Predicted sensitivity to endocrine therapy for stage II-III hormone receptor-positive and HER2-negative (HR+/HER2-) breast cancer before chemo-endocrine therapy.

BACKGROUND: We proposed that a test for sensitivity to the adjuvant endocrine therapy component of treatment for patients with stage II-III breast cancer (SET2,3) should measure transcription related to estrogen and progesterone receptors (SETER/PR index) adjusted for a baseline prognostic index (BPI) combining clinical tumor and nodal stage with molecular subtype by RNA4 (ESR1, PGR, ERBB2, and AURKA). PATIENTS AND METHODS: Patients with clinically high-risk, hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative (HR+/HER2-) breast cancer received neoadjuvant taxane-anthracycline chemotherapy, surgery with measurement of residual cancer burden (RCB), and then adjuvant endocrine therapy. SET2,3 was measured from pre-treatment tumor biopsies, evaluated first in an MD Anderson Cancer Center (MDACC) cohort (n = 307, 11 years' follow-up, U133A microarrays), cut point was determined, and then independent, blinded evaluation was carried out in the I-SPY2 trial (n = 268, high-risk MammaPrint result, 3.8 years' follow-up, Agilent-44K microarrays, NCI Clinical Trials ID: NCT01042379). Primary outcome measure was distant relapse-free survival. Multivariate Cox regression models tested prognostic independence of SET2,3 relative to RCB and other molecular prognostic signatures, and whether other prognostic signatures could substitute for SETER/PR or RNA4 components of SET2,3. RESULTS: SET2,3 added independent prognostic information to RCB in the MDACC cohort: SET2,3 [hazard ratio (HR) 0.23, P = 0.004] and RCB (HR 1.77, P < 0.001); and the I-SPY2 trial: SET2,3 (HR 0.27, P = 0.031) and RCB (HR 1.68, P = 0.008). SET2,3 provided similar prognostic information irrespective of whether RCB-II or RCB-III after chemotherapy, and in both luminal subtypes. Conversely, RCB was most strongly prognostic in cancers with low SET2,3 status (MDACC P < 0.001, I-SPY2 P < 0.001). Other molecular signatures were not independently prognostic; they could effectively substitute for RNA4 subtype within the BPI component of SET2,3, but they could not effectively substitute for SETER/PR index. CONCLUSIONS: SET2,3 added independent prognostic information to chemotherapy response (RCB) and baseline prognostic score or subtype. Approximately 40% of patients with clinically high-risk HR+/HER2- disease had high SET2,3 and could be considered for clinical trials of neoadjuvant endocrine-based treatment.

Loss mitigation in plasmonic solar cells: aluminium nanoparticles for broadband photocurrent enhancements in GaAs photodiodes.

We illustrate the important trade-off between far-field scattering effects, which have the potential to provide increased optical path length over broad bands, and parasitic absorption due to the excitation of localized surface plasmon resonances in metal nanoparticle arrays. Via detailed comparison of photocurrent enhancements given by Au, Ag and Al nanostructures on thin-film GaAs devices we reveal that parasitic losses can be mitigated through a careful choice of scattering medium. Absorption at the plasmon resonance in Au and Ag structures occurs in the visible spectrum, impairing device performance. In contrast, exploiting Al nanoparticle arrays results in a blue shift of the resonance, enabling the first demonstration of truly broadband plasmon enhanced photocurrent and a 22% integrated efficiency enhancement.

Quantification of background enhancement in breast magnetic resonance imaging.

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.

I-SPY 2: an adaptive breast cancer trial design in the setting of neoadjuvant chemotherapy.

I-SPY 2 (investigation of serial studies to predict your therapeutic response with imaging and molecular analysis 2) is a process targeting the rapid, focused clinical development of paired oncologic therapies and biomarkers. The framework is an adaptive phase II clinical trial design in the neoadjuvant setting for women with locally advanced breast cancer. I-SPY 2 is a collaborative effort among academic investigators, the National Cancer Institute, the US Food and Drug Administration, and the pharmaceutical and biotechnology industries under the auspices of the Foundation for the National Institutes of Health Biomarkers Consortium.

MRI methods for evaluating the effects of tyrosine kinase inhibitor administration used to enhance chemotherapy efficiency in a breast tumor xenograft model.

PURPOSE: To evaluate whether quantitative MRI parameters are sensitive to the effects of the tyrosine kinase inhibitor gefitinib and can discriminate between two different treatment protocols. MATERIALS AND METHODS: Untreated mice with BT474 breast tumor xenografts were characterized in a preliminary study. Subsequently, tumor volume, apparent diffusion coefficient (ADC), transendothelial permeability (K(ps)), and fractional plasma volume (fPV) were measured in three groups of mice receiving: 1) control vehicle for 10 days, or gefitinib as 2) a single daily dose for 10 days or 3) a 2-day pulsed dose. RESULTS: Gefitinib treatment resulted in significant tumor growth inhibition (pulsed: 439 +/- 93; daily: 404 +/- 53; control: 891 +/- 174 mm(3), P < 0.050) and lower cell density (pulsed: 0.15 +/- 0.01, daily: 0.17 +/- 0.01, control: 0.24 +/- 0.01, P < 0.050) after 9 days. Tumor ADC increased in treated groups but decreased in controls (P > 0.050). Tumor K(ps) decreased with pulsed treatment but rebounded afterwards and increased with daily treatment (P > 0.050). Tumor fPV increased in both treated groups, decreasing afterwards with pulsed treatment (P > 0.050). CONCLUSION: Quantitative MRI can provide a sensitive measure of gefitinib-induced tumor changes, potentially distinguish between treatment regimens, and may be useful for determining optimal treatment scheduling for enhancing chemotherapy delivery.

Quantification of breast tissue index from MR data using fuzzy clustering.

The study objective was to develop a segmentation technique to quantify breast tissue and total breast volume from magnetic resonance imaging (MRI) data to obtain a breast tissue index (BTI) related to breast density. Our goal is to quantify MR breast density to improve breast cancer risk assessment for certain high-risk populations for whom mammography is of limited usefulness due to high breast density. A semi-automatic 3D segmentation technique was implemented based on a fuzzy c-means technique (FCM) to segment fibroglandular tissue from fat in the breast images. After validation on a phantom, our FCM technique was first used to test the breast tissue measures reproducibility in two consecutive MR examinations of the same patients. The technique was then applied to measure the BTI on 10 high-risk patients. Results of BTI obtained with the semi-automated FCM method were compared with BTI results for the same patients using two other techniques, manual delineation and global threshold. BTI measures correlated well with mammographic densities (Pearson coefficients r = 0.78 using MR manual delineation, and r = 0.75 using MR FCM). The breast tissue index could therefore become a common measure for future studies of using noncontrast MRI data.

Magnetic resonance imaging for primary breast cancer management: current role and new applications.

Techniques for magnetic resonance (MR) imaging of the breast have been evolving over the past decade. The opportunities for integration of MR imaging into clinical breast cancer management and clinical research are increasing. In this paper, we will review the principles behind the creation of standard and MR images and use this as a platform to evaluate clinical studies and indications for the use and study of MR. In particular, we will focus on those areas where MR has the capability of changing care and/or improving our understanding of the biology of breast cancer. In addition, we will address areas where MR is not yet capable of adding value or where MR may lead to unnecessary procedures.

Menstrual cycle variation of apparent diffusion coefficients measured in the normal breast using MRI.

Recent investigations have shown that tumors may be distinguished from benign lesions in the breast based on differences in apparent diffusion coefficient (ADC) values. The goal of this study was to assess the magnitude of normal variations in the measured ADC of breast parenchyma during the menstrual cycle. Eight healthy female subjects were scanned once a week for 4 weeks, using a diffusion-weighted single-shot fast spin-echo (DW-SSFSE) sequence. The ADC of breast fibroglandular tissue was calculated for each woman at each time point. Results showed a trend of decreased ADC during the second week of the cycle, and increased ADC during the final week. However, no significant influence of menstrual cycle on breast ADC values was identified. The results of this study show that the normal fluctuation of breast ADC is relatively small, and the coefficient of variation was determined to be 5.5% for our group of volunteers during a menstrual cycle. Nonetheless, breast diffusion measurements for tumor differentiation and evaluation of treatment response should be interpreted with consideration of normal variability.

Vascularity assessment of breast lesions with gadolinium-enhanced MR imaging.

Gadolinium-enhanced MR imaging of the breast can be used to characterize both tumor morphology and vascularity. An empirical three-point method using high resolution three-dimensional MR imaging that combines high spatial resolution with an estimate of tumor pharmacokinetics is described. This technique appears to improve diagnostic specificity of breast MR imaging and may provide a noninvasive method of tumor characterization of prognostic value.

MRI phenotype is associated with response to doxorubicin and cyclophosphamide neoadjuvant chemotherapy in stage III breast cancer.

BACKGROUND: The preferred management for women with stage II or locally advanced breast cancer (LABC) is neoadjuvant chemotherapy. Pathologic response to chemotherapy has been shown to be an excellent predictor of outcome. Surrogates that can predict pathologic response and outcome will fuel future changes in management. Magnetic resonance imaging (MRI) demonstrates that patients with LABC have distinct tumor patterns. We investigated whether or not these patterns predict response to therapy. METHODS: Thirty-three women who received neoadjuvant doxorubicin and cyclophosphamide chemotherapy for 4 cycles and serial breast MRI scans before and after therapy were evaluated for this study. Response to therapy was measured by change in the longest diameter on the MRI. RESULTS: Five distinct imaging patterns were identified: circumscribed mass, nodular tissue infiltration diffuse tissue infiltration, patchy enhancement, and septal spread. The likelihood of a partial or complete response as measured by change in longest diameter was 77%, 37.5%, 20%, and 25%, respectively. CONCLUSIONS: MRI affords three-dimensional characterization of tumors and has revealed distinct patterns of tumor presentation that predict response. A multisite trial is being planned to combine imaging and genetic information in an effort to better understand and predict response and, ultimately, to tailor therapy and direct the use of novel agents.

Challenges to interpretation of breast MRI.

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.

Development, standardization, and testing of a lexicon for reporting contrast-enhanced breast magnetic resonance imaging studies.

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 (kappa) 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 (kappa = 0.63) and moderate agreement for lesion type (kappa = 0.57), mass margins (kappa = 0.55), and mass shape (kappa = 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.

Integration of breast imaging into cancer management.

This article reviews the use of breast imaging for screening, diagnosis, and staging. Its focus is on the ways in which imaging techniques can most effectively be integrated into clinical management.

MR imaging of the breast in patients with positive margins after lumpectomy: influence of the time interval between lumpectomy and MR imaging.

OBJECTIVE: Postsurgical contrast enhancement resulting from inflammatory changes at the site of surgery limits the accuracy of MR imaging of the breast in diagnosing residual breast cancer. This study was undertaken to evaluate the influence of the time interval between lumpectomy and MR imaging on the diagnosis of residual breast cancer. MATERIALS AND METHODS: Sixty-eight patients who had undergone excisional biopsy with positive resection margins underwent MR imaging for evaluation of residual breast cancer and possible breast conservation. Patients were retrospectively stratified according to the time interval between lumpectomy and MR imaging. Dynamic and morphologic enhancement features were used for lesion characterization. Imaging findings were correlated with results of histopathology. Sensitivity, specificity, positive predictive value, and negative predictive value were calculated for patients waiting 7, 14, 21, 28, 35, and 42 days after initial surgery before undergoing MR imaging of the breast. RESULTS: The time interval between lumpectomy and MR imaging of the breast had the greatest influence on the specificity and negative predictive value of MR imaging, increasing progressively over time. A plateau of highest values of 75% specificity and 86% negative predictive value was reached at 28 and 35 days after surgery, respectively. Although the sensitivity and positive predictive value showed smaller variations over time, peak values of 95% sensitivity and 92% positive predictive value were obtained at 35 and 28 days after surgery, respectively. CONCLUSION: We recommend scheduling patients with positive resection margins no earlier than 28 days after initial surgery for evaluation of residual cancer using MR imaging of the breast.

Dynamic high-spatial-resolution MR imaging of suspicious breast lesions: diagnostic criteria and interobserver variability.

OBJECTIVE: Our study was undertaken to develop diagnostic rules and to assess the reproducibility of dynamic and morphologic parameters for the characterization of suspicious breast lesions using dynamic high-spatial-resolution MR imaging. MATERIALS AND METHODS: Fifty-seven patients with suspicious mammographic or palpable findings underwent preoperative contrast-enhanced MR imaging of the breast using a three-time-point method of acquisition. Each lesion was prospectively analyzed by two independent radiologists for morphologic and visual dynamic enhancement characteristics. A classification and regression tree was used to examine the optimal order, cutoff points, and combination of imaging parameters to build a diagnostic rule separating benign from malignant lesions using histopathology findings as the standard of reference. Kappa statistics were used to determine observer variability. RESULTS: Among 23 benign and 34 malignant lesions (12 invasive, three ductal carcinoma in situ, and 19 mixed cancer), margin morphology (p = 0.001) and enhancement pattern (p = 0.001) were the most significant MR imaging findings for lesion characterization. Focal mass lesions were classified as malignant when spiculated margins or both the washout enhancement pattern and "nonsmooth" margins were present. Interobserver agreement was almost perfect for washout pattern and substantial for margin assessment. In the limited population tested retrospectively, the diagnostic rule yielded a sensitivity and positive predictive value of 97% each and a specificity and negative predictive value of 96% each. CONCLUSION: The washout enhancement pattern combined with lesion margin assessment on dynamic contrast-enhanced high-resolution MR imaging of the breast allows reproducible lesion characterization and may be a highly specific diagnostic tool.

Semi-automated analysis for MRI of breast tumors.

Magnetic resonance imaging (MRI) techniques have the potential to greatly improve breast cancer detection, diagnosis, and treatment. Currently, a major problem associated with breast MRI is the overwhelming amount of data acquired during an exam, and the time-intensive analysis required to evaluate the images. We have developed a software platform for semi-automated analysis to assess both the tumor extent and overall grade or severity based on our diagnostic criteria. In a test subset of over 50 patients, the automated program produced results more accurate overall than those measurements taken manually, with a reduction in time for analysis from approximately 45 minutes down to 5 minutes per patient study.

Utility of magnetic resonance imaging in the management of breast cancer: evidence for improved preoperative staging.

PURPOSE: The staging and treatment for breast cancer are changing; there is an increase in the incidence of ductal carcinoma-in-situ, the use of fine-needle aspiration and stereotactic biopsy for diagnosis, and the use of neoadjuvant chemotherapy. Thus, there is a need for a tool to assess more precisely the extent of cancer in the breast before surgery. To better plan surgical and chemotherapeutic interventions, we evaluated high-resolution magnetic resonance imaging (MRI) as such a tool. PATIENTS AND METHODS: Fifty-seven patients with 58 cases of breast cancer were evaluated preoperatively with MRI using a technique called the triple-acquisition rapid gradient echo technique to maximize anatomic detail. Imaging results were compared with mammography and subsequent pathology results. RESULTS: Magnetic resonance imaging correctly identified residual or primary cancer in 55 of 58 cases and accurately predicted the extent of the cancer in 54 of 58 cases. The anatomic extent was more accurately defined with MRI compared with mammography (98% v 55%). Magnetic resonance imaging added the greatest value in cases of multifocal disease. CONCLUSION: By applying MRI selectively to patients with a known diagnosis of cancer and focusing on defining the extent of malignant lesions, we were able to obtain clear and accurate anatomic information. Our results suggest that MRI could provide very valuable information for preoperative planning and single-stage resection in breast cancer. Based on preliminary data from our series, MRI would be valuable as a staging tool in the preoperative setting even if the cost is in the range of $1,300 to $2,000. It is already significantly less than the target cost, so it is reasonable to refine this technique for clinical use to help plan the most appropriate surgical intervention and possibly reduce costs as well. A careful prospective study is warranted to validate our findings.

Vascularity assessment of breast lesions with gadolinium-enhanced MR imaging.

Gadolinium-enhanced MR imaging techniques can be used to assess both breast tumor morphology and vascularity. Pharmacokinetic models can be used to extract physiological parameters related to tumor vascularity from signal intensity-time curves. This article describes an empirical method, using three-point high resolution MR imaging, that also provides assessment of tumor vascularity. These techniques appear to improve diagnostic specificity of breast MR imaging and provide a noninvasive method for tumor characterization that may have prognostic value.