[en] The NeoAzure study has demonstrated that the use of the bisphosphonate zoledronic acid (Zol) in the neoadjuvant setting increases the rate of complete response in primary breast cancer and therefore indicates direct antitumor activity. The purpose of this study was to compare the antitumor effect of Zol with standard chemotherapy in primary breast cancer cells using ATP-tumor chemosensitivity assay (ATP-TCA). Breast cancer specimens were obtained from patients with breast cancer who underwent primary breast cancer surgery at the Department of Obstetrics and Gynecology, Tübingen, Germany, between 2006 through 2009. Antitumor effects of Zol, TAC (Docetaxel, Adriamycin, Cyclophosphamide) and FEC (5-Fluorouracil, Epirubicin, Cyclophosphamide) were tested in 116 fresh human primary breast cancer specimens using ATP-TCA. ATP-TCA results were analyzed with different cut-off levels for the half maximal inhibitory concentration (IC50), for IC90 and for the sensitivity index (IndexSUM). Each single agent or combination was tested at six doubling dilutions from 6.25, 12.5, 25, 50, 100, and 200% of test drug concentrations (TDC) derived from the plasma peak concentrations determined by pharmacokinetic data. The assay was carried out in duplicate wells with positive and negative controls. The median IndexSUM value was lower for Zol than for the combined regimen FEC (36.8%) and TAC (12.9%), respectively, indicating increased antitumor activity of Zol in primary breast cancer cells. The difference regarding Zol and FEC was significant (p < 0.05). The median IC50 value for Zol (8.03% TDC) was significantly lower than the IC50 values for FEC (33.5% TDC) and TAC (19.3% TDC) treatment (p < 0.05). However, the median IC90 value for Zol (152.5% TDC) was significantly higher than the IC90 value obtained with TAC (49.5% TDC; p < 0.05), but similar to the IC90 value for FEC (180.9% TDC). In addition a significant positive correlation was observed for the IndexSum of Zol and the ER status (p < 0.01). Zoledronic acid has a strong antitumor effect on primary breast cancer cells in vitro which is equal or superior to commonly used chemotherapeutic regimens for treating breast cancer

[en] SPECT/CT after pericervical injection of technetium-99 m-nanocolloid was shown to be suitable for sentinel lymph node (SLN) mapping in endometrial cancer (EC). The aim of this study was to analyze factors affecting successful SLN detection by means of SPECT/CT such as imaging findings, patient characteristics and tumor biology in a large cohort of patients. One hundred and forty-five consecutive patients suffering from EC who received pre-surgical SLN mapping at our institution between 2011 and 2016 were included in this analysis. SPECT/CT data of abdomen and pelvis (mean 4:20 ± 1:20 h p.i.) were acquired after pericervical injection of technetium-99 m-nanocolloid (mean 230 ± 45 MBq) in all patients. Surgical staging was performed on the day after. Acquisition parameters, patient characteristics, SPECT/CT findings as well as histopathological results were collected. A total of 282 SLNs were identified by means of SPECT/CT. Overall, preoperative and intraoperative SLN detection rates were 86%, 76% and 74% respectively. The most important factor associated with failure to detect SLNs was the presence of high bone marrow on SPECT/CT (p = 0.005). Peritoneal/abdominal radioactivity was also associated with missed SLN detection in SPECT/CT (p = 0.02). However, the presence of liver/spleen uptake on its own was not predictive for detection failure. Low numbers of detected SLNs in SPECT/CT were slightly related with older age and lower injected activity. No significant influence was found for the parameters of tumor histology and stage, lymph node involvement and the time gap between injection and imaging. Venous drainage as indicated by bone marrow uptake is the most important factor associated with scintigraphic SLN detection failure. Moreover, high peritoneal and abdominal activity was also associated with detection failure. Thus, meticulous application of the radiotracer is crucial in EC. (orig.)

[en] The aim of this study was to evaluate the use of [¹⁸F]fluorothymidine (FLT) as a positron emission tomography (PET) tracer for the diagnosis of breast cancer. To this end, 12 patients with 14 primary breast cancer lesions (T2-T4) were studied by FLT-PET. For comparison, [¹⁸F]fluorodeoxyglucose (FDG) PET scans were performed in six patients. Thirteen of the 14 primary tumours demonstrated focally increased FLT uptake (SUV_mean=3.4±1.1). Seven out of eight patients with histologically proven axillary lymph node metastases showed focally increased FLT uptake in the corresponding areas (SUV_mean=2.4±1.2). The lowest SUV (mean =0.7) was observed in one of two inflammatory cancers. The contrast between primary tumours or metastases and surrounding tissue was high in most cases. In direct comparison to FDG-PET, the SUVs of primary tumours (5/6) and axillary lymph node metastases (3/4) were lower in FLT-PET (SUV_FLT: 3.2 vs SUV_FDG: 4.7 in primary tumours and SUV_FLT: 2.9 vs SUV_FDG: 4.6 in lymph node metastases). Since FLT uptake in surrounding breast tissue was also lower, tumour contrast was comparable to that with FDG. It is of note that normal FLT uptake was very low in the mediastinum, resulting in a higher tumour-to-mediastinum ratio as compared to FDG (P=0.03). FLT-PET is suitable for the diagnosis of primary breast cancer and locoregional metastases. High image contrast may facilitate the detection of small foci, especially in the mediastinum. (orig.)

[en] The purpose of this study was to analyze the probability and time course of fibrotic changes in breast reconstruction before or after postmastectomy radiotherapy (PMRT). Between 1995 and 2004, 109 patients were treated with PMRT at Tuebingen University and underwent heterologous (HL) or autologous (AL) breast reconstruction prior or subsequent to radiation therapy. Fibrosis of the reconstructed breast after radiotherapy was assessed using the Baker score for HL reconstructions and the Common Terminology Criteria for Adverse Events (CTCAE) for all patients. Actuarial rates of fibrosis were calculated for the maximum degree acquired during follow- up and at the last follow-up visit documented. Median time to follow-up was 34 months (3-227 months). Radiotherapy was applied with a median total dose of 50.4 Gy. A total of 44 patients (40.4%) received a boost treatment with a median dose of 10 Gy. Breast reconstruction was performed with AL, HL, or combined techniques in 20, 82, and 7 patients, respectively. The 3-year incidence of ≥ grade III maximum fibrosis was 20% and 43% for Baker and CTCAE scores, respectively. The corresponding figures for fibrosis at last follow-up visit were 18% and 2%. The 3-year rate of surgical correction of the contralateral breast was 30%. Initially unplanned surgery of the reconstructed breast was performed in 39 patients (35.8%). Boost treatment and type of cosmetic surgery (HL vs. AL) were not significantly associated with the incidence of fibrosis. We found severe fibrosis to be a frequent complication after PMRT radiotherapy and breast reconstruction. However, surgical intervention can ameliorate the majority of high grade fibrotic events leading to acceptable long-term results. No treatment parameters associated with the rate of fibrosis could be identified. (orig.)

[en] Purpose: A voluntary, external, science-based benchmarking program was established in Germany in 2003 to analyze and improve the quality of breast cancer (BC) care. Based on recent data from 2009, we aim to show that such analyses can also be performed for individual interdisciplinary specialties, such as radiation oncology (RO). Methods: Breast centers were invited to participate in the benchmarking program. Nine guideline-based quality indicators (QIs) were initially defined, reviewed annually, and modified, expanded, or abandoned accordingly. QI changes over time were analyzed descriptively, with particular emphasis on relevance to radiation oncology. Results: During the 2003-2009 study period, there were marked increases in breast center participation and postoperatively confirmed primary BCs. Starting from 9 process QIs, 15 QIs were developed by 2009 as surrogate indicators of long-term outcome. During 2003-2009, 2/7 RO-relevant QIs (radiotherapy after breast-conserving surgery or after mastectomy) showed considerable increases (from 20 to 85% and 8 to 70%, respectively). Another three, initially high QIs practically reached the required levels. Conclusion: The current data confirm proof-of-concept for the established benchmarking program, which allows participating institutions to be compared and changes in quality of BC care to be tracked over time. Overall, marked QI increases suggest that BC care in Germany improved from 2003-2009. Moreover, it has become possible for the first time to demonstrate improvements in the quality of BC care longitudinally for individual breast centers. In addition, subgroups of relevant QIs can be used to demonstrate the progress achieved, but also the need for further improvement, in specific interdisciplinary specialties. (orig.)

[en] The main study objectives were: to establish a nationwide voluntary collaborative network of breast centres with independent data analysis; to define suitable quality indicators (QIs) for benchmarking the quality of breast cancer (BC) care; to demonstrate existing differences in BC care quality; and to show that BC care quality improved with benchmarking from 2003 to 2007. BC centres participated voluntarily in a scientific benchmarking procedure. A generic XML-based data set was developed and used for data collection. Nine guideline-based quality targets serving as rate-based QIs were initially defined, reviewed annually and modified or expanded accordingly. QI changes over time were analysed descriptively. During 2003–2007, respective increases in participating breast centres and postoperatively confirmed BCs were from 59 to 220 and from 5,994 to 31,656 (> 60% of new BCs/year in Germany). Starting from 9 process QIs, 12 QIs were developed by 2007 as surrogates for long-term outcome. Results for most QIs increased. From 2003 to 2007, the most notable increases seen were for preoperative histological confirmation of diagnosis (58% (in 2003) to 88% (in 2007)), appropriate endocrine therapy in hormone receptor-positive patients (27 to 93%), appropriate radiotherapy after breast-conserving therapy (20 to 79%) and appropriate radiotherapy after mastectomy (8 to 65%). Nationwide external benchmarking of BC care is feasible and successful. The benchmarking system described allows both comparisons among participating institutions as well as the tracking of changes in average quality of care over time for the network as a whole. Marked QI increases indicate improved quality of BC care

[en] Tumour size in breast cancer influences therapeutic decisions. The purpose of this study was to evaluate sizing of primary breast cancer using mammography, sonography and magnetic resonance imaging (MRI) and thereby establish which imaging method most accurately corresponds with the size of the histological result. Data from 121 patients with primary breast cancer were analysed in a retrospective study. The results were divided into the groups “ductal carcinoma in situ (DCIS)”, invasive ductal carcinoma (IDC) + ductal carcinoma in situ (DCIS)”, “invasive ductal carcinoma (IDC)”, “invasive lobular carcinoma (ILC)” and “other tumours” (tubular, medullary, mucinous and papillary breast cancer). The largest tumour diameter was chosen as the sizing reference in each case. Bland-Altman analysis was used to determine to what extent the imaging tumour size correlated with the histopathological tumour sizes. Tumour size was found to be significantly underestimated with sonography, especially for the tumour groups IDC + DCIS, IDC and ILC. The greatest difference between sonographic sizing and actual histological tumour size was found with invasive lobular breast cancer. There was no significant difference between mammographic and histological sizing. MRI overestimated non-significantly the tumour size and is superior to the other imaging techniques in sizing of IDC + DCIS and ILC. The histological subtype should be included in imaging interpretation for planning surgery in order to estimate the histological tumour size as accurately as possible

[en] The expression of HER2, estrogen (ER) and progesterone (PR) receptor can change during the course of the disease in breast cancer (BC). Therefore, reassessment of these markers at the time of disease progression might help to optimize treatment decisions. In this context, characterization of circulating tumor cells (CTCs) could be of relevance since metastatic tissue may be difficult to obtain for repeated analysis. Here we compared HER2/ER/PR expression profiles of primary tumors, metastases and CTCs. Ninety-six patients with metastatic BC from seven University BC Centers in Germany were enrolled in this study. Blood was obtained at the time of first diagnosis of metastatic disease or disease progression and analyzed for CTCs using the AdnaTest BreastCancer (QIAGEN Hannover GmbH, Germany) for the expression of EpCAM, MUC-1, HER2, ER and PR. HER2 expression on CTCs was additionally assessed by immunocytochemistry using the CellSearch® assay. The detection rate for CTCs using the AdnaTest was 43 % (36/84 patients) with the expression rates of 50 % for HER2 (18/36 patients), 19 % for ER (7/36 patients) and 8 % for PR (3/36 patients), respectively. Primary tumors and CTCs displayed a concordant HER2, ER and PR status in 59 % (p = 0.262), 39 % (p = 0.51) and 44 % (p = 0.62) of cases, respectively. For metastases and CTCs, the concordance values were 67 % for HER2 (p = 0.04), 43 % for ER (p = 0.16) and 46 % for PR (p = 0.6). Using the CellSearch® assay, the CTC-positivity rate was 53 % (42/79 patients) with HER2 expressed in 29 % (12/42) of the patients. No significant concordance (58 % and 53 %) was found when HER2 on CTCs was compared with HER2 on primary tumors (p = 0.24) and metastases (p = 0.34). Interestingly, primary tumors and metastases were highly concordant for HER2 (84 %, p = 1.13E-08), ER (90 %, p = 3.26E-10) and PR (83 %, p = 2.09E-09) and ER-and PR-positive metastases were significantly found to be of visceral origin (p = 0.03, p = 0.02). Here we demonstrate that the molecular detection of HER2 overexpression in CTC is predictive of the HER2 status on metastases. Detailed analysis of ER and PR expression rates in tissue samples and CTCs may provide useful information for making treatment decisions

[en] In recent years, preoperative volume reduction of locally advanced breast cancers, resulting in higher rates of breast-conserving surgery (BCS), has become increasingly important also in postmenopausal women. Clinical interest has come to center on the third-generation nonsteroidal aromatase inhibitors (AIs), including letrozole, for such neoadjuvant endocrine treatment. This usually lasts 3–4 months and has been extended to up to 12 months, but optimal treatment duration has not been fully established. This study was designed as a multicenter, open-label, single-arm, exploratory phase IIb/III clinical trial of letrozole 2.5 mg, one tablet daily, for 4–8 months. The primary objective was to investigate the effect of neoadjuvant treatment duration on tumor regression and BCS eligibility to identify optimal treatment duration. Tumor regression (by clinical examination, mammography, and ultrasound), shift towards BCS eligibility, and safety assessments were the main outcome measures. Standard parametric and nonparametric descriptive statistics were performed. Letrozole treatment was received by 32 of the enrolled 33 postmenopausal women (median (range): 67.0 (56–85) years) with unilateral, initially BCS-ineligible primary breast cancer (clinical stage ≥ T2, N0, M0). Letrozole treatment duration in the modified intent-to-treat (ITT; required 4 months' letrozole treatment) analysis population (29 patients) was 4 months in 14 patients and > 4 months in 15 patients. The respective per-protocol (PP) subgroup sizes were 14 and 11. The majority of partial or complete responses were observed at 4 months, though some beneficial responses occurred during prolonged letrozole treatment. Compared with baseline, median tumor size in the ITT population was reduced by 62.5% at Month 4 and by 70.0% at final study visit (Individual End). Similarly, in the PP population, respective reductions were 64.0% and 67.0%. Whereas initially all patients were mastectomy candidates, letrozole treatment enabled BCS (lumpectomy) in 22 ITT (75.9%) and 18 PP (72.0%) patients. Over half of patients become BCS-eligible within 4 months of preoperative letrozole treatment. While prolonged treatment for up to 8 months can result in further tumor volume reduction in some patients, there is no clear optimum for treatment duration. Letrozole has a favorable overall safety and tolerability profile. ClinicalTrials.gov identifier NCT00535418

[en] The SRY-related HMG-box family of transcription factors member SOX2 has been mainly studied in embryonic stem cells as well as early foregut and neural development. More recently, SOX2 was shown to participate in reprogramming of adult somatic cells to a pluripotent stem cell state and implicated in tumorigenesis in various organs. In breast cancer, SOX2 expression was reported as a feature of basal-like tumors. In this study, we assessed SOX2 expression in 95 primary tumors of postmenopausal breast cancer patients. Samples from 95 patients diagnosed and treated at the University of Tuebingen Institute of Pathology and Women's Hospital were analyzed by immunohistochemistry for SOX2 expression in the primary tumor samples and in corresponding lymph node metastasis, where present. Furthermore, SOX2 amplification status was assessed by FISH in representative samples. In addition, eighteen fresh frozen samples were analyzed for SOX2, NANOG and OCT4 gene expression by real-time PCR. SOX2 expression was detected in 28% of invasive breast carcinoma as well as in 44% of ductal carcinoma in situ (DCIS) lesions. A score of SOX2 expression (score 0 to 3) was defined in order to distinguish SOX2 negative (score 0) from SOX2 positive samples (score 1-3) and among latter the subgroup of SOX2 high expressors (score 3 > 50% positive cells). Overall, the incidence of SOX2 expression (score 1-3) was higher than previously reported in a cohort of lymph node negative patients (28% versus 16.7%). SOX2 expression was detected across different breast cancer subtypes and did not correlate with tumor grading. However, high SOX2 expression (score 3) was associated with larger tumor size (p = 0.047) and positive lymph node status (0.018). Corresponding metastatic lymph nodes showed higher SOX2 expression and were significantly more often SOX2 positive than primary tumors (p = 0.0432). In this report, we show that the embryonic stem cell factor SOX2 is expressed in a variety of early stage postmenopausal breast carcinomas and metastatic lymph nodes. Our data suggest that SOX2 plays an early role in breast carcinogenesis and high expression may promote metastatic potential. Further studies are needed to explore whether SOX2 can predict metastatic potential at an early tumor stage