Outcome analysis of patients with primary breast cancer initially treated at a certified academic breast unit.

INTRODUCTION: Evaluation of oncological outcome and prognostic factors of patients with primary breast cancer treated at a certified academic breast unit. PATIENTS AND METHODS: We prospectively collected data of 3338 patients, diagnosed with primary breast cancer between 01.01.2003 and 31.12.2010 and treated at the Breast Unit Heidelberg, Germany, in order to analyze outcome in clinical practice. We evaluated local control rate (LCR), disease-free survival (DFS), distant disease-free survival (DDFS), observed overall survival (OS) and age-adjusted relative overall survival (ROS). In addition, the impact of known prognostic factors on these outcome variables was examined in univariate and multivariate analyses. RESULTS: Of all patients, 368 (11.0%) had carcinoma in situ (CIS) and 197 (5.9%) had bilateral cancers. For the 2970 patients with invasive cancer, of which 49 patients (1.7%) had metastastic disease at time of diagnosis, DFS, LCR, DDFS, OS and ROS at 5 years were 79.8%, 84.7%, 81.2%, 86.3%, and 89.8%, respectively. In multivariate analysis age, pT category, nodal status, hormone receptor status and grading were identified as independent prognostic factors for OS. CONCLUSION: Compared with recent population-based reports from Germany, more favourable patient characteristics and nominally higher survival was found among this large cohort of patients with primary breast cancer treated at a single certified breast unit.

Do patients with invasive lobular breast cancer benefit in terms of adequate change in surgical therapy from a supplementary preoperative breast MRI?

BACKGROUND: Breast magnetic resonance imaging (MRI) has been introduced in the preoperative management of invasive lobular breast cancer (ILC). We analysed if MRI leads to adequate changes in surgical management. PATIENTS AND METHODS: We carried out a single-centre retrospective confirmatory analysis of 92 patients with ILC and a preoperative breast MRI. By applying a blinded tumour board method, we analysed if surgical procedures were altered due to breast MRI. In case of alteration, we analysed whether the change was adequate according to the postoperative pathology findings. We considered an adequate rate of change>5% to be a clinically relevant benefit. RESULTS: A change in surgical therapy due to the MRI findings occurred in 23 of 92 patients (25%). According to the postoperative pathology findings, this change was adequate for 20 of these patients (22%; 95% confidence interval [CI] 14%-31%, P<0.0001). An overtreatment occurred for three patients (3%; 95% CI 0%-6%) who underwent a mastectomy following the results of breast MRI. Patients with larger tumours did likely benefit more from preoperative breast MRI. CONCLUSIONS: Patients with ILC might benefit from a preoperative breast MRI. Possible harm from overtreatment should be minimised by diligent use of preoperative histological clarification.

[Indications and contraindications for contrast-enhanced MRI and CT during pregnancy]. / Indikationen und Kontraindikationen kontrastmittelverstärkter MRT- und CT-Untersuchungen in der Schwangerschaft.

There are no reports about negative effects on the fetus of the application of gadolinium-containing contrast media to pregnant mothers. Iodine-containing contrast media may lead to a transient hypothyroidism in the newborn. This will be detected with certainty by the neonatal TSH screening. Iodine- or gadolinium-containing contrast media may be used in pregnant women if indispensable. In the gut of breastfed children less than 1% of the recommended pediatric doses of contrast media are found after both types of contrast media have been given to their mothers. Therefore there are no reasons against the use of contrast media during the nursing period.

[Neoadjuvant chemotherapy of breast carcinomas: what post-therapeutic (preoperative) information is provided by quantitative dynamic MRI?]. / Neoadjuvante Chemotherapie des Mammakarzinoms : Welche posttherapeutischen (präoperativen) Informationen liefert die quantitative dynamische MRT?

PURPOSE: The aim of this study was to evaluate whether quantitative changes in contrast enhancement (CE) after neoadjuvant chemotherapy (NC) are associated with histological signs of tumor regression and whether quantitative dynamic MRI (dMRI) is capable of accurately assessing preoperative tumor size compared to mammography (MG) and ultrasound (US). METHODS: Thirty-one patients with breast cancer underwent MRI before and after NC. Dynamic CE was measured using a turbo-FLASH sequence and quantified by a two-compartment model, where two parameters, k(ep) (distribution constant rate) and A (amplitude), were calculated and color mapped. RESULTS: When tumors had signs of histological regression in the operative specimen (n=17) decrease of the parameters A and k(ep) was significantly more marked compared to tumors without regression (n=12). The correlation between tumor size measured by dMRI and histopathology was 0.81 when areas of unspecific CE were included; when they were not included the correlation was 0.66 and tumor size was systematically underestimated. In 26 patients dMRI was retrospectively compared with MG (r=0.51; dMRI, r=0.80) and in 22 patients with US (r=0.60; dMRI, r=0.75). CONCLUSION: Changes in dynamic CE are associated with histological tumor regression. Quantitative dMRI enables a valid assessment of tumor residue and is superior to MG and US. Remaining unspecific CE within the original tumor site should be considered as potentially malignant.

Accuracy of tumor size measurement in breast cancer using MRI is influenced by histological regression induced by neoadjuvant chemotherapy.

The aim of this study was to evaluate whether regressive changes after neoadjuvant chemotherapy for breast cancer affect the accuracy of preoperative MRI measurements of tumor size. Thirty-one patients with breast cancer underwent MRI before and after neoadjuvant treatment. Besides pre- and post-contrast T1-weighted MRI, dynamic MRI with high temporal resolution (turbo-FLASH) was performed. Contrast enhancement in dynamic MRI was quantified using a pharmacokinetic two-compartment model, where two parameters, amplitude and k(ep), were calculated and color coded on transversal parameter maps. Considering the conventional MR images, tumor diameters were measured on the color maps and compared with histological tumor size. Histological regression was scored on a five-point scale regarding cytopathic effects, reactive changes, and tumor cell reduction. The correlation between tumor sizes measured by MRI and histopathology was 0.83 ( p<0.0007) in 12 tumors without regressive changes (score 0), and 0.48 ( p<0.051) in 17 tumors with regressive changes scored 1 or 2, without any tendency for systematic over- or underestimation. In two cases without residual tumor (score 4), MRI likewise showed no signs of persistent tumor. The decrease of the contrast enhancement parameters was significantly more marked in tumors with signs of histological regression than in those without. Whenever MRI is used to judge the response of breast cancer to chemotherapy, the reader must be aware that therapy-induced changes may cause significant over- or underestimation of tumor size. We saw a high precision only when there was either no response - according to histological criteria - or when the tumor had regressed completely.

Evaluation of neoadjuvant chemotherapeutic response of breast cancer using dynamic MRI with high temporal resolution.

The aim of this study was to evaluate changes in both size and contrast enhancement of breast tumors during neoadjuvant chemotherapy, using dynamic MRI with high temporal resolution. Patients with advanced breast cancer (n=21) underwent a 1.5-T MRI scan prior to and following neoadjuvant chemotherapy with four cycles. Dynamic contrast enhancement was measured using a fast turbo-FLASH sequence and quantified using a two-compartment model with the parameters k(ep) and amplitude. Image analysis was done on images overlayed with a color map of parameters. The correlation between tumor diameter measured by histopathology and MRI was 0.7 (p<0.003). A reduction of tumor size after chemotherapy of more than 25% was associated with a decrease of both analyzed contrast enhancement parameters (k(ep): p<0.002; amplitude: p<0.006), where k(ep) began to drop already after the first cycle of chemotherapy (p<0.008). A clear reduction of tumor size was only noted after the third cycle (p<0.008). In patients without tumor regression there was also a trend towards an early reduction of contrast enhancement. We assume that MRI with high temporal resolution and color mapping is a novel tool to assess therapeutic effects of neoadjuvant chemotherapy in breast tumors, which deserves further prospective evaluation.

[Comparison of methods for quantifying contrast enhancement exemplified by dynamic MRI mammography]. / Methodenvergleich zur Quantifizierung der Kontrastmittelanreicherung am Beispiel der dynamischen MR-Mammographie.

AIM: Aim of this study was to demonstrate and compare different quantification techniques to assess contrast enhancement in dynamic MRI studies. The diagnostic potential of dynamic MRI studies is increasingly appreciated and already used in different organ systems. METHOD: A patient population of 314 histologically verified breast lesions (138 malignant, 176 benign) were evaluated using a high temporal resolved dynamic sequence. Different quantification techniques such as the use of a cutoff line, time dependent and pharmacokinetic assessment were comparatively evaluated. RESULTS: Time dependent quantification methods revealed higher diagnostic potential which was further improved by in vivo normalization of the contrast availability in the vascular system. Significant differences in the enhancement characteristics were determined between malignant and benign as well within the different histological entities. CONCLUSION: Time dependent quantification methods enable an angiogenic characterization of lesions to improve diagnostic interpretation as well as monitoring during therapy. They are also the basis for automated, color-coded visualization of dynamic studies.

Comparison of pharmacokinetic MRI and [18F] fluorodeoxyglucose PET in the diagnosis of breast cancer: initial experience.

It was the aim of this methodology-oriented clinical pilot study to compare the potential of dynamic MRI and 2-[18F]fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) for the detection and characterization of breast cancer. Fourteen women with suspicious breast lesions were examined. The MRI data were acquired with a turbo fast low-angle shot sequence and analyzed using a pharmacokinetic model. Emission data were detected in the sensitive 3D modus, iteratively reconstructed, and superimposed onto corresponding transmission images. In the 14 patients, 13 breast masses with a suspicious contrast enhancement and FDG uptake were detected. For these lesions, no statistically significant correlation between evaluated MR and PET parameters was found. Of the 9 histologically confirmed carcinomas, 8 were correctly characterized with MRI and PET. Two inflammatory lesions were concordantly classified as cancer. Moreover, dynamic MRI yielded another false-positive finding. In 6 patients, PET detected occult lymph node and/or distant metastases. Although both functional imaging techniques provide independent tissue information, the results concerning the diagnosis of primary breast lesions were almost identical. An advantage of PET, however, is its ability to localize lymph node involvement and distant metastases as an integral part of the examination.

[Concept and implementation of model projects for mammography screening in Germany]. / Konzept und Durchführung der Modellprojekte für Mammographiescreening in Deutschland.

The carriers of the German Statutory Health Care System have recognized that only mammographic screening according to the European Guidelines for the Quality Assurance of Mammography Screening will permit early detection of breast cancer with an acceptable risk/benefit ratio. In the German pilot projects, regional mammography screening programmes according to the European guidelines are being tested in the framework of the German health care system. The European guidelines require comprehensive quality assurance of all relevant steps in the chain of events involved in screening, from invitation on to therapy and follow-up. Such comprehensive quality assurance involves several medical specialities and other professional groups dealing with out-patient and in-patient health care and requires long-term cooperation with public institutions (population registries, cancer registries). The objective of the pilot projects is to test the organizational and legal conditions essential to introduction of a mammographic screening programme according to the European quality assurance guidelines in Germany.

Immunoscintigraphy with positron emission tomography: gallium-68 chelate imaging of breast cancer pretargeted with bispecific anti-MUC1/anti-Ga chelate antibodies.

Pretargeting techniques that are based on the sequential administrations of bispecific antitumor/antimetal chelate antibodies (BS-MAbs), a blocker to saturate the anti-chelate binding sites of the BS-MAb still present in the circulation, and the radiolabeled chelate are suitable to increase tumor-to-normal tissue contrasts and enable positron emission tomography (PET) as an imaging method. As demonstrated in the nude mouse model, a combination of pretargeted immunoscintigraphy and PET markedly improved the detection of tumor xenografts. With the presented preliminary clinical trial, we attempted to assess the efficacy of pretargeting and PET for breast cancer localization in patients. The BS-MAb used for pretargeting was synthesized from the F(ab')(2) fragments of the anti-MUC1 MAb 12H12, which reacts with the vast majority of breast tumors, and the F(ab') fragments of an anti-gallium (Ga) chelate MAb via a mixed functional chemical linker. For labeling of the Ga-chelate, we used the short-lived positron emitter Ga-68 (t(1/2), 68 min; beta(+), 88%). The dose and time schedule of pretargeting was deduced from previous animal experiments. Ten patients with biopsy-proven, primary breast carcinoma were infused with 10 mg of the BS-MAB: Eighteen h later, they received i.v. injections of 10.7 mg of a blocker and, 15 min later, 9.6 microg of the Ga chelate labeled with 230-300 MBq of (68)GA: PET imaging was started 60-90 min after injection of the (68)Ga chelate. Average tumor-to-blood and tumor:normal breast tissue ratios were 0.9 and 3.0 at 1 h postinjection. Tumor uptake amounted to approximately 0.003% iD/g corresponding to a standard uptake value of approximately 2. Blood clearance of the (68)Ga chelate showed a t(1/2) beta of approximately 100 min. Fourteen of 17 known lesions, averaging 25 +/- 16 mm in size, were clearly visualized as foci of increased activity with PET. No false-positive but three false-negative readings were obtained. An enhanced, bilateral activity uptake in the whole breast parenchyma, found in 4 of the 10 patients, compromised the recognition of these tumor sites. Although the shedding of the MUC1 antigen and the comparatively low tumor affinity of the BS-MAb, common to all anti-mucin MAbs, proved not to be optimal for increasing tumor:tissue ratios with a pretargeting technique, PET imaging offered better sensitivity for the detection of breast cancer at low tumor contrasts than conventional immunoscintigraphy. This could be demonstrated by the clear visualization of tumor sites 10 mm in size, which contrasted only by a factor of 2 from surrounding normal breast tissue.

Pathophysiologic basis of contrast enhancement in breast tumors.

While the diagnostic benefits of gadolinium (Gd)-chelate contrast agents are firmly established in magnetic resonance imaging (MRI) of tumors, the pathophysiologic basis of the enhancement observed and its histopathologic correlate remained vague. Tumor angiogenesis is fundamental for growth and metastasis and also of interest in new therapeutic concepts. By correlative analysis of a) histology; b) vascular density (CD31); and c) vascular permeability (vascular permeability factor/vascular endothelial growth factor [VPF/VEGF]), we found a) significantly (P < 0.001) faster exchange rates in malignant compared with benign breast lesions; b) distinct differences in enhancement characteristics between the histologic types (invasive ductal carcinoma, invasive lobular carcinoma, and ductal carcinoma in situ); and c) dependence of enhancement kinetics on the VPF/VEGF expression. The pathophysiologic basis for the differences in contrast enhancement patterns of tumors detectable by MRI is mainly due to vascular permeability, which leads to more characteristic differences than vascular density. MRI is able to subclassify malignant breast tumors due to their different angiogenetic properties.

[Multiple reader analysis for evaluation of functional MR mammography]. / Multi-Reader-Analyse zur Beurteilung der funktionellen MR-Mammographie.

The diagnostic impact and reproducibility of the different methods used within the concept of functional MR-Mammography (FMRM) was assessed by a multi-reader-analysis. By four experienced readers, 100 histologically confirmed cases were evaluated in six different sessions. Per session, one of the following components was analyzed: clinical history (I), static MRM (II), color-coded projection images (III), time-signal curves of contrast enhancement within a large ROI (IV) and the strongest enhancing pixel (V) obtained from the histologically confirmed lesion and the complete FMRM reading (VI). The functional methods (IV-VI) revealed significantly (p < 0.05) higher specificities than the others (I-III). The highest reproducibility between the readers was observed for (IV) phi chi = 0.80, (V) phi chi = 0.76 and FMRM (VI) phi chi = 0.63. These three methods also presented the best ROC-curves and showed the highest complementarity with respect to the false positive classifications in x-ray mammography. FMRM is a reader independent, reproducible method. The analysis of the contrast enhancement time-intensity curves with high temporal resolution allows an improved differentiation of malignant and benign findings.

Colour Doppler sonography in breast tumours: an update.

The aim of our study was to reassess the diagnostic performance of image-based, computer-assisted colour Doppler quantification under routine conditions. We used a computer-assisted protocol that quantitatively characterises a colour Doppler image by the relative amount of colour pixels (colour pixel density, CPD) and the colour hues (numerically expressed by the mean colour value, MCV) in 44 patients with breast carcinoma and 49 patients with benign breast lesions. Studies were carried out over two periods by two examiners, subsequently in charge of breast ultrasound. During the first period, the sensitivity of the MCV was 92 %, the specificity 75 %; the sensitivity of the CPD was 80 %, the specificity 81 %. During the second period, the sensitivity of the MCV was 58 %, the specificity 77 %; the sensitivity of the CPD was 68 %, the specificity 71 %. Despite measures to create uniform examination conditions, the diagnostic performance of this method may decline under routine conditions.

[Imaging methods for evaluating the response of breast carcinoma to preoperative chemotherapy]. / Bildgebende Verfahren zur Beurteilung des Ansprechens des Mammakarzinoms auf eine präoperative Chemotherapie.

Neoadjuvant chemotherapy with epirubicin and cyclophosphamide makes breast conserving therapy possible in patients with large tumors, which are primarily not suited for this treatment. The regression of the tumor can be followed by mammography, ultrasound and MRI. Mammography is reproducible and easily available. Tumors, which cannot be measured mammographically, usually can be followed with ultrasound. MR allows imaging of the tumor independent of structure and density of the parenchyma. In addition the measurement of functional parameters is possible. All methods are restricted in the imaging of tumor residuals after neoadjuvant chemotherapy, because imaging of small microscopic foci of invasive or even non invasive tumorresiduals is hardly possible. Of special concern are tumor specific microcalcifications, which only can be shown on mammograms, in this respect. They do not regress under chemotherapy, even if the invasive tumor regresses, and they typically hint for non invasive tumor residuals. For planning surgery the pretherapeutic tumor extent always has to be taken into account, because of the restricted ability to image small tumor residuals.

[Fast MRI contrast medium dynamics for characterization of tumors. Experiences with functional MR-mammography]. / Schnelle MR-Kontrastmitteldynamik zur Charakterisierung von Tumoren. Erfahrungen bei der funktionellen MR-Mammographie.

METHODS: MRI studies with high temporal resolution can be achieved with an optimized saturation recovery TurboFLASH sequence, which allows a more detailed characterization of contrast enhancement in tissue as is available with the current FLASH 3D techniques. A two compartment model allows characterization of signal time curves with three parameters, Amp (amplitude), k21 (distribution rate constant) and kel (elimination rate constant). RESULTS: In a prospective study on 314 patients with indetermined breast lesions signal-time-curves revealed differences in the k21 parameter between benign (0.56 +/- 0.46) and malignant lesions (1.25 +/- 0.80) (p < 0.0001) as well as between different histological classifications. CONCLUSION: The introduced MR-technique enables a better evaluation of the vascular permeability for the MR contrast media in lesions. Distinct differences were detected, which are influenced by elevated expression of angiogenesis factors such as the vascular endothelial growth factor.