Novel frontiers of dedicated molecular imaging in breast cancer diagnosis

General introduction

Breast cancer (BC) is the most common tumour in women worldwide, with an estimated 252,710 cases and 40,610 deaths in the United States of America (USA), in 2017 (1). Currently, mammography (MG) is the primary screening test for BC (2). However, MG has a limited ability to detect breast lesions in dense breasts (3). Since the detection of BC in an early stage is associated with better prognosis (4), other imaging modalities have been introduced as complementary tools to MG (2). Indeed, magnetic resonance imaging (MRI) is recommended for BC screening in high-risk women (5-7). However, this procedure is limited in patients with obesity, claustrophobia, presence of implanted devices and renal insufficiency (8). In the last years, there has been an increasing interest towards nuclear medicine imaging techniques that enable the visualization of malignant functional changes in breast tissue. Several dedicated molecular imaging devices, including both single-photon and positron emission-based systems, are nowadays used as adjunct modalities to improve the detection of breast malignancies (9). Until now the main approach using dedicated molecular breast imaging (MBI) has been oriented to the complementary aspects provided by this modality for assessing extent of primary disease in patients with newly diagnosed BC and for problem solving, especially in patients with very dense breasts (10). However, a new area of interest has recently been delineated on the basis of the potential visualization of heterogeneity in locally advanced breast cancer (LABC). In this respect, and thanks to a better resolution, dedicated molecular breast devices appear to be more suitable than conventional tomographic imaging (PET/CT, SPECT/CT) opening a new diagnostic window for tumour characterization and biopsy (11). In this review we discuss these advances in dedicated breast imaging with an emphasis on recently introduced dedicated devices and radiotracers.

Dedicated nuclear medicine breast imaging

In Table 1, the characteristics of some commercially available dedicated breast imaging devices are summarized.

Table 1 Summary of characteristics of some commercially available dedicated breast imaging devices
Full table

MBI

The terminology MBI is habitually used to refer to dedicated breast devices based on the use of single-photon emitting radiotracers like ^99mTc-sestamibi (^99mTc-MIBI) (12). One of the first devices using MBI technology was a single detector system known as breast-specific gamma imaging (BSGI) developed by Dilon Diagnostics (Newport News, Virginia, USA) (13). More recently, dual-head detector MBI systems like Discovery NM750b and LumaGem 3200s were introduced by GE Healthcare (Milwaukee, Wisconsin, USA) and by Gamma Medica, Inc. (Northridge, California, USA), respectively (14). All these devices are generically included in the MBI modality using a positioning similar to that of MG. In particular, the breast is placed between a compression paddle and the detector for BSGI or between two detectors when using the MBI device. The advantages of single-head configuration are lower costs and the possibility to perform a biopsy using an available complementary tool (15,16). The advantages of dual-head configuration are higher spatial resolution and therefore a potentially higher detection rate of small breast tumours and the possibility to use lower injected doses of ^99mTc-MIBI (17,18). The clinical protocol consists of an intravenous administration of the radiotracer (740–1,100 MBq ^99mTc-MIBI for single-head or 150–300 MBq for dual-head systems) into the arm contralateral to the breast lesion. Image acquisition starts 5–10 minutes after injection of the radiotracer and includes acquisitions of 8–10 minutes in both craniocaudal (CC) and mediolateral oblique (MLO) projections of each breast (Figure 1), with a duration of approximately 40 minutes in total per study (19). Since for MBI positioning is analogous to that of MG, nuclear medicine technologists need to receive an additional training in mammographic positioning. MBI images are interpreted according to a functional BI-RADS classification lexicon (19,20). Sun et al. reported a meta-analysis including a total of 19 studies on clinical usefulness of MBI for diagnosis of BC. The authors showed pooled sensitivity of 95% (95% CI: 93–96%) and pooled specificity of 80% (95% CI: 78–82%) for detecting BC, including eight studies and 2,183 lesions (21). MBI examinations are well tolerated by patients, no preparation (e.g., fasting) is required and the acquisition is performed in a comfortable upright position of the patient. Nevertheless, MBI examinations require the use of ionizing radiation. Newest MBI devices allow a reduced administered dose of 150–300 MBq ^99mTc-MIBI (18) resulting in an effective whole body dose of 1.2–2.4 mSv (22).

Figure 1 (A) Breast-specific gamma imaging (BSGI) device with in foreground the gamma camera detector and a compression paddle to immobilize the breast during image acquisition. BSGI craniocaudal (B) and latero-oblique (C) images of both breasts in a 49-year-old woman showing an 18-mm invasive ductal carcinoma in the left breast.

Positron emission mammography (PEM)

PEM is a dedicated breast imaging device, commercially introduced by CMR-Naviscan Corporation (Carlsbad, California, USA), based on the use of positron-emitting radiopharmaceuticals like ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG). PEM uses two flat detectors with mild compression of the breast and the patient in seated position. The PEM images are comparable to CC and MLO projections of MG (23). Unlike whole body positron emission tomography combined with computed tomography (PET/CT), PEM allows the detection of small breast lesions using lower ¹⁸F-FDG doses with shorter acquisition times (24). The clinical PEM imaging protocol includes an intravenous injected dose of ¹⁸F-FDG (approximately 370 MBq) into an antecubital vein contralateral to the breast lesion. Prior to ¹⁸F-FDG injection, all patients have to fast for at least 4–6 hours and the blood glucose level has to be below 200 mg/dL. Images are acquired 60–120 minutes after radiotracer injection and require approximately 20 minutes per breast (10 minutes per CC and 10 minutes per MLO views) (25). PEM images are interpreted according to a functional BI-RADS classification (26). The sensitivity of PEM has been found to be 93% for known index lesions as small as 3 mm. Although this sensitivity is comparable to MRI, specificity of PEM is higher than MRI (74% vs. 48%) for the identification of unsuspected lesions (27). A meta-analysis evaluating 8 studies and 873 patients showed pooled sensitivity and specificity for PEM of 85% (95% CI: 83–88%) and 79% (95% CI: 74–83%) respectively (28). Advantages of PEM in comparison to PET/CT are in depicting small lesions as well as the possibility to perform breast biopsies using a special module (29). Despite the radiation exposure, PEM is considered an alternative tool in case of contraindications for MRI like overweight, claustrophobia, presence of implanted devices and renal insufficiency.

Dedicated breast PET devices

MAMmography with Molecular Imaging (MAMMI)-PET is a new breast dedicated PET system. MAMMI-PET is manufactured by Oncovison (Valencia, Spain) with a single or double full ring of detectors for tomographic image reconstruction with high resolution (1.6 mm). MAMMI-PET does not require compression of the breast; actually, the patient is positioned in prone position with hanging breast (30,31) as illustrated in Figure 2. Although there are few studies on MAMMI-PET, this device enables the visualization of small tumours as well as tumours with heterogeneous ¹⁸F-FDG uptake (11,32). In an extensive evaluation including 234 index lesions of at least 5 mm size in BC patients, MAMMI-PET was found to be more sensitive than standard PET/CT for lesions within the field of view (FOV) (33). Similar to other dedicated breast imaging devices (23), proper positioning of the breast is essential for MAMMI-PET examinations and some difficulties of the device to visualize breast lesions located close to the pectoralis muscle have been reported causing the need of a technical optimization of the bed for prone patient positioning (33). The MAMMI-PET protocol provides an intravenous administration of the radiotracer (180–240 MBq of ¹⁸F-FDG) according to the body mass index. Images are obtained 60–120 minutes after the radiotracer injection with an acquisition time of approximately 5–15 minutes per breast depending on the breast size and type of device used (single or double ring) (11). The use of standardized terminology to report MAMMI-PET images has not been defined yet. One of the advantages of MAMMI-PET is the ability to perform semiquantitative analysis by measuring the standardized uptake value (SUV). Compared to the whole body PET/CT, MAMMI-PET offers lower doses as well as shorter acquisition times.

Figure 2 MAMMI-PET device for breast imaging with patient in prone position (A) with hanging breast configuration thanks to the special bed and ring camera (B). On the right, internal view of the scanner showing a version with a single (C) and a double (D) full ring of detectors. MAMMI, MAMmography with Molecular Imaging; PET, positron emission tomography.

Recently, another dedicated breast PET (dbPET) device, known as O-scanner (Shimadzu, Kyoto, Japan) has been developed (34). This device consists of 36 detector modules arranged in three contiguous full rings with an estimated spatial resolution of 1.5 mm at the centre of FOV. Working protocols using O-scanner are comparable to the MAMMI-PET but acquisition times are shorter due to a transaxial effective FOV of 180 mm. Nishimatsu et al. have evaluated the diagnostic performance of O-scanner compared to whole body PET/CT including 179 index BC lesions in 150 patients. Based on pathological findings, the authors did not find a significant difference between both devices in term of sensitivity per patient and per lesions (95% and 92% for O-scanner vs. 95% and 88% for PET/CT, respectively). However, tumour-to-background ratios were significantly higher for O-scanner increasing levels of confidence in the diagnosis by observers thanks to higher tumour conspicuousness.

The same group of investigators also evaluated a dbPET with an open end through which the patient’s arms can be placed. This device known as C-scanner, consists of 24 detector blocks arranged in two contiguous rings. Its evaluation in 159 women showed a lesion-based sensitivity of 81.1% increasing to 93% when lesions outside the FOV of the system were excluded (35).

Current indications

Currently, dedicated nuclear breast imaging is considered as a complementary imaging tool to MG and ultrasound (US) in patients with the following conditions: (I) with newly diagnosed BC to exclude multicentric, multifocal or contralateral disease and to assess response to neoadjuvant chemotherapy; (II) with suspected recurrence, especially when previous malignancy is occult on MG and US; (III) with indeterminate breast lesions and remaining diagnostic concerns; (IV) with technically difficult breast imaging like dense breast tissue, prosthesis; (V) with contraindication to MRI like claustrophobia, presence of implanted devices, renal insufficiency (19).

Dedicated breast devices for radioguided biopsy

In addition to dedicated breast imaging various complementary tools using radioguidance for lesion localization and vacuum-assisted biopsy have recently been developed.

MBI-guided biopsy

MBI-guided biopsy is a tool based on the use of ^99mTc-MIBI as guiding radiotracer. One of the first developed devices (GammaLōc^®, Dilon Technologies, Newport News, USA) has been validated and approved by the Food and Drug Administration (FDA) in 2009 for complementary use with the BSGI camera. The tool is equipped with a small, single-head detector with a slant-hole collimator for dedicated stereotactic localization (Figure 3). The patient is in seated position and the breast is mildly compressed between the grid paddle and the detector. The biopsy protocol is based on a 5-step procedure: (I) scout image and two stereotactic images (±20 degree angle) are obtained to determine the positioning of the lesion; (II) the software measures the index lesion coordinates; (III) the trocar needle is placed into the breast; (IV) subsequently, the verification of the correct needle placement is performed using Cerium-139 (¹³⁹Ce) as source; (V) this is followed by the biopsy using a vacuum-assisted device (VAD), a clip marker is placed at the biopsy site, a postbiopsy specimen scan is performed to confirm adequate biopsy specimens and postbiopsy MG is acquired to evaluate the placing of the clip (16). Recently, the first clinical study has been performed including 38 patients (38 lesions). This biopsy tool was technically successful in all ^99mTc-MIBI avid lesions. Indeed, all biopsy samples were radioactive and proved adequate for histopathology analysis. The mean procedure time was 71 minutes (range, 44–112 minutes). All biopsy procedures were well-tolerated by the patients (two hematomas and three vasovagal reactions). Based on these results, this new biopsy tool appears to be technically feasible to obtain accurate radioactive samples (36). However, further studies are needed to investigate the role of this device in the clinical work-up.

Figure 3 Biopsy device for complementary use with the BSGI device now equipped with a grid paddle for both breast immobilization and vacuum-assisted biopsy. For calculation of the depth of the primary breast lesion two stereotactic images are acquired using a slant-hole collimator placed oppositely to the biopsy device. BSGI, breast-specific gamma imaging.

PEM-guided biopsy

PEM-guided biopsy is a biopsy device using principally ¹⁸F-FDG as radiotracer. This device has been validated in 2001 (37) and has been approved by FDA in 2008. PEM-guided biopsy is a portable and compact device comprising two plate PET detectors and stereotactic technology (Stereo Navigator^TM Naviscan, Carlsbad, California, USA) to calculate the coordinates of the breast lesion. The patient is in seated position and the breast is placed between both PET detectors with mild compression. The biopsy procedure involves five steps as follows: (I) initial biopsy scan to identify and target the lesion; (II) alignment scan to verify the correct position of the needle using Germanium-68 (⁶⁸Ge) as line source; (III) prebiopsy scan to confirm the correct positioning with biopsy needle in the breast; (IV) postbiopsy scan to ensure appropriate lesion is removed and (V) specimen scan to confirm adequate biopsy specimens. Postbiopsy MG is performed to ensure that clip placement corresponds with the biopsy site (29). To date, one multicentre study has been performed including 19 patients (24 lesions) showing that this biopsy device proved technically successful in all cases and was well-tolerated by patients. The authors reported a median procedure time of 32 minutes (range, 19–119 minutes), and 58% (14/24) of biopsied lesions were smaller than 10 mm (29). Based on these results, PEM-guided biopsy appears to be a promising biopsy tool for ¹⁸F-FDG-avid breast lesions. In particular, this device allows re-imaging of the biopsied breast and biopsy sampling to ensure adequate biopsy without injection of an additional radiotracer. Recently, Argus et al. evaluated the feasibility of performing diagnostic PEM and PEM-guided biopsy on the same day, including 20 patients (27 lesions). The authors showed that it is possible for most patients (24/27 lesions) reducing radiation dose for both patient and medical staff (38).

MAMMI-guided biopsy

Recently, a semi-robotized system for MAMMI-guided biopsy tool was developed in the context of the European Union FP7-SME-2013-606017 MAMMOcare project and has technically been validated in 2017 (39). This biopsy tool comprises a dedicated dual-ring PET-detector with automated lesion localization software together with a vacuum-assisted biopsy needle attached to a robot-controlled arm (Figure 4). The patient is in prone position and the breast is placed in the opening of the device without compression (hanging freely). The biopsy procedure requires five steps. (I) First, acquisition of the whole hanging breast with closed PET-ring is acquired to determine the index lesion coordinates, afterward the system automatically calculates the shortest needle trajectory and subsequently positions the biopsy needle in that trajectory. (II) Second, scanning with the closed PET-ring and mild compression is obtained including only the part of breast with the index lesion. This step aims to adjust the new index lesion coordinates due to breast compression. (III) Third step involves placing a biopsy needle into the index lesion, with the affected breast in compression and opened PET-ring. (IV) A new acquisition is performed with needle in place to verify the correct needle position in the index lesion. (V) Finally, biopsy is performed manually using VAD. Based on phantom experiment, the estimated time per lesion is approximately 30 minutes (39). Until now, only a technical evaluation has been performed showing an accuracy of 0.5, 0.6 and 0.4 mm for the x/y/z-axes. The system has been developed to optimize both conventional histopathology and ribonucleic acid (RNA)-based molecular diagnostics but no clinical study has yet been reported in the current literature.

Figure 4 Prototype of the MAMMOcare device composed of a special bed for prone position of the patient, a PET-ring detector for image acquisition and a semi-robotized arm for vacuum-assisted biopsy (A). For biopsy, the PET-ring moves from a closing stand to an opening one (B) facilitating introduction of the needle (C). PET, positron emission tomography.

Future applications

Targeted biopsy and precision breast cancer medicine

In the last years, the interest toward molecular analysis in routine practice has been increasing. This analysis is based on the tumour’s gene expression profiles measuring RNA levels for selected genes. Several genomic tests have been developed for breast tumours (40,41). Among them, the MAMMAPrint (Agendia, Amsterdam, The Netherlands) test measures the expression of 70 genes through microarray analysis (42) for predicting the risk for tumour recurrence and for better selecting patients for adjuvant chemotherapy (43). Therefore, the goal of breast biopsy is to obtain an adequate sampling not only for increasing the likelihood of finding tumour tissue, but also for assessing the tumour subtype and genetic expression profile. This will facilitate stratifying patients and planning target-specific therapies in the context of a recently introduced concept of precision medicine in BC (44). Buyse et al. reported that only 81% of the tumour samples obtained with US-guided biopsy contained sufficient RNA for genetic analysis (45). Radioguided biopsy offers the possibility to obtain radioactive tumour samples that correspond with vital tumour areas clear of both necrotic and stromal tissue. Therefore, radioguided biopsy may be able to obtain sufficient RNA in the sampling useful for genetic expression profiles based on the principle of radiotracer uptake that associates areas with higher ¹⁸F-FDG uptake with those parts of the tumour with increased glycolysis, representing the most proliferative parts of the tumour. As reported in the literature, high ¹⁸F-FDG uptake in the primary tumour is associated with poor prognostic features such as grade 3 and triple negative BC (46,47). A similar working model is assumable using ^99mTc-MIBI which also shows a positive association between the level of tracer uptake in breast tumours and the amount of viable tumour tissue. Hence, the possibility for biopsy of the most proliferative part of the tumour may increase the accuracy of tumour sampling for genetic analysis, and consequently lead to better individual treatment planning with possible improvement of patient outcome.

This new clinical possibility for targeted biopsy using radioguidance was the rationale for design of the precision biopsy device described in the above mentioned MAMMOcare project. This may be of interest in LABC, principally in tumours with heterogeneous uptake (Figure 5) enabling selection of those areas with highest tracer uptake, avoiding sampling of necrotic or fat tissues. Indeed, Koolen et al. reported non-correspondence of ≥2 cm between the core biopsy location indicated with a marker and the tumour area with highest ¹⁸F-FDG uptake in 28 (14%) of 203 tumours in stage II and III BC (48). Further studies are needed to evaluate the feasibility of this potential application.

Figure 5 Heterogeneous uptake of ^99mTc-MIBI in invasive ductal breast carcinoma with a 3-cm lesion (A) and a 5-cm lesion (B) as shown using breast-specific gamma imaging. In another patient, heterogeneous uptake of ¹⁸F-FDG is seen after the first cycle of neoadjuvant chemotherapy in the superior part of the lesion (D), which was homogenous at baseline acquisition (C) with a dedicated hanging breast PET scanner. ¹⁸F-FDG, ¹⁸F-fluorodeoxyglucose; PET, positron emission tomography.

Use of new radiotracers for MBI, PEM, MAMMI

^99mTc-MIBI and ^99mTc-tetrofosmin are currently used as gamma-emitting radiotracers to detect BC. ^99mTc-MIBI is the preferred radiotracer for MBI due to its uptake inside mitochondria (49), thus reflecting mitochondrial activity and electric transmembrane potential of BC cells (50,51). ^99mTc-tetrofosmin is similar to ^99mTc-MIBI with localization mostly within cytosol (49,52,53). Another potential gamma-emitting radiotracer is ^99mTc-maraciclatide, also known as ^99mTc-NC100692, which is an angiogenesis marker. Indeed, ^99mTc-maraciclatide binds to receptors of integrins, such as αvβ3, which are significantly upregulated in endothelial cells during angiogenesis (54). In a series evaluating 39 patients ^99mTc-maraciclatide showed comparable lesion uptake to ^99mTc-MIBI in both malignant and benign breast lesions (55). Furthermore, as shown in Table 2, there are new radiotracers like ^99mTc-annexin V for apoptosis (56), ^99mTc-bombesine for gastrin-releasing peptide receptor (57) and ¹²³I-labeled estrogen receptor (ER) ligand (58).

Table 2 Some existing and potential radiotracers for dedicated molecular breast imaging
Full table

Regarding the positron-emission radiotracers, ¹⁸F-FDG is the most used tracer in BC. ¹⁸F-FDG is a glucose analogue, and so it is used for assessing the metabolism of breast tumour cells. In the last years, several new radiotracers (as shown in Table 2) have been developed: (I) ¹⁸F-fluoromisonidazole (¹⁸F-FMISO) as a marker of tumour hypoxia; (II) ¹⁸F-fluorothymidine (¹⁸F-FLT) reflecting cell proliferation; (III) ¹⁸F-galacto-recognizing arginine-glycine-aspartic acid (¹⁸F-Galacto-RGS) as an angiogenesis tracer; (IV) ¹⁸F-annexin as an apoptosis radiotracer; (V) radiopharmaceuticals with receptor affinity like ¹⁸F-fluoroestradiol (¹⁸F-FES) for estrogen receptor (ER); ¹⁸F-fluoro furanyl norprogesterone (¹⁸F-FFNP) for progesterone receptor (PR), and ⁸⁹Zr-trastuzumab for human epidermal growth factor receptor 2 (HER2) (59).

Dedicated hybrid systems

Another important advance in BC imaging is the development of dedicated hybrid devices combining anatomic and functional imaging. Various prototypes concerning these hybrid systems have been introduced in recent years.

Dual-modality breast tomosynthesis (DMT)

DMT is a new hybrid scanner, which includes the digital X-ray detector and an MBI detector. Both detectors rotate around a common axis with mild breast compression (60). DMT provides co-registered anatomic and functional breast images in three dimensions (3D). Although the results of the clinical pilot studies are encouraging, further studies will be necessary in order to optimize patient positioning and the acquisition protocol as well as to assess the additional value of this device relative to the separate modalities (60).

Dedicated breast SPECT/CT

Recently, a new dedicated hybrid system has been developed using single photon emission computed tomography combined with low-dose CT technology (breast SPECT/CT) (61). Compared to planar devices, dedicated breast SPECT/CT enables 3D imaging, and functional and anatomic fused images, without the necessity for breast compression, making it more comfortable for the patients and with possibility to perform in vivo quantification of ^99mTc-MIBI uptake.

MBI/US system

An integrated MBI/US prototype composed of an upper US mesh panel and a lower MBI detector has recently been developed (62). An optical tracking system provides the real-time position of the US probe relative to the breast lesion. A software application enables projection of the US FOV onto the MBI images. Therefore, this prototype system allows to integrate the anatomical US images with the functional MBI images. Hence, MBI/US may resolve positive findings on MBI that are occult on MG, as well as obtain a better lesion correlation between US and MBI (62).

Concluding remarks

The increasing use of dedicated devices for molecular imaging in BC goes hand in hand with an evolution concerning their clinical applications. Based on the initial experience with these devices in detection of small breast lesions, there is a growing interest in studying the metabolic heterogeneity in LABC, opening a future window for tumour characterization and selection of areas for biopsy. In the context of precision medicine, the contribution of dedicated BC imaging using different radiotracers may become important not only to personalize therapeutic approaches on an individual basis, but also to monitor primary tumour response. Finally, the incorporation of allied technologies tends to gradually transform the current generation of dedicated nuclear medicine devices into hybrid systems with the ability to simultaneously evaluate the functional and morphological characteristics of BC.

Acknowledgments

The authors thank Annette F. van der Hoeven for her support concerning the figures. The authors are grateful to Marianne Valdés Olmos for reviewing and editing the manuscript.

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Cancer Research for the series “Update of Current Evidences in Breast Cancer Multidisciplinary Management”. The article has undergone external peer review.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tcr.2017.10.28). The series “Update of Current Evidences in Breast Cancer Multidisciplinary Management” was commissioned by the editorial office without any funding or sponsorship. AMS and RM served as the unpaid Guest Editors of the series. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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