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Background: ER+/HER2- breast cancers have a proclivity for late recurrence. A personalised estimate of relapse risk after 5 years of endocrine treatment can improve patient selection for extended hormonal therapy., Methods: A total of 1702 postmenopausal ER+/HER2- breast cancer patients from two adjuvant phase III trials (ABCSG6, ABCSG8) treated with 5 years of endocrine therapy participated in this study. The multigene test EndoPredict (EP) and the EPclin score (which combines EP with tumour size and nodal status) were predefined in independent training cohorts. All patients were retrospectively assigned to risk categories based on gene expression and on clinical parameters. The primary end point was distant metastasis (DM). Kaplan-Meier method and Cox regression analysis were used in an early (0-5 years) and late time interval (>5 years post diagnosis)., Results: EP is a significant, independent, prognostic parameter in the early and late time interval. The expression levels of proliferative and ER signalling genes contribute differentially to the underlying biology of early and late DM. The EPclin stratified 64% of patients at risk after 5 years into a low-risk subgroup with an absolute 1.8% of late DM at 10 years of follow-up., Conclusion: The EP test provides additional prognostic information for the identification of early and late DM beyond what can be achieved by combining the commonly used clinical parameters. The EPclin reliably identified a subgroup of patients who have an excellent long-term prognosis after 5 years of endocrine therapy. The side effects of extended therapy should be weighed against this projected outcome.

Background: In early estrogen receptor (ER)-positive/HER2-negative breast cancer, the decision to administer chemotherapy is largely based on prognostic criteria. The combined molecular/clinical EndoPredict test (EPclin) has been validated to accurately assess prognosis in this population. In this study, the clinical relevance of EPclin in relation to well-established clinical guidelines is assessed., Patients and Methods: We assigned risk groups to 1702 ER-positive/HER2-negative postmenopausal women from two large phase III trials treated only with endocrine therapy. Prognosis was assigned according to National Comprehensive Cancer Center Network-, German S3-, St Gallen guidelines and the EPclin. Prognostic groups were compared using the Kaplan-Meier survival analysis., Results: After 10 years, absolute risk reductions (ARR) between the high- and low-risk groups ranged from 6.9% to 11.2% if assigned according to guidelines. It was at 18.7% for EPclin. EPclin reassigned 58%-61% of women classified as high-/intermediate-risk (according to clinical guidelines) to low risk. Women reclassified to low risk showed a 5% rate of distant metastasis at 10 years., Conclusion: The EPclin score is able to predict favorable prognosis in a majority of patients that clinical guidelines would assign to intermediate or high risk. EPclin may reduce the indications for chemotherapy in ER-positive postmenopausal women with a limited number of clinical risk factors.

The anti Her-2/neu monoclonal antibody Trastuzumab has strong inhibiting effects on tumor growth in vitro and in vivo and is therefore used for immunotherapy in breast cancer patients. Due to necessity of frequent applications, however, cost intensiveness of Trastuzumab treatment and its limited duration of affectivity, an active immunization inducing a perhaps preventive and long-term immunity to Her-2/neu remains a desirable goal. We attempted to induce anti Her-2/neu antibodies by peptide vaccination and to test their efficacy in inhibiting tumor cell growth in vitro. By computer aided analyses, 7 putative B cell epitopes of Her-2/neu were defined and synthesized. These peptide epitopes were coupled to tetanus toxoid and used for immunization in BALB/c mice. Among these peptides, immunizations with 2 single peptides or a combination of 2 peptides induced anti-peptide antibody levels, primarily of the IgG1 isotype. These antibodies were also directed against the native Her-2/neu antigen, as shown in precipitation assays and ELISA with cell lysates of the Her-2/neu overexpressing breast cancer cell line SK-BR-3. Isolated IgG fractions from immune sera incubated with SK-BR-3 cells led to a moderate inhibition of the tumor cell growth in vitro, as well as to complement dependent cell lyses comparable to that achieved by incubation with Trastuzumab. Moreover, peptide immunization in rabbits generated anti-Her 2-neu IgG that, in contrast to mouse sera, were able to mediate a 31-46% lysis of SK-BR-3 cells in ADCC experiments. We conclude from our data that immunization with Her-2/neu peptides successfully induced humoral immune response with anti-tumor activity in an animal model., (Copyright 2003 Wiley-Liss, Inc.)

To assess a potential common pattern of genetic alterations in chemotherapy-resistant tumors we analyzed four tumors from breast cancer patients (patients 1-4) after neoadjuvant chemotherapy, by comparative genome hybridization (CGH) and conventional chromosome banding analysis. All patients showed structural aberrations involving chromosomes 1, 5, 11, 16, and 17. In CGH analysis, the patients showed typical imbalances for ductal breast cancer: gains of 1q (3 patients), 5q (2 patients), 8q (3 patients), and X (4 patients) and losses of 1p33 approximately p36 (3 patients), 16q (3 patients), 17p (3 patients), 19 (4 patients), and 22q (4 patients). Other recurrent imbalances of atypical pattern for ductal breast cancer were gain of 4q21 approximately q32 (2 patients), 20q21 approximately q22 (2 patients), and 21 (2 patients) and loss of 20p (3 patients). Three patients showed involvement of several regions bearing genes of drug resistance (MDR1 [HUGO symbol: ABCB1], BCRP [HUGO symbol: ABCG2], MRP1 [HUGO symbol: ABCC1], RFC1); the fourth patient displayed an amplification in the region of MYC (alias c-myc), thus providing--at the level of the light microscope--an explanatory background for the ability of their tumors to survive anthracycline-, taxane- and cyclophosphamide-based chemotherapy. Conventional cytogenetic analysis and CGH displayed highly coincidental findings in the tumors of four patients after neoadjuvant chemotherapy for breast cancer.

Kinetic studies of cell proliferation rates shed light on the growth dynamics of cancer. Most such studies are based on measurements of cell numbers that were evaluated in time intervals of about 12 h. Studies of the initial tumour growth with short measuring intervals are rare. This study was therefore designed with 1 h measuring intervals over a 24 h period. Human breast cancer cell lines (ZR-75-1, SK-BR-3, MCF-7) and a benign cell line (HBL-100) were used to study the hourly thymidine uptake as a measure of cells in synthesis. In parallel experiments, the same cell lines were also exposed to tumour necrosis factor alpha (TNF-alpha) to explore the effect of an apoptosis-inducing substance on initial tumour growth kinetics. In time-evolution plots, there was an oscillation of the labelling index of thymidine uptake for all investigated cell lines, with and without TNF-alpha. Based on the results obtained, a mathematical model was developed mimicking the real experiment. To describe the system dynamically a cellular automaton model was studied. The growth kinetics revealed by the simulation were in accordance with our experimental data. Two- and three-dimensional growth simulations of this computer model yielded objects morphologically similar to real images of human breast cancer. Almost identical fractal dimensions of the virtual and real tumours further supported this visual similarity. The cellular automata models could, therefore, be seen as a bridge towards realistic in vivo scenarios. From a clinical point of view, the results obtained may be applicable not only to primary tumours, but even to tumour cell microfoci and small metastases, which are a major concern in early metastasizing tumours such as breast cancer., (Copyright 2002 John Wiley & Sons, Ltd.)

Since few years a new vacuum-assisted biopsy is used in addition to the common gun-needle biopsy in suspicious lesions of the mamma. Aim of our study was to compare these two techniques in regard to their histological outcome. Retrospectively, 149 of the 1997 performed biopsies and the corresponding operation specimens were evaluated. The biopsied lesions were divided in star-like densities, roundish opacities and different forms of microcalcifications. We found both stereotactical methods very accurate. In vacuum-assisted biopsies more representative material could be obtained in cases of microcalcifications. The better quality of the tissues made the histological result more reliable. In concern to other lesions in the mammogram there was no difference between the two techniques at all. In summary, both stereotactical methods revealed comparable and valuable results whereas in any form of microcalcifications we suggest to apply the vacuum-assisted method.

Fractal analysis techniques are common tools in physics and image processing. In the past few years they have gained increasing attention in medical sciences, e.g., cardiology, pathology and radiology, respectively. This article intends to describe this new technique by applying fractal analysis to the instant of a breast carcinoma. One of the advantages of fractal analysis is the ability to describe an irregular and complex object by a measureable value, called the fractal dimension. The fractal dimension can be determined by using the box-counting method. We applied this technique to the mammography as well as to the histologic section of a breast carcinoma. The application of fractal analysis provides a specific measureable value of the growth pattern of a tumor. Thus, the fractal dimension serves in addition to the common used metric diameter.