Neoadj Chemo Breast CA

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  AJR:208, February 2017 1 with triple-negative BC and tumors positive for ErbB-2, also known as HER2/neu; no clear relationship between the pathologic complete response rate and the event-free survival and overall survival rates was found for the entire trial cohorts. This may be ex-plained, in part, by the absence of a univer- sally accepted denition of pathologic com - plete response, which may inuence trial reporting and interpretation. The most com- monly recognized denition of pathologic complete response is the absence of invasive disease, with or without in situ disease, in the breast and axillary lymph nodes [1]. Patho-logic complete response rates have been shown to vary depending on the tumor bio-logic subtype. A large meta-analysis of 11,695 subjects in 30 studies showed that tu-mor subtype was associated with the patho-logic complete response rate and was lowest for hormone receptor–positive and ErbB-2–negative tumors (8%), followed by hormone receptor–positive and ErbB-2–positive tu-mors (19%); it was highest for the triple-neg-ative BC (31%) and hormone receptor–nega-tive and ErbB-2–positive (39%) subtypes [4].Noninvasive imaging monitoring of treat-ment response during neoadjuvant chemo-therapy may help predict which patients will achieve a pathologic complete response ear-ly in treatment to provide alternate options for treatment and avoid unnecessary toxic-ity in patients who do not experience a re- Multimodality Imaging for Evaluating Response to Neoadjuvant Chemotherapy in Breast Cancer  Gaiane M. Rauch 1 Beatriz Elena Adrada 2 Henry Mark Kuerer 3 Raquel F. D. van la Parra 3 Jessica W. T. Leung 2 Wei Tse Yang 4 Rauch GM, Adrada BE, Kuerer HM, van la Parra RFD, Leung JWT, Yang WT 1 Department of Diagnostic Radiology, Unit 1473, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030-4009. Address correspondence to G. M. Rauch ( 2 Department of Diagnostic Radiology, Unit 1350, The University of Texas MD Anderson Cancer Center, Houston, TX. 3 Department of Breast Surgical Oncology, Unit 1434, The University of Texas MD Anderson Cancer Center, Houston, TX. 4 Department of Diagnostic Radiology, Unit 1459, The University of Texas MD Anderson Cancer Center, Houston, TX.  Women’s Imaging ã Review AJR   2017; 208:1–100361–803X/17/2082–1© American Roentgen Ray Society P resurgical neoadjuvant chemo-therapy is becoming the standard of care in the treatment of locally advanced breast cancer (BC) and is a treatment option for patients with early-stage BC. Adjuvant systemic therapy is ad-ministered after surgery with the aim of re-ducing the risk of distant recurrence by treating clinically occult micrometastasis. Neoadjuvant chemotherapy refers to system-ic therapy administration in the preoperative setting, with the main goal of downstaging primary tumors to increase the breast con-servation rate. Studies have shown that neo-adjuvant chemotherapy has multiple advan-tages over traditional adjuvant therapy [1–5] (Table 1). Although randomized controlled clinical trials have shown similar disease-free and overall survival rates for neoadju-vant chemotherapy and adjuvant chemother-apy in patients with BC [1, 4, 6], these trials found that patients who experienced a patho-logic complete response after neoadjuvant chemotherapy had signicantly higher sur -vival rates than did patients with residual tu-mor [4, 7, 8]. A meta-analysis of 12 interna-tional trials led by the U.S. Food and Drug Administration with a total of 11,955 patients found associations between the achievement of a pathologic complete response and long- term survival benets [9]. The association between pathologic complete response and long-term outcomes was strongest in patients Keywords:  breast cancer, breast MRI, breast PET, molecular breast imaging, neoadjuvant chemotherapyDOI:10.2214/AJR.16.17223Received August 24, 2016; accepted after revision September 22, 2016. OBJECTIVE.  Neoadjuvant chemotherapy is becoming the standard of care for patients with locally advanced breast cancer. Conventional imaging modalities used for the assess-ment of tumor response to neoadjuvant chemotherapy rely on changes in size or morphologic characteristics and, therefore, are inherently limited. CONCLUSION.  Functional imaging technologies evaluate vascular, metabolic, bio- chemical, and molecular changes in cancer cells and have a unique ability to detect specic biologic tumor markers, assess therapeutic targets, predict early response to neoadjuvant che-motherapy, and guide individualized cancer therapy. Rauch et al.Imaging After Neoadjuvant Chemotherapy for Breast CancerWomen’s ImagingReview    D  o  w  n   l  o  a   d  e   d   f  r  o  m   w  w  w .  a   j  r  o  n   l   i  n  e .  o  r  g   b  y   T  u   f   t  s   U  n   i  v  e  r  s   i   t  y  o  n   1   1   /   0   7   /   1   6   f  r  o  m    I   P  a   d   d  r  e  s  s   1   3   0 .   6   4 .   1   1 .   1   5   3 .   C  o  p  y  r   i  g   h   t   A   R   R   S .   F  o  r  p  e  r  s  o  n  a   l  u  s  e  o  n   l  y  ;  a   l   l  r   i  g   h   t  s  r  e  s  e  r  v  e   d  2 AJR:208, February 2017 Rauch et al. sponse. However, there is currently no stan-dard approach for the imaging evaluation and follow-up of patients undergoing neoad- juvant chemotherapy. The aim of this article is to discuss the accuracy, advantages, limi-tations, and future directions of various di-agnostic imaging modalities for the monitor-ing of neoadjuvant chemotherapy response in patients with BC, with an emphasis on func-tional imaging modalities. Clinical Examination Historically, patients treated with neoad- juvant chemotherapy have been monitored with regular physical examination (PE) of the breast and axilla for palpable masses and lymphadenopathy, respectively; a decrease in size or complete resolution of the breast mass constitutes a treatment response. However, PE is known to be inaccurate in evaluating the re-sponse to neoadjuvant chemotherapy. In a data synthesis of six studies, the overall accuracy of PE was 57%, the positive predictive value (PPV) was 91%, and the negative predictive value (NPV) was 31% [10]. The PE of tumors smaller than 2 cm is limited, especially in pa-tients with dense breasts, those whose tumors have poorly dened margins, and those who experience residual brosis after neoadjuvant chemotherapy [11]. PE is notably unreliable after neoadjuvant chemotherapy for small ear-ly-stage cancers. Thus, accurate imaging for close monitoring of neoadjuvant chemothera-py in patients with BC is essential. Conventional Imaging Mammography and breast ultrasound are the most commonly used imaging modalities for tumor diagnosis and neoadjuvant chemo-therapy follow-up. However, they have variable accuracy for assessing residual tumors after neoadjuvant chemotherapy because of post-treatment changes, such as the development of fragmentation or brosis. A study of 189 pa -tients by Chagpar et al. [12] evaluated the accu-racy of PE, ultrasound, and mammography in predicting the residual size of breast tumors af-ter neoadjuvant chemotherapy and showed that size estimates were only moderately correlated with residual pathologic tumor size (correlation coefcients: 0.42, 0.42, and 0.41, respectively), with an accuracy of plus or minus 1 cm in 66% of patients by PE, 75% by ultrasound, and 70% by mammography.The initial mammographic appearance of the tumor inuences the accuracy of mam -mography in predicting residual tumor size. Huber et al. [13] found that, for tumors pre-senting as masses with well-delineated mar-gins on pretreatment mammography, the ac-curacy of posttreatment mammography was high ( r  = 0.77), whereas masses with ill-de- ned margins had a lower correlation ( r  = −0.19). Decreases in the size and density of the mass on mammography are the most re-liable and common indicators of treatment response, whereas changes in calcications associated with malignancy are often mis- leading. Microcalcications can increase, decrease, or remain stable after neoadjuvant chemotherapy [14]. A recent report retrospec-tively analyzed 494 patients with invasive car-cinoma who underwent neoadjuvant chemo-therapy [14]. Although the decrease in tumor size was correlated with pathologic complete response, there was no correlation between the change in the extent of the calcications after neoadjuvant chemotherapy and patho- logic complete response. Calcications seen on mammography after neoadjuvant chemo-therapy were associated with malignant histo-pathologic type in 49% of tumors and benign ndings in 41% of tumors at surgery. Patients with estrogen receptor–positive tumors had a signicantly higher proportion of residual malignant calcications than did patients with estrogen receptor–negative tumors, suggest-ing that patterns of response are based on tu-mor biologic characteristics.Reportedly, ultrasound is more accurate than mammography in estimating residual tu-mors [11, 15, 16]. Keune et al. [11] retrospec-tively analyzed 192 patients with primary BCs and reported that breast ultrasound was more accurate than mammography in measuring residual disease after neoadjuvant chemother-apy; ultrasound was able to size the residu-al disease in 91.3% of cases compared with only 51.9% by mammography (  p  < 0.001). However, there was no difference in the abil-ity of mammography and ultrasound to pre-dict pathologic complete response. When both mammography and ultrasound found no resid-ual disease, the likelihood of pathologic com-plete response was 80% [11]. The use of both imaging modalities improved the accuracy of predicting a pathologic complete response to neoadjuvant chemotherapy to a greater degree than did the use of either modality alone [17]. Functional Imaging Conventional imaging modalities rely on changes in size or morphologic characteristics to evaluate tumor response. Therefore, they are inherently limited in assessing residual disease and cannot reliably predict patholog-ic response. Functional imaging technologies evaluate vascular, metabolic, biochemical, and molecular changes in cancer cells. These changes occur before morphologic changes, allowing the earlier assessment of response to neoadjuvant chemotherapy. An advantage of functional imaging is its unique ability to detect specic biologic tumor markers, assess therapeutic targets, evaluate and predict ear-ly response to neoadjuvant chemotherapy, and tailor neoadjuvant chemotherapy for individu-alized cancer therapy.  MRI Dynamic contrast-enhanced (DCE) MRI can detect tumor angiogenesis, associated changes in tumor microcirculation, and up-take of contrast material as a result of the in-creased permeability of the new vessels that form in growing tumors. Therefore, it pro-vides insight into the pathophysiology of tu-mor response to neoadjuvant chemotherapy and allows an earlier and more accurate as-sessment of tumor response than does ana-tomic imaging (Figs. 1 and 2). The report- ed sensitivity, specicity, and accuracy of DCE-MRI for residual disease evaluation are 86–92%, 60–89%, and 76–90%, respec-tively [2, 10, 16, 18–24]. A meta-analysis of 44 studies between 1990 and 2008, including TABLE 1: Advantages of Neoadjuvant Chemotherapy for the Treatment of Locally Advanced Breast Cancer  AdvantageEffectReduction in tumor burdenDecrease in extent of breast surgery: segmentectomy versus mastectomyDownstaging of axillary nodal diseaseDecrease in extent of axillary surgery and surgical morbidityEarly assessment of tumor responseProvide option for alterations in neoadjuvant regimens and opportunities to participate in adaptive clinical trialsIn vivo assessment of tumor biologyIndividualization of systemic treatment, development of targeted  therapiesPathologic complete responsePredict long-term patient outcomes    D  o  w  n   l  o  a   d  e   d   f  r  o  m   w  w  w .  a   j  r  o  n   l   i  n  e .  o  r  g   b  y   T  u   f   t  s   U  n   i  v  e  r  s   i   t  y  o  n   1   1   /   0   7   /   1   6   f  r  o  m    I   P  a   d   d  r  e  s  s   1   3   0 .   6   4 .   1   1 .   1   5   3 .   C  o  p  y  r   i  g   h   t   A   R   R   S .   F  o  r  p  e  r  s  o  n  a   l  u  s  e  o  n   l  y  ;  a   l   l  r   i  g   h   t  s  r  e  s  e  r  v  e   d  AJR:208, February 2017 3 Imaging After Neoadjuvant Chemotherapy for Breast Cancer  2050 patients who underwent imaging eval-uation of residual disease after neoadjuvant chemotherapy, found that MRI had generally high sensitivity (83–87%) and heterogeneous specicity (54–83%) [22]. A DCE-MRI neoadjuvant chemotherapy response analysis uses either a semiquanti-tative analysis, based mainly on tumor size, volume or enhancement, or fully quantitative methods, based on complex pharmacokinet-ic modeling [25–28]. The ACRIN 6657/I-spy trial showed that volumetric measurement of tumor size had the greatest advantage in pre-dicting tumor response early in treatment [29]. The follow-up analysis showed that function-al tumor volume, as measured by MRI, was a strong predictor of recurrence-free survival [30]. A systemic review of 13 studies evalu-ating the accuracy of DCE-MRI showed that the sensitivity and specicity pairs for the prediction of early pathologic response were highest in studies measuring reductions in quantitative dynamic contrast measurements and tumor volume and were lowest in studies measuring reductions in unidimensional or bi-dimensional tumor size [31].Cho et al. [32] showed that a voxel-based parametric response map analysis of DCE-MRI is an accurate method for the early prediction (after the rst cycle) of the effectiveness of che -motherapy in BC. Pretreatment MRI features, such as peritumoral edema, have been shown to be associated with pathologic complete re-sponse and recurrence-free survival [33].Texture analysis, a quantitative measure of tumor heterogeneity based on statistical modeling, may depict regional phenotypic variations within a tumor that reect differ -ent biologic processes and therefore have dif-ferent prognostic potential [26, 27, 34–36]. Changes in textural features can be evalu-ated on contrast-enhanced and T2-weighted sequences and have shown promise in pre-dicting response to neoadjuvant chemother-apy. Wu et al. [34] performed a texture anal-ysis of DCE-MRI in 35 patients with stage II and III BC and found that intratumor par- titioning identied spatially resolved subre -gions within tumors, each with distinct en-hancement characteristics on DCE-MRI; specically, heterogeneity of the tumor sub -region that was associated with fast washout on DCE-MRI was predictive of the patholog-ic response to neoadjuvant chemotherapy. A texture analysis based on T2-weighted imag-ing, performed for 61 women with BC who were undergoing neoadjuvant chemotherapy, found that changes in T2 heterogeneity were associated with response to neoadjuvant che-motherapy, particularly in patients with tri-ple-negative BC [37].DWI and its quantitative derivative, the ap- parent diffusion coefcient (ADC), can be used as a surrogate biomarker for the early de-tection of therapeutic response on the basis of the diffusivity of water, tumor cellularity, and cell membrane integrity [38–40]. A retrospec-tive study of DWI in 53 patients undergoing neoadjuvant chemotherapy showed statistical- ly signicantly lower ADC values in respond -ers versus nonresponders (  p  = 0.004). Fur-thermore, the mean percentage ADC increase in responders was higher than that in nonre-sponders (  p  < 0.001) [41]. A meta-analysis of 34 studies showed that the sensitivity and spec- icity of DWI versus DCE-MRI were 93% and 82% versus 68% and 91%, respectively [38]. Limitations to DWI methods include low spa-tial resolution, methodologic differences in ROI measurements, and cutoff values, with re-ports showing different sensitivity on the basis of the biologic subtype of BC.The reported accuracy of MRI in estimat-ing residual disease after neoadjuvant chemo-therapy varies by tumor subtype [6, 39, 42–45]. A retrospective analysis of serial DCE-MRI in 166 patients showed that it was the most ac-curate at predicting tumor response to ther-apy in triple-negative BC, ErbB-2–positive tumors, and high-grade tumors, with the high-est sensitivity for MRI scans performed after two cycles of neoadjuvant chemotherapy [42]. A multicenter study of 746 patients showed that the NPV was highest for patients who had hormone receptor–negative and ErbB-2–positive tumors and triple-negative BC, and it was still only about 60%. Among patients who achieved a complete response on imag-ing, hormone receptor positivity and low tu-mor grade were most commonly associated with residual disease [46]. FDG PET Imaging  Fluorine-18 FDG PET imaging is a meta-bolic functional imaging modality that can show changes in tumor metabolism early dur-ing neoadjuvant chemotherapy, before mor-phologic changes are apparent [47–49]. A study of 40 patients with invasive ductal carci-noma showed that the relative change in stan-dardized uptake value (SUV) after the second course of neoadjuvant chemotherapy was sta- tistically signicantly higher in patients with pathologic complete response than in those without a pathologic complete response (  p  = 0.001) [48]. A meta-analysis of 19 studies with 920 patients reported that the pooled sensitiv- ity, specicity, PPV, and NPV of FDG PET in the early detection of response were 84%, 66%, 50%, and 91%, respectively [50]. The major limitation of FDG PET/CT is its inabil-ity to reliably detect subcentimeter breast le-sions because of its lower spatial resolution, resulting in a high false-negative rate.There is variability in the cutoff values for the relative changes in tumor metabolic activi-ty (change in SUV) to predict response to neo-adjuvant chemotherapy, ranging from 25% to 70%; the best reported correlation with patho- logic ndings is seen at a change in SUV of 55–65% [51–53]. The optimal timing of the interim FDG PET/CT is not well established, with higher reported accuracy after one or two cycles of neoadjuvant chemotherapy than after three or more cycles (76% vs 65%;  p  = 0.001) [50, 54]. The histologic BC subtype and biologic phenotype inuence the FDG uptake. Invasive ductal carcinoma, high-grade and tri-ple-negative BC, and ErbB-2–negative tumors show higher baseline uptake than do invasive lobular carcinoma and low-grade tumors [55–58]. Groheux et al. [58] found that the change in maximum SUV and total lesion glycolysis were the most adequate quantitative indexes used for triple-negative BC and estrogen re-ceptor–positive and ErbB-2–negative can-cers, whereas the absolute maximum SUV after two cycles of neoadjuvant chemothera-py was best for the ErbB-2–positive subtype of BC. The chemotherapy regimen may affect the ability of FDG PET to predict response to neoadjuvant chemotherapy, with the SUV cut-off value higher for dose-dense versus con-ventional dose therapy [52, 59].Dedicated high-resolution positron emis-sion mammography is a novel molecular imaging modality with reportedly high sen- sitivity (87%) and specicity (85%) for the detection of BC [60]. A study of 388 pa-tients found that it had comparable sensitiv- ity to and greater specicity than MRI in a presurgical setting [61]. However, to our knowledge, there are no published reports on the use of positron emission mammogra-phy in the population receiving neoadjuvant chemotherapy. PET/MRI is a new hybrid imaging modality that has not yet been well studied in patients with BC; it may allow di-rect comparisons between kinetic, textural, and diffusion-weighted parameters of MRI and glucose metabolism indexes of FDG PET/CT, combining the strengths and over-coming the weaknesses of these two func-tional imaging modalities.    D  o  w  n   l  o  a   d  e   d   f  r  o  m   w  w  w .  a   j  r  o  n   l   i  n  e .  o  r  g   b  y   T  u   f   t  s   U  n   i  v  e  r  s   i   t  y  o  n   1   1   /   0   7   /   1   6   f  r  o  m    I   P  a   d   d  r  e  s  s   1   3   0 .   6   4 .   1   1 .   1   5   3 .   C  o  p  y  r   i  g   h   t   A   R   R   S .   F  o  r  p  e  r  s  o  n  a   l  u  s  e  o  n   l  y  ;  a   l   l  r   i  g   h   t  s  r  e  s  e  r  v  e   d  4 AJR:208, February 2017 Rauch et al.  Molecular Breast Imaging  Another functional imaging modality that is used for the diagnostic and neoadjuvant evaluation of BC is 99m Tc-sestamibi scan-ning. The accumulation of 99m Tc-sestamibi in BC is due to increased angiogenesis and an increased concentration of mitochon-dria in cancer cells [62]. A meta-analysis of 45 studies with 6339 patients showed that 99m Tc-sestamibi had an overall sensitivity of 83% and specicity of 85% for BC diagno - sis [63]. However, its sensitivity and specic -ity for palpable versus nonpalpable lesions were 87% and 86% versus 59% and 89%, re-spectively. Scintimammography uses large-FOV conventional gamma cameras, with poor spatial resolution, and is unable to re-liably detect lesions smaller than 1 cm, lim-iting its widespread clinical use. Dedicated breast nuclear imaging systems in a mammo- graphic conguration with a rst-generation single-headed scintillation detector are re- ferred to as breast-specic gamma imaging, and second-generation dual-headed direct conversion semiconductor detectors are re-ferred to as molecular breast imaging. A me-ta-analysis showed that the pooled sensitivity of breast-specic gamma imaging for de - tecting BC was 95%, and the specicity was 80%; the sensitivity for detecting subcenti-meter BC was 84% [64]. Dedicated breast gamma imaging and MRI are well correlat-ed and have similar sensitivities (88–95% vs 89–98%) for cancer detection; however, over- all, gamma imaging showed better specic -ity (74–90% vs 40–65%) [65–67].A recent meta-analysis of scintimammog-raphy for the prediction of neoadjuvant che-motherapy response included 14 studies with 503 patients and showed a pooled sensitivity of 86% and specicity of 69%. For the pre -diction of pathologic complete response, the sensitivity and specicity were 86% and 67%, respectively [68]. The use of newer dedicated breast imaging gamma cameras should im-prove their diagnostic performance; howev-er, currently, there is a paucity of reports on their use in the neoadjuvant setting.The diagnostic performance of breast-spe- cic gamma imaging for residual tumor de -tection was evaluated in 122 patients and compared with that of MRI, using patholog-ic examination as the reference standard. The sensitivity and specicity of breast-specic gamma imaging were 74% and 72%, respec-tively, comparable to those of MRI (82% and 72%, respectively;  p  < 0.001). A tumor sub-type analysis showed that the residual tumor size was statistically signicantly underesti - mated by breast-specic gamma imaging in the luminal subtype (  p  = 0.008) and by MRI in the luminal (  p  < 0.001) and ErbB-2 sub-types (  p  = 0.032), with a signicantly lesser degree of underestimation by breast-specic gamma imaging than MRI in both subtypes. In the triple-negative BC subtype, both breast- specic gamma imaging and MRI generated accurate tumor size measurements [69].A pilot study by Mitchell et al. [70] evalu-ated the ability of molecular breast imaging to predict early response to neoadjuvant che-motherapy in 19 patients and showed that it predicted the presence of residual disease at surgery with a diagnostic accuracy of 89.5%, sensitivity of 92.3%, and specicity of 83.3%. Tumor size after neoadjuvant chemotherapy on molecular breast imaging was better cor-related with pathologic tumor size than was tumor size according to mammography, ul-trasound, or clinical assessment [70]. Further prospective studies are needed to validate this method in the BC patients receiving neo-adjuvant therapy. If molecular breast imag-ing is an accurate in vivo functional imaging modality for the evaluation and prediction of neoadjuvant chemotherapy response in BC, then it could become a low-cost standard of care for these patients (Fig. 3). Novel Ultrasound-Based Imaging  Breast elastography objectively evaluates tumor stiffness, in addition to the tumor’s morphologic characteristics and vascularity evaluated by ultrasound. Research has found that tumor stiffness is associated with tumor progression, including carcinogenesis and stromal factors [71, 72]. Hayashi et al. [71] found that tumors with low elastography had statistically signicantly higher pathologic complete response rates than did those with high elastography (  p  = 0.003) and suggested that elastography has predictive value for re-sponse to neoadjuvant chemotherapy. Evans et al. [72] showed that shear-wave elastography measurements of pretreatment tumor stiffness showed a statistically signicant relationship with the pathologic response of invasive BC to neoadjuvant chemotherapy. Jing et al. [73] found that tumor stiffness after two cycles of neoadjuvant chemotherapy was statistical- ly signicantly decreased in responders (  p  < 0.001) but not in nonresponders (  p  = 0.172).Contrast-enhanced ultrasound has shown promise, both qualitatively and quantitative- ly, in evaluating tumor blood ow changes in the neoadjuvant setting. Perubutane, the contrast medium used for contrast-enhanced ultrasound, comprises microbubbles that re- main within tumor vessels, reects tumor neovascularization, and displays detailed images of tumor vessels and blood ow [74]. It was shown that contrast-enhanced ultra-sound measured tumor size more accurate-ly than did conventional ultrasound, detected areas of central necrosis without liquefac-tion (which were not seen on conventional ultrasound), and showed high correlation be-tween blood perfusion changes and neoadju- vant chemotherapy efcacy [74–76]. The re - ported sensitivity, specicity, PPV, and NPV of contrast-enhanced ultrasound to predict pathologic complete response after neoadju-vant chemotherapy were 80%, 98%, 88.9%, and 96% [77]. Amioka et al. [74] compared contrast-enhanced ultrasound with MRI and FDG PET/CT in 63 patients undergoing neo-adjuvant chemotherapy and found that the specicity and accuracy were greater for contrast-enhanced ultrasound than for FDG PET/CT (78% vs 53% [  p  = 0.02] and 84% vs 70% [  p  = 0.057], respectively). The sen-sitivity of contrast-enhanced ultrasound was statistically signicantly greater than that of MRI (96% vs 70%;  p  = 0.047) [74]. Other possible advantages of contrast-enhanced ul-trasound are that it is cost effective, it can be performed by the patient’s bedside, adverse effects are rare, and there is no risk of radia-tion exposure or nephrotoxicity. Quantitative Ultrasound and Optical Imaging  Quantitative ultrasound is a tissue charac-terization technique that examines the fre-quency content of radiofrequency backscatter ultrasound signals from tissues. Quantitative ultrasound monitors the effectiveness of neo-adjuvant chemotherapy by detecting tumor cell death in tumors early in treatment [78, 79]. Diffuse optical spectroscopy imaging is a near-infrared optical imaging technique that is based on the visualization of the he-modynamic status of the tissue, such as oxy-hemoglobin and deoxyhemoglobin concen- trations, and reects the status of the tissue microvasculature and hence angiogenesis. In addition, it measures water and lipid con-tents, which have been shown to be associat-ed with alterations during neoadjuvant che-motherapy [78, 80]. Tran et al. [78] reported that quantitative ultrasound and diffuse op-tical spectroscopy imaging parameters are statistically signicant markers for a patho -logic response to neoadjuvant chemothera-py after 1 week of treatment (  p  < 0.001) and    D  o  w  n   l  o  a   d  e   d   f  r  o  m   w  w  w .  a   j  r  o  n   l   i  n  e .  o  r  g   b  y   T  u   f   t  s   U  n   i  v  e  r  s   i   t  y  o  n   1   1   /   0   7   /   1   6   f  r  o  m    I   P  a   d   d  r  e  s  s   1   3   0 .   6   4 .   1   1 .   1   5   3 .   C  o  p  y  r   i  g   h   t   A   R   R   S .   F  o  r  p  e  r  s  o  n  a   l  u  s  e  o  n   l  y  ;  a   l   l  r   i  g   h   t  s  r  e  s  e  r  v  e   d


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