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Background The change in apparent diffusion coefficient (ADC) measured from diffusion-weighted imaging (DWI) has been shown to be predictive of pathologic complete response (pCR) for patients with locally invasive breast cancer undergoing neoadjuvant chemotherapy. Purpose To investigate the additive value of tumor ADC in a multicenter clinical trial setting. Study type Retrospective analysis of multicenter prospective data. Population In all, 415 patients who enrolled in the I-SPY 2 TRIAL from 2010 to 2014 were included. Field strength/sequence 1.5T or 3T MRI system using a fat-suppressed single-shot echo planar imaging sequence with b-values of 0 and 800 s/mm2 for DWI, followed by a T1-weighted sequence for dynamic contrast-enhanced MRI (DCE-MRI) performed at pre-NAC (T0), after 3 weeks of NAC (T1), mid-NAC (T2), and post-NAC (T3). Assessment Functional tumor volume and tumor ADC were measured at each MRI exam; pCR measured at surgery was assessed as the binary outcome. Breast cancer subtype was defined by hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) status. Statistical tests A logistic regression model was used to evaluate associations between MRI predictors with pCR. The cross-validated area under the curve (AUC) was calculated to assess the predictive performance of the model with and without ADC. Results In all, 354 patients (128 HR+/HER2-, 60 HR+/HER2+, 34 HR-/HER2+, 132 HR-/HER2-) were included in the analysis. In the full cohort, adding ADC predictors increased the AUC from 0.76 to 0.78 at mid-NAC and from 0.76 to 0.81 at post-NAC. In HR/HER2 subtypes, the AUC increased from 0.52 to 0.65 at pre-NAC for HR+/HER2-, from 0.67 to 0.73 at mid-NAC and from 0.72 to 0.76 at post-NAC for HR+/HER2+, from 0.71 to 0.81 at post-NAC for triple negatives. Data conclusion The addition of ADC to standard functional tumor volume MRI showed improvement in the prediction of treatment response in HR+ and triple-negative breast cancer. Level of evidence 2 Technical Efficacy Stage: 4 J. Magn. Reson. Imaging 2019;50:1742-1753.

Background Quantitative diffusion-weighted imaging (DWI) MRI is a promising technique for cancer characterization and treatment monitoring. Knowledge of the reproducibility of DWI metrics in breast tumors is necessary to apply DWI as a clinical biomarker. Purpose To evaluate the repeatability and reproducibility of breast tumor apparent diffusion coefficient (ADC) in a multi-institution clinical trial setting, using standardized DWI protocols and quality assurance (QA) procedures. Study type Prospective. Subjects In all, 89 women from nine institutions undergoing neoadjuvant chemotherapy for invasive breast cancer. Field strength/sequence DWI was acquired before and after patient repositioning using a four b-value, single-shot echo-planar sequence at 1.5T or 3.0T. Assessment A QA procedure by trained operators assessed artifacts, fat suppression, and signal-to-noise ratio, and determine study analyzability. Mean tumor ADC was measured via manual segmentation of the multislice tumor region referencing DWI and contrast-enhanced images. Twenty cases were evaluated multiple times to assess intra- and interoperator variability. Segmentation similarity was assessed via the Sorenson-Dice similarity coefficient. Statistical tests Repeatability and reproducibility were evaluated using within-subject coefficient of variation (wCV), intraclass correlation coefficient (ICC), agreement index (AI), and repeatability coefficient (RC). Correlations were measured by Pearson's correlation coefficients. Results In all, 71 cases (80%) passed QA evaluation: 44 at 1.5T, 27 at 3.0T; 60 pretreatment, 11 after 3 weeks of taxane-based treatment. ADC repeatability was excellent: wCV = 4.8% (95% confidence interval [CI] 4.0, 5.7%), ICC = 0.97 (95% CI 0.95, 0.98), AI = 0.83 (95% CI 0.76, 0.87), and RC = 0.16 * 10-3 mm2 /sec (95% CI 0.13, 0.19). The results were similar across field strengths and timepoint subgroups. Reproducibility was excellent: interreader ICC = 0.92 (95% CI 0.80, 0.97) and intrareader ICC = 0.91 (95% CI 0.78, 0.96). Data conclusion Breast tumor ADC can be measured with excellent repeatability and reproducibility in a multi-institution setting using a standardized protocol and QA procedure. Improvements to DWI image quality could reduce loss of data in clinical trials. Level of evidence 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2019;49:1617-1628.

Purpose To estimate the accuracy of predicting response to neoadjuvant chemotherapy (NACT) in patients with locally advanced breast cancer using MR spectroscopy (MRS) measurements made very early in treatment. Materials and methods This prospective Health Insurance Portability and Accountability Act (HIPAA)-compliant protocol was approved by the American College of Radiology and local-site institutional review boards. One hundred nineteen women with invasive breast cancer of ≥3 cm undergoing NACT were enrolled between September 2007 and April 2010. MRS measurements of the concentration of choline-containing compounds ([tCho]) were performed before the first chemotherapy regimen (time point 1, TP1) and 20-96 h after the first cycle of treatment (TP2). The change in [tCho] was assessed for its ability to predict pathologic complete response (pCR) and radiologic response using the area under the receiver operating characteristic curve (AUC) and logistic regression models. Results Of the 119 subjects enrolled, only 29 cases (24%) with eight pCRs provided usable data for the primary analysis. Technical challenges in acquiring quantitative MRS data in a multi-site trial setting limited the capture of usable data. In this limited data set, the decrease in tCho from TP1 to TP2 had poor ability to predict either pCR (AUC = 0.53, 95% confidence interval [CI]: 0.27-0.79) or radiologic response (AUC = 0.51, 95% CI: 0.27-0.75). Conclusion The technical difficulty of acquiring quantitative MRS data in a multi-site clinical trial setting led to a low yield of analyzable data, which was insufficient to accurately measure the ability of early MRS measurements to predict response to NACT. Level of evidence 1 Technical Efficacy: Stage 2 J. MAGN. RESON. IMAGING 2017;46:290-302.

Purpose To assess the ability of a recent, anatomically designed breast phantom incorporating T1 and diffusion elements to serve as a quality control device for quantitative comparison of apparent diffusion coefficient (ADC) measurements calculated from diffusion-weighted MRI (DWI) within and across MRI systems. Materials and Methods A bilateral breast phantom incorporating multiple T1 and diffusion tissue mimics and a geometric distortion array was imaged with DWI on 1.5 Tesla (T) and 3.0T scanners from two different manufacturers, using three different breast coils (three configurations total). Multiple measurements were acquired to assess the bias and variability of different diffusion weighted single-shot echo-planar imaging sequences on the scanner-coil systems. Results The repeatability of ADC measurements was mixed: the standard deviation relative to baseline across scanner-coil-sequences ranged from low variability (0.47, 95% confidence interval [CI]: 0.22–1.00) to high variability (1.69, 95% CI: 0.17–17.26), depending on material, with the lowest and highest variability from the same scanner-coil-sequence. Assessment of image distortion showed that right/left measurements of the geometric distortion array were 1 to 16% larger on the left coil side compared with the right coil side independent of scanner-coil systems, diffusion weighting, and phase-encoding direction. Conclusion This breast phantom can be used to measure scanner-coil-sequence bias and variability for DWI. When establishing a multisystem study, this breast phantom may be used to minimize protocol differences (e.g., due to available sequences or shimming technique), to correct for bias that cannot be minimized, and to weigh results from each system depending on respective variability. J. Magn. Reson. Imaging 2016. J. MAGN. RESON. IMAGING 2016;44:846–855.

Purpose We present a breast phantom designed to enable quantitative assessment of measurements of T1 relaxation time, apparent diffusion coefficient (ADC), and other attributes of breast tissue, with long-term support from a national metrology institute. Materials and Methods A breast phantom was created with two independent, interchangeable units for diffusion and T1/T2 relaxation, each with flexible outer shells. The T1 unit was filled with corn syrup solution and grapeseed oil to mimic the relaxation behavior of fibroglandular and fatty tissues, respectively. The diffusion unit contains plastic tubes filled with aqueous solutions of polyvinylpyrrolidone (PVP) to modulate the ADC. The phantom was imaged at 1.5T and 3.0T using magnetic resonance imaging (MRI) scanners and common breast coils from multiple manufacturers to assess T1 and T2 relaxation time and ADC values. Results The fibroglandular mimic exhibited target T1 values on 1.5T and 3.0T clinical systems (25–75 percentile range: 1289 to 1400 msec and 1533 to 1845 msec, respectively) across all bore temperatures. PVP solutions mimicked the range of ADC values from malignant tumors to normal breast tissue (40% PVP median: 633 × 10−6 mm2/s to 0% PVP median: 2231 × 10−6 mm2/s) at temperatures of 17–24°C. The interchangeable phantom units allowed both the diffusion and T1/T2 units to be tested on the left and right sides of the coil to assess any variation. Conclusion This phantom enables T1 and ADC measurements, fits in a variety of clinical breast coils, and can serve as a quality control tool to facilitate the standardization of quantitative measurements for breast MRI. J. Magn. Reson. Imaging 2016.

Purpose To evaluate a gradient nonlinearity correction (GNC) program for quantitative apparent diffusion coefficient (ADC) measurements on phantom and human subject diffusion-weighted (DW) magnetic resonance imaging (MRI) scans in a multicenter breast cancer treatment response study Materials and Methods A GNC program using fifth-order spherical harmonics for gradient modeling was applied retrospectively to qualification phantom and human subject scans. Ice-water phantoms of known diffusion coefficient were scanned at five different study centers with different scanners and receiver coils. Human in vivo data consisted of baseline and early-treatment exams on 54 patients from four sites. ADC maps were generated with and without GNC. Regions of interest were defined to quantify absolute errors and changes with GNC over breast imaging positions. Results Phantom ADC errors varied with region of interest (ROI) position and scanner configuration; the mean error by configuration ranged from 1.4% to 19.9%. GNC significantly reduced the overall mean error for all sites from 9.9% to 0.6% (P = 0.016). Spatial dependence of GNC was highest in the right-left (RL) and anterior-posterior (AP) directions. Human subject mean tumor ADC was reduced 0.2 to 12% by GNC at different sites. By regression, every 1-cm change in tumor ROI position between baseline and follow-up visits resulted in an estimated change of 2.4% in the ADC early-treatment response measurement. Conclusion GNC is effective for removing large, system-dependent errors in quantitative breast DWI. GNC may be important in ensuring reproducibility in multicenter studies and in reducing errors in longitudinal treatment response measures arising from spatial variations in tumor position between visits. J. Magn. Reson. Imaging 2015;42:908–919.

SYSTEMIC CHEMOTHERAPY for locally advanced breast cancer has become the mainstay of treatment because of its correlation with improved survival and reduced overall morbidity (1). Although preoperative, neoadjuvant, compared to postoperative chemotherapy does not result in a survival benefit, it does confer the advantage of increasing the possibility for breast-conserving surgery (2). Neoadjuvant chemotherapy (NACT) provides the further advantage of allowing the primary tumor response to be monitored during treatment. Multiple clinical trials have demonstrated that the response of the primary tumor to NACT correlates with patient survival (3–5), suggesting that tumor response may be an important prognostic indicator. Tumor response is most accurately determined by assessing the presence or stratifying the degree of residual cancer that remains in the breast at the completion of neoadjuvant therapy and at the time of definitive surgical resection (6). Several noninvasive methods for assessing response to NACT have been evaluated, including clinical exam, mammography, and ultrasound. In the past, clinical exam was most commonly used to assess response during NACT. However, in recent decades primary breast tumor response to NACT has been shown to be more accurately assessed by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) as compared with clinical exam, mammography, or ultrasound (7,8). MRI measurements have been strongly correlated with the standard of reference of histologic response (8). Only a moderate correlation between clinical exam, mammography, and ultras2ound has been shown with pathologic measurements of tumor after surgical resection (9). Limited literature has been published on sonography alone in assessing response to NACT; however, a recent study showed a lack of correlation of both sonographic 3D and unidimensional measurements of tumor with pathologic outcome (10). PET (positron emission tomography) has also been evaluated in the evaluation of response to neoadjuvant therapy, with changes in size, vascularity, and tumor metabolism highly correlated between 18F-FDG-PET (fluorodeoxyglucose-PET) and DCE-MRI (11). In addition, it has been demonstrated that changes in PET values in patients with locally advanced breast cancer is associated with outcome, with lack of decrease in SUV (standardized uptake value), the measurement of radiotracer uptake in patient’s tumors compared to background, from baseline to mid-treatment carrying an elevated mortality risk (12). One technique that has been shown to accurately characterize functional tumor volume (FTV) uses quantitative breast MRI parameters, the signal enhancement ratio (SER) and percent enhancement (PE), that both can be measured from standard clinical breast MR images. Multiple studies have evaluated MRI as a marker of response, using predefined criteria as imaging predictors. A previous study published by our group (13) used a specific PE threshold of 70% to define tumor volume and found that when MRI was compared to clinical breast examination, tumor size at pathology, and number of positive lymph nodes, MRI tumor volume was the stronger predictor of recurrence-free survival (RFS). More recent work by Yi et al (14) in patients receiving NACT determined that smaller reduction in tumor size and smaller reduction in washout kinetics over the course of treatment was associated with worse RFS and overall survival. However, the group did not evaluate the effects of varying thresholds in their evaluation. Similarly, Heldahl et al (15) found that total enhancing volume as measured on pre-treatment MRIs in 32 patients undergoing NACT was associated with survival. However, percent enhancement thresholds were not varied in their study. The specific aim of our study was to evaluate how enhancement thresholds influence the performance of functional volumetric tumor measurements and to determine the optimal PE and SER thresholds for predicting recurrence-free survival (RFS) in patients with breast cancer undergoing NACT, for whom 6–10 years of survival data was available. RFS was used as the endpoint to determine if patients had relapsed during the study period.

Purpose To determine whether readout-segmented echo-planar diffusion imaging (RESOLVE) improves separation of malignant versus benign lesions compared to standard single-shot echo-planar imaging (ss-EPI) on BI-RADS 4/5 lesions detected on breast magnetic resonance imaging (MRI). Materials and Methods Consecutive 3T breast MRI studies with BI-RADS 4/5 designation and subsequent biopsy or benign mastectomy were retrospectively identified. Freehand regions of interest (ROIs) were drawn on lesions and also on normal background fibroglandular tissue for comparison. Lesion-to-background contrast was evaluated by normalizing signal intensity of the lesion ROI by the normal background tissue ROI at b = 800. Statistical analysis used the Mann–Whitney/Wilcoxon rank-sum test for unpaired and Wilcoxon signed-rank for paired comparisons. Results Of 38 lesions in 32 patients, 10 were malignant. Lesion-to-background contrast was higher on RESOLVE than ss-EPI (1.80 ± 0.71 vs. 1.62 ± 0.63, P = 0.03). Mean apparent diffusion coefficient (ADC) was the same or lower on RESOLVE than ss-EPI, and this effect was largest in malignant lesions (RESOLVE 0.90 ± 0.13; ss-EPI 1.00 ± 0.13; median difference −0.10 (95% confidence interval [CI]: −0.17, −0.02) × 10−3mm2/sec; P = 0.014). By either diffusion method, there was a statistically significant difference between benign and malignant mean ADC (P < 0.001). Conclusion Increased lesion-to-background contrast and improved separation of benign from malignant lesions by RESOLVE compared to standard diffusion suggests that RESOLVE may show promise as an adjunct to clinical breast MRI. J. Magn. Reson. Imaging 2014;40:674–681. © 2013 Wiley Periodicals, Inc.

Purpose To evaluate diffusion changes in the breast tumor–stromal boundary and adjacent tissue in response to neoadjuvant chemotherapy using high resolution diffusion-weighted imaging (HR-DWI). Materials and Methods Seven patients with invasive breast cancer were imaged with HR-DWI before and early during treatment. The mean apparent diffusion coefficient (ADC) was plotted in 1-mm increments around the tumor boundary. Early change in ADC was measured for tumor, tumor boundary, and stromal regions, and the relationship to treatment response was evaluated using Spearman's correlation. Results Statistically significant correlations between treatment response and early changes in ADC were found for: (i) whole tumor (ρ = 0.93, 95% confidence interval [CI] = (0.58, 0.99), P = 0.003); (ii) tumor rim (ρ = 0.75, 95% CI = (−0.007, 0.96), P = 0.05); and (iii) boundary transition region (ρ = 0.86, 95% CI = (0.29, 0.98), P = 0.01). Early change in ADC of distal stroma had a marginally statistically significant positive correlation to treatment response (ρ = 0.71, 95% CI = (−0.084, 0.95), P = 0.07). Conclusion Proximity-dependent evaluation of HR-DWI data in the breast tumor–stromal boundary and adjacent tissue may provide information about response to therapy. J. Magn. Reson. Imaging 2014;39:1308–1313. © 2013 Wiley Periodicals, Inc.

Purpose: To present a novel technique for measuring tissue enhancement in breast fibroglandular tissue regions on contrast-enhanced breast magnetic resonance imaging (MRI) aimed at quantifying the enhancement of breast parenchyma, also known as “background enhancement.” Materials and Methods: Our quantitative method for measuring breast MRI background enhancement was evaluated in a population of 16 healthy volunteers. We also demonstrate the use of our new technique in the case study of one subject classified as high risk for developing breast cancer who underwent 3 months of tamoxifen therapy. Results: We obtained quantitative measures of background enhancement in all cases. The high-risk patient exhibited a 37% mean reduction in background enhancement with treatment. Conclusion: Our quantitative method is a robust and promising tool that may allow investigators to quantify and document the potential adverse effect of background enhancement on diagnostic accuracy in larger populations. J. Magn. Reson. Imaging 2011;33:1229–1234. © 2011 Wiley-Liss, Inc.

Purpose—To determine if inhibitors of the human growth factor receptor (HER) family can be used to enhance tumor vascular permeability and perfusion and optimize the efficacy of cytotoxic chemotherapeutics. Poor tumor vascular function limits the delivery and efficacy of cancer chemotherapeutics and HER family tyrosine kinases mediate tumor-endothelial signaling in both of these compartments. Materials and Methods—BT474 human breast cancer tumors were established in mice and the biologic effects of the HER tyrosine kinase inhibitor (TKI) gefitinib on tumor vascular function was determined by dynamic contrast enhanced MRI (DCE-MRI), and on tumor vascular architecture and perfusion by immunofluorescence microscopy. Results—A brief dose of gefitinib enhances the anti-tumor activity of paclitaxel in vivo but not in cell culture, suggesting that its chemo enhancing activity involves the in vivo microenvironment. A brief high dose of gefitinib induces a decrease in endothelial transfer constant Kps and a concomitant increase in tumor fractional plasma volume (fPV). These changes are accompanied by a rapid reduction in tumor volume likely due to decreased tumor edema, and modestly improved tumor vascular architecture and perfusion on microscopy. Conclusion—These data suggest that HER family TKIs have the potential to optimize the tumor microenvironment for delivery of cytotoxic chemotherapeutics.

This review describes the current knowledge and challenges of lesion interpretation with MRI of the breast according to different image interpretation strategies. Particular emphasis is given to patient- and tumor-related factors that influence image interpretation. The impacts of the menstrual cycle, prior surgery, radiation therapy, and chemotherapy are summarized. Particular enhancement features of ductal carcinoma in situ (DCIS) or invasive lobular carcinoma are described. Finally, an adequate diagnosis at MRI of the breast should take into account the results of the patient's history, physical examination, and all imaging tests performed before MRI. J. Magn. Reson. Imaging 2001;13:821-829.

The purpose of this study was to develop, standardize, and test reproducibility of a lexicon for reporting contrast-enhanced breast magnetic resonance imaging (MRI) examinations. To standardize breast MRI lesion description and reporting, seven radiologists with extensive breast MRI experience developed consensus on technical detail, clinical history, and terminology reporting to describe kinetic and architectural features of lesions detected on contrast-enhanced breast MR images. This lexicon adapted American College of Radiology Breast Imaging and Data Reporting System terminology for breast MRI reporting, including recommendations for reporting clinical history, technical parameters for breast MRI, descriptions for general breast composition, morphologic and kinetic characteristics of mass lesions or regions of abnormal enhancement, and overall impression and management recommendations. To test morphology reproducibility, seven radiologists assessed morphology characteristics of 85 contrast-enhanced breast MRI studies. Data from each independent reader were used to compute weighted and unweighted kappa (κ) statistics for interobserver agreement among readers. The MR lexicon differentiates two lesion types, mass and non-mass-like enhancement based on morphology and geographical distribution, with descriptors of shape, margin, and internal enhancement. Lexicon testing showed substantial agreement for breast density (κ = 0.63) and moderate agreement for lesion type (κ = 0.57), mass margins (κ = 0.55), and mass shape (κ = 0.42). Agreement was fair for internal enhancement characteristics. Unweighted kappa statistics showed highest agreement for the terms dense in the breast composition category, mass in lesion type, spiculated and smooth in mass margins, irregular in mass shape, and both dark septations and rim enhancement for internal enhancement characteristics within a mass. The newly developed breast MR lexicon demonstrated moderate interobserver agreement. While breast density and lesion type appear reproducible, other terms require further refinement and testing to lead to a uniform standard language and reporting system for breast MRI. J. Magn. Reson. Imaging 2001;13:889–895. © 2001 Wiley-Liss, Inc.