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Magnetic Resonance Imaging, Digital Mammography, and Sonography: Tumor Characteristics and Tumor Biology in Primary Setting

Magnetic Resonance Imaging, Digital Mammography, and Sonography: Tumor Characteristics and Tumor... Abstract The use of imaging in the arena of primary treatment for breast cancer is gaining importance as a technique for assessing response to chemotherapy as well as assessing the underlying tumor biology. Both mammography and ultrasound have traditionally been used, in addition to clinical evaluation, to evaluate response to treatment although they have shed little light on the underlying biological processes. Functional magnetic resonance imaging techniques have the ability to assess response to treatments in addition to providing valuable information on changes in tumor perfusion, vascular permeability, oxygenation, cellularity, proliferation, and metabolism both at baseline and after treatment. This noninvasive method of evaluating cellular function is of importance both as endpoints for clinical trials and to our understanding of the biological mechanisms of cancer. Imaging modalities have become increasingly valuable tools in the assessment of breast cancer, particularly in the arena of primary disease. They are used routinely in the diagnosis and assessment of breast cancer as well as in the evaluation of response to primary chemotherapy. These techniques have evolved over the past 30 or so years since they were introduced into routine practice and have significantly different roles compared with their original use as a diagnostic adjunct to clinical evaluations. They now play a role not only in screening and diagnosis but also in assessing operability and need for primary systemic therapy and assessing changes in response to treatment. As well as providing morphological assessments of breast cancer they can also give us insights into the biology and behavior of the disease leading to their classification as imaging biological markers. These imaging biomarkers are of particular value in the early assessment of response to therapy which is of interest in identifying nonresponders early in their treatment journey and switching to potentially more effective therapy. The biological features that imaging and in particular magnetic resonance imaging (MRI), can provide information on are perfusion, oxygenation, vascularity, and cellularity (1). Imaging as a biomarker is noninvasive making it practical to be used for serial measurements, instead of repeat biopsies. Biological endpoints are also of potential utility in early stage clinical trials to evaluate novel treatments for further development (2) as they can address the potential mechanism of action of such treatments. Neoadjuvant chemotherapy for breast cancer is used primarily for patients who have locally advanced disease that would not be amenable to breast conserving surgery in their current state. The intention of neoadjuvant chemotherapy is to allow breast conservation to take place whilst offering the other advantage of adjuvant chemotherapy, the treatment of micrometastatic disease. This setting provides a unique opportunity to use imaging biomarkers to assess tumor response to chemotherapy in comparison to pathological response to treatment. Pathological complete response (pCR) has been shown on meta-analysis to predict for relapse-free survival, disease-free survival, and overall survival (3). However, recent data has shown a variance of the ability of pCR to predict for outcome depending on histological parameters (4). Those with lower proliferating tumors including the luminal A and luminal B/HER2-positive groups displayed no prognostic benefit to pCR, whereas those with the more aggressive characteristics including the luminal B/HER2-negative, HER2-positive (nonluminal), and triple-negative tumors showed a significant prognostic impact of pCR. Despite this pCR still provides an excellent surrogate endpoint for higher risk patients and is also now used to accelerate drug approval in the United States (5). In this review we will focus on what imaging can tell us about tumor biology and behavior at diagnosis and after neoadjuvant chemotherapy with specific reference to digital mammography, ultrasonography, and MRI. Mammography Mammography has a well-established role in breast cancer management and most commonly in screening and diagnosis, but also in the assessment of response to therapy. Screen-film mammography has been considered to be the “gold standard” for many years although this is now being steadily replaced by “digital mammography” which allows easier storage of data as well as showing better rates of cancer detection in younger women, those with denser breast tissue, and women who are pre- and perimenopausal (6) as well as an equivalence to screen-film mammography for screening (7). Other advantages include a higher contrast resolution, a higher signal to noise ratio, and a slightly lower radiation dose although at the expense of lower spatial resolution (8). The use of mammography for screening has been controversial although most studies have shown that there is a reduction in mortality. This may be at the cost of “overdiagnosis” (9,10). Features of breast cancer seen on mammography include a dense mass with a poorly defined border, a spiculate irregular mass, distortion of the breast tissue, asymmetric soft tissue, and specific formations of calcification including pleomorphism, linear and branching patterns, and fine clusters (11). However, mammography is very limited in the information it can provide about the underlying biology or behavior of breast cancer at the point of diagnosis. Newer mammographic techniques such as digital breast tomosynthesis, contrast-enhanced digital mammography, and dual energy mammography (spectral mammography) remain in development and their advantages over digital mammography are not yet proven (12). Mammography has been used in the assessment of response to therapy in the breast after neoadjuvant chemotherapy to determine the extent of residual disease. As imaging techniques have changed with the advent of multimodality approaches most of these studies were performed more than 15 years ago. A study of 49 patients receiving Cyclophosphamide, Methotrexate, Fluorouracil (CMF) chemotherapy showed clinical examination predicted more responders than mammography (65.7% vs 54.3%) (13). A retrospective study looked at mammograms of 95 patients taken before and after neoadjuvant chemotherapy and found that five of the eight patients thought to have a complete pathological response actually had residual tumor and of the eight patients that actually had a complete pathological response only three were predicted by mammography (14). Another retrospective review reported 56 patients who received neoadjuvant chemotherapy and found that mammography had a better sensitivity than clinical examination for prediction of residual disease (79% vs 49%) but was less specific (77% vs 92%) (15). To our knowledge there have been no studies evaluating the routine use of mammography throughout a course of neoadjuvant chemotherapy to assess response, but instead is only performed at the end of chemotherapy, which reduces the utility in the earlier identification of nonresponders. However, there may be a role in the evaluation of disease progression during chemotherapy (16). Overall, mammography does not offer a great deal of information to the observer in terms of a morphological assessment of response, although it may complement other imaging methods and clinical examination in evaluating disease extent before surgery. It also has little to offer the observer in terms of assessment of tumor biology. Ultrasonography Ultrasound is a widely used technique for the imaging of primary breast cancer and axillary nodes. Unlike mammography, ultrasound does not have a routine role in screening for breast cancer but is used in particular for the characterization of the morphology of lesions as well as for image-guided interventions including biopsies. Breast cancers are typically solid on ultrasound, have irregular margins, and cast acoustic shadows distally (11). The use of ultrasound in addition to that of mammography has been shown to increase sensitivity (97% vs 74%) in the detection of primary breast cancer but also to have a false-positive rate of 2.4% (17). In terms of the assessment of response to neoadjuvant therapy most studies have compared ultrasound to mammography, either on their own, or the utility of adding ultrasound to mammography for assessment of the primary lesion. A retrospective study of 100 patients found that ultrasound had a worse correlation with pathological outcome after neoadjuvant chemotherapy than physical examination or mammography. However, it was better correlated with lymph node response (18). Other studies have found that the accuracy of ultrasound is not significantly different to that of mammography (19) and its addition to mammography does not improve accuracy (20). A more recent review provided contradictory data showing that overall accuracy was greatest with ultrasound compared with clinical examination and mammography (21). A smaller study of 42 patients compared physical examination alone, a combination of mammography and ultrasound, and a combination of all three (22). The most accurate combination was found to be mammography and ultrasound although still with an accuracy rate of 67%. Doppler ultrasound has also been used to evaluate response assessment to chemotherapy for breast cancer. One study has found an increased sensitivity above clinical response for predicting pathological response after six cycles of chemotherapy (23) and a second study has found a similar outcome after three cycles of chemotherapy (24). The German Breast Group has made a similar observation in a study of 285 patients (25). They demonstrated that after two cycles of neoadjuvant chemotherapy (NAC), ultrasound assessment was more accurate than clinical examination in predicting nonresponding patients as well as patients who went on to have a pCR. Newer ultrasound techniques are providing increasing information, in particular with regard to the underlying biology of breast cancers. Three-dimensional power Doppler ultrasound has been used to help classify breast lesions by identification of specific vascular features (26). It provides information on the underlying vascular network of larger vessels and this has application to the understanding of angiogenesis as well as being of value in the evaluation of antiangiogenic therapies. Another recent technical advance is the use of microbubble ultrasound which has been shown in selective series to increase the accuracy of diagnosis of primary breast lesions (27). Other novel techniques in ultrasound have attempted to improve diagnostic accuracy and interobserver variability include automated whole breast ultrasound, three-dimensional ultrasound, and sonoelastography (12). These techniques should still be regarded as experimental. Overall with regard to ultrasound the data on the assessment of response of primary breast cancer to neoadjuvant therapy is mixed but does not seem to add significantly to the diagnostic accuracy of mammography and clinical examination. The studies seem to suffer from the same issues as those looking at mammography, namely only comparisons made at the end of chemotherapy, which does not aid response assessments during treatment. Explanations behind the failure of ultrasound to aid response assessments include the difficulty of posttreatment fibrosis. However, ultrasound is still used in routine practice for the assessment of response during chemotherapy and also has a role in the placement of tumor bed markers to guide surgeons in cases of good pathological response. Newer techniques promise to provide insights into the biology of tumors but have not yet been shown to aid our understanding of the changes in tumor behavior in response to chemotherapy. Morphological MRI MRI has an increasing role in the preoperative assessment of primary breast cancer. Its particular strengths include the imaging of mutifocal and multicentric disease, women with dense breasts, assessment of lobular carcinoma, post wide local excision with involved margins and patients presenting with involved axillary lymph nodes. MRI has also been shown to be of value in the assessment of breast cancer response to treatment. Most of the data to date has been using MRI to make anatomical assessment, in particular change in the size of tumors. The first significant study to address this question prospectively evaluated 39 patients pre– and post–neoadjuvant chemotherapy with a dedicated breast MRI and found that MRI predicted the pathological response in 97% of cases (28). This accuracy was far superior to that of mammography or clinical examination. Other studies that have compared the accuracy of differing modalities in predicting for response have shown both MRI and mammography to be superior to ultrasound and clinical examination (89%, 89%, 82%, and 75%, respectively) (19). Yi et al. (29) reviewed the MRI scans of 187 women who had received six cycles of NAC and found that a smaller reduction in tumor volume was an independent predictor of worse recurrence-free and overall survival. A short meta-analysis, which did not include the data of Yi, of between 230 and 301 patients across the modalities has been recently performed. The results from this study are summarized below (Table 1) (21). Overall the data shows that MRI as a single modality had the best accuracy, positive predictive value, and negative predictive value. It is however second to ultrasound in its sensitivity and second to clinical examination in its specificity. Table 1. Meta-analysis of accuracy in prediction of tumor response; from Croshaw et al. (21)* Characteristics  Clinical examination  Digital mammography  Ultrasound  MRI  Accuracy  57%  74%  79%  84%  Positive predictive value  91%  85%  85%  93%  Negative predictive value  31%  41%  44%  65%  Sensitivity  50%  81%  90%  86%  Specificity  82%  48%  33%  79%  Characteristics  Clinical examination  Digital mammography  Ultrasound  MRI  Accuracy  57%  74%  79%  84%  Positive predictive value  91%  85%  85%  93%  Negative predictive value  31%  41%  44%  65%  Sensitivity  50%  81%  90%  86%  Specificity  82%  48%  33%  79%  *MRI = magnetic resonance imaging. View Large MRI is mainly used in assessing response to therapy using an anatomical approach. However the use of functional MRI has increased, mainly in clinical trial settings, and this can add a substantial amount of information to more traditional morphologic approaches. Functional MRI can also be known as quantitative MRI as it is able to measure intrinsic tissue properties, and using an appropriate model, compute these to provide numerical outcomes (30). Dynamic Contrast-Enhanced MRI Dynamic contrast-enhanced MRI is one commonly used functional MRI technique. This allows the detection of changes in T1 relaxation times caused by the passage of a gadolinium-based contrast agent through the tissue being studied. Multiple images are taken through the time course of contrast injection and uptake signal changes allow the computation of parameters such as Ktrans which is the contrast transfer rate constant showing blood vessel perfusion and permeability, ve which is the extravascular, extracellular volume fraction, and vp which is the plasma volume fraction (30) (Figure 1). Figure 1. View largeDownload slide DCE-MRI representative parametric maps of a 42-year-old woman with a 72mm G2 IDC of the breast ER- and HER2-positive, who had a complete pathological response and remains alive and disease free at 5 years. a) Ktrans map pre NAC, b) Ktrans map post two cycles of docetaxel NAC, c) Ve map pre-NAC, d) Ve map post two cycles of docetaxel NAC. DCE-MRI = dynamic contrast-enhanced magnetic resonance imaging; ER = estrogen receptor; IDC = invasive ductal carcinoma; NAC = neoadjuvant chemotherapy. Figure 1. View largeDownload slide DCE-MRI representative parametric maps of a 42-year-old woman with a 72mm G2 IDC of the breast ER- and HER2-positive, who had a complete pathological response and remains alive and disease free at 5 years. a) Ktrans map pre NAC, b) Ktrans map post two cycles of docetaxel NAC, c) Ve map pre-NAC, d) Ve map post two cycles of docetaxel NAC. DCE-MRI = dynamic contrast-enhanced magnetic resonance imaging; ER = estrogen receptor; IDC = invasive ductal carcinoma; NAC = neoadjuvant chemotherapy. There are a number of studies that have used dynamic contrast-enhanced-MRI to assess response to neoadjuvant chemotherapy. We have previously shown that changes in kinetic dynamic contrast-enhanced-MRI parameters and Ktrans in particular can predict for both clinical and pathological response, where change in tumor size was not predictive (31). We subsequently reported that posttreatment Ktrans was also predictive of overall survival (32). A recent study has demonstrated that, after six cycles of NAC, a smaller reduction in the washout component was associated with worse disease-free and overall survival (29), a finding consistent with our data. A systematic review was conducted by Marinovich et al. (33) which identified 13 studies looking at dynamic contrast-enhanced-MRI in assessment of pathological response to NAC in breast cancer. The results were difficult to interpret mainly due to the heterogeneity of the studies involved but suggested that tumor volume, Ktrans, and early contrast uptake showed the highest sensitivity and specificity for prediction of pathological response. The biological basis for these changes and in particular those of Ktrans are not entirely understood. However, it is likely to relate to the changes within the microvasculature due to withdrawal of tissue vascular endothelial growth factor levels as a result of tumor cell death leading to endothelial cell apoptosis and a reduction in the proportion of proliferating blood vessels (31). The direct effect of chemotherapy on proliferating endothelial cells is considered to be a minor effect. Blood Oxygen Level–Dependent MRI Another biological process that MRI has a role in assessing in primary breast cancer is blood oxygenation and flow using blood oxygen level–dependent MRI. This technique uses the paramagnetic properties of deoxyhemoglobin, creating variations in the magnetic field, and reducing the relaxation rate (R2*) of water in blood and surrounding tissues. Hypoxia will therefore lead to an increased deoxyhemoglobin and a faster R2* (34). This technique has mainly been used in neuroradiology but also in cancer and specifically breast cancer. In a study of 31 patients with breast cancer treated with NAC we found increases in R2* after two cycles of treatment, with greater changes in those who went on to achieve a pathological response (32). However, this was not as useful as Ktrans in predicting a response. The likely hypothesis for increased R2* in response to chemotherapy is an increase in tumor hypoxia, although the data for this is mainly drawn from animal xenograft models. Diffusion-Weighted MRI Diffusion-weighted MRI is a functional imaging technique that can be used to measure water diffusivity and does not require the use of contrast agents. Modified fat-suppressed T2-weighted spin-echo sequences are used and the application of diffusion-sensitizing gradients with differing amplitudes allows the calculation of water diffusivity, often called the apparent diffusion coefficient (ADC) (35). The ADC value depends on the freedom of movement of water at the cellular level allowing the differentiation of benign and malignant tissues. Within cancers the diffusion of water can also be affected by the cell density with an increased proliferation leading to an increase in the “packing” of cells thereby reducing the freedom of water and the ADC (30). Of particular interest is the ability for this technique to pick up changes in ADC in response to therapy. As tumor cells die, a process of cell death and apoptosis causes rupture of cell membranes increasing water diffusivity and ADC. Most of the work using diffusion-weighted MRI in primary breast cancer has focused on the differentiation of benign and malignant lesions. These studies have found a significant difference in the ADC value between differing types of tissue as well as difference associated with cellularity within malignant lesions (36). This technique has been used to assess response to therapy after neoadjuvant chemotherapy. Two small studies from the same group found conflicting results with regard to ADC changes, one with 10 patients showing significant changes after the first and second cycle (37) and the other with 16 patients showing that ADC did not display an early response (38). However, this second study did show that early changes in fat:water ratios and water T2 could be used to predict a final tumor volume response. A third study with 11 patients demonstrated that ADC was particularly sensitive to changes in tumor status (39). These findings have been corroborated by a much larger study with 56 participants with locally advanced cancers and 25 nonmalignant controls (40). This study showed that ADC was more useful than typical morphological changes on MRI at predicting tumor response. This finding is consistent with two of the three earlier and smaller studies. MR Spectroscopy MR spectroscopy uses the behavior of hydrogen (1H) to demonstrate metabolic changes in cancer cells, in particular using molecules such as choline that are known to be elevated in malignant tissues. MR spectroscopy can detect these elevated levels to increase the specificity of a malignant diagnosis. Tozaki et al. (41) have assessed it in the setting of response to neoadjuvant therapy. A study of 16 patients found an improved ability to predict pathological responders by reductions in the choline signal after two cycles of NAC in breast cancer. A second study by the same authors (42) looked at seven cases of breast cancer after one cycle of NAC and found a correlation between the change in choline signal and the change in lesion size. The same correlation was not observed between a change in ADC using diffusion-weighted MRI and a change in size. These studies suggest that the normalization of these high concentrations of tumor metabolites is associated with a response to treatment, perhaps because of reduced cellular activity or burden of disease after treatment. Additional Approaches Other MRI approaches are in development including MR elastography, which assesses tissue stiffness, although has not yet been used to assess response to primary therapy. Other non-MRI functional imaging techniques include positron emission tomography, which uses a radiotracer, most commonly [18F]2-fluoro-2-d-glucose, to assess tumor activity. This approach been used to demonstrate that [18F]2-fluoro-2-d-glucose reduction after a single cycle of NAC is predictive of a pathological response to treatment (43), and at least 10 other studies reviewed by Groheux et al. (44) have addressed this question, showing a correlation between early changes in the SUVmax and final pathological response. The other positron emission tomography tracer of particular interest is [18F]fluorothymidine which is a potential biomarker of proliferation. [18F]fluorothymidine-positron emission tomography uptake has been shown to be well correlated in breast cancer with the gold standard marker of proliferation, Ki-67 by immunohistochemistry (45), and reduction in [18F]fluorothymidine uptake after chemotherapy has been demonstrated to predict clinical response (46). Perfusion computed tomography has also been studied in breast cancer and found to be of utility in predicting response to NAC (47). It uses changes in tissue attenuation after administration of contrast media to allow the modeling (48) of kinetic parameters including changes in blood flow, blood volumes, and permeability, which are characteristics of tumor angiogenesis and therefore of potential value in the assessment of antiangiogenic therapies. Conclusions Mammography, ultrasound, and morphological MRI play essential everyday roles in the management of breast cancer. In the setting of NAC they have been shown to increase the accuracy of response prediction in comparison to clinical examinations. However, once one moves beyond morphological assessment to a biological approach to tumor imaging their utility is limited. Functional MRI approaches can reveal the underlying biological processes both before treatment and after chemotherapy, shedding new light on the pathophysiological nature of breast cancer in a noninvasive way, and without the use of ionizing radiation. These techniques allow us to assess cellularity, vascularity, oxygenation, and metabolism of tumors. They also provide the potential to act as clinical trial endpoints in the era of biological-targeted therapies although further work to validate these approaches is required. We acknowledge the Breast Cancer Campaign and the Breast Cancer Research Trust who providing funding for our work. References 1. Gore JC Manning HC Quarles CC Waddell KW Yankeelov TE . Magnetic resonance in the era of molecular imaging of cancer. Magn Reson Imaging . 2011; 29( 5): 587– 600. 2. Leach MO Morgan B Tofts PS et al.   ; Experimental Cancer Medicine Centres Imaging Network Steering Committee. Imaging vascular function for early stage clinical trials using dynamic contrast-enhanced magnetic resonance imaging. Eur Radiol . 2012; 22( 7): 1451– 1464. 3. Kong X Moran MS Zhang N Haffty B Yang Q . 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Magnetic Resonance Imaging, Digital Mammography, and Sonography: Tumor Characteristics and Tumor Biology in Primary Setting

JNCI Monographs , Volume 2015 (51) – Jun 10, 2015

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Abstract

Abstract The use of imaging in the arena of primary treatment for breast cancer is gaining importance as a technique for assessing response to chemotherapy as well as assessing the underlying tumor biology. Both mammography and ultrasound have traditionally been used, in addition to clinical evaluation, to evaluate response to treatment although they have shed little light on the underlying biological processes. Functional magnetic resonance imaging techniques have the ability to assess response to treatments in addition to providing valuable information on changes in tumor perfusion, vascular permeability, oxygenation, cellularity, proliferation, and metabolism both at baseline and after treatment. This noninvasive method of evaluating cellular function is of importance both as endpoints for clinical trials and to our understanding of the biological mechanisms of cancer. Imaging modalities have become increasingly valuable tools in the assessment of breast cancer, particularly in the arena of primary disease. They are used routinely in the diagnosis and assessment of breast cancer as well as in the evaluation of response to primary chemotherapy. These techniques have evolved over the past 30 or so years since they were introduced into routine practice and have significantly different roles compared with their original use as a diagnostic adjunct to clinical evaluations. They now play a role not only in screening and diagnosis but also in assessing operability and need for primary systemic therapy and assessing changes in response to treatment. As well as providing morphological assessments of breast cancer they can also give us insights into the biology and behavior of the disease leading to their classification as imaging biological markers. These imaging biomarkers are of particular value in the early assessment of response to therapy which is of interest in identifying nonresponders early in their treatment journey and switching to potentially more effective therapy. The biological features that imaging and in particular magnetic resonance imaging (MRI), can provide information on are perfusion, oxygenation, vascularity, and cellularity (1). Imaging as a biomarker is noninvasive making it practical to be used for serial measurements, instead of repeat biopsies. Biological endpoints are also of potential utility in early stage clinical trials to evaluate novel treatments for further development (2) as they can address the potential mechanism of action of such treatments. Neoadjuvant chemotherapy for breast cancer is used primarily for patients who have locally advanced disease that would not be amenable to breast conserving surgery in their current state. The intention of neoadjuvant chemotherapy is to allow breast conservation to take place whilst offering the other advantage of adjuvant chemotherapy, the treatment of micrometastatic disease. This setting provides a unique opportunity to use imaging biomarkers to assess tumor response to chemotherapy in comparison to pathological response to treatment. Pathological complete response (pCR) has been shown on meta-analysis to predict for relapse-free survival, disease-free survival, and overall survival (3). However, recent data has shown a variance of the ability of pCR to predict for outcome depending on histological parameters (4). Those with lower proliferating tumors including the luminal A and luminal B/HER2-positive groups displayed no prognostic benefit to pCR, whereas those with the more aggressive characteristics including the luminal B/HER2-negative, HER2-positive (nonluminal), and triple-negative tumors showed a significant prognostic impact of pCR. Despite this pCR still provides an excellent surrogate endpoint for higher risk patients and is also now used to accelerate drug approval in the United States (5). In this review we will focus on what imaging can tell us about tumor biology and behavior at diagnosis and after neoadjuvant chemotherapy with specific reference to digital mammography, ultrasonography, and MRI. Mammography Mammography has a well-established role in breast cancer management and most commonly in screening and diagnosis, but also in the assessment of response to therapy. Screen-film mammography has been considered to be the “gold standard” for many years although this is now being steadily replaced by “digital mammography” which allows easier storage of data as well as showing better rates of cancer detection in younger women, those with denser breast tissue, and women who are pre- and perimenopausal (6) as well as an equivalence to screen-film mammography for screening (7). Other advantages include a higher contrast resolution, a higher signal to noise ratio, and a slightly lower radiation dose although at the expense of lower spatial resolution (8). The use of mammography for screening has been controversial although most studies have shown that there is a reduction in mortality. This may be at the cost of “overdiagnosis” (9,10). Features of breast cancer seen on mammography include a dense mass with a poorly defined border, a spiculate irregular mass, distortion of the breast tissue, asymmetric soft tissue, and specific formations of calcification including pleomorphism, linear and branching patterns, and fine clusters (11). However, mammography is very limited in the information it can provide about the underlying biology or behavior of breast cancer at the point of diagnosis. Newer mammographic techniques such as digital breast tomosynthesis, contrast-enhanced digital mammography, and dual energy mammography (spectral mammography) remain in development and their advantages over digital mammography are not yet proven (12). Mammography has been used in the assessment of response to therapy in the breast after neoadjuvant chemotherapy to determine the extent of residual disease. As imaging techniques have changed with the advent of multimodality approaches most of these studies were performed more than 15 years ago. A study of 49 patients receiving Cyclophosphamide, Methotrexate, Fluorouracil (CMF) chemotherapy showed clinical examination predicted more responders than mammography (65.7% vs 54.3%) (13). A retrospective study looked at mammograms of 95 patients taken before and after neoadjuvant chemotherapy and found that five of the eight patients thought to have a complete pathological response actually had residual tumor and of the eight patients that actually had a complete pathological response only three were predicted by mammography (14). Another retrospective review reported 56 patients who received neoadjuvant chemotherapy and found that mammography had a better sensitivity than clinical examination for prediction of residual disease (79% vs 49%) but was less specific (77% vs 92%) (15). To our knowledge there have been no studies evaluating the routine use of mammography throughout a course of neoadjuvant chemotherapy to assess response, but instead is only performed at the end of chemotherapy, which reduces the utility in the earlier identification of nonresponders. However, there may be a role in the evaluation of disease progression during chemotherapy (16). Overall, mammography does not offer a great deal of information to the observer in terms of a morphological assessment of response, although it may complement other imaging methods and clinical examination in evaluating disease extent before surgery. It also has little to offer the observer in terms of assessment of tumor biology. Ultrasonography Ultrasound is a widely used technique for the imaging of primary breast cancer and axillary nodes. Unlike mammography, ultrasound does not have a routine role in screening for breast cancer but is used in particular for the characterization of the morphology of lesions as well as for image-guided interventions including biopsies. Breast cancers are typically solid on ultrasound, have irregular margins, and cast acoustic shadows distally (11). The use of ultrasound in addition to that of mammography has been shown to increase sensitivity (97% vs 74%) in the detection of primary breast cancer but also to have a false-positive rate of 2.4% (17). In terms of the assessment of response to neoadjuvant therapy most studies have compared ultrasound to mammography, either on their own, or the utility of adding ultrasound to mammography for assessment of the primary lesion. A retrospective study of 100 patients found that ultrasound had a worse correlation with pathological outcome after neoadjuvant chemotherapy than physical examination or mammography. However, it was better correlated with lymph node response (18). Other studies have found that the accuracy of ultrasound is not significantly different to that of mammography (19) and its addition to mammography does not improve accuracy (20). A more recent review provided contradictory data showing that overall accuracy was greatest with ultrasound compared with clinical examination and mammography (21). A smaller study of 42 patients compared physical examination alone, a combination of mammography and ultrasound, and a combination of all three (22). The most accurate combination was found to be mammography and ultrasound although still with an accuracy rate of 67%. Doppler ultrasound has also been used to evaluate response assessment to chemotherapy for breast cancer. One study has found an increased sensitivity above clinical response for predicting pathological response after six cycles of chemotherapy (23) and a second study has found a similar outcome after three cycles of chemotherapy (24). The German Breast Group has made a similar observation in a study of 285 patients (25). They demonstrated that after two cycles of neoadjuvant chemotherapy (NAC), ultrasound assessment was more accurate than clinical examination in predicting nonresponding patients as well as patients who went on to have a pCR. Newer ultrasound techniques are providing increasing information, in particular with regard to the underlying biology of breast cancers. Three-dimensional power Doppler ultrasound has been used to help classify breast lesions by identification of specific vascular features (26). It provides information on the underlying vascular network of larger vessels and this has application to the understanding of angiogenesis as well as being of value in the evaluation of antiangiogenic therapies. Another recent technical advance is the use of microbubble ultrasound which has been shown in selective series to increase the accuracy of diagnosis of primary breast lesions (27). Other novel techniques in ultrasound have attempted to improve diagnostic accuracy and interobserver variability include automated whole breast ultrasound, three-dimensional ultrasound, and sonoelastography (12). These techniques should still be regarded as experimental. Overall with regard to ultrasound the data on the assessment of response of primary breast cancer to neoadjuvant therapy is mixed but does not seem to add significantly to the diagnostic accuracy of mammography and clinical examination. The studies seem to suffer from the same issues as those looking at mammography, namely only comparisons made at the end of chemotherapy, which does not aid response assessments during treatment. Explanations behind the failure of ultrasound to aid response assessments include the difficulty of posttreatment fibrosis. However, ultrasound is still used in routine practice for the assessment of response during chemotherapy and also has a role in the placement of tumor bed markers to guide surgeons in cases of good pathological response. Newer techniques promise to provide insights into the biology of tumors but have not yet been shown to aid our understanding of the changes in tumor behavior in response to chemotherapy. Morphological MRI MRI has an increasing role in the preoperative assessment of primary breast cancer. Its particular strengths include the imaging of mutifocal and multicentric disease, women with dense breasts, assessment of lobular carcinoma, post wide local excision with involved margins and patients presenting with involved axillary lymph nodes. MRI has also been shown to be of value in the assessment of breast cancer response to treatment. Most of the data to date has been using MRI to make anatomical assessment, in particular change in the size of tumors. The first significant study to address this question prospectively evaluated 39 patients pre– and post–neoadjuvant chemotherapy with a dedicated breast MRI and found that MRI predicted the pathological response in 97% of cases (28). This accuracy was far superior to that of mammography or clinical examination. Other studies that have compared the accuracy of differing modalities in predicting for response have shown both MRI and mammography to be superior to ultrasound and clinical examination (89%, 89%, 82%, and 75%, respectively) (19). Yi et al. (29) reviewed the MRI scans of 187 women who had received six cycles of NAC and found that a smaller reduction in tumor volume was an independent predictor of worse recurrence-free and overall survival. A short meta-analysis, which did not include the data of Yi, of between 230 and 301 patients across the modalities has been recently performed. The results from this study are summarized below (Table 1) (21). Overall the data shows that MRI as a single modality had the best accuracy, positive predictive value, and negative predictive value. It is however second to ultrasound in its sensitivity and second to clinical examination in its specificity. Table 1. Meta-analysis of accuracy in prediction of tumor response; from Croshaw et al. (21)* Characteristics  Clinical examination  Digital mammography  Ultrasound  MRI  Accuracy  57%  74%  79%  84%  Positive predictive value  91%  85%  85%  93%  Negative predictive value  31%  41%  44%  65%  Sensitivity  50%  81%  90%  86%  Specificity  82%  48%  33%  79%  Characteristics  Clinical examination  Digital mammography  Ultrasound  MRI  Accuracy  57%  74%  79%  84%  Positive predictive value  91%  85%  85%  93%  Negative predictive value  31%  41%  44%  65%  Sensitivity  50%  81%  90%  86%  Specificity  82%  48%  33%  79%  *MRI = magnetic resonance imaging. View Large MRI is mainly used in assessing response to therapy using an anatomical approach. However the use of functional MRI has increased, mainly in clinical trial settings, and this can add a substantial amount of information to more traditional morphologic approaches. Functional MRI can also be known as quantitative MRI as it is able to measure intrinsic tissue properties, and using an appropriate model, compute these to provide numerical outcomes (30). Dynamic Contrast-Enhanced MRI Dynamic contrast-enhanced MRI is one commonly used functional MRI technique. This allows the detection of changes in T1 relaxation times caused by the passage of a gadolinium-based contrast agent through the tissue being studied. Multiple images are taken through the time course of contrast injection and uptake signal changes allow the computation of parameters such as Ktrans which is the contrast transfer rate constant showing blood vessel perfusion and permeability, ve which is the extravascular, extracellular volume fraction, and vp which is the plasma volume fraction (30) (Figure 1). Figure 1. View largeDownload slide DCE-MRI representative parametric maps of a 42-year-old woman with a 72mm G2 IDC of the breast ER- and HER2-positive, who had a complete pathological response and remains alive and disease free at 5 years. a) Ktrans map pre NAC, b) Ktrans map post two cycles of docetaxel NAC, c) Ve map pre-NAC, d) Ve map post two cycles of docetaxel NAC. DCE-MRI = dynamic contrast-enhanced magnetic resonance imaging; ER = estrogen receptor; IDC = invasive ductal carcinoma; NAC = neoadjuvant chemotherapy. Figure 1. View largeDownload slide DCE-MRI representative parametric maps of a 42-year-old woman with a 72mm G2 IDC of the breast ER- and HER2-positive, who had a complete pathological response and remains alive and disease free at 5 years. a) Ktrans map pre NAC, b) Ktrans map post two cycles of docetaxel NAC, c) Ve map pre-NAC, d) Ve map post two cycles of docetaxel NAC. DCE-MRI = dynamic contrast-enhanced magnetic resonance imaging; ER = estrogen receptor; IDC = invasive ductal carcinoma; NAC = neoadjuvant chemotherapy. There are a number of studies that have used dynamic contrast-enhanced-MRI to assess response to neoadjuvant chemotherapy. We have previously shown that changes in kinetic dynamic contrast-enhanced-MRI parameters and Ktrans in particular can predict for both clinical and pathological response, where change in tumor size was not predictive (31). We subsequently reported that posttreatment Ktrans was also predictive of overall survival (32). A recent study has demonstrated that, after six cycles of NAC, a smaller reduction in the washout component was associated with worse disease-free and overall survival (29), a finding consistent with our data. A systematic review was conducted by Marinovich et al. (33) which identified 13 studies looking at dynamic contrast-enhanced-MRI in assessment of pathological response to NAC in breast cancer. The results were difficult to interpret mainly due to the heterogeneity of the studies involved but suggested that tumor volume, Ktrans, and early contrast uptake showed the highest sensitivity and specificity for prediction of pathological response. The biological basis for these changes and in particular those of Ktrans are not entirely understood. However, it is likely to relate to the changes within the microvasculature due to withdrawal of tissue vascular endothelial growth factor levels as a result of tumor cell death leading to endothelial cell apoptosis and a reduction in the proportion of proliferating blood vessels (31). The direct effect of chemotherapy on proliferating endothelial cells is considered to be a minor effect. Blood Oxygen Level–Dependent MRI Another biological process that MRI has a role in assessing in primary breast cancer is blood oxygenation and flow using blood oxygen level–dependent MRI. This technique uses the paramagnetic properties of deoxyhemoglobin, creating variations in the magnetic field, and reducing the relaxation rate (R2*) of water in blood and surrounding tissues. Hypoxia will therefore lead to an increased deoxyhemoglobin and a faster R2* (34). This technique has mainly been used in neuroradiology but also in cancer and specifically breast cancer. In a study of 31 patients with breast cancer treated with NAC we found increases in R2* after two cycles of treatment, with greater changes in those who went on to achieve a pathological response (32). However, this was not as useful as Ktrans in predicting a response. The likely hypothesis for increased R2* in response to chemotherapy is an increase in tumor hypoxia, although the data for this is mainly drawn from animal xenograft models. Diffusion-Weighted MRI Diffusion-weighted MRI is a functional imaging technique that can be used to measure water diffusivity and does not require the use of contrast agents. Modified fat-suppressed T2-weighted spin-echo sequences are used and the application of diffusion-sensitizing gradients with differing amplitudes allows the calculation of water diffusivity, often called the apparent diffusion coefficient (ADC) (35). The ADC value depends on the freedom of movement of water at the cellular level allowing the differentiation of benign and malignant tissues. Within cancers the diffusion of water can also be affected by the cell density with an increased proliferation leading to an increase in the “packing” of cells thereby reducing the freedom of water and the ADC (30). Of particular interest is the ability for this technique to pick up changes in ADC in response to therapy. As tumor cells die, a process of cell death and apoptosis causes rupture of cell membranes increasing water diffusivity and ADC. Most of the work using diffusion-weighted MRI in primary breast cancer has focused on the differentiation of benign and malignant lesions. These studies have found a significant difference in the ADC value between differing types of tissue as well as difference associated with cellularity within malignant lesions (36). This technique has been used to assess response to therapy after neoadjuvant chemotherapy. Two small studies from the same group found conflicting results with regard to ADC changes, one with 10 patients showing significant changes after the first and second cycle (37) and the other with 16 patients showing that ADC did not display an early response (38). However, this second study did show that early changes in fat:water ratios and water T2 could be used to predict a final tumor volume response. A third study with 11 patients demonstrated that ADC was particularly sensitive to changes in tumor status (39). These findings have been corroborated by a much larger study with 56 participants with locally advanced cancers and 25 nonmalignant controls (40). This study showed that ADC was more useful than typical morphological changes on MRI at predicting tumor response. This finding is consistent with two of the three earlier and smaller studies. MR Spectroscopy MR spectroscopy uses the behavior of hydrogen (1H) to demonstrate metabolic changes in cancer cells, in particular using molecules such as choline that are known to be elevated in malignant tissues. MR spectroscopy can detect these elevated levels to increase the specificity of a malignant diagnosis. Tozaki et al. (41) have assessed it in the setting of response to neoadjuvant therapy. A study of 16 patients found an improved ability to predict pathological responders by reductions in the choline signal after two cycles of NAC in breast cancer. A second study by the same authors (42) looked at seven cases of breast cancer after one cycle of NAC and found a correlation between the change in choline signal and the change in lesion size. The same correlation was not observed between a change in ADC using diffusion-weighted MRI and a change in size. These studies suggest that the normalization of these high concentrations of tumor metabolites is associated with a response to treatment, perhaps because of reduced cellular activity or burden of disease after treatment. Additional Approaches Other MRI approaches are in development including MR elastography, which assesses tissue stiffness, although has not yet been used to assess response to primary therapy. Other non-MRI functional imaging techniques include positron emission tomography, which uses a radiotracer, most commonly [18F]2-fluoro-2-d-glucose, to assess tumor activity. This approach been used to demonstrate that [18F]2-fluoro-2-d-glucose reduction after a single cycle of NAC is predictive of a pathological response to treatment (43), and at least 10 other studies reviewed by Groheux et al. (44) have addressed this question, showing a correlation between early changes in the SUVmax and final pathological response. The other positron emission tomography tracer of particular interest is [18F]fluorothymidine which is a potential biomarker of proliferation. [18F]fluorothymidine-positron emission tomography uptake has been shown to be well correlated in breast cancer with the gold standard marker of proliferation, Ki-67 by immunohistochemistry (45), and reduction in [18F]fluorothymidine uptake after chemotherapy has been demonstrated to predict clinical response (46). Perfusion computed tomography has also been studied in breast cancer and found to be of utility in predicting response to NAC (47). It uses changes in tissue attenuation after administration of contrast media to allow the modeling (48) of kinetic parameters including changes in blood flow, blood volumes, and permeability, which are characteristics of tumor angiogenesis and therefore of potential value in the assessment of antiangiogenic therapies. Conclusions Mammography, ultrasound, and morphological MRI play essential everyday roles in the management of breast cancer. In the setting of NAC they have been shown to increase the accuracy of response prediction in comparison to clinical examinations. However, once one moves beyond morphological assessment to a biological approach to tumor imaging their utility is limited. Functional MRI approaches can reveal the underlying biological processes both before treatment and after chemotherapy, shedding new light on the pathophysiological nature of breast cancer in a noninvasive way, and without the use of ionizing radiation. 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Published: Jun 10, 2015

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