be detected with a PET scanner 45–90 min after FDG injection (Fig. 1). The limited anatomical information obtained from FDG-PET alone has been improved by integrated PET/CT or a PET/MR scanner that provides fusion images of PET with CT or MRI [26–28]. FDG-PET has been found to be helpful for primary tumor detection and diagnosis, staging of locoregional and distant metastases, and in monitoring response to therapy. In a pre-operative setting, high FDG uptake by tumors was observed, particularly in ductal carcinomas [29]. FDG uptake itself, however, is not tumor specific, and it can be difficult to distinguish between malignant and benign breast cells. Moreover, falsepositive results can occur when activated inflammatory cells such as granulocytes and macrophages exist [30]. For early detection and diagnosis of breast cancer, the ability to detect non-palpable, small malignancies less than 1 cm in diameter is desirable; however, whole body FDG-PET has not been extensively used for this purpose because the spatial resolution of previous-generation clinical PET cameras is limited [8, 31]. High-resolution, high-sensitivity positron emission mammography (PEM) has been developed for detection and diagnosis of early-stage breast cancer (Fig. 2). PEM using FDG can detect primary breast cancer lesions as small as 3 mm in diameter [32, 33]. Its clinical utility for screening or as an adjunct to mammography has to be demonstrated by future studies.
FLT-PET imaging The pyrimidine analogue PET tracer 18F-fluoro-L-thymidine (FLT) has been developed to image increased cellular DNA synthesis. FLT-PET imaging shows normal physiological uptake in liver, bone marrow and the urinary tract (Fig. 3). In breast cancer patients, small studies have been reported. In a group of 12 breast cancer patients, FLT uptake was seen in 92 % of primary breast tumors and 87 % of axillary lymph node metastases [34]. Another
Breast Cancer Fig. 1 Typical images of whole body FDG-PET/CT showing breast cancer. Both Maximumintensity projection (MIP) image (a) and PET/CT fusion image (b) showed nodular lesion of 1.5 cm in diameter in lt breast of a 64-year-old woman. Following core needle biopsy revealed invasive ductal carcinoma
study compared FDG and FLT for monitoring and predicting tumor response to chemotherapy in 14 patients with primary or metastatic breast cancer. This study showed a strong correlation between the percentage decrease in FLT uptake within the tumor 2 weeks after initiating chemotherapy and the reduction in tumor size measured by CT at a later interval (average, 3.3 months). No correlation was found between FDG uptake changes over the first 2 weeks and these response measurements [35]. Based on these results, FLT-PET may help predict patient response to therapy [36].
Hormone receptor PET imaging Up to 70 % of breast cancer patients show tumors positive for hormone receptors. The majority of them are positive for estrogen receptor (ER) and more than 95 % of tumors positive for progesterone receptor (PR) are also ER-positive. Immunohistochemical determination of ER and PR expression at the time of primary diagnosis is a part of standard care. Anti-hormonal treatment strategies are based on hormone receptor expression, which is predictive of response to such treatment. Hormone receptor expression, however, can vary between primary and recurrent tumors in approximately 30 % of cases [37, 38]. The other study demonstrated that the discordance between the ER status of the primary tumor and the distant metastases was 41 % for bone marrow metastases, and 44 % for liver metastases [39]. In addition, anti-hormonal treatment induces ER loss in a number of patients with acquired hormonal resistance [40]. Thus, monitoring hormone receptor expression in
primary tumor and metastatic sites throughout the course of the disease might help a physician determine if anti-hormonal treatment should be used during the different phases of treatment. To monitor hormone receptor status in a noninvasive and repeated fashion, the PET tracer 16a-18Ffluoro-17b-estradiol (FES) was developed as a receptor ligand for ER [24]. Several studies using FES-PET have been performed in breast cancer patients and revealed the correlation of FES tumor uptake with immunohistochemical ER tumor density [41–44]. These studies suggested a potential role for FES-PET in assessing ER status, especially in patients with multiple tumors or tumors that are difficult to perform a biopsy on. Comparing the tumor uptakes of FES and FDG, as well as ER status among 43 patients showed an 88 % overall agreement between FES uptake and ER status. In contrast, there was no observed correlation either between FDG uptake and ER status or between FES and FDG uptake [41]. In 47 patients with immunohistochemically ER-positive tumors, FES-PET was performed at baseline either prior to or shortly after the initiation of anti-hormonal therapy. FES uptake by tumors at baseline was subsequently compared with the response determined by a combination of clinical assessment and modified RECIST criteria 6 months after the therapy. In patients with low FES uptake by tumor lesions at baseline (n = 15), no response was shown. In a group comprising 32 patients with a high FES tumor uptake at baseline, 34 % of the patients responded to anti-hormonal therapy [45, 46]. Therefore, FES-PET could not be recommended as a routine imaging technique for the workup of a breast cancer patient. It could, however, be useful for predicting response to anti-hormonal therapy.
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Breast Cancer Fig. 2 Typical images of PEM showing breast cancer. a Mediolateral oblique (MLO) view of PEM; b cranio-caudal (CC) views of PEM; c MIP image of whole body PET/CT. Within lt breast of a 73-year-old woman, PEM images could visualize a lesion of 7 mm in diameter that whole-body PET/ CT scanner could hardly detect. Courtesy of Dr. Masami Kawamoto, Yuai-Clinic, Yokohama, Japan
HER2 PET imaging HER2, which is overexpressed in 25–30 % of breast cancer patients is involved in tumor cell survival, proliferation, maturation, metastasis, and angiogenesis [47, 48]. Trastuzumab, a humanized monoclonal antibody against HER2 is widely used and targeting HER2 with trastuzumab is a well-established therapeutic strategy for HER2-positive breast cancer [49–53]. HER2 expression is routinely determined using immunohistochemistry (IHC) or fluorescence in situ hybridization [54], however, technical problems can arise when lesions cannot be easily accessed by core needle biopsy [55]. In addition, HER2 expression can vary during the course of the disease [56] and even between tumor lesions in the same patient [57]. To overcome these problems, a novel non-invasive technique such as HER2 PET imaging is required to determine HER2 expression. So far, full-length HER2 monoclonal antibodies have been labeled with 124I, 86Y, 76Br, 89Zr, and 64Cu for HER2 PET imaging [58, 59]. The smaller HER2 targeting antibody fragments, proteins, and peptides have been labeled with 18F, 68Ga, 64Cu, 124I, and 76Br for HER2 PET imaging [58]. With use of 64Cu-trastuzumab PET imaging technique, for example, primary tumor lesions larger than 2 cm in diameter and metastatic brain lesions larger than 1 cm in diameter could be visualized [59, 60]. The typical 64Cu-DOTA-trastuzumab PET images within HER2-positive breast cancer patients are shown in Fig. 4. In human subjects, an autoradiogram of a frozen section prepared from the removed tumor specimen revealed high accumulation in the area where HER2-positive cells were
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Fig. 3 Normal uptake of FLT-PET/CT. An MIP image of whole body FLT-PET/CT in a 64-year-old woman. FLT has been developed to visualize the activity of DNA synthesis that is increased in tumor cells compared to normal cells. Physiological high uptakes of FLT were also shown in normal organs of liver, bone marrow and the urinary tract
seen by IHC (Fig. 5), confirming the HER2 specificity of Cu-DOTA-trastuzumab PET imaging. Another HER2 PET imaging technique, 89Zrtrastuzumab PET imaging, also have succeeded to visualize
64
Breast Cancer Fig. 4 64Cu-DOTAtrastuzumab PET images of HER2-positive breast cancer and metastatic brain lesion. a Primary lesion of HER2positive breast cancer in a 69-year-old woman was visualized by whole body PET/ CT with use of 64Cu-DOTAtrastuzumab. Compared to the normal breast tissue, higher uptake was found within the tumor. Upper panel axial PET/ CT fusion image; lower panel magnified PET/CT fusion image (94). b Metastatic brain lesion in a 54-year-old woman having HER2-positive breast cancer was also visualized by 64CuDOTA-trastuzumab PET/CT (upper panel). A significant uptake was found in the areas corresponding to the brain metastatic lesion that was detected by MRI (lower panel)
HER2 positive tumor in a human. Due to the relatively longer half-life of Zr-89, 89Zn-trastuzumab provides clearer images; however, it induces higher radiation exposure [61]. In contrast, the shorter half-life of 64Cu induces lower radiation exposure but provides images with non-specific activity in the blood [59, 62]. Recently, several novel HER2 inhibitors have been developed and approved, including lapatinib, pertuzumab, and trastuzumab emtansine (T-DM1). Monitoring changes in HER2 expression at tumor sites may help physicians to determine which kind of HER2 inhibitors should be used during the different phases of treatment or if other nonHER2 inhibitors should be used instead. Preclinical results with HER2 imaging are abundant and promising; however, clinical data are still limited. The findings with clinical HER2 PET imaging may support the further development and exploration of the potential of this technique.
Other targets for PET imaging of breast cancer Triple-negative breast cancer, a type of breast cancer that is immunohistochemically negative for ER, PR, and HER2, typically has a poor prognosis [63–65]. Much research is
ongoing to identify the biological processes and targets that drive the behaviors of triple-negative breast cancer. Molecular imaging of these targets may aid target identification, drug development, and in predicting and evaluating response to therapy. For example, EGFR overexpression is seen in 57 % of triple-negative breast cancers. Several tracers have been developed for EGFR imaging, including radiolabeled EGFR tyrosine kinase inhibitors, epidermal growth factor, and EGFR antibodies [66]. The EGFR-directed monoclonal antibody cetuximab has been successfully radiolabeled with 64Cu at our institute [67].
Future direction of molecular imaging with PET Molecular imaging of breast cancer is not commonly used in daily clinical practice; however, its applications are expected and promised for improving breast cancer management. We have reported results made with sensitive PET molecular imaging techniques but these techniques still have limitations, including feasible capacity and spatial resolution, which impede early tumor detection. The resolutions of PEM and the latest generation of PET/CT
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Breast Cancer Fig. 5 HER2 specificity of 64 Cu-DOTA-trastuzumab. a HER2-positive breast cancer in a 55-year-old woman; b metastatic brain tumor in a 61-year-old woman having HER2-positive breast cancer. Frozen section specimens removed from the lesions showing high uptake on 64CuDOTA-trastuzumab PET/CT images (upper panels) were used for IHC (middle panels) and autoradiogram (lower panels). High accumulations of autoradiogram (red arrows) were observed in the area where HER2-positive cells (black arrows) were seen by IHC, confirming the HER2 specificity of 64Cu-DOTA-trastuzumab PET imaging in human subjects
and PET/MR scanners have improved and may lead to improved anatomical interpretation of the images. In addition to the innovations in imaging modalities, the indirect combination of PET imaging and other novel modalities such as optical imaging could serve other purposes. The molecular target and its tracer for the novel modality still have to be validated for clinical use. In a combined setting, more sensitive PET imaging can be used for the target and tracer validation. Thus, molecular imaging with PET could prove to be a powerful tool for novel tracer discovery and development. Another potential application of molecular PET imaging could lie in clinical trials. In combination with pharmacokinetic and pharmacodynamic studies, molecular imaging studies in a clinical trial would provide a more powerful approach to explore appropriate ways of using molecularly targeted drugs. Moreover, during preclinical phase or phase 0 trials, molecular imaging with
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PET can provide proof of concept and further the development of new therapeutic agents. Acknowledgments The authors thank Dr. Masami Kawamoto for providing appropriate PEM images. The authors thank Mr. Takayuki Namma and the staff of Sumitomo Heavy Industries for supporting 64 Cu-DOTA-trastuzumab/cetuximab production, and Mr. Akira Hirayama and the staff of GE Healthcare for optimizing PET/CT scan. We also thank Ms. Riako Onoe for secretarial support during this study. Conflict of interest of interest.
The authors declare that they have no conflict
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