Breast cancer imaging: A perspective for the next decade

Abstract

Breast imaging is largely indicated for detection, diagnosis, and clinical management of breast cancer and for evaluation of the integrity of breast implants. In this work, a prospective view of techniques for breast cancer detection and diagnosis is provided based on an assessment of current trends. The potential role of emerging techniques that are under various stages of research and development is also addressed. It appears that the primary imaging tool for breast cancer screening in the next decade will be high-resolution, high-contrast, anatomical x-ray imaging with or without depth information. MRI and ultrasonography will have an increasingly important adjunctive role for imaging high-risk patients and women with dense breasts. Pilot studies with dedicated breast CT have demonstrated high-resolution three-dimensional imaging capabilities, but several technological barriers must be overcome before clinical adoption. Radionuclide based imaging techniques and x-ray imaging with intravenously injected contrast offer substantial potential as a diagnostic tools and for evaluation of suspicious lesions. Developing optical and electromagnetic imaging techniques hold significant potential for physiologic information and they are likely to be of most value when integrated with or adjunctively used with techniques that provide anatomic information. Experimental studies with breast specimens suggest that phase-sensitive x-ray imaging techniques can provide edge enhancement and contrast improvement but more research is needed to evaluate their potential role in clinical breast imaging. From the technological perspective, in addition to improvements within each modality, there is likely to be a trend towards multi-modality systems that combine anatomic with physiologic information. We are also likely to transition from a standardized screening, where all women undergo the same imaging exam (mammography), to selection of a screening modality or modalities based an individual-risk or other classification.

INTRODUCTION

Imaging of the breast is indicated almost exclusively for the detection, diagnosis, and clinical management of cancer and for the assessment of the integrity of breast implants. Commonly used imaging modalities include mammography, ultrasonography, magnetic resonance imaging (MRI), scintimammography, single photon emission computed tomography (SPECT), and positron emission tomography (PET). The goal of this work is to provide a prospective view of breast imaging, primarily for detection and diagnosis.

In addition to standard recommendations for imaging based screening, self breast examination (SBE) has long been recommended because it is not unusual for women to feel anatomic changes in the breast that turn out to be malignant. Clinical breast examination (CBE) is commonly practiced as a part of routine physical examination by health providers or when prompted by a concern arising from SBE. The scientific evidence is inconclusive on the effectiveness of SBE and CBE in reducing breast cancer mortality. However, a recent study demonstrated a modest improvement in sensitivity when combined with mammography.¹

MAMMOGRAPHY

Mammography is essentially the only widely used imaging modality for breast cancer screening. Various forms of radiographic imaging of the breast have been used for nearly one hundred years but mammography with dedicated equipment and technique did not emerge as a screening tool until the mid-1960s.² The importance of physical compression of the breast and the significant association between microcalcifications and breast carcinoma were recognized in the early 1950s by Leborgne.³ While Gershon-Cohen in the United States and Gros in Europe were strong advocates for breast cancer screening, the development of a low kVp, high mAs technique that can be performed in a reproducible manner in 1960 by Egan enabled an organized breast cancer screening program.⁴ In 1966, Compagnie Générale de Radiologie (CGR, France) in collaboration with Gros developed the first dedicated mammography unit. This unit featured a molybdenum anode with a nominal 0.7-mm focal spot. Subsequently, several system manufacturers developed dedicated mammography units that facilitated its widespread availability.

Several large randomized clinical trials have shown that mammography reduces mortality from breast cancer.^{5, 6, 7, 8, 9, 10} While clinical trials have been essential in establishing the efficacy of mammography as a screening tool, the critical role of physics in the evolution of mammography cannot be overemphasized. Key developments in mammography include the invention of sensitive high-resolution image-intensifying screens, improved films, low x-ray absorption cassettes, and dedicated mammography film processors that enabled major dose reduction.¹¹ The development of an x-ray tube with molybdenum (Mo) target; molybdenum filter, and beryllium (Be) window, and with a small focal spot¹² that was specifically designed for mammography represents another major technological breakthrough. The concept of the projection geometry in which the central ray grazes the chest wall and meets the image receptor close to the chest wall is unique to mammography, and it represents a crucial design element that enables maximum inclusion of breast tissue. The development of low-ratio, high primary transmission moving grids and subsequently cellular grids are also important contributors to the high image quality achieved by modern mammography systems.

Screen-film mammography has long been considered as a “gold standard” for breast cancer screening. In addition to its ability to provide adequate visualization of soft tissue abnormalities, its particular strength is the ability to depict subtle calcifications. While screen-film mammography is a powerful tool for initial detection and subsequent follow-up of suspicious lesions, it has certain inherent limitations which are difficult to overcome. The most important and widely acknowledged weaknesses of screen-film mammography are associated with its limited dynamic range, contrast characteristics, susceptibility to suboptimal film processing conditions, and granularity. It also presents significant limitations in detecting very subtle lesions, especially in the presence of dense glandular tissue. These limitations were well elucidated during the preliminary development stages of digital mammography.¹³ Additional investment to develop improved screen-film technology is unlikely because of the emergence of digital mammography that provides wide dynamic range and offers the convenience of digital image manipulation, communication, and archival.

The term “digital mammography” is used for any technology which employs a single or multiple detector assembly to capture an electronic image of the x-rays transmitted through the breast that can be displayed, stored, and communicated electronically.¹⁴ Digital mammography is now a standard tool for breast cancer imaging and is steadily replacing screen-film mammography as the preferred tool for screening. As of this writing, approximately 36% of all mammography units in the United States are digital,¹⁵ and considering the higher throughput of digital than screen-film, it is likely that more than 36% of the examinations are performed with digital mammography. The conversion to digital is likely to accelerate and within the next three to five years digital mammography will be the dominant modality. The zero-spatial frequency detective quantum efficiency DQE(0) of digital mammography systems is in the range of 0.45 to 0.65, which is substantially higher than ∼0.35 or lower for screen-film systems.^{16, 17, 18} Clinical trials comparing digital mammography with screen-film mammography in a screening population demonstrate equivalency for cancer detection,^{19, 20, 21} and digital mammography performed significantly better for pre- and perimenopausal women younger than 50 years with dense breasts.²²

Current technological approaches for digital mammography that are in clinical use can be broadly classified into “fixed-detector” and “flexible-detector” installations. In a “fixed-detector” installation, the dedicated detector is hard-wired to the support column of the mammography system and is not removable. Examples of such “fixed-detector” installations include indirect conversion hydrogenated amorphous silicon (a-Si:H) based detectors and direct conversion amorphous selenium (a-Se) based detectors. In contrast, a “flexible-detector” installation uses the x-ray cassette holder of a mammography system to house the detector. An example of such a “flexible-detector” system is computed radiography (CR) technology. One advantage of the flexible-detector installation is the ease of conversion of an existing screen-film mammography system to a digital system.

An indirect conversion system uses an intermediary stage, typically a scintillator to convert the transmitted x-rays to light photons, followed by detection of the converted light photons using an optical sensor. The scintillator of choice for indirect conversion systems is CsI:Tl, which, due to its columnar structure, suppresses lateral light diffusion and, hence, results in better preservation of spatial resolution. Development of a-Si:H arrays was an important contributor for adaptation to large field of view (full-field) imaging.²³ Physical characterization indicate a substantial improvement in DQE (∼0.55 at zero-spatial frequency) characteristics compared to screen-film mammography.^{18, 24}

A direct conversion system does not use an intermediary stage and conversion is made from x-rays to electrons after interaction in a photoconductive layer, typically a-Se. While a-Se was used more than four decades ago in xeroradiography and xeromammography, the development of advanced charge readout methods enabled its adaptation to digital mammography.^{25, 26} The elimination of the intermediate scintillator layer with direct detection systems allows such systems to achieve high spatial resolution,²⁷ and higher DQE characteristics (0.54 to 0.64 at zero-spatial frequency) compared to screen-film mammography.¹⁷ In addition, a slot-scan photon-counting digital mammography system that uses silicon strip detectors is in clinical use in some countries. This approach, in addition to providing efficient scatter rejection due to the slot-scan geometry,^{28, 29} substantially reduces electronic noise contribution to the acquired image resulting in improved detective quantum efficiency.³⁰

Computed radiography (CR) uses a photostimulable phosphor plate typically consisting of BaF(Br,I):Eu²⁺ crystals on a suitable substrate in the form of a portable cassette. When exposed to x rays, f-centers are created in proportion to x-ray exposure and remain stable for several hours. This latent image is “read out” by stimulating the photostimulable phosphor plate with a laser beam, typically in a raster fashion, resulting in the emission of light photons in the ultraviolet-blue region. The emitted light is detected by a photosensor, typically a photomultiplier tube, to generate an electronic image. While CR has been in clinical use for radiographic applications for nearly three decades, the development of a dual-side readout that uses a transparent phosphor substrate and light collection from both sides of the photostimulable phosphor plate³¹ was an important contributor for improved DQE (∼0.54 at zero-spatial frequency) of such systems.^{16, 32} Outside the United States, CR based single-side read digital mammography systems using BaFI-, BaSrFBrI-, and BaF(Br,I)-photostimulable phosphor plates are also in clinical use.³³ Recent reviews of technological approaches for digital mammography have been published.^{14, 34, 35}

While there is no consensus on spatial resolution requirements in digital mammography, current research suggests that for indirect detection approaches, a low noise detector with smaller pixel size than that used in current practice may enhance visual perception of small objects such as microcalcifications.³⁶ Recently, it was observed that noise had a more dominant effect than display resolution for the tasks of detecting microcalcifications and discrimination of masses.³⁷

Research and development to improve digital mammography system performance characteristics and to develop new detector technologies, are in progress. In indirect-type a-Si:H based detectors, a recent important advancement is the development of a continuous photodiode design rather than the traditionally used discrete a-Si:H photodiode array.³⁸ This would increase the fill factor, resulting in improved signal transfer characteristics and dose efficiency. Also, incorporation of compensation lines with a-Si:H based detectors has been shown to reduce correlated electronic noise arising from external and ambient sources.³⁹ Methods to limit lateral diffusion of light within the scintillator either by laser etching columnar CsI: Tl⁴⁰ or by infusion of crystalline CsI:Tl within a tungsten grid matrix⁴¹ hold promise for improved spatial resolution, but have not yet been translated to practice.

Recent research with direct-conversion a-Se based detectors have been focused mainly on understanding the temporal imaging characteristics (image lag) and ghosting properties.^{42, 43, 44} Knowledge of these properties will be essential for emerging techniques of digital breast tomosynthesis (DBT) and contrast enhanced digital mammography (CEDM) that require fast image acquisition and readout. Ongoing investigations are aimed at improving the gain of a-Se based detectors through avalanche multiplication process and in understanding its implication on noise.^{45, 46} The development of low-noise detectors with improved sensitivity would also be beneficial to the promising technique of DBT that requires low dose per projection view. Attempts to adapt materials such as gallium arsenide (GaAs), cadmium zinc telluride (CdZnTe), mercuric iodide (HgI₂) and lead iodide (PbI₂) that hold promise of improved quantum efficiency are yet to bear fruition due to challenges such as charge-traps, higher leakage current, and spatial nonuniformity.^{47, 48, 49, 50}

In CR technology, some of the important advances include the development of columnar stimulable phosphor screens based on CsBr,⁵¹ development of linear readout (line scan) technology for faster readout of the phosphor,⁵² and integration of these approaches.^{53, 54} However, we are not aware of their transition to digital mammography as yet, but that could likely occur in the near future.

Another area of substantial interest in detector technology is the development of energy-resolving large-area photon-counting detectors, which has been challenging. While several approaches for photon-counting detectors have been proposed including scintillation detection using micro-channel plates⁵⁵ and gaseous detectors, it appears that semiconductor-based direct-conversion photon-counting systems may be better suited for medical imaging.⁵⁶ Some of the semiconductor materials that are considered promising for photon-counting detectors include Si, GaAs, CdTe, and CdZnTe, typically bonded to a two-dimensional readout with application specific integrated circuits, and are commonly referred to as hybrid detectors. Several collaborative research projects to develop hybrid detectors exist,^{57, 58} increasing the prospects for their availability in the next decade.

The advent of digital mammography has prompted reconsideration of several aspects of mammographic imaging that translated from screen-film imaging. These include anode material, x-ray spectra, technique factors, and radiation dose. In addition to the common target-filter combinations of Mo-Mo, Mo-Rh, and Rh-Rh, there is an increasing trend to use other combinations such as W–Rh, W–Ag, and W–Al with digital mammography. These alternative W-target techniques may allow for modest reduction in radiation dose with no apparent reduction in image quality.^{59, 60, 61} In addition, the exploration of techniques such as contrast-enhanced digital mammography (CEDM) and DBT that may require x-ray tubes with increased heat capacity and output also have an influence on the choice of anode material. In addition, radiation dose reduction with photon counting detectors,⁶² a-Si:H indirect conversion detectors,^{63, 64} and CR⁶⁵ have also been reported. While phantom studies indicated the possibility of 50% dose reduction with digital mammography,⁶⁶ studies with clinical backgrounds indicate that such a drastic dose reduction could adversely affect detection of microcalcifications and discrimination of masses substantially, and to a lesser extent adversely affect detection of masses.^{67, 68} Continuing technological improvements and technique refinements could lead to further dose reduction while maintaining image quality.

Extensive investigations on radiation dose to the breast and its dependence on breast composition, breast thickness, and x-ray spectral characteristics have been documented.^{69, 70, 71, 72} While it was believed that radiation dose to other organs including the uterus would be low during a mammography exam, until recently quantitative estimates were unavailable.^{73, 74} A Monte Carlo computational study with an anthropomorphic software phantom indicates that the dose to the uterus during the first trimester, where a women may be unaware of her pregnancy, is less than 0.03 μGy per imaged breast during a bilateral two-view mammography exam.⁷⁵ The use of a lead-shield further reduces this dose by a factor of 2 to 7, suggesting that if it is clinically necessary for a woman in her first trimester of pregnancy to undergo mammography, then the radiation dose to the fetus would be minimal.⁷⁵

The advantages of vigorous physical compression of the breast in terms of adequate tissue separation, x-ray scatter, and radiation dose, for producing good mammographic image quality are well known. Unfortunately, to this date, the scientific community has been unable to overcome the vigorous breast compression needs of mammography. In screen-film mammography, it is well established that the use of anti-scatter grids improves contrast for breasts of average and above average compressed thickness. However, the usefulness of anti-scatter grid is not firmly established for thin and mainly adipose breasts. Current practice is to perform mammography with the anti-scatter grid in place for all imaging needs, except for magnification views. In spite of its advantages, anti-scatter grids do suffer from deficiencies such as incomplete suppression of scattered radiation, reduction in primary radiation reaching the detector, and artifacts.^{29, 76, 77}

With the advent of digital mammography that would allow for numerical scatter correction techniques, the possibility of imaging without the anti-scatter grid were studied and showed promise of improved performance.^{78, 79, 80} However, another study indicated that removal of the anti-scatter grid could provide a modest reduction of ∼8% in radiation dose to the subject.⁸¹ Although scatter correction for images acquired without the anti-scatter grid using numerical techniques have been reported,^{82, 83, 84} its impact on contrast, resolution, noise, and artifacts are yet to be studied. At present, digital mammography, with the exception of slot-scanning systems, uses anti-scatter grids for scatter reduction. The emergence of DBT where the use of an anti-scatter grid is impractical, could further advance the research on scatter correction algorithms that may translate to digital mammography in the future.

We will continue to observe increased transition to digital from screen-film mammography. Also, improvements in detector technology and transition to higher kVp techniques will provide for substantial reduction in radiation dose. The prospects of a large-area photon-counting detector with the ability to provide energy resolution appears brighter.

ULTRASONOGRAPHY

The role of B-mode ultrasound in breast imaging has been largely limited to applications such as distinguishing between cystic versus solid masses, evaluation of palpable masses, and for needle core biopsy of masses. In recent years, the number of indications has been greatly expanded and breast ultrasonography is now an essential modality in breast imaging. A center frequency above 10 MHz is now recommended for adequate spatial resolution by the American College of Radiology (ACR). B-mode imaging works well for the established indications of breast ultrasonography, but its imaging ability is limited by the beam direction that is fixed and perpendicular to the face of the transducer.

In compound ultrasonography, the beam is electronically steered for improved sampling of the anatomy that may lie parallel to the ultrasound beam, rendering a more complete image. Harmonic imaging techniques take advantage of the variation of the velocity of the ultrasonic wave through different tissues that produces harmonic frequencies. The processing of harmonic signals leads to better selection of signals by suppressing effects such as side-lobe artifacts, beam defocusing, and reverberations, resulting in improved images.^{85, 86, 87} Color Doppler and more recently sensitive power Doppler ultrasound has been used for further evaluation of the breast.

In 2002, Kolb et al. published a landmark article that showed improved sensitivity (97% versus 74%) when adjunctively used with mammography compared to physical examination with mammography.⁸⁸ They also observed an improvement in sensitivity for dense breasts with ultrasound compared to mammography. In addition, they noted that the time taken to perform an ultrasound exam was comparable to that of a clinical breast exam. However, he also observed an increased in false positive rates with the use of ultrasound as an adjunct to mammography. In recently published results of an ACRIN trial that included 2637 women with heterogeneously dense breast in at least one quadrant observed that the diagnostic accuracy improved from 0.78 to 0.91 when ultrasound was adjunctively used with mammography.⁸⁹ However, there was also a substantial decrease in positive predictive value with mammography plus ultrasound (11.2%) compared to mammography (22.6%) alone. Also, the median time to perform a bilateral ultrasound exam was 19 min. Hence, the improved diagnostic accuracy provided by adjunctive use of ultrasound to mammography has to be carefully weighed against the decrease in positive predictive value and exam duration. From the technological perspective, it can be inferred that there may be a need for a combined dual-modality mammography-ultrasound system. Even if ultrasound is not adapted for screening, such a system is likely to be of benefit for diagnostic evaluation as it provides for co-registered dual-modality images.

Development of a semi-automated scanning ultrasound device integrated with a digital breast tomosynthesis (DBT) system was recently reported.⁹⁰ Figure 1 shows the combined DBT-US system. Performance characteristics of the DBT component indicates minimal in-plane blur and better management of artifacts with reconstruction using generalized filtered backprojection.⁹¹ Identification of compression paddles suitable for both x-ray and ultrasound imaging,⁹² as well as techniques to address coverage and motion issues during ultrasound scan⁹³ have been described. Recently, development of an ultrasound computed tomography system that generates reflection, attenuation, and sound speed images has been reported.⁹⁴ Spatial resolution measurements indicate in-plane resolutions of 0.5 and 4 mm in reflection and transmission modes, respectively. A pilot clinical study with 50 subjects indicate the ability to routinely detect masses greater than 15 mm in size.⁹⁵

Figure 1.

Integrated dual-modality digital breast tomosynthesis and scanning ultrasound system. Provided by Paul L. Carson and Mitchell M. Goodsitt at the University of Michigan and Kai Thomenius at GE Global Research, Niskayuna, NY. This system was developed with support by NIH R01CA 91713 and Office of Naval Research grant MDA905-00-10041.

Technological improvements in transducer technology and signal processing have contributed to the extensive adoption of ultrasonography for diagnostic evaluation of the breast and for biopsy guidance. There is a possibility that ultrasound could have an adjunctive role to screening mammography for hetereogeneously dense breasts.

MAGNETIC RESONANCE IMAGING

In vitro measurements of relaxation times of tumors and normal tissue with nuclear magnetic resonance (NMR) was reported by Damadian in 1971.⁹⁶ Subsequent to the development and application of local gradient fields that made imaging (NMR zeugmatography as proposed by Lauterbur⁹⁷) feasible, Mansfield et al. reported on imaging with surgical breast tissue samples.⁹⁸ Ross et al. and El Yousef et al. reported on some of the earliest in vivo breast MRI studies in the early 80’s.^{99, 100, 101} Development of a coil specifically designed for breast imaging was an important technological advancement.¹⁰² The development of gadolinium diethylene triamine pentaacetic acid (Gd-DTPA) contrast agent and its application to human imaging was an important milestone in the advancement of MRI.^{103, 104, 105, 106, 107, 108} Following the application of Gd-DTPA for contrast-enhanced breast MRI,¹⁰⁹ initial interpretation criteria were based on morphology and contrast enhancement that were obtained with long acquisition times. However, this did not provide substantial contrast between tumor and proliferative changes. Hence, further research was focused on developing fast pulse sequences^{110, 111, 112, 113} that ushered the era of dynamic contrast enhancement studies. Another important advancement was the development of a bilateral breast coil that facilitated simultaneous imaging of both breasts. This allowed comparison of enhancement patterns between the breasts at reduced cost and time.

Currently dynamic contrast enhanced breast MRI is clinically used to provide volumetric three-dimensional (3-D) anatomical information and physiologic information that are indicative of increased vascular density and vascular permeability changes associated with angiogenesis.¹¹⁴ Clinical breast MRI studies have demonstrated its ability to provide accurate diagnosis, extent of disease and multi-centricity,¹¹⁵ and the ability to detect mammographically occult cancers in the contralateral breast.^{116, 117, 118, 119} Independent clinical trials for women at high-risk of hereditary breast cancer indicate increased sensitivity with breast MRI than mammography but with variable specificity.^{120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131} These studies have prompted the American Cancer Society to recommend the use of MRI as a adjunct to screening mammography for women with a lifetime risk of 20%–25% or greater.¹³² A recent meta analysis that included 44 prior studies indicate that breast MRI has a sensitivity of 0.9 and specificity of 0.72.¹³³ Importantly, this analysis indicated that variability in specificity was due to cancer prevalence in the individual studies and due to interpretative criteria used to differentiate benign and malignant lesions.¹³³ With the development of lexicons for breast MRI interpretation¹³⁴ and standardization of procedures, variation in specificity is likely to be reduced. A recent two-part review addresses the current status of breast MRI.^{135, 136} Dynamic contrast enhanced MRI (DCE-MRI) is a very important tool for detection, diagnosis, and clinical management of breast cancer. However, it requires intravenous injection of Gd-contrast agent that entails some elevated risk.^{137, 138} Hence, by its nature contrast-enhanced MRI is likely to be limited to a subgroup of patients.

Another promising technique that has garnered substantial interest recently is proton $\left({}^1\mathrm{H}\right)$ magnetic resonance spectroscopy (MRS). This technique allows for quantitative characterization of total or composite choline concentration that has been shown to be elevated in malignant tumors compared to normal breast tissue.¹³⁹ While initial works were focused on ${}^{31}\mathrm{P}$ MRS,^{140, 141, 142, 143} recent research has been primarily on the use of ${}^1\mathrm{H}$ MRS,^{144, 145, 146, 147} in part due to its higher sensitivity compared to ${}^{31}\mathrm{P}$ MRS.¹⁴⁸ MRS is a nonvasive technique that does not require contrast injection; however, most of current research has been on spectroscopic analysis of regions localized from prior DCE-MRI. Current studies have shown the correlation between DCE-MRI and MRS,^{149, 150} and demonstrated improved sensitivity and specificity when used as an adjunct to breast MRI.^{151, 152, 153} While there are interesting aspects of this technique, most of the studies were performed at 1.5 T with voxel volume of ∼1 cm³ indicating better suitability for large tumors. Since total choline concentration may be indicative of cell replication,¹⁵⁴ MRS is being actively investigated and show promise for early determination of the effectiveness of neoadjuvant chemotherapy for locally advanced breast cancer.^{155, 156, 157, 158, 159} In addition, studies on MR spectroscopic imaging (MRSI) primarily to improve specificity have been reported.^{160, 161, 162} Importantly, one of the studies describe a method to improve signal-to-noise ratio and reduce acquisition time with sub-centimeter voxel volume.¹⁶² If this technique can evolve to the point of replacing contrast-enhanced MRI, then risks associated with contrast media and injection can be eliminated. Although this technique is in its infancy, the concept of a screening MR exam that provides high resolution morphological information with MRSI to provide physiologic information without contrast media is highly appealing. Recent reviews address the clinical prospects and challenges of MRS and allied techniques.^{163, 164, 165, 166}

MRI already has a very important role in breast imaging as an adjunctive tool for screening and as a diagnostic tool for imaging lesions that are indeterminate from other modalities. MRI is also widely used for assessing the structural integrity of breast implants. Its role will continue to expand with the development of novel image acquisition techniques and technological improvements.

RADIONUCLIDE IMAGING

Radionuclide based imaging techniques such as scintimammography, single-photon emission computed tomography (SPECT), positron emission mammography (PEM), and positron emission tomography (PET) are additional imaging techniques that provide for physiologic information.

Scintimammography and SPECT typically use ${}^{99\mathrm{m}}\mathrm{Tc}$-sestamibi or ${}^{99\mathrm{m}}\mathrm{Tc}$-tetrofosmin for breast cancer imaging. Scintimammography is used for imaging mostly palpable lesions that were occult or indeterminate from other imaging modalities. For palpable mass, a meta-analysis indicates that the sensitivity and specificity were 87.8% and 87.5%, which is high.¹⁶⁷ However, for nonpalpable lesions the sensitivity was reduced to 66.8%.¹⁶⁷ In an another study, the sensitivity reduced from 74.2% for larger lesions to 48.2% for lesions smaller than 1 cm.¹⁶⁸ New technological advances such as the development of dedicated cameras for scintimammography with improved spatial resolution has renewed interest in this field.¹⁶⁹ Characterization of a dedicated scintimammography system was recently reported to achieve detection of ∼7 mm spheres bearing ${}^{99\mathrm{m}}\mathrm{Tc}$.¹⁷⁰ A clinical study to evaluate its potential with 100 subjects scheduled to undergo biopsy of 2 cm or smaller masses indicated a substantial improvement in sensitivity for imaging lesions smaller than 1 cm.¹⁷¹ In an another study in which 94 high-risk subjects with normal mammographic exam were evaluated with a dedicated scintimammography camera using ${}^{99\mathrm{m}}\mathrm{Tc}$-sestamibi detected two malignancies, both of which were smaller than 1 cm.¹⁷² However, false-positives due to fibrocystic change, fibroadenoma, and fat necrosis were also observed. A study comparing dedicated scintimammography with conventional SPECT indicated no differences in sensitivity, but observed better performance for 1 cm or smaller lesions with the dedicated scintimammography system.¹⁷³ Further improvements, such as development of a dual-head camera and with increased spatial resolution may improve sensitivity for smaller lesions.

The primary advantage of SPECT is its ability to provide 3-D information. In SPECT imaging, the development a dedicated system for breast imaging in a prone patient position with pendant breast geometry has been reported.¹⁷⁴ This system uses a scanning trajectory that closely follows the breast contour. A more recent work described the development of a dedicated breast SPECT system using CdZnTe detectors.¹⁷⁵ Integration of the dedicated SPECT system with a dedicated breast CT system to provide for co-registered dual-modality imaging is also in progress.¹⁷⁶

For detection of primary tumors, ${}^{18}\mathrm{F}$-FDG-PET have been reported to have similar sensitivity as that of SPECT.¹⁷⁷ A meta-analysis of whole body ${}^{18}\mathrm{F}$-FDG-PET that included 13 studies indicated an overall sensitivity of 89% and specificity of 80%.¹⁷⁸ However, the mean tumor size in those studies ranged from 2 to 4 cm. Characterization of a dedicated breast PET system using four detector heads comprising of LYSO crystals coupled to position-sensitive photomultiplier tubes (PSPMTs) with multi-angle tomographic image acquisition capabilities was reported to achieve ∼2 mm spatial resolution.¹⁷⁹ Development of PET detector modules with lutetium oxyorthosilicate (LSO) crystals coupled to PSPMTs,¹⁸⁰ and more recently LSO coupled to position sensitive avalanche photodiodes with depth-of-interaction capabilities have been reported.^{181, 182} These systems can play an important role in monitoring effectiveness of therapeutic regimens.

To overcome the limited sensitivity and spatial resolution of whole-body PET systems, a PEM system was developed^{183, 184} and showed promising results in a pilot clinical study.¹⁸⁵ Development of PEM systems using gadolinium orthosilicate (GSO) and yttrium-aluminium perovskite (YAP) scintillators have been reported.^{186, 187} A collaborative effort to develop a dedicated PEM system using cerium- and yttrium-doped lutetium orthosilicate (LYSO) scintillator elements coupled to avalanche photodiodes is also underway.¹⁸⁸ These systems offer the potential of improved resolution and sensitivity. A pilot clinical study evaluating a prototype system using lutetium gadolinium oxyorthosilicate (LGSO) scintillator elements showed the ability to detect smaller lesions.¹⁸⁹ All of the aforementioned dedicated PEM systems use stationary detector heads. A multi-institutional clinical study of a commercially available PEM system using translational detector heads that enrolled 94 subjects with known breast cancer or suspicious lesions showed high sensitivity and specificity and the ability to detect small lesions.¹⁹⁰

A recent review address the clinical aspects and limitations of various radionuclide-based techniques for breast cancer imaging.¹⁹¹ With continued advancement of detector technology, radionuclide-based imaging systems dedicated to breast imaging are likely to play a significant role in therapeutic monitoring of known cancers and in diagnostic imaging of suspicious breast lesions.

INVESTIGATIONAL MODALITIES

Volumetric x-ray imaging techniques

While there have been considerable advances in mammography, there is one major inherent limitation in that the mammographic image reduces the three-dimensional anatomy of the breast into a two-dimensional image. This resulting superposition of normal breast structures, which causes a visually distracting mask, is often referred to as anatomical noise and has been shown to impair lesion detection.^{192, 193, 194} In addition, tissue superposition can mimic the presence of a lesion, resulting in increased recall rates and in increased biopsy rates, that add to the inconvenience and anxiety of the recalled subject. Hence, there is a need to develop techniques that provide depth information in breast x-ray imaging. Currently, stereoscopic digital mammography (SDM), digital breast tomosynthesis (DBT), and dedicated breast computed tomography (BCT) are three modalities that are being actively investigated.

Stereoscopic digital mammography

In stereoscopic digital mammography, two projection images spaced a few degrees apart are acquired with a digital mammography system. A dedicated stereoscopic workstation displays orthogonally polarized images and are viewed by the observer using passive cross-polarized glasses, so that each eye visualizes one image to provide depth perception. Studies evaluating the accuracy of depth perception indicate that 0.2 mm depth discrimination can be achieved using projection pair images acquired at an angular separation of ±6° and with geometric magnification.^{195, 196} Observer studies comparing standard monoscopic imaging with stereoscopic imaging using breast biopsy specimens indicate an improvement in detection of masses and microcalcifications, and an improved confidence for the estimation of likelihood of malignancy.¹⁹⁷ Interim results from an ongoing prospective screening trial with high-risk women suggest that SDM reduces false-positive lesion detections by 39% and false-negative lesion detections by 46% compared to digital mammography, providing for significant improvements in sensitivity and specificity.¹⁹⁸ However, the study used twice the dose of mammography. While contrast-detail experiments with a phantom indicates that ∼10% more radiation dose is needed for SDM compared to mammography,¹⁹⁹ further research is needed to understand the dose requirements with clinical backgrounds. If ongoing and future clinical trials demonstrate its efficacy, it has the potential for quick adaptation due to the ready availability of digital mammography systems and dedicated stereoscopic displays.²⁰⁰

Digital breast tomosynthesis

Digital breast tomosynthesis (DBT), a technique that relies upon acquisition of multiple projection views over a limited angular range to reconstruct a volumetric image, has gained substantial interest primarily due to the availability of flat-panel detectors.^{91, 201, 202, 203} Subsequent to the landmark article in 1997 by Niklason et al. that demonstrated feasibility by modification of a digital mammography system,²⁰⁴ a similar system was used to study contrast-detail characteristics of several reconstruction algorithms.^{205, 206}

Although in principle, implementation of DBT with a digital mammography system is straightforward, there are some design aspects that have to be considered. In a well-designed DBT system, the x-ray tube assembly has to avoid interference with the patient’s head during rotational movement and the rotational mechanics must provide for minimal vibration. Also, the x-ray beam collimation must adapt asymmetrically during the scan to ensure that the x-ray field does not extend marginally beyond the lateral edges of the detector. The acquisition of multiple frames in ∼10 s to minimize the potential for patient motion requires a detector that has rapid frame acquisition capability and with minimal image lag.

Current implementations of clinical prototype DBT systems use indirect conversion a-Si:H detectors with a 100-μm pixel pitch⁹¹ or direct conversion a-Se detectors.^{202, 207} Depending upon the manufacturer, a-Se based DBT system use a detector with 70-μm pixel pitch operated in a 2×2 binned mode²⁰² or a detector with 85-μm pixel pitch operated in unbinned or 2×1 asymmetric binned mode.^{207, 208} Pixel binning approaches allow for faster readout of the detector, albeit at reduced resolution. As with digital mammography, the detector pixel pitch and the overall spatial resolution requirements for breast tomosynthesis are not well defined. After reconstruction, there is some degradation of in-plane (plane parallel to the detector) spatial resolution due to several factors including oblique x-ray incidence,^{209, 210} blur due to tube motion within the acquired projection view,²⁰⁸ mechanical vibration of the gantry, and reconstruction related blur such as that due to interpolation. There is considerable loss of spatial resolution along the depth-direction (perpendicular to the detector plane) due to limited angular sampling. Hence, there is a some concern about its ability to detect subtle structures such as amorphous microcalcifications.

Until recently, estimates of glandular breast dose during DBT were based on conversion factors for mammography. A Monte Carlo study provided conversion factors for DBT that showed variation in glandular dose with projection angle,²¹¹ facilitating the application towards advanced techniques such as tube-current modulation with changing projection angle, if needed. While the objective for a DBT acquisition is not to exceed the dose of a two-view mammogram, in a 15 projection acquisition for example, the detector receives substantially less signal per projection compared to a mammographic view. To some extent, this can be compensated by increasing the beam transmission though the breast with the use of W anode and higher kVp than in conventional mammography, as suggested by modeling and phantom studies,^{212, 213, 214} but may change as more experience is gained through clinical trials. Research in developing detectors with performance characteristics suitable for DBT seems well justified, in particular if higher kVp is used in the future for techniques such as contrast-enhanced DBT.

The adverse effects of scatter on projection imaging and computed tomography are well known. However, its adverse effects in DBT have not yet been quantified. Recently, comprehensive Monte Carlo based estimates of scatter and hence, scatter-to-primary ratio (SPR) was reported.²¹⁵ SPR trends showed high dependence on compressed thickness and weak dependence on x-ray spectrum and breast glandularity, similar to mammography. Importantly, substantial spatial variation of SPR at oblique projections was observed. One interesting observation in that study²¹⁵ was the increase in SPR observed at breast periphery, which was apparently due to the large component of x-ray scatter from the breast support plate compared to the primary x-ray component under the breast tissue. Conventional anti-scatter grids are not used in DBT because of the required increase in dose (bucky factor) and problems due to grid cut-off at oblique projection angles. While it may be possible to develop anti-scatter grids that are designed specifically for DBT, such designs have not yet materialized. Hence, accurate characterization of x-ray scatter during a DBT exam can be extremely useful in the development of computational techniques for scatter correction.

DBT reconstruction algorithms either use variants of back-projection technique or iterative techniques. Optimization of these reconstruction methods, quantification of their effect on resolution, noise, and artifacts as well as comparative analysis of these methods have been the subject of ongoing research.^{216, 217, 218, 219, 220, 221, 222} There are two important concerns with DBT, viz., its ability to provide adequate visualization of microcalcifications²²³ and “out-of-plane” artifacts that occur due to limited angular sampling. With regards to microcalcification visibility, a technique that could provide for improved morphology using back-projection or its variants was recently published.²¹⁷ Also, improved image quality has been reported with an iterative algebraic reconstruction technique.²¹⁸ Techniques specifically designed for suppressing artifacts are being actively investigated.^{219, 224, 225, 226}

In spite of some challenges, DBT enables better separation of overlying tissues than mammography and it is likely to play an important role in breast imaging. Breast tomosynthesis has the potential of detecting occult lesions, particularly soft tissue abnormalities that can be extremely difficult to detect in the presence of dense glandular tissue. Currently, several clinical studies with human subjects are being conducted to evaluate the clinical potential of DBT. Early indications from ongoing clinical studies suggest that DBT show promise.^{223, 227} In a recently published study on their initial experience with DBT, most of the soft tissue abnormalities were subjectively rated as either equivalent or superior to mammography.²²³ Figure 2 shows a clinical case of a woman with 1.6 cm low-grade invasive ductal carcinoma with ductal carcinoma in situ (DCIS), where the carcinoma is better visualized with DBT (right) than with mammography (left). Interim results after accrual of 1957 women from an ongoing clinical trial indicate that DBT reduces recall rate to 4.4% compared to 7.5% with digital mammography, and unlike mammography does not appear to show dependence with breast density.²²⁷ With further refinements, breast tomosynthesis is likely to become a clinical tool for screening, particularly for women with dense breasts.

Figure 2.

A clinical case showing 1.6 cm low-grade invasive ductal carcinoma with minor ductal carcinoma in situ (DCIS) component. Better visualization of the tumor is observed with DBT (right, B) compared to mammography (left, A). (Courtesy: Steven P. Poplack, Dartmouth Hitchcock Medical Center)

Dedicated breast computed tomography

Another technique that will overcome the tissue superposition problem is dedicated breast computed tomography (BCT), in which the subject is in a prone position and the pendant breast is imaged. The concept of a dedicated BCT system was envisioned in the 1970s²²⁸ and a system was built. Clinical trials using the dedicated BCT system²²⁹ and with a conventional CT scanner²³⁰ suggested that injected contrast media enhanced CT could differentiate malignant from benign lesions. However, it did not translate to clinical practice due to the limitations with the technology available at that time. Subsequently in the mid-1990s, images of surgical biopsy specimens acquired with a state-of-the-art scanner at that time were compared with specimen radiography images, and indicated that CT imaging can significantly improve the confidence to detect mass but was inferior for microcalcifications.²³¹

In 2001, a landmark article by Boone et al. provided quantitative estimates of radiation dose from a dedicated BCT exam and image quality achieved with cadaveric breast.²³² The development of high-frame-rate flat-panel detectors accelerated further exploration of this technique. Works addressing radiation dose to the imaged breast^{232, 233, 234} and other organs,²³⁵ x-ray scatter,^{236, 237} system design,^{238, 239} imaging trajectory,^{240, 241} image acquisition technique factors,^{242, 243, 244} resolution,²⁴⁵ noise,²⁴⁶ and artifacts ²⁴⁷ have been published.

Independent studies with surgical mastectomy specimens²⁴⁸ and with limited number of subjects²⁴⁹ suggest that BCT provides for excellent anatomical detail and soft tissue lesion visualization. Figure 3 shows multi-planar reconstructions acquired with a clinical prototype dedicated BCT system and a MLO view projection image acquired with a digital mammography system. Excellent 3-D visualization of the anatomy and soft tissue lesion is observed. A recent study that compared visualization in BCT with lesions detected in screen-film mammography in 65 subjects, suggest that BCT was superior for visualization of masses but was inferior for visualization of microcalcifications.²⁵⁰

Figure 3.

Clinical images of a soft tissue lesion with digital mammography (A: MLO view) and multi-planar reconstructions (B: Coronal, C: Axial, and D: Sagittal views) with dedicated BCT. (Courtesy: Koning Corporation, West Henrietta, NY)

Some of the challenges with breast CT include simultaneous inclusion of medial and axillary aspects of the breast during the scan and adequate visualization of microcalcifications.²⁵⁰ Limitations in breast coverage with dedicated breast CT has been inferential, and as yet there have been no quantitative studies comparing tissue inclusion with mammography. Improved breast coverage can be potentially achieved through system design including novel table design²⁵¹ and imaging trajectories,^{240, 241} and with appropriate patient positioning. Current prototype systems used in clinical studies utilize circular scan,^{250, 252} and we are aware of only one implementation using a non-circular trajectory for breast imaging with a laboratory prototype system.²⁴⁰ Further studies are needed to understand tissue coverage with dedicated breast CT for the various source-detector trajectories.

Initial computer simulation study and independently a receiver operating characteristic study with computer simulated BCT images suggested the possibility of detecting microcalcifications in the range of 175 to 200 μm.^{238, 253} However, experimental studies with phantoms suggest that visibility of microcalcifications may be limited to ∼300 μm with current technology.^{254, 255} Considering that these studies point to a noticeable improvement with increased dose or reduced breast size,^{254, 255} it is likely that image noise rather than resolution may be a dominant factor for limited visibility of microcalcifications. Hence, techniques for noise suppression²⁴⁶ may be beneficial. However, further research is needed to study its effect on artifacts, resolution, and lesion visualization. Additional improvements in microcalcification visualization can be potentially achieved with the use of high-resolution, low-noise detector technology such as photon-counting detectors²⁵⁶ or electron-multiplying CCDs,²⁵⁷ which are not yet available for large field of view imaging. A recent review article addresses the potential advantages of BCT and the challenges that need to be overcome for routine clinical use.²⁵⁸

While the role of BCT and its efficacy need to be ascertained through clinical studies, BCT has one major advantage in that it does not require physical compression of the breast, thus greatly alleviating patient discomfort. Ongoing clinical studies have shown exquisite anatomical detail and soft tissue lesion morphology. If visibility of microcalcifications is improved, breast CT allows for 3-D visualization of its distribution that could potentially improve specificity. While each of the aforementioned techniques that are targeted towards overcoming the tissue superposition problem are in various stages of research, an observer study with computer simulated images comparing digital mammography, DBT and BCT showed improved accuracy to detect masses,²⁵⁹ highlighting the potential advantage of DBT and BCT over digital mammography. Among the three techniques (SDM, DBT, and BCT) that are being investigated to provide depth information, the body of knowledge is too limited to obtain meaningful inferences about the superiority of one technique versus the other.

Contrast-enhanced x-ray imaging

While investigations into the applicability of digital subtraction angiography of the breast in the mid-1980s showed the potential for differential diagnosis for malignant and benign tumors,^{260, 261} the lack of appropriate imaging system was a major limitation. The advent of digital mammography has stimulated the exploration of quicker and cost-effective alternative for breast MRI such as intravenously injected iodinated contrast media enhanced imaging of the breast for angiogenesis imaging. Two approaches for contrast-enhanced digital mammography are being explored. In dual-energy K-edge subtraction, two images at different energies that straddle the K-edge of the contrast media are acquired after contrast administration and subtracted.²⁶² In temporal subtraction, an image acquired prior to contrast administration is subtracted from the image(s) acquired after contrast administration.²⁶³ The former method reduces the likelihood of misregistration between the two images, while the latter is better suited for dynamic contrast enhancement studies and would require image processing for proper registration.

Multiple pilot clinical studies, each with a small number of subjects who had suspicious findings and underwent contrast-enhanced digital mammography, indicate enhancement of tumor and vasculature that are qualitatively similar to breast MRI.^{262, 263, 264, 265, 266} There have also been studies on optimization of the x-ray spectrum,^{267, 268} on determination of the minimum concentration of iodine required,^{267, 269} and on investigation of elements other than iodine that may provide for alternate contrast media.^{270, 271, 272}

A pilot clinical study evaluating the potential of contrast enhanced DBT, showed characteristics that were concordant with digital mammography and breast MRI.²⁷³ Contrast-enhanced DBT is being actively investigated, particularly in terms of imaging technique optimization and quantification of iodine concentration.^{268, 274, 275} The role of contrast-enhanced conventional CT in management of breast cancer such as lymph node imaging, tumor staging, identifying tumor extent for breast conservative surgery, treatment planning for radiotherapy, and in monitoring of cancer therapy is well established. A pilot study with contrast-enhanced dedicated BCT showed enhancement of malignant lesions similar to MRI.²⁵⁰ One potential advantage of contrast-enhanced x-ray imaging is that signal intensity changes are typically linear with contrast agent uptake, unlike MRI.¹³⁵ All of the aforementioned x-ray-based contrast-enhanced imaging techniques are in various stages of research.

While there are promising aspects, all of these techniques require intravenous injection, which entails a slightly elevated risk.¹³⁷ While contrast media used with x-ray imaging are considered relatively safe, risks including allergic reactions and contrast nephropathy, though uncommon, are of concern. Hence, there is a need to develop contrast agents with minimal or no adverse effects. Further improvements in specificity are achievable with development of tumor-targeted agents^{276, 277} and with better understanding of the criteria for determining malignancy such as morphology, tumor enhancement due to agent uptake, and agent uptake kinetics.

Alternative modalities

X-ray phase sensitive imaging such as in-line phase contrast x-ray imaging^{278, 279} and diffraction enhanced imaging^{280, 281, 282, 283} are currently being investigated. The theoretical basis and design considerations for phase contrast imaging^{284, 285} and method to retrieve the phase map from attenuation and phase contrast images²⁸⁶ have been well addressed. Development of a dual-detector system that uses two CR cassettes for simultaneous acquisition of conventional (attenuation) and phase contrast images, from which the phase map is retrieved was recently published.²⁸⁷ Figure 4 shows conventional (attenuation) and phase contrast images of ACR-recommended accreditation phantom and of a lumpectomy specimen acquired with a prototype system. Substantial improvement in contrast and edge-enhancement is observed. These techniques are at present limited to imaging specimens. Further research is needed to translate them to clinical use.

Figure 4.

Conventional (attenuation) images (A, C) and phase contrast images (B, D) of accreditation phantom (top row) and lumpectomy specimen (bottom row). All images were acquired at 40 kVp with same entrance exposure for attenuation and phase contrast images. These images were acquired using prototype systems developed at the University of Oklahoma (Hong Liu), in collaboration with University of Alabama at Birmingham (Xizeng Wu) and University of Iowa (Laurie L. Fajardo). (Courtesy: Hong Liu, University of Oklahoma)

Optical imaging of the breast such as diffuse optical tomography (DOT), diffuse optical imaging, and diffuse optical spectroscopy is being investigated as an adjunct technique. This emerging technique uses light in the near-infrared (NIR) regime to noninvasively image total hemoglobin, oxygen saturation, water content, optical scattering, and lipid concentration.^{288, 289, 290} While substantial variations in optical properties for normal tissues²⁹¹ and tumors²⁹² have been observed, a recent study indicates that normal and tumor tissues can be differentiated based on total hemoglobin, hemoglobin oxygen saturation, and other parameters.²⁹³ Leaky, densely packed vasculature associated with tumor angiogenesis could contribute to increased total hemoglobin, and increased metabolism in tumors could result in decreased oxygen saturation. NIRS has an inherent resolution of ∼4 to 6 mm because of the highly scattering nature of light. Ntziachristos et al.²⁹⁴ demonstrated that combining DOT with MRI anatomical maps can improve spatial resolution. More accurate quantification of NIRS parameters have been reported by incorporating structural priors from MRI during NIRS reconstruction.²⁹⁵ In order to obtain co-registered dual-modality images, investigators at Dartmouth have incorporated NIR spectroscopy instrumentation within an open-frame MR breast coil (Fig. 5). This combined approach has been used to demonstrate feasibility by imaging more than 25 women with both normal²⁹⁶ and disease indications from mammography.²⁹⁷ Correlation between indocyanine green enhancement and Gd-enhanced MRI,²⁹⁸ and its ability to differentiate cysts from solid tumors²⁹⁹ have also been reported. Ongoing investigations indicate that DOT in combination with MRI hold promise for early determination of the effectiveness of neoadjuvant chemotherapy.^{300, 301, 302} In addition to NIRS-MRI systems, development of DOT imaging systems in combination with DBT and ultrasound are also underway.^{303, 304, 305} A recent article provides an assessment of its future role in breast imaging.³⁰⁶

Figure 5.

Dual-modality MRI-NIR system with insert showing the NIR transmitter-receiver incorporated within the open breast coil. (Courtesy: Brian W. Pogue, Thayer School of Engineering, Dartmouth College)

Electrical impedance spectroscopy (EIS) and microwave imaging spectroscopy (MIS) are also being explored for potential use in breast cancer detection. A recent study suggests that EIS could potentially be used as a risk assessment tool for young women who are not routinely screened for breast cancer.³⁰⁷In vivo microwave imaging of women with normal mammographic exam suggests that dielectric properties are heterogeneous and correlate with radiographic density.³⁰⁸ A recent two-part series on measurements of ultra-wideband dielectric properties from normal and cancer tissue samples indicate substantial variations in dielectric properties for normal tissues, and that the contrast in dielectric properties between malignant and adipose tissues could be as high as 10:1, whereas that of malignant to fibroglandular tissue could be no more than 10%.^{309, 310} A pilot clinical study that evaluated EIS, MIS, and NIRS indicate substantial contrast difference between abnormal and normal breast tissue.³¹¹ A recent article addresses the status of these imaging modalities.³¹²

CONCLUSION

Intense efforts are currently under way to improve the technological aspects of the aforementioned modalities. Those include advances in x-ray and gamma ray detector technology, MRI coil design, MRI pulse sequences, tomographic image reconstruction, signal processing, computational speed, and mechanical design. Based on current understanding and results from ongoing research, it appears that high-resolution, high-contrast, anatomical x-ray imaging either in 2-D (mammography) or with added depth information will be the primary screening modality in the next decade. However, MRI and ultrasound will have an increasingly important role for imaging high risk patients and for imaging women with dense breasts. With increasing field strength and improved homogeneity, MRS is likely to add value to dynamic contrast enhanced MRI studies. Contrast-enhanced x-ray imaging, scintimammography with dedicated cameras, dedicated SPECT, and dedicated PET offer great potential as diagnostic evaluation tools and for clinical management. While prototype BCT systems have been developed and pilot clinical studies demonstrate the ability to provide high-resolution 3-D anatomical information, there are some challenges that need to be addressed. NIR diffuse optics-based imaging and electromagnetic imaging techniques such as EIS and MIS could provide for physiologic information and is likely to be of most value when integrated with or adjunctively used with modalities that provide for anatomical structure such as x-ray, ultrasound, or MRI. At present, phase-sensitive x-ray imaging that provides for improved contrast and edge-enhancement has been demonstrated with specimens and would require substantial amount of translational research to bring it to clinical use. From the technological perspective, in addition to improvements with each modality, we are likely to observe an increasing trend towards multi-modality systems that combine the relative strengths of each modality.

Importantly, we are likely to observe a paradigm shift in the manner in which breast cancer screening will be performed in future. Breast cancer screening is currently performed in a standard manner for all women with mammography. However, this level of standardization is likely to be replaced by a screening program where the selection of an imaging modality or modalities would depend on an individual’s risk and other classifications. Already elements of this change can be observed with the recommendation by American Cancer Society to adjunctively use breast MRI for screening of high-risk subjects. This transformation to individual-risk or other classification based screening is likely to be of benefit to women. However this added layer, which can be referred to as pre-screening, does place an onus on the manner in which such classifications or risk assessments are performed and need to be carefully studied. In summary, ongoing research and recent advances indicate that the prospects of substantial improvements in early detection, accurate diagnosis, and improved monitoring of therapeutic response of breast cancer are highly promising.