Breast Neoplasms: Harbeck N

Sturgeon CM, Duffy MJ, Stenman UH, Lilja H, Brünner N, Chan DW, Babaian R, Bast RC, Dowell B, Esteva FJ, Haglund C, Harbeck N, Hayes DF, Holten-Andersen M, Klee GG, Lamerz R, Looijenga LH, Molina R, Nielsen HJ, Rittenhouse H, Semjonow A, Shih IeM, Sibley P, Sölétormos G, Stephan C, Sokoll L, Hoffman BR, Diamandis EP, Anonymous00039. · Department of Clinical Biochemistry, Royal Infirmary of Edinburgh, Edinburgh, UK. · Clin Chem. · Pubmed #19042984 No free full text.

Abstract: BACKGROUND: Updated National Academy of Clinical Biochemistry (NACB) Laboratory Medicine Practice Guidelines for the use of tumor markers in the clinic have been developed. METHODS: Published reports relevant to use of tumor markers for 5 cancer sites--testicular, prostate, colorectal, breast, and ovarian--were critically reviewed. RESULTS: For testicular cancer, alpha-fetoprotein, human chorionic gonadotropin, and lactate dehydrogenase are recommended for diagnosis/case finding, staging, prognosis determination, recurrence detection, and therapy monitoring. alpha-Fetoprotein is also recommended for differential diagnosis of nonseminomatous and seminomatous germ cell tumors. Prostate-specific antigen (PSA) is not recommended for prostate cancer screening, but may be used for detecting disease recurrence and monitoring therapy. Free PSA measurement data are useful for distinguishing malignant from benign prostatic disease when total PSA is <10 microg/L. In colorectal cancer, carcinoembryonic antigen is recommended (with some caveats) for prognosis determination, postoperative surveillance, and therapy monitoring in advanced disease. Fecal occult blood testing may be used for screening asymptomatic adults 50 years or older. For breast cancer, estrogen and progesterone receptors are mandatory for predicting response to hormone therapy, human epidermal growth factor receptor-2 measurement is mandatory for predicting response to trastuzumab, and urokinase plasminogen activator/plasminogen activator inhibitor 1 may be used for determining prognosis in lymph node-negative patients. CA15-3/BR27-29 or carcinoembryonic antigen may be used for therapy monitoring in advanced disease. CA125 is recommended (with transvaginal ultrasound) for early detection of ovarian cancer in women at high risk for this disease. CA125 is also recommended for differential diagnosis of suspicious pelvic masses in postmenopausal women, as well as for detection of recurrence, monitoring of therapy, and determination of prognosis in women with ovarian cancer. CONCLUSIONS: Implementation of these recommendations should encourage optimal use of tumor markers.

Harbeck N. · Frauenklinik der Technischen Universität München, München, Germany. · Curr Med Res Opin. · Pubmed #18954499 No free full text.

Abstract: BACKGROUND: Breast cancer is the most common cancer diagnosed in Europe, with an estimated 429,900 new cases diagnosed in 2006. For over 20 years, tamoxifen was the standard adjuvant (postoperative) endocrine treatment for hormone receptor-positive (i.e., endocrine-responsive) early breast cancer. Yet, even after the first 5 years, patients with hormone receptor-positive tumours are at risk of relapse. Particularly in endocrine-responsive disease, most instances of relapse and breast cancer mortality occur after the first 5 years. SCOPE: Extended adjuvant aromatase inhibitor therapy (EAT) now offers postmenopausal women the opportunity to further protect themselves against late relapse. METHODS: This review summarises the clinical evidence and gives practical recommendations for discussing EAT with patients. Relevant information on patients receiving extended or late extended adjuvant endocrine therapy was obtained from databases and congress websites. The most substantial evidence for EAT is provided by the MA.17 trial using letrozole, with similar results obtained from smaller studies using anastrozole or exemestane. FINDINGS: Extended adjuvant letrozole reduced the risk of recurrence by 42% and the risk of distant metastases by 40%, it was well tolerated compared to placebo; among lymph node-positive patients, overall survival was significantly improved. Ideally, EAT should be started within 3 months of finishing tamoxifen therapy, and evidence supports its use for at least 4 years, showing increasing benefit with longer treatment duration. It is also effective, even after a longer time period, following completion of tamoxifen therapy. When deciding whether or not to use EAT after tamoxifen, clinicians and patients should consider the residual risk of relapse, comorbidities and individual preferences.

Annecke K, Schmitt M, Euler U, Zerm M, Paepke D, Paepke S, von Minckwitz G, Thomssen C, Harbeck N. · Frauenklinik und Poliklinik der Technischen Universität München, München 81675, Germany. · Adv Clin Chem. · Pubmed #18429492 No free full text.

Abstract: The plasminogen activator system is a complex system with multiple interactions and members participating in fibrinolysis, cell migration, angiogenesis, wound healing, embryogenesis, tumor cell dissemination, and metastasis in a variety of solid tumors. Increased levels of uPA and/or PAI-1 in primary tumor tissues of breast cancer patients correlate with tumor aggressiveness and poor clinical outcome. Patients with high tumor tissue antigen content of uPA and/or PAI-1 have a worse probability of disease-free and overall survival than patients with low levels of both of the biomarkers, serving as prognostic markers. The clinical utility of uPA and PAI-1 has been proven on the highest level of evidence (LOE-I). Next to being clinically useful prognostic factors allowing estimates of the course of disease in early breast cancer, uPA and PAI-1 may also serve as predictive factors predicting response to systemic therapy. Node-negative primary breast cancer patients with high uPA/PAI-1 levels benefit significantly from adjuvant chemotherapy. The aim of the ongoing NNBC-3 trial is to determine the benefits of a sequential anthracycline-docetaxel regimen in high-risk node-negative breast cancer patients compared to the current standard of anthracycline-based chemotherapy. At present, uPA and PAI-1 provide the unique opportunity to allow validated and clinically relevant risk assessment of breast cancer patients, over and above that provided by established risk factors. Therefore, in the evidence-based, annually updated AGO guidelines for breast cancer management, the German Working Group for Gynecological Oncology (AGO) has recommended both biomarkers as risk-group-classification markers for routine clinical decision making in node-negative breast cancer, next to established clinical and histomorphological factors.

Harbeck N, Haidinger R. · Frauenklinik der Technischen Universität München, Ismaninger Strasse 22, Münich 81675, Germany. · Breast Cancer Res Treat. · Pubmed #17912639 links to  free full text

Abstract: The impact of improved treatments for the management of hormone-sensitive breast cancer extends beyond clinical responses. Thanks to appropriate literature and access to the internet, patient awareness of treatment options has grown and patients are now, in many cases, able to engage their oncologists in informed conversations regarding treatment and what to expect in terms of efficacy and safety. Indeed, patients realize that although there is no cure for metastatic disease, treatment can greatly reduce the risk of progression and in the adjuvant setting, where treatment is administered with a curative intent, current treatment options reduce the risk of relapse. The approval of letrozole throughout the breast cancer continuum has provided patients with many reassuring options. The improvement in outcome with letrozole is achieved without a detrimental effect on overall quality of life. Adverse events such as hot flushes, arthralgia, vaginal dryness, and potential osteoporosis are most significant from the patient's perspective, and it is important that caregivers pay attention to patients experiencing these events, as they can impact compliance unless effectively explained and managed. The major benefits of letrozole are to improve prospects for long-term survivorship in the adjuvant setting and to delay progression and the need for chemotherapy in the metastatic setting.

Vescia S, Baumgärtner AK, Jacobs VR, Kiechle-Bahat M, Rody A, Loibl S, Harbeck N. · German Breast Group, Neu Isenburg, Germany. · Ann Oncol. · Pubmed #17846025 links to  free full text

Abstract: BACKGROUND: Over the last decades, many changes have occurred in oncology with new chemotherapy combinations and more complex application schemes becoming available. Central venous catheters and implantable venous port systems have become widely used and have facilitated the problem of vascular access. However, important complications are associated with permanent central venous catheters. Material and methods: This review summarizes evidence on venous port system use published in Medline up to February 2007. Moreover, recent guidelines for the prevention and management of catheter-related infections issued by the Infectious Diseases Society of America, the American College of Critical Care Medicine, the Society for Healthcare Epidemiology of America, the Center for Disease Control and Prevention, Atlanta, and the Infectious Diseases Working Party of the German Society of Hematology and Oncology are included. RESULTS: Sterile precautions are essential when implanting and accessing port systems. Infections must be treated with adequate antimicrobial therapy. Catheter-related thromboembolic complications were found at a rate of 12-64% in retrospective studies. Five current clinical trials investigated the effect of prophylactic anticoagulation with either low molecular weight heparin or warfarin in cancer patients with central venous devices. On the basis of these results, routine anticoagulation cannot be recommended. CONCLUSIONS: This article reviews the current literature on long-term complications of venous port systems, focusing on infection and thrombosis. In addition, it summarizes the evidence regarding routine maintenance of port systems in follow-up care.

Paepke S, Jacobs VR, Ohlinger R, Warm M, Kümmel S, Thomas A, Harbeck N, Kiechle-Bahat M. · Interdisciplinary Breast Center, Operative Senology, Frauenklinik (OB/GYN), Technical University Munich, Ismaninger Strasse 22, 81675 Munich, Germany. · J Cancer Res Clin Oncol. · Pubmed #17805570 No free full text.

Abstract: Several large, well-controlled clinical trials have now established that the aromatase inhibitors (AIs), including letrozole, anastrozole, and exemestane, are more effective than tamoxifen when used as adjuvant endocrine therapy in postmenopausal women with breast cancer. Yet, it is an open question as to how these drugs should be best integrated into the adjuvant treatment regimen. Both letrozole and anastrozole have shown efficacy over tamoxifen when used as initial adjuvant therapy (initiated just following surgery for breast cancer), while exemestane and anastrozole have been used as switching adjuvant therapy, i.e., following 2-3 years of initial adjuvant tamoxifen therapy, with proven efficacy over continued tamoxifen. Studies demonstrate that recurrence risk peaks in the early period after surgery, and that distant metastases in particular, accounting for most of the early recurrences, have worse survival rates when compared with other types of recurrences. Treatments that reduce recurrences, especially distant metastases, in this early period are therefore likely to improve overall survival (OS) and reduce mortality from breast cancer. In this review, we discuss early recurrence risk among postmenopausal women with successfully treated early breast cancer, the efficacy of the different AIs in reducing early recurrences and distant metastases when incorporated into adjuvant therapy, and the evidence for increased OS when AIs are used as initial or switch adjuvant therapy.

Harbeck N, Schmitt M, Paepke S, Allgayer H, Kates RE. · Department of Obstetrics and Gynecology, Technical University of Munich, Munich, Germany. · Crit Rev Clin Lab Sci. · Pubmed #17364692 No free full text.

Abstract: This review considers the past, present, and projected future clinical relevance of the serine protease urokinase-type plasminogen activator (uPA), and its inhibitor, plasminogen activator inhibitor-type 1 (PAI-1), in breast cancer. These factors play a key role in tumor invasion and metastasis in many cancers. In primary breast cancer, their prognostic and predictive impact has been validated at the highest level of evidence by a multicenter therapy trial (Chemo N0) and a large European Organisation for Research and Treatment Cancer-Receptor and Biomarker Group EORTC RBG pooled analysis (n = 8377). The greatest clinical use is in node-negative breast cancer, where the test can avoid over-treatment by adjuvant chemotherapy in patients with non-aggressive disease. In intermediate-risk patients as defined by the international St. Gallen consensus, it can be used to identify patients who should receive chemotherapy because their tumor is more aggressive than classical pathological factors would suggest. Gene expression signatures are already being used in clinical trials to define the population of patients with breast cancer who should receive chemotherapy. The decision for treatment ignores the highly validated information that could be provided by uPA/PAI-1. A current and future challenge is to integrate the information provided by tumor biological factors, particularly uPA/PAI-1, into refined risk assessment and decision support algorithms incorporating gene expression signatures. This article describes a paradigm ("marker fusion") for doing so and a bioinformatics approach based on this paradigm. This concept could be useful in assessing and maximizing the performance of risk assessment and the quality of therapeutic indications.

Gelmon K, Chan A, Harbeck N. · British Columbia Cancer Agency, Vancouver, Canada. · Oncologist. · Pubmed #16971739 links to  free full text

Abstract: Capecitabine is an important drug in the therapeutic armamentarium for metastatic breast cancer. A comprehensive worldwide clinical trial program involving >10,000 patients with locally advanced and metastatic breast cancer has provided evidence for the current treatment strategies. On the basis of data demonstrating consistent activity across several trials in patients with heavily pretreated breast cancer, capecitabine was approved in the U.S. in 1998 for the treatment of patients with metastatic disease resistant to paclitaxel and anthracycline-containing therapy, with later European Union approval for single-agent capecitabine in the metastatic setting. Capecitabine plus docetaxel (XT) was approved by the U.S. Food and Drug Administration for the treatment of metastatic breast cancer in 2001 on the basis of the large phase III trial comparing XT with docetaxel alone, which showed a survival advantage for combination therapy compared with single-agent therapy. This was shortly followed by European approval for the combination in metastatic breast cancer. The clinical utility of capecitabine in the management of breast cancer is supported by its convenient oral dosing schedule and favorable safety profile, as well as its excellent clinical activity in primary and metastatic breast cancer. Recently, clinical trials have studied single-agent capecitabine as first-line treatment and evaluated other capecitabine-containing combinations with cytotoxic and novel targeted agents.

Paepke S, Jacobs VR, Paepke D, Euler U, Blohmer JU, Warm M, Ohlinger R, Fischer T, Kiechle M, Harbeck N. · Frauenklinik des Universitätsklinikums rechts der Isar, Technische Universität München, Germany. · Onkologie. · Pubmed #16679783 No free full text.

Abstract: Even in elderly patients, greater consideration is now being given to tumor volume reduction in locally advanced breast cancer, with increased subsequent breast-conserving surgery. Neoadjuvant endocrine therapy offers the possibility of testing therapeutic efficacy in vivo, which is of great importance for optimal adjuvant treatment. Resulting therapy modifications can be expected to increase disease-free as well as overall survival. Recent results indicate that remission rates with primary chemotherapy are significantly lower in receptor-positive than in receptor-negative breast cancer and that efficacy parameters in receptor-positive tumors tend to favor primary endocrine therapy, highlighting the increased importance of this type of treatment. Aromatase inhibitors are superior to tamoxifen in terms of clinical response as well as breast conservation rate. Results from a small number of studies suggest that prolonged preoperative aromatase inhibitor therapy for up to 12 months can increase the rate of clinical and pathological complete remissions. In conclusion, primary endocrine therapy is a valid therapeutic option for postmenopausal patients with locally advanced hormone receptor-positive breast cancer and significant comorbidity, increased risk of complications with regard to anesthesia and surgery, desire for breast-conserving surgery and/or reduced suitability for chemotherapy, as well as in very old patients.

Krol J, Paepke S, Jacobs VR, Paepke D, Euler U, Kiechle M, Harbeck N. · Frauenklinik der Technischen Universität München, Klinikum rechts der Isar, Munich, Germany. · Onkologie. · Pubmed #16601374 No free full text.

Abstract: The most common chemotherapeutic agents in the treatment of breast cancer are anthracyclines and taxanes. The major dose-limiting toxicities associated with these agents are myelosuppression and associated febrile neutropenia (FN). FN can significantly impact the ability to deliver full-dose chemotherapy on schedule and as a result may increase the risk of disease recurrence and eventual disease-related mortality. The use of granulocyte colony stimulating factors (G-CSFs) significantly improves the management of FN, both in a therapeutic and in a prophylactic approach. Nevertheless, the high cost of these agents limits their widespread prophylactic use. Therefore, the identification of patients who are at a higher risk of developing FN and who will benefit from the prophylactic use of G-CSFs has become the subject of several clinical and cost-effectiveness studies. Recently, new data have been accumulated concerning the risk of FN in different chemotherapy regimens, and different risk models have been developed to assess the neutropenic risk with all its complications. This article reviews and summarizes cutting-edge, disease-specific data as well as national and international guidelines regarding the use of G-CSFs to prevent chemotherapy-induced FN, with focus on the treatment of breast cancer.

Janni W, Rack B, Lindemann K, Harbeck N. · Department of Obstetrics and Gynecology,Ludwig-Maximilians University, Munich, Germany. · Oncologist. · Pubmed #16079315 links to  free full text

Abstract: Minimal residual disease (MRD), or isolated tumor cells (ITCs) in bone marrow, may be the source of potentially fatal overt distant metastases in solid tumors even years after primary treatment. MRD can be detected by immunohistochemical methods using antibodies directed against cytokeratins or cell-surface markers or molecular, polymerase chain reaction-based techniques. Among solid tumors, the clinical relevance of MRD has been most extensively studied in breast cancer patients. Recently, the highest level of evidence for the prognostic impact of MRD in primary breast cancer was reached by a pooled analysis comprising more than 4,000 patients, showing poor outcome in patients with MRD at primary therapy. Yet the clinical application of MRD detection is hampered by the lack of a standardized detection assay. Moreover, clinical trial results demonstrating the benefit of a therapeutic intervention determined by bone marrow status are still absent. Recent results suggest that, in addition to its prognostic impact, MRD can be used for therapy monitoring or as a potential therapeutic target after phenotyping of the tumor cells. Persistent MRD after primary treatment may lead to an indication for extended adjuvant therapy. However, until clinically relevant data regarding successful therapy of MRD are available, treatment interventions on the basis of MRD should only be performed within clinical trials.

Willems A, Gauger K, Henrichs C, Harbeck N. · Department of Obstetrics and Gynecology, Technical University of Munich, Germany. · Anticancer Res. · Pubmed #16033049 No free full text.

Abstract: Targeted therapies against tumor biological properties are an essential part of individualized therapy concepts in breast cancer. Next to risk-adapted strategies using conventional chemo- and/or endocrine therapies, antibody therapy has become an additional option. The humanized monoclonal antibody trastuzumab (Herceptin) is the first novel targeted therapy approved for routine clinical application in advanced breast cancer. Patients with HER2/neu protein overexpression as assessed by immunohistochemistry (IHC) and/or gene amplification as assessed by fluorescence in-situ hybridization (FISH) in their tumors respond well to palliative trastuzumab therapy, either as single agent or in combination with chemotherapy. New combinations with endocrine therapy are currently being evaluated in clinical trials. Trastuzumab therapy is generally well-tolerated. So far, considerable cardiotoxicity was seen only in combination with doxorubicin. Thus, extensive cardiomonitoring is now performed in trials assessing further chemotherapeutic partners. Clinical trials looking at early trastuzumab therapy in the adjuvant (e.g. HERA, BOND 006) or neoadjuvant (e.g. TECHNO) setting are still open for recruitment in Germany. Since only about those 25 % of breast cancers which are HER2/neu-positive are eligible for trastuzumab, novel targeted therapeutics for the remaining HER2/neu-negative tumors are needed. Another therapeutic antibody, 2C4 (Pertuzumab, Omnitarg), is currently under clinical evaluation. It binds to a different epitope on HER2/neu than trastuzumab and inhibits heterodimerization with other HER receptors. Phase I data showed that 2C4 is well tolerated and clinically active.

Harbeck N, Kates RE, Schmitt M, Gauger K, Kiechle M, Janicke F, Thomassen C, Look MP, Foekens JA. · Department of Obstetrics and Gynecology, Technical University of Munich, Germany. · Clin Breast Cancer. · Pubmed #15585071 No free full text.

Abstract: Combined determination of urokinase-type plasminogen activator (uPA) and its inhibitor, activator inhibitor type 1 (PAI-1), supports risk-adapted individualized therapy concepts, particularly in node-negative breast cancer. The prognostic impact of both factors in primary breast cancer was substantiated by a pooled analysis of > 8000 patients with breast cancer and a multicenter prospective randomized therapy trial in node-negative breast cancer; findings achieved the highest level of evidence for tumor biomarkers. Patients with node-negative breast cancer with low antigen levels of uPA and PAI-1 in their primary tumor tissue have a very good prognosis and therefore may be spared the burden of adjuvant chemotherapy, whereas those with elevated uPA/PAI-1 antigen levels carry an increased risk of disease recurrence. Recent retrospective analysis of > 3000 patients indicated that patients with breast cancer with high uPA/PAI-1 values derive a significantly greater benefit from adjuvant chemotherapy than patients with low uPA/PAI-1 levels. Similarly, in the multicenter prospective Chemo N0 trial, administration of cyclophosphamide/methotrexate/5-fluorouracil-based chemotherapy led to a substantial reduction in risk of disease recurrence in patients with high uPA/PAI-1. However, benefit from adjuvant endocrine therapy appears to be independent of a patient's uPA/PAI-1 status. In metastatic breast cancer, retrospective studies showed that elevated uPA or PAI-1 present in the primary tumor tissue are associated with a poor response to later palliative endocrine therapy. These findings suggest that high levels of uPA and/or PAI-1 do reflect an aggressive phenotype that may be overcome or suppressed by early systemic therapy in the adjuvant setting but may be too advanced for response to palliative therapy at a later stage.

Daidone MG, Paradiso A, Gion M, Harbeck N, Sweep F, Schmitt M. · Research Unit # 10, Department of Experimental Oncology, Istituto Nazionale Tumori, Via Venezian 1, 20133 Milan, Italy. · Eur J Nucl Med Mol Imaging. · Pubmed #15095022 No free full text.

Abstract: Breast cancer is a heterogeneous disease and its consequent complexity is a major challenge for physicians and biologists. Notwithstanding its potential curability due to the availability of treatment modalities which are effective in the presence of favourable clinical or pathobiological features, there is still a great deal of controversy over its clinical management. In recent decades, tumour biomarkers that are indicative of or related to cell traits characterising malignancy--that is self-sufficiency in proliferative growth signals, insensitivity to growth inhibitory signals, evasion of apoptosis, limitless replicative potential, and activation of pathways leading to neo-angiogenesis, invasion and metastasis--have provided information that has been proven to be associated with disease progression. However, when these biomarkers have been analysed individually, their prognostic relevance has been found to be modest, the only remaining clinically useful biomarkers being cell proliferation and plasminogen activation-related factors for prognosis, and steroid hormone receptors and the oncogene HER2/neu for prediction of response to hormonal therapy or to the novel targeted anti-HER2/neu therapy. It therefore remains necessary to reduce the intrinsic complexity of breast cancer in order to improve its clinical outcome. One way to achieve this objective derives directly from the concept that cancer is a genetic disease at the somatic level and from the recent availability of high-throughput post-genomic analytical tools such as gene and protein expression techniques for global gene expression analysis. Following these novel approaches, a number of recent studies have produced gene expression profiles in breast cancer that are markedly associated with disease progression and directed to answer different clinical and biological questions. However, the outcome of these novel studies still needs to be validated, which will entail cooperation between different specialists and integration of all the different skills involved in translational research in oncology.

Harbeck N, Kates RE, Gauger K, Willems A, Kiechle M, Magdolen V, Schmitt M. · Department of Obstetrics and Gynecology, Technical University of Munich, Germany. · Thromb Haemost. · Pubmed #14983219 No free full text.

Abstract: Urokinase-type plasminogen activator (uPA) and its inhibitor, PAI-I, play a key role in tumor invasion and metastasis. They were the first novel tumor biological factors to be validated at the highest level of evidence (LOE I) regarding their clinical utility in breast cancer. Their antigen levels are determined in tumor tissue extracts by standardized, quality-assured immunometric assays (ELISA). Since the late 1980s, numerous independent studies have demonstrated that patients with low levels of uPA and PAI-I in their primary tumor tissue have a significantly better survival than patients with high levels of either factor. These prognostic data have recently been validated by an EORTC (European Organization for Research and Treatment of Cancer) pooled analysis comprising more than 8,000 breast cancer patients. In addition, results from a multicenter prospective randomized therapy trial in node-negative breast cancer ("Chemo N(0)") showed that node-negative breast cancer patients with low levels of uPA and PAI-I in their primary tumor have a very good prognosis, and may thus be candidates for being spared the burden of adjuvant chemotherapy. In contrast, node-negative patients with high uPA/PAI-I are at substantially increased risk of disease recurrence, comparable to that of patients with three or more tumor cell positive axillary lymph nodes. The "Chemo N(0)" trial as well as retrospective data also indicate that these high-risk patients benefit from adjuvant chemotherapy. In conclusion, over a period of about 15 years sufficient evidence has been put forward to demonstrate that determination of uPA and PAI-I in primary breast cancer patients supports risk-adapted individualized therapy decisions, particularily in patients with node-negative disease.

Harbeck N. · Frauenklinik, Klinikum rechts der Isar, Technischen Universität Munich. · Onkologie. · Pubmed #14716137 No free full text.

Abstract: Adjuvant chemotherapy reduces the relative risk of relapse by about 25%--independent of the nodal status. Anthracycline-containing regimens are considered standard for adjuvant chemotherapy. In single studies, superiority to CMF has only been shown for anthracycline-containing polychemotherapies with at least three substances or a sequential anthracycline-CMF therapy. Recent data show that adding taxanes to anthracycline-containing regimens may lead to significant survival advantages. Based on trial results published so far, taxanes are a valid adjuvant therapy option in node-positive breast cancer. In Germany, their optimal use is currently being evaluated in several clinical trials (i.e. NNBC-3, ECDoc, ADEBAR). Up-to-date evidence-based therapy recommendations for adjuvant chemotherapy can be found in the S2 guidelines of the working group on gynecological oncology (AGO) expert panel 'breast' (www.agoonline. de).

Thomssen C, Jänicke F, Harbeck N. · Klinik und Poliklinik für Gynäkologie, Universitäts-Klinikum Eppendorf, Hamburg, Germany. · Onkologie. · Pubmed #14605459 No free full text.

Abstract: In node-negative breast cancer, advices for adjuvant therapy are based on traditional factors like age, tumour size, grade of differentiation, and steroid hormone receptor status. Several new factors that may better describe tumour behaviour, like proliferation rate (determined by thymidine labelling index, S-phase fraction, mitotic index, or Ki-67), presence of disseminated tumour cells, as well as expression of invasion factors (urokinase-type plasminogen activator uPA and its inhibitor PAI-1) and of cell cycle genes (cyclin E), as well as gene expression patterns ('genomic profiling') are currently discussed as future methods of risk assessment and also as tools for prediction of response to specific therapy modalities. Recommendations for routine use should be based on criteria of evidence-based medicine and on their impact on clinical decision making. Among the aforementioned factors, only the invasion factors uPA and PAI-1 have reached the highest levels of evidence and are mature enough to be transferred into clinical routine: their prognostic impact has been shown in several retrospective and prospective studies and in a pooled analysis of almost 3,500 node-negative patients. Their clinical impact was demonstrated in a prospective therapy trial. In addition, a predictive value with regard to chemotherapy efficacy has recently been supposed. Thus, in order to correctly assess the individual risk and to design an adequate adjuvant treatment plan for node-negative breast cancer patients, we recommend to use uPA and PAI-1 as additional criteria together with grading and age.

Harbeck N. · Frauenklinik der Technischen Universität München, Germany. · Zentralbl Gynakol. · Pubmed #14569511 No free full text.

Abstract: The 2003 St. Gallen consensus on primary therapy of early breast cancer confirmed the importance of adjuvant chemotherapy. In endocrine non-responsive tumors, chemotherapy is adjuvant treatment of choice, independent of patient age or lymph node status. In endocrine-responsive disease, chemotherapy plays an important role next to endocrine treatment. The questions, which patients need combined chemo-endocrine therapy, and for whom endocrine therapy alone is sufficient, are still unsolved. Anthracyclines are standard adjuvant chemotherapy; superiority over CMF has only been shown for anthracyclin-containing polychemotherapy with at least 3 substances. Recent published evidence suggest that adding taxanes to anthracyclin regimens may benefit patient survival and that taxanes are a valid therapeutic option in node-positive, hormone receptor negative breast cancer. The optimal use of taxanes in different risk collectives is currently being investigated in clinical trials. Generally, adjuvant chemotherapy should be administered before radiotherapy, and endocrine therapy should be given sequentially. In view of the international St. Gallen panel, the final publication may only represent a minimal consensus. Individual countries are requested to adapt these recommendations to national conditions. In Germany, up-to-date evidence-based therapy recommendations have just been issued by the AGO "breast" expert panel. Interdisciplinary S3 breast cancer guidelines are currently being finalized.

Kates R, Schmitt M, Harbeck N. · Klinische Forschergruppe der Frauenklinik, Technische Universität München, Ismaningerstr. 22, 81675 Munich, Germany. · Recent Results Cancer Res. · Pubmed #12790325 No free full text.

Abstract: Adequate staging procedures are the prerequisite for individualized therapy concepts in cancer, particularly in the adjuvant setting. Molecular staging markers tend to characterize specific, fundamental disease processes to a greater extent than conventional staging markers. At the biological level, the course of the disease will almost certainly involve interactions between multiple underlying processes. Since new therapeutic strategies tend to target specific processes as well, their impact will also involve interactions. Hence, assessment of the prognostic impact of new markers and their utilization for prediction of response to therapy will require increasingly sophisticated statistical tools that are capable of detecting and modeling complicated interactions. Because they are designed to model arbitrary interactions, neural networks offer a promising approach to improved staging. However, the typical clinical data environment poses severe challenges to high-performance survival modeling using neural nets, particularly the key problem of maintaining good generalization. Nonetheless, it turns out that by using newly developed methods to minimize unnecessary complexity in the neural network representation of disease course, it is possible to obtain models with high predictive performance. This performance has been validated on both simulated and real patient data sets. There are important applications for design of studies involving targeted therapy concepts and for identification of the improvement in decision support resulting from new staging markers. In this article, advantages of advanced statistical methods such as neural networks for definition of new staging models will be illustrated using breast cancer as an example.

Roggel F, Hocke S, Lindemann K, Sinz S, Welk A, Bosl M, Pabst M, Nusser N, Braun S, Schmitt M, Harbeck N. · Klinische Forschergruppe der Frauenklinik, Technische Universität München, Ismaninger Strasse 22, 81675 Munich, Germany. · Recent Results Cancer Res. · Pubmed #12790324 No free full text.

Abstract: In breast cancer, about 35% of patients without any clinical signs of overt distant metastases already have disseminated tumor cells in bone marrow aspirates at the time of primary therapy. A significant prognostic impact of these disseminated tumor cells has been shown by many international studies: patients with tumor cells in their bone marrow have a significantly worse prognosis than those without them. Even in malignancies where the skeletal system is not a preferred location for distant metastasis, such as ovarian cancer, early presence of minimal residual disease (MRD) is correlated with poor patient outcome. Thus, besides analysis of the primary tumor, detection of MRD can be used for assessment of patient prognosis and for prediction or monitoring of response to systemic therapy. Disseminated tumor cells are also the targets for novel tumor biological therapy approaches such as specific antibody-based therapies against target cell-surface antigens such as HER2, Ep-CAM (17-1A), and uPA-R. In breast cancer, a first antibody-based tumor therapy against HER2 (Herceptin) has already been approved for clinical use in recurrent disease. However, patient selection for such tumor biological therapies becomes rather difficult due to phenotype changes, which may manifest themselves as differences between primary lesion and disseminated tumor cells. Therefore, not only identification of disseminated tumor cells but even more so their characterization at the protein and gene levels have become increasingly important. In conclusion, characterization of tumor biological properties of disseminated tumor cells allows identification of patients with breast cancer or gynecological malignancies at risk for relapse who are likely to benefit from systemic treatment and/or novel tumor biological therapy approaches.

Schindlbeck C, Janni W, Schaffer P, Shabani N, Schmitt M, Harbeck N, Sommer H, Braun S. · I. Frauenklinik, Klinikum der Ludwig-Maximilians-Universität, Maistrasse 11, D-80337 München, Deutschland. · Acta Med Austriaca Suppl. · Pubmed #12506757 No free full text.

Abstract: The immunocytochemical detection of isolated disseminated tumor cells (ITC) in the bone marrow of breast cancer patients, what is called minimal residual disease (MRD), has been demonstrated to be of prognostic value in all stages of the disease. In order to definitely prove the origin of these cells from the primary tumor it is necessary to identify common factors on both tumor tissue and ITC, furthermore a more detailed characterization could help to improve their prognostic impact by defining certain subgroups and possibly establish new therapeutic strategies. We examined the expression/amplification of HER2neu, CD 44 adhesion molecule and CD 31 angiogenetic factor on more than 200 primary tumor tissues by immunohistochemistry or fluorescence in situ hybridisation, resp., and found no sign. correlation with the detection of ITC. After a median follow-up of 32 months only ITC in the bone marrow were of prognostic significance. In a small number of patients we examined the expression of topoisomerase II alpha, a key enzyme of DNA replication, and its predictive value of eliminating ITC by anthracyclin based chemotherapy. No correlation with the presence of ITC before or after chemotherapy could be found, yet pat. with topoisomerase II alpha neg. tumors showed a trend to reduced disease free survival. Because of the very low number of ITC per bone marrow sample, the direct characterization of these factors on ITC stays difficult without the possibility of tumor cell enrichment or cell culture. Preliminary results on multi colour stained samples indicate that a selection of certain biological factors takes place during tumor cell dissemination.

Von Minckwitz G, Brunnert K, Costa SD, Friedrichs K, Jackisch Ch, Gerber B, Harbeck N, Junkermann H, Möbus V, Nitz U, Schaller G, Scharl A, Thomssen Ch, Untch M, Anonymous00149. · Universitäts-Frauenklinik Frankfurt, Germany. · Zentralbl Gynakol. · Pubmed #12232814 No free full text.

This publication has no abstract.

Von Minckwitz G, Costa SD, Brunnert K, Dall P, Nitz U, Diel I, Fersis N, Friedrich M, Friedrichs K, Thomssen Ch, Gerber B, Göhring UJ, Harbeck N, Hanf V, Schaller G, Scharl A, Schmutzler R, Simon WE, Untch M, Anonymous00148. · Universitäts-Frauenklinik Frankfurt, Germany. · Zentralbl Gynakol. · Pubmed #12232813 No free full text.

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Harbeck N, Schmitt M, Kates RE, Kiechle M, Zemzoum I, Jänicke F, Thomssen C. · Department of Obstetrics & Gynecology, Technical University of Munich, Munich, Germany. · Clin Breast Cancer. · Pubmed #12196277 No free full text.

Abstract: Invasion factors urokinase-type plasminogen activator (uPA) and its plasminogen activator inhibitor (PAI-1) are the only novel tumor biological prognostic factors validated at the highest level of evidence with regard to their clinical utility in breast cancer. Antigen levels of both factors present in extracts of primary tumor tissue are determined by standardized, quality-assured enzyme-linked immunosorbent assays. Numerous studies showed that patients with low levels of uPA and PAI-1 have a significantly better survival than patients with high levels of either factor. Recently, these data have been validated by a European Organization for Research and Treatment of Cancer pooled analysis comprising more than 8000 breast cancer patients. The particular combination of both factors, uPA/PAI-1 (both low vs. either or both factors high), outperforms the single factors as well as other traditional prognostic factors with regard to risk group assessment, particularly in node-negative breast cancer. Node-negative breast cancer patients with low levels of uPA and PAI-1 have a very good prognosis and, as such, may be candidates for being spared the burden of adjuvant chemotherapy. In contrast, node-negative patients with high uPA/PAI-1 are at a substantially increased risk of relapse, comparable to that of patients with > or = 3 involved axillary lymph nodes. First results from a multicenter prospective randomized therapy trial in node-negative breast cancer (Chemo N(0)) as well as recent retrospective analyses indicate that these high-risk patients benefit from adjuvant chemotherapy. Thus, combined determination of the invasion factors uPA and PAI-1 supports risk-adapted individualized therapeutic strategies in patients with primary breast cancer, particularly in those with node-negative breast cancer.

Braun S, Kiechle M, Harbeck N. · Frauenklinik & Poliklinik, Technischen Universität München, Klinikum rechts der Isar. Ismaninger Strasse 22, 81675 München. · Internist (Berl). · Pubmed #11963718 No free full text.

This publication has no abstract.