Imaging diagnosis of metastatic breast cancer

Numerous imaging modalities may be used for the staging of women with advanced breast cancer. Although bone scintigraphy and multiplanar-CT are the most frequently used tests, others including PET, MRI and hybrid scans are also utilised, with no specific recommendations of which test should be preferentially used. We review the evidence behind the imaging modalities that characterise metastases in breast cancer and to update the evidence on comparative imaging accuracy.


Introduction
Due to the rising incidence of breast cancer, it is estimated that breast cancer-related deaths will increase by 43% globally from 2015 to 2030 [1]. At presentation, 4-10% of breast cancers are metastatic [2] and accurate staging of breast cancer is crucial for guiding treatment and optimising patient outcome. Imaging provides information regarding the presence, extent and distribution of metastatic disease. The aim of this review is to critically evaluate the current imaging techniques for the detection of metastatic disease in breast cancer, highlighting the new and emerging methods to optimally stage patients with advanced disease.

Literature search strategy and selection criteria
Using a software based on statistical text mining and machine learning methods [3], we identified 33 relevant articles in PubMed on staging of advanced breast cancer, metastatic breast cancer, bone disease and distant metastases between 2009 and 2019. We identified papers in English language, both original studies and review articles. Additionally, we searched the references listed for additional relevant papers, using a total of 40 scientific papers.

Staging of breast cancer for metastatic disease
The most common staging system for breast cancer is the American Joint Committee on Cancer (AJCC) TNM [4], which is based on tumour size and the degree of locoregional invasion by the primary tumour (T), the extent of regional lymph node involvement (N) and presence (or absence) of distant metastases (M) [5] ( Table 1). M1 indicates the presence of any metastases to distant organs, implying a stage IV disease (regardless of the T or N status). Breast cancer may be stage IV at first diagnosis, or it can be recurrent from previous breast cancer. Stage IV disease showed a 5-year survival rate of approximately 22%, although this rate varies according to other factors, such as the hormone receptor status [6]. The median survival for patients with breast cancer and bone metastases is 65 months in the oestrogen/progesterone-receptor-positive (ER/PR-positive) groups, and 40 months in both the human epidermal growth factor receptor 2 (HER-2) positive and 'triple-negative' group [7].
Multi-modality imaging is widely used clinically for disease staging. However, all cancers are potentially systemic diseases and whole-body imaging techniques, such as whole-body hybrid imaging (PET-CT and/or PET-MRI) or whole-body magnetic resonance imaging (WBMRI) are increasingly performed to reflect this.
The approach to the patient with suspected advanced breast cancer There are now effective lines of treatment for patients with metastatic disease, which can improve symptoms, prevent complications and prolong life [8][9][10][11][12][13]. Furthermore, oligometastatic disease (typically < 5 metastases), may be suitable for aggressive local therapy in combination with systemic treatment. Hence, the combined assessment of local disease and whole-body staging, together with better understanding of the tumour molecular characteristics, is key to individualised treatment [14,15].
The detection of breast cancer metastases in breast cancer varies according to disease stage. In early breast cancer, routine staging evaluations are directed at locoregional disease [16] as in stages T1 and T2 primary breast cancers, the incidence of distant metastases is < 2% [17] compared with 15-20% in stage T3 or T4 [18]. Accordingly, the American Society of Clinical Oncology (ASCO), the European Society for Medical Oncology (ESMO) and the Royal College of Radiologists (UK), in their clinical practice guidelines for breast cancer (updated in 2018, 2019 and 2014, respectively), do not recommend routine imaging for the M-staging of asymptomatic patients with early  [16,19]. The incidence of bone metastases in ER/PR positive cancer, which may establish upwards of 10-20 years after initial diagnosis [20], is significantly higher than the incidence of other site of metastases, namely is reportedly 18.7% (in luminal A subtype) to 30.4% (in luminal B subtype) [21]. Furthermore, the molecular subtype of the breast cancer influences the likelihood of metastatic spread: women with ER/PR-negative tumours have a higher risk of metastatic relapse in the first 5 years [20,21] compared with ER/PR-positive tumours.
Current international guidelines lack consensus as to whom and how to image for metastatic disease [22]. Traditionally, high-risk patients were screened for occult metastases using bone scintigraphy (BS), chest radiography and abdominal ultrasound or bone scintigraphy and CT of the chest abdomen and pelvis. However, the use of next generation imaging, such as hybrid imaging (PET-CT and/or PET-MRI) and WBMRI, has increased over the years [17]. Indeed, traditional conventional imaging frequently detects bone disease and visceral metastases in late stages, which are associated with poorer outcomes. Moreover, these methods often fail to demonstrate the heterogeneity of the tumour biology, leading to delay in the detection of treatment resistance and the opportunity for therapeutic modifications [15].
The ESMO's guidelines recommend performing chest, and abdominal imaging (US, CT or MRI scan) and a bone scan can be considered for patients with clinically positive axillary nodes, large tumours (T3/4) or tumours with aggressive biology. If such methods are inconclusive, dual imaging methods combining functional and anatomical information such as 18 F-FDG PET-CT are suggested [16].
The Royal College of Radiologists (UK) recommends staging with CT of the chest abdomen and pelvis for patients with large (T4) tumours or with heavy lymph node burden (N2 disease) with or without bone scan and a PET-CT for suspected inflammatory breast cancer.
The latest North American National Comprehensive Cancer Network (NCCN) guidelines [23] recommend BS, abdominal CT/MRI (including the pelvis if symptomatic), chest CT/ 18 F-NaF PET-CT, in symptomatic patients or in stage I-IIB breast cancer and abnormal liver function test, elevated serum alkaline phosphatase, localised bone pain. The 18 F-FDG PET-CT is often recommended when the findings of conventional imaging are suspicious or uncertain. BS or 18 F-NaF PET-CT may be bypassed when 18 F-FDG PET-CT has already detected skeletal metastasis. Other requests for imaging may result from multi-disciplinary team discussions, e.g. in patients with triple negative invasive carcinoma, or in ipsilateral recurrence within the breast [24].
Regarding bone metastases, every above-mentioned imaging modality evaluates different aspects of the tumour: BS estimates osseous remodelling and osteoblastic activity, CT reveals bone destruction and/or presence of sclerosis, diffusion-weighted MRI assesses tissue cellularity and PET-CT using FDG tracer evaluates increased glycolytic metabolism [25]. Conventional imaging is limited when detecting small bone metastases: BS may have an unsatisfactory performance for lytic lesions, metastases with low bone turnover and low vascularity. CT usually demonstrates lytic lesions associated with bone destruction, but disease confined to the bone marrow may be missed [25].
In the next section, we review the diagnostic utility of conventional imaging (BS, CT and MRI) and next generation imaging (PET-CT, PET-MRI and WBMRI) for assessing the presence, extent and biological characteristics of bone and visceral metastases in patients with breast cancer.

Radionuclide bone scan Planar bone scintigraphy (BS)
Planar BS is clinically easy to read, widely available and cost effective [26], and has been recommended as the primary technique to detect bone metastases in asymptomatic high-risk breast cancer women [17].

SPECT bone scan
An overall improvement was observed when BS was augmented using single-photon emission computerised tomography (SPECT) in the lower thoracic and lumbar spine, or across the entire axial skeleton (whole-body SPECT) ( Fig. 1) [37,[39][40][41]. On a per-patient basis in breast cancer, SPECT showed a higher specificity of 94% compared with 74% using BS [42]. Although some preclinical SPECT scanners can provide a sub-millimetre spatial resolution, clinical gamma cameras yield a tomographic resolution of about 10 mm [38]. Hence, like planar BS, the spatial resolution of SPECT is limited [41]. Accordingly, the diagnostic effectiveness of SPECT has been questioned and patients with uncertain findings often demand other radiological exams to characterise indeterminate findings [43][44][45].
Combining SPECT with CT partially improves the performance for metastatic bone disease, by lowering the number of equivocal lesions detected on planar BS [26,36,46]. However, such combined technique may not be widely available because of higher equipment costs, and image quality may be reduced by patient movement and CT artefacts [26].

CT
In clinical practice, plain radiographs are often used as an adjunct to BS, to evaluate symptomatic bone pain. Bone scan findings are often corroborated using CT [17], which shows a good specificity although a poor sensitivity (95% and 73% respectively, according to Heindel et al.) [47]. Metastases appear on CT as areas of lucency or sclerosis, and rarely as well-defined radiodensity within the bone marrow [21].
Generally, HER2-expressing breast cancers tend to metastasise to the liver more frequently than ER/PRpositive breast cancers [52,53]. Portal venous phase of CT shows liver metastases as irregular hypodense lesions with peripheral contrast enhancement [54]. Nevertheless, liver metastases may appear isodense with the hepatic parenchyma ( Fig. 2) and their extent may be underestimated or, when diffuse, entirely missed [21].  No differences were observed in the CT appearances of liver metastases according to the molecular hormonal receptor status [55]. Similarly, higher percentages of brain metastases are found in hormone ER/PR-negative breast cancers when compared with the hormone-positive subtypes [52]. Moreover, triple negative breast cancer subtype shows higher risk of developing brain metastases [56]. Performing CT of the brain is commonly induced by clinical symptoms such as mental status change, headache or vomiting/nausea. In this setting, MRI is preferred, where and when available, due to its enhanced sensitivity [21]. From the radiologist's perspective, although innovative treatment may prolong overall survival, a higher rate of cerebral metastases is reported in such patients, as novel therapeutics may not be effective across the blood-brain barrier [57].
Lung metastases from breast cancer may be showed on CT in a number of radiological patterns: singular or multiple pulmonary nodules, endobronchial localisation, air-space consolidation and lymphangitic carcinomatosis, which may simulate other primaries such as pulmonary adenocarcinoma or lymphoma [21] (Fig. 3). Pleural localisation frequently reveals as a unilateral (and ipsilateral to the breast cancer) pleural effusion, with no specific features compared with benign effusions [21].

Conventional MRI
In metastatic breast cancer, malignant cells displace and replace normal bone marrow fat cells causing a reduction in fat content, whereas successful management is associated with return of healthy bone marrow fat [58].
MRI can differentiate healthy from pathological bone marrow acting as an effective and non-invasive test to recognise bone metastases [17,28,59,60]. MRI sequences including T1WI, diffusion-weighted imaging (DWI) and Dixon quantitative chemical shift imaging (which estimates water and fat fraction) can evaluate the anatomical and functional features of bone marrow [58,61]. Therefore, a trained radiologist can discriminate bone metastases (which manifest with nodular focal metastatic lesions or marrow infiltration/replacement) from benign marrow alterations (such as marrow hyperplasia induced by chemotherapy) [28].
Studies evaluated MRI as the primary screening technique for diagnosing skeletal deposits to associate the advantages of high sensitivity and specificity with improved spatial resolution, demonstrating the diagnostic superiority of MRI over BS for identifying bone metastases [62,63]. Particularly, an updated meta-analysis showed a pooled sensitivity of 97% for MRI versus 79% for BS and a pooled specificity of 95% versus 82%, respectively [29].
Additionally, MRI is commonly used to clarify equivocal findings from BS [28] and to detect complications associated with bone metastases (such as compression of spinal cord or nerves), which can alter management decisions [64]. Altehoefer et al. [65] showed how MRI guided the need for local therapy in sites that were negative on BS; Kim et al. [66] highlighted the value of MRI for the evaluation of single 'hot spots' on BS [67]. However, interpretation of bone MRI needs an understanding of the evolution of normal bone marrow with age: indeed in younger patients, highly cellular hematopoietic year-old woman with breast cancer and deranged liver function. The liver appears normal on both CT and T1-W post-contrast MRI but multiple high signal foci are present throughout the liver (white arrows) on the diffusion-weighted sequence in keeping with diffuse liver metastases marrow may make it more difficult to diagnose small metastases [68].
With an 80-82% and 96-98% reported ranges of sensitivity and specificity, respectively [49][50][51], MRI is an appropriate modality to detect hepatic metastases [69]. Breast cancer metastases in liver are typically hypo-to isointense on T1WI, iso-to hyperintense on T2WI and, since breast metastases are frequently hypovascular, they usually show perilesional enhancement [70] in the arterial phase of contrast enhancement. However, hypervascular metastases may also occur, which can be associated with disease progression (Fig. 4). In addition, DWI can aid the detection of small liver metastases easily overlooked on other sequences [69]. Pretreatment enhancement features of liver metastases at MRI, such as the degree of hypervascularity of the tumour rim, may also predict disease progression [71].
For the detection of brain metastases, contrastenhanced MRI has higher sensitivity than CT [72], due to its higher soft tissue resolution and its better detection of parenchymal and leptomeningeal involvement [21]. Lesions are usually supratentorial, and they can be solitary or multiple, arising at the grey-white matter junction and at watershed zones of major arterial territories [73] (Fig. 5). Moreover, MRI showed higher sensitivity and specificity than PET-CT for brain metastases [74] as the high background activity present in the cortex and basal ganglia (due to intrinsic high glucose consumption of these structures) can substantially degrade signal-to-noise ratio of FDG PET [72], therefore adversely affect the ability of PET to detect especially small metastatic lesions.
Nevertheless, according to the updated ASCO's guidelines, clinicians should not perform routine MRI to screen all the breast cancer patients for brain metastases but only in patients with HER2-positive advanced breast cancer because their high incidence of brain metastases [75].
Lungs are frequently involved by breast cancer metastases: with advanced MR techniques, lung metastases may be visualised as foci of high signal on DWI [10].

Advanced imaging
Among the various imaging modalities currently available for distant metastases detection, hybrid techniques which fuse morphological and functional data are the most sensitive and specific, and PET-CT and PET-MRI will probably continue to evolve and become increasingly important in this field. Different imaging modalities are often used in combination to optimally detect bone metastases. Although conventional imaging has frequently been used for cancer staging, these methods have been found to be less sensitive and less specific in providing accurate data in a clinically relevant time frame. Owing to positive recent developments in advanced imaging, the current trend is toward whole-body imaging in a single session. The choice of modality is usually based on the clinical situation and the type of primary tumour. Further research is warranted to further address the impact of these costly and labourintensive imaging methods on treatment strategies and on the course of illness. Below, we discuss recent evidences on advanced imaging methods including PET-CT, PET-MRI and WBMRI. These modalities generally show improvements in diagnostic accuracy for detection of metastases over conventional imaging methods, with the ability to quantify biological processes related to the bone microenvironment as well as tumour cellularity. Comparative studies between conventional and advanced imaging techniques have also been carried out in subjects selected for further investigation after bone scan, and the contribution of hybrid imaging and WBMRI to evaluate bone/visceral lesions or suspicious symptoms have been reported [67].

Hybrid imaging
The use of hybrid imaging (PET-CT and PET-MRI) has increased thanks to the increased access to commercial radiopharmaceutical production facilities and to the widespread availability of scanners [76]. The net clearance of 18F-sodium fluoride ( 18 F-NaF) in breast cancer bone metastases is 3-10 times greater than that in healthy bone, conferring the capacity to detect both osteolytic and osteosclerotic metastases [77]. The mechanism of uptake of 18F-NaF tracer into bones is like that of 99m Tc diphosphonates, being related to local blood flow and osteoblastic activity, with rapid initial uptake into bone mineral as fluorapatite. 18 F-NaF PET-CT has better diagnostic performance than 18 F-NaF PET alone without the CT component [78].
In oncological staging, 18F-fludeoxyglucose ( 18 F-FDG) is the most widely used radiotracer [76]: its uptake in skeletal metastases is pretended to be largely within tumour cells acting as a breast cancer-specific tracer rather than reflecting alterations in the bone microenvironment [79] (Fig. 6).
The Royal College of Radiologists (UK) recommends the consideration of PET-CT for staging breast cancer patients in those with multifocal disease, suspected recurrence when breast MRI is not possible and in symptomatic patients with an equivocal MRI. In addition, breast cancer patients under the age of 40 may benefit from PET-CT in early disease as this may result in upstaging of systemic sequelae [19].
The underlying histologic subtype of breast cancer may also influence the choice of PET imaging. Untreated invasive lobular carcinoma may have poorer 18 F-FDG uptake of the osteoblastic metastases compared with invasive ductal or mixed subtypes [80]. Similarly, previous treatment history is significant, as 18 F-FDG-negative skeletal metastases may show increased sclerotic following successful systemic therapy, which renders tumour cells nonviable even though ongoing reparative osteoblastic activity, as detected by BS or 18 F-NaF PET may endure [81].

PET-CT
There is increasing evidence that PET-CT detects distant metastases with higher sensitivity than conventional imaging [82], although in cases of lobular cancers and low-grade tumours, PET-CT may be less sensitive [83].
Minamimoto et al. [85] prospectively evaluated combined 18 F-NaF and 18  The higher lung tissue contrast of the CT and its lower susceptibility to motion artefacts facilitate the detection of lung lesions [68] and, some authors support PET-CT as currently the best advanced imaging method for detecting lung metastases, with a sensitivity of 89% for PET-CT compared to 82% for WBMRI and 74% for PET-MRI [86,87].
Additionally, PET-CT is useful for the detection of metastatic mediastinal and supraclavicular lymph nodes and a recent meta-analysis [88] reported a sensitivity, specificity, positive predictive value, negative predictive value and accuracy for detecting nodal spread of 84%, 92%, 74%, 82% and 81%, respectively. According to Schmidt et al. [89], PET-CT appears to have an increased specificity for neoplastic axillary and mediastinal lymph nodes compared to WBMRI, namely 90% versus 86%.

PET-MRI
The combination of PET with MRI may benefit from the high soft tissue contrast of MRI with the additional use of multi-parametric MRI. Moreover, PET-MRI systems overcome pitfalls of PET-CT, such as uptake in bowel loops and ureters, which may lead to false positive findings [90].
However, while claustrophobia is not an issue with PET-CT, many patients do experience it with PET-MRI due to a combination of the relatively narrower and longer bore and the use of whole-body anterior surface coils and a head coil required for the MRI portion of the exam [91]. Moreover, PET-CT protocols are usually completed within 30 min, which are faster than PET-MRI that is designed to take advantage of multisequences MRI, resulting in studies that may exceed an hour in length with discomfort of many cancer patients who are unable to remain supine and still for long time due to pain [91]. Although some authors proposed faster and abbreviated PET-MRI protocols [92][93][94][95] that allow PET-MRI to rival PET-CT for speed, such protocols often do not take full advantage of PET-MRI and may fail to justify the additional expense of PET-MRI.
Tumours that are assessed by both PET-CT and MRI could be transferred to PET-MRI [76] as it allows combined local and whole-body staging in breast cancer, providing an improved lesion detection in the brain, breast, liver, kidneys and bones. Indeed, MRI can provide an anatomic correlate for an FDG-avid lesions and it can detect bone metastases with low FDG uptake (which are not detectable on PET-CT) [82,96]. According to Melsaether et al. [87], PET-MRI outperformed PET-CT in the detection of metastatic breast cancer and it showed, at the same time, a dose reduction averaging of 50%. Even though PET-CT detects more pulmonary lesions than PET-MRI, the clinical significance of lung lesions missed on PET-MRI is unclear [97]. On the other hand, Riola-Parada et al. [98] in their systematic review of 57 articles evaluating the PET-MRI versus PET-CT in the metastases detection showed a similar diagnostic performance between the two modalities except for small lung metastases, for which PET-CT was superior. Although PET-CT has the advantage in terms of overall acquisition time due to the rapid nature of CT scanning, PET-MRI may acquire higher quality PET images due to longer time available for acquisition and the ability to use MRI respiratory gating information to improve PET data [91]. Usually, MRI exams are obtained in the anatomic target/region of interest and hence extra time spent at this bed position permits a longer PET acquisition providing increased detector counts and improved image quality. Moreover, because MRI sequences are typically obtained during breath-holds or using respiratory gating, PET data can be reconstructed with selected data at motion free time points, allowing for decrease in motion artefact [91].
In conclusion, PET-CT is currently an established technology already in widespread and accepted use worldwide, while PET-MRI has higher cost and major complexity of operating and interpreting the findings. However, PET-MRI can decrease radiation dose and improve motion correction [91].

Whole-body MRI
The introduction of DWI and apparent diffusion coefficient (ADC) improved the accuracy of MRI for metastases detection [99][100][101]. Using whole-body DWI with STIR fat suppression in free breathing optimises the image signal-to-noise ratio and image quality [102,103]. In addition to axially acquired DWI, T1WI, STIR and/or T2-weighted fat-suppressed images are usually also obtained [104]. Regarding the choice of b value, at least two b values are suggested: the higher b value chosen usually ranges between 600 and 1000 s/mm 2 , while the lower b value ranges between 0 and 100 s/mm 2 [102]. The protocol currently used for WBMRI is feasible, reproducible and can be performed in a relatively short time [10].
In metastatic breast cancer, DWI appears equally sensitive but less specific than 19F-FDG PET-CT in the bone metastases evaluation, indicating that it should not be read in isolation but in correlation with morphologic imaging [105]. In 2010, a prospective study [106] enrolling 36 patients with prostate or breast cancer showed a better performance of WBMRI in detecting malignant skeletal lesions (sensitivity 97% vs. 91%) compared to BS (sensitivity 97% and 48%, respectively). The recent SKE-LETA trial [124] compared the diagnostic accuracy of BS, SPECT, SPECT-CT, 19 F-NaF PET-CT and WBMRI for the detection of bone metastases in 26 breast and 27 prostate cancer patients, reporting the following sensitivity values, 62%, 74%, 85%, 93% and 91%, respectively, resulting in an analogous diagnostic accuracy to 19F-NaF PET-CT and outperformed SPECT-CT and BS.
Yang et al.
[128] performed a meta-analysis in several tumour types, including breast cancer, and showed that WBMRI and PET-CT resulted superior to CT and BS in terms of both sensitivity and specificity to detect bone metastases. Particularly, the sensitivity rates for PET-CT, CT, MRI and BS were 89.7%, 72.9%, 90.6% and 86.0%, respectively, and the specificity rates were 96.8%, 94.8%, 95.4% and 81.4%, respectively. Results of singular studies are showed in Table 3.
The reasons for false positive results on WBDWI include bone marrow oedema caused by benign conditions, which can be overcome by correlating the high b value DWI with related ADC maps and conventional MRI sequences based on T1W.
A number of studies translationally analysed the differences between normal bone marrow and metastatic lesions, correlating ADC with cellularity and other histological characteristics in bone metastases [58,108,109]: this is essential for qualification of MRI as a prognostic biomarker in metastatic breast cancer [17,20,21,52].
In addition, WBMRI can play a role in the assessment of visceral metastases [62,110], where WBMRI has a better sensitivity than PET-CT to evaluate small hepatic and brain metastases (Fig. 7) [69,89]. There is also an evolving role for the use of WBDWI to assess the treatment response of metastatic bone disease to systemic and targeted therapies (Fig. 8).

Future perspectives
Nowadays, the processes of breast cancer metastasis have been well characterised at the molecular level and numerous biomarkers of tumour aggressiveness have been discovered and are ready to be tested in clinics. As we have discussed, molecular imaging offers the opportunity to depict specific cell markers relevant to tumour aggressiveness. For instance, Harmon et al. [111] recently compared in a prospective way the 18 F-NaF PET-CT with 18 F-N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-4-F-fluorobenzyl-L-cysteine (DCFBC) PET-CT in patients with prostate cancer. Interestingly, this study appears to show that such tracer uptake depends on the disease course and treatment status, which may indicate a functional difference in bone metastases. The study showed that 18 F-DCFBC PET-CT detected significantly less bone lesions, especially in patients who were found to be castrate sensitive. On the other hand, in more advanced disease, there was good concordance between the two radiotracers. 18 F-DCFBC, though, demonstrates a high blood-pool uptake and such second-generation tracer may elucidate more functional information on the pathophysiology of bone metastases.
Although target-specific molecular imaging probes for tumour invasiveness have been developed for PET (i.e. proteases associated with tumour invasion, such as specific matrix metalloproteinases or cathepsins, can be targeted 'in vivo' with PET), they have not yet been widely used with MRI [112]. Novel MRI contrast agents based on iron oxide and dendrimer nanomaterials allow for better characterisation of tumour metastases [112]. Particularly, ultrasmall superparamagnetic particles of iron oxide (USPIOs) imaged with MRI does not require ionising radiation, yet can detect small metastases [113]. The rationale for the use of USPIO is that, after intravenous injection, the nanoparticles are phagocytosed by macrophages in circulation which then enter the interstitial space and are taken up by lymphatics [114][115][116][117]. Since iron oxide is superparamagnetic, it becomes strongly magnetic in the strong magnetic field of the MRI leading to spin dephasing and susceptibility effects which result in signal loss. Therefore, the signal intensity is markedly reduced in healthy tissues due to the magnetic susceptibility and T2WI shortening effects of the USPIO particles [114,118]. Conversely, in areas of metastases, there is much less uptake of USPIO particles and, therefore, those portions of the LNs remain unchanged in signal on T2WI 24-48 h after intravenous injection of a USPIO [114][115][116][117]. Current limits of USPIOs' use include the difficulty of image acquisition/interpretation and the lack of approved USPIOs themselves which are clinically available hinders adoption and larger studies.
Organ-specific MRI contrast agents are also used to identify metastatic disease in the liver. Superparamagnetic iron oxide particles (SPIO) have been approved for clinical practice use as a 'negative contrast agent' for the normal liver parenchyma in order to visualise benign and malignant hepatic cancers [119]. Dendrimer-based macromolecular MRI contrast agents as diaminobutane (DAB) dendrimers, that differ from polyamidoamine (PAMAM) dendrimers because they have a pure aliphatic polyamine interior, homogeneously enhance the liver parenchyma and are excreted more rapidly through both the liver and kidney than the analogous PAMAM dendrimer of similar molecular size [120]. Kobayashi et al. were able to detect small metastatic lesions on the liver from colon cancer cells using DAB dendrimers [120]. Additionally, gadolinium ethoxybenzyl diethylenetriaminepentaacetic acid (Gd-EOB-DTPA) has been developed as a liver-specific contrast agent by a small It was also assessed that staging with WBMRI is feasible at 1.5 and 3 T, noting that scan time is reduced at 3 T with identical resolution. As Gd-EOB-DTPA is taken up by hepatocytes, the normal liver parenchyma can be visualised by increased signal intensity at T1WI, generating a positive contrast enhancement, where normal liver parenchyma is bright on T1WI and the liver metastases are shown as focal areas of relative hypointensity [121]. Finally, hybrid imaging techniques of combining WBMRI with 18 F-choline PET have recently showed to have a significantly higher sensitivity (93.5%) when compared to BS (63.6%) and WBMRI on its own (72.7%) [122]. The results are promising, but with limited access to PET-MRI and its high cost, a defined role of PET and newer advanced hybrid imaging techniques are needed [113]. Stratifying patients according to disease course and treatment status may prove beneficial in the future. Nevertheless, a hybrid role of functional imaging provided by biomarkers with the anatomical detail provided by imaging techniques will offer a valuable insight into disease status.

Limitations
Substantial heterogeneity was evident in the published literature that were reviewed. Firstly, the quality of the reference standard was variable, relying on combinations of biopsy and/or follow-up. Secondly, there was also variability in the prevalence of bone and visceral metastases across studies. Moreover, we observed that most studies did not quantify how detection of metastases, especially when asymptomatic, influenced the management. As information on treatment and survival were not integrated into such studies, it is not possible to infer the likely prognostic implications of the imaging performance in this patient cohort.

Conclusions
Accurate M-staging is crucial in the selection of the most appropriate treatment for patients with advanced breast cancer. Although CT, BS and conventional MRI are still the most widely used imaging modalities in this disease setting, advanced imaging techniques are increasingly employed for the earlier and more accurate detection of metastatic disease, for both bones and visceral disease.

Guarantor
The scientific guarantor of this publication is Prof. Dow Mu-Koh.

Statistics and biometry
No complex statistical methods were necessary for this paper. Final approval of manuscript: all authors. All authors approved the submitted version and agreed both to be personally accountable for the authors' own contributions and to ensure that questions related to the accuracy or integrity of any part of the work are appropriately investigated, resolved and the resolution documented in the literature.

Authors' information
Filippo Pesapane is a founder member of the Artificial Intelligence for Oncology (AIFO) working group and he currently works as a radiologist at the European Institute of Oncology (Milan, Italy) at the Breast Imaging Division headed by Prof. Dr. Enrico Cassano. He was a former colleague of

Funding
The authors state that this work has not received any funding. Dow Mu-Koh is supported by the funding to the NIHR Clinical Research Facilities and the NIHR Bio-medical Research Centre at the Royal Marsden Hospital and the Institute of Cancer Research.
Availability of data and materials Data originating the tables are available on request sent to the corresponding author.
Ethics approval and consent to participate Institutional Review Board approval was not required because the research does not involve human populations or animals.

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The authors of the manuscript have read and agreed to its content and are accountable for all aspects of the accuracy and integrity of the manuscript in accordance with ICMJE criteria. That the article is original, has not already been published in a journal, and is not currently under consideration by another journal. Other consent of publications was not required because the research does not involve human populations or animals.

Competing interests
The authors of this manuscript declare no relationships with any companies, whose products or services may be related to the subject matter of the article.