Breast Neoplasms: Kreienberg R

Albert US, Altland H, Duda V, Engel J, Geraedts M, Heywang-Köbrunner S, Hölzel D, Kalbheim E, Koller M, König K, Kreienberg R, Kühn T, Lebeau A, Nass-Griegoleit I, Schlake W, Schmutzler R, Schreer I, Schulte H, Schulz-Wendtland R, Wagner U, Kopp I. · Faculty of Medicine, Philipps-University, Marburg, Germany. · J Cancer Res Clin Oncol. · Pubmed #18661152 No free full text.

Abstract: INTRODUCTION: The goal of the 2008 updated guideline: early detection of breast cancer in Germany is to support physicians as well as healthy and affected women in the decision-making process involved in the diagnostic chain for the early detection of breast cancer by providing them with evidence- and consensus-based recommendations. The updated guideline replaces the guideline issued in 2003. MATERIALS AND METHODS: The guideline forms the basis for developing an effective and efficient national early breast cancer detection program that meets the standards set by the Council of Europe and WHO for cancer control programs. The guideline presents the current, evidence- and consensus-based state of scientific knowledge in a multidisciplinary approach for the entire diagnostic chain, consisting of history taking and risk consultation, information on health behavior, clinical breast examination, diagnostic imaging, image-guided percutaneous tissue-acquisition techniques, open surgical excisional biopsy and pathomorphological tissue evaluation. The guideline recommends a set of quality indicators to assure resource availability, performance quality and outcomes enhancing total quality management for early breast cancer diagnosis. CONCLUSION: Currently, early detection of breast cancer offers the most promising possibility to optimize the diagnosis and treatment of breast cancer and, as a result, reduce breast cancer mortality and improve health related quality of life in women.

Albert US, Altland H, Duda V, Engel J, Geraedts M, Heywang-Köbrunner S, Hölzel D, Kalbheim E, Koller M, König K, Kreienberg R, Kühn T, Lebeau A, Nass-Griegoleit I, Schlake W, Schmutzler R, Schreer I, Schulte H, Schulz-Wendtland R, Wagner U, Kopp I. · Planungskommission und Arbeitsgruppenleiter der Konzertierten Aktion Brustkrebs-Früherkennung in Deutschland, Deutschland. · Chirurg. · Pubmed #18463837 No free full text.

Abstract: The updated 2008 German Guideline for Early Detection of Breast Cancer provides evidence-based and consensus-based recommendations of the knowledge gained by the German Society for Surgery and the German Society of Plastic, Aesthetic, and Reconstructive Surgeons together with 29 professional societies, associations, and nonmedical organizations. The guideline is meant to assist physicians, healthy women, and patients in medical decisions with recommendations regarding the diagnostic chain in early detection of breast cancer. In addition to these recommendations, the guideline also includes descriptions of quality assurance for resources, procedures, outcomes, and evaluation using a set of quality indicators. It updates the previous version from 2003. The guideline's recommendations are presented. They are described in detail in the full publication (in German) Geburtsh Frauenh 2008; 68:251-261. The long version of the Guideline, methods report, and evidence report are available on the internet at www.awmf-leitlinien.de (reg. no. 077/001) with free access.

Albert US, Altland H, Duda V, Engel J, Geraedts M, Heywang-Köbrunner S, Hölzel D, Kalbheim E, Koller M, König K, Kreienberg R, Kühn T, Lebeau A, Nass-Griegoleit I, Schlake W, Schmutzler R, Schreer I, Schulte H, Schulz-Wendtland R, Wagner U, Kopp I. · Planungskommission und Arbeitsgruppenleiter der Konzertierten Aktion Brustkrebs-Früherkennung in Deutschland. · Rofo. · Pubmed #18438746 No free full text.

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Kuehn T, Kreienberg R. · No affiliation provided · Arch Gynecol Obstet. · Pubmed #11129507 No free full text.

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Strunz K, Deissler H, Kreienberg R, Sauer G. · Universitatsfrauenklinik Ulm, Ulm, Deutschland. · Gynakol Geburtshilfliche Rundsch. · Pubmed #18566527 No free full text.

Abstract: Molecular staging of breast cancer with microarray technologies leads to different gene expression profiles distinguishing 4 special groups: luminal A and B subtype, HER2 subtype and basal subtype. These 4 groups show a different prognosis as well as different behaviours and responses to adjuvant therapy. The development of gene expression profiles to classify breast cancer may contribute to the targeted institution of adjuvant therapies. Especially the 21-gene recurrence score (Oncotype DX) and the 70-gene profile (Mamma-print) have become intensively examined prognostic and predictive tools. As chemotherapy is an integral component of adjuvant therapy in early breast cancer but estrogen-receptor-positive breast cancer is the most common type, patient selection for adjuvant chemotherapy is of particular interest. In instances when the benefit from chemotherapy seems modest, there is a decision making tool beside traditional histopathological parameters that might provide additional objective prognostic and predictive information. Those genomic decision making approaches may yield more rational treatment choices and may keep patients from systemic treatment modalities of lower value.

Varga D, Vogel W, Bender A, Surowy H, Maier C, Kreienberg R, Deissler H, Sauer G. · Department of Gynecology and Obstetrics, University of Ulm Medical School, Ulm, Germany. · Strahlenther Onkol. · Pubmed #18040608 No free full text.

Abstract: PURPOSE: This paper briefly summarizes the research on increased radiosensitivity in breast cancer patients measured by the micronucleus test (MNT) and its association to genetic variants in DNA repair genes. More preliminary data are presented on the distribution of chromosomes and chromosome fragments in micronuclei (MN) in order to gain more information on clastogenic and aneugenic effects and better understand the phenotype of increased radiosensitivity. MATERIAL AND METHODS: Reports of relevant studies obtained from a search of PubMed and studies referenced in those reports were reviewed. In four patients with high MN frequency (three cancer patients, one control) and four probands with low MN frequency, the presence of chromosome fragments or whole chromosomes in MN was determined by fluorescence in situ hybridization analysis for chromosomes 1, 7, and 17. RESULTS: An increased MN frequency in breast cancer patients compared to controls has consistently been reported with high significance. Higher MN frequencies were observed in 20-50% of breast cancer patients. Chromosomal fragments of chromosome 17, but not of chromosomes 1 and 7 were more frequent in the probands with high MN frequency than in those with low frequency (p = 0.045). CONCLUSION: The MNT detects a cellular phenotype common to a portion of sporadic breast cancer patients. This phenotype is very likely to be genetically determined. For the genetic dissection of breast cancer susceptibility this phenotype may turn out to be more efficient than breast cancer itself. Additional parameters which can be measured simultaneously with the MN frequency may be able to further enhance its usefulness.

Sauer R, Sautter-Bihl ML, Budach W, Feyer P, Harms W, Souchan R, Wollwiener D, Kreienberg R, Wenz F. · Department of Radiation Oncology, University of Erlangen, Erlangen, Germany. · Cancer. · Pubmed #17647249 links to  free full text

Abstract: BACKGROUND: Breast-conserving surgery followed by whole-breast radiotherapy (WBRT) has become the standard treatment for the majority of patients with early breast cancer. Whereas the indications for systemic adjuvant treatment have continuously expanded, there is a tendency to restrict postoperative radiotherapy to accelerated partial breast irradiation (APBI) instead of WBRT. METHODS: The different techniques of APBI are described and their respective advantages or potential drawbacks outlined. Moreover, the results described in the literature are briefly reviewed as a basis for the consensus statements and recommendations of the German Society of Radiation Oncology, the German Society of Senology, and the Working Group for Gynecological Oncology of the German Cancer Society. RESULTS: The methods mainly used for APBI are: interstitial radiotherapy with multicatheter technique, intraoperative radiotherapy (IORT) using either electrons produced by linear accelerators or 50 kV x-rays (Intrabeam), the balloon-catheter technique (MammoSite), or 3D conformal external beam radiotherapy. These techniques have marked differences in dose distribution and homogeneity. The published range of local recurrence rates varies between 0% to 37%, the median follow-up from 8 to 72 months. CONCLUSIONS: To date, follow-up times mostly do not yet permit a definite judgment concerning the long-term effectiveness and side effects of APBI. The relevant societies in Germany support randomized clinical studies comparing APBI with WBRT in a well-defined subset of low-risk patients. However, the authors expressly discourage the routine use of APBI outside clinical trials. Until definite results show that APBI neither impairs therapeutic outcome nor cosmetic results, WBRT remains the gold standard in the treatment of early breast cancer.

Ralhan R, Kaur J, Kreienberg R, Wiesmüller L. · Department of Biochemistry, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029, India. · Cancer Lett. · Pubmed #16854521 No free full text.

Abstract: DNA double strand break (DSB) repair dysfunction increases the risk of familial and sporadic breast cancer. Advances in the understanding of genetic predisposition to breast cancer have also been made by screening naturally occurring polymorphisms. These studies revealed that subtle defects in DNA repair capacity arising from low-penetrance genes, or combinations thereof, are modified by other genetically determined or environmental risk factors and correlate to breast cancer risk. Overexpression of DSB repair enzymes, absence of surveillance factors and mutation or loss of heterozygosity in any of these genes contributes to the pathogenesis of sporadic breast cancers. The results identifying DSB repair defects as a common denominator for breast cancerogenesis focus attention on functional assays in order to assess DSB repair capacity as a diagnostic tool to detect increased breast cancer risk and to enable therapeutic strategies specifically targeting the tumor.

Sauer G, Kurzeder C, Heilmann V, Kreienberg R, Deissler H. · Department of Gynaecology and Obstetrics, University of Ulm Medical School, Ulm, Germany. · Curr Pharm Des. · Pubmed #16248802 No free full text.

Abstract: Besides the traditional therapeutic options, treatment with antibodies specific for the receptor tyrosine kinase HER-2/neu has been established as a standard therapy in the clinical management of advanced breast cancer. Ongoing clinical studies focus on the improvement of application protocols in order to minimize side effects and evaluate the potential therapeutic benefit of anti-HER-2/neu antibodies in combination with conventional chemotherapy. Various similar strategies to target other tumour-associated antigens or proangiogenic factors with inhibitory antibodies are currently investigated in promising preclinical and clinical trials. In addition, research efforts are made to develop procedures to generate tumour-specific cellular immune responses in breast cancer patients. Therapeutic vaccination is, however, still at an early stage of development, despite encouraging results of animal studies. We summarise and discuss vaccination strategies with tumour-specific proteins or peptides, pulsed dendritic cells, and modified tumour cells as well as antibody-based therapeutic concepts to target HER-2/neu, EGF receptor, MUC-1, uPA/uPAR, and VEGF.

Sauer G, Strnad V, Kurzeder C, Kreienberg R, Sauer R. · Department of Gynecology, University of Ulm, Germany. · Strahlenther Onkol. · Pubmed #15660187 No free full text.

Abstract: BACKGROUND: The standard technique of postoperative radiotherapy after breast-conserving surgery is percutaneous irradiation of the entire breast to a total dose of 45-50 Gy which is usually followed by a tumor bed boost. Since the majority of local recurrences in selected patients occur close to the former tumor bed, the question arises whether a sole tumor bed irradiation might be a therapeutic alternative to total breast irradiation. METHODS: A systematic review of relevant literature concerning partial breast irradiation (PBI) up to November 2004 was undertaken. Studies of any design were included for comparison and discussion. RESULTS: Nine unique brachytherapy studies using the multi-catheter technique, one the balloon technique (MammoSite), and eight particular intraoperative radiotherapy (IORT) trials were located of which only one was a randomized trial. Only minor postoperative complications were reported. Preliminary results are similar in terms of local tumor control, disease-free and overall survival. However, the current evidence base of IORT studies is poor. CONCLUSION: Despite controversies regarding PBI after breast-conserving surgery, results of phase I-II trials suggest that sole tumor bed irradiation might be an appropriate therapeutic alternative for selected breast cancer patients. However, more experience and data from ongoing phase III trials are required to define these new methods to be an appropriate treatment option. Therefore, total breast irradiation still remains the standard irradiation modality even in the treatment of early breast cancer, and PBI should be considered investigational.

Kühn T, Kreienberg R. · Frauenklinik Gifhorn. · Dtsch Med Wochenschr. · Pubmed #14961447 No free full text.

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Sauer G, Deissler H, Kurzeder C, Kreienberg R. · Department of Gynecology and Obstetrics, University of Ulm Medical School, Ulm, Germany. · Strahlenther Onkol. · Pubmed #11962188 No free full text.

Abstract: BACKGROUND: The development of new chemotherapeutic agents and concepts of radiation therapy, administered as primary, adjuvant and palliative therapy, has led to new perspectives in breast cancer therapy. Apart from conventional chemotherapy, recently developed novel agents interfere with molecular mechanisms that are altered in cancer cells. Those targets are not necessarily breast cancer-specific. In this review we will focus on novel agents with potential or already proved benefit to breast cancer patients. Promising strategies include inhibition of growth factor receptors, blocking of tumor angiogenesis and signal transduction pathways, modulation of apoptosis, cancer vaccination, and inhibition of invasion and metastasis. METHODS: Reports of relevant studies obtained from a search of MEDLINE and studies referenced in those reports were reviewed. RESULTS: Apart from trastuzumab, other further developed compounds show promising results in clinical studies as a second generation of growth factor inhibitors. Different approaches in anti-angiogenetic therapy are under preclinical and clinical phase-II trials. Pro-apoptotic agents show synergistic effects with docetaxel in a clinical phase-I trial. Other compounds that target HSP 90, histone deacetylase and HMG-CoA reductase target atypical apoptotic pathways being lethal to tumor cells only but not to normal tissue, suggesting a tumor-specific way of action. MMP inhibitors have been demonstrating promising results in patients with refractory malignant pleural effusion in a phase-I trial. Several tyrosine kinase inhibitors currently under clinical investigation preliminarily show hopeful results in patients with advanced breast cancer. Furthermore, recent progress in defining the immunogenic epitopes of tumor antigens has rejuvenated the interest in cancer vaccines. CONCLUSION: Typical dose escalation studies leading to the highest clinically still tolerated dose do not appear to be equally appropriate for the estimation of efficiency of those compounds as for conventional cytotoxic regimes. Rather, escalation up to an amount of therapeutic agent that is sufficient for maximum target inhibition should be promoted, where classical measures of cytoreduction such as complete or partial remission are replaced both by time to progression and treatment failure as an appropriate measure of the efficacy of an agent.

Untch M, Möbus V, Kuhn W, Muck BR, Thomssen C, Bauerfeind I, Harbeck N, Werner C, Lebeau A, Schneeweiss A, Kahlert S, von Koch F, Petry KU, Wallwiener D, Kreienberg R, Albert US, Lück HJ, Hinke A, Jänicke F, Konecny GE. · Helios Klinikum, Campus Berlin Buch, Berlin, Germany. · J Clin Oncol. · Pubmed #19364964 No free full text.

Abstract: PURPOSE: To compare preoperative intense dose-dense (IDD) chemotherapy with conventionally scheduled preoperative chemotherapy in high-risk primary breast cancer (BC). PATIENTS AND METHODS: In this randomized phase III trial a total of 668 eligible primary BC patients stratified for tumors > or = 3 cm (n = 567) or inflammatory BC (n = 101) were randomly assigned to receive concurrent preoperative epirubicin/paclitaxel every 3 weeks or dose-dense and dose-escalated sequential epirubicin followed by paclitaxel every 2 weeks. All patients received three cycles of cyclophosphamide, methotrexate, and fluorouracil chemotherapy after surgery. RESULTS: IDD treatment significantly improved pathologic complete response rate (18% v 10%; odds ratio [OR] 1.89; P = .008), disease-free survival (DFS; hazard ratio [HR], 0.71; P = .011), and overall survival (OS; HR, 0.83; P = .041) compared to epirubicin/paclitaxel. Patients with inflammatory BC had a particularly poor prognosis and did not appear to benefit from IDD therapy in this trial (DFS HR, 1.10; P = .739; OS HR, 1.25; P = .544). In contrast, patients with noninflammatory BC significantly benefited from IDD treatment (DFS HR, 0.65, P = .005; OS HR, 0.77, P = .013). Treatment effects in multivariate analysis were significant for noninflammatory BC (DFS HR, 0.65, P = .015; OS HR, 0.79, P = .034), but not for all patients (DFS HR, 0.76; P = .088; OS HR, 0.82; P = .059). IDD therapy was associated with significantly more nonhematologic toxicities, anemia, and thrombocytopenia, but with similar neutropenia and infection rates. CONCLUSION: Our results support the efficacy and short-term safety of IDD as preoperative chemotherapy. IDD was less well tolerated compared to standard treatment, but improved clinical outcomes in patients with noninflammatory high-risk primary BC.

Chan S, Romieu G, Huober J, Delozier T, Tubiana-Hulin M, Schneeweiss A, Lluch A, Llombart A, du Bois A, Kreienberg R, Mayordomo JI, Antón A, Harrison M, Jones A, Carrasco E, Vaury AT, Frimodt-Moller B, Fumoleau P. · Nottingham University Hospital, City Campus, Nottingham, UK. · J Clin Oncol. · Pubmed #19273714 No free full text.

Abstract: PURPOSE: Patients with metastatic breast cancer who are pretreated with anthracyclines frequently receive taxane-based combinations. This phase III study compared the efficacy and safety of gemcitabine-docetaxel (GD) with capecitabine-docetaxel (CD) in advanced breast cancer. PATIENTS AND METHODS: Patients were randomly assigned to GD (G 1,000 mg/m(2) days 1 and 8; D 75 mg/m(2) day 1) or CD (C 1,250 mg/m(2) twice daily days 1 through 14; D 75 mg/m(2) day 1) every 21 days. Comparison of progression-free survival (PFS) was the primary objective. RESULTS: Patient characteristics were balanced between arms (N = 305). Median PFS was 8.05 months (95% CI, 6.60 to 8.71) for GD and 7.98 (95% CI, 6.93 to 8.77) for CD (log-rank P = .121). Overall response rate (ORR) was 32% in both arms, and overall survival (OS) was not different between arms (P = .983). Time to treatment failure (TTF; defined as discontinuation, progressive disease, death as a result of any cause, or the start of a new anticancer therapy) was superior in the GD arm (P = .059). Hematologic toxicity was similar in both arms, except for grades 3 to 4 leukopenia (GD, 78%; CD, 66%; P = .025) and transfusions (GD, 17%; CD, 7%; P = .0051). Grades 3 to 4 diarrhea, mucositis, and hand-and-foot syndrome were significantly higher in the CD arm. Fewer patients in the GD arm discontinued because of drug-related adverse events (13% v 27% in CD; P = .002). CONCLUSION: No difference was observed between GD and CD arms in PFS, ORR, and OS. TTF was longer in the GD arm. These findings, combined with a nonhematologic toxicity profile that favors GD over approved doses of CD, suggest that gemcitabine may be a better option than capecitabine in combination with docetaxel in this clinical setting.

Schmid P, Krocker J, Kreienberg R, Klare P, Kittel K, Sommer H, Heinrich G, Steck T, Lichtenegger W, Elling D, Kümmel S. · Department of Medical Oncology, Charing Cross Hospital, Imperial College London, Fulham Palace Road, London, W6 8RF, UK. · Cancer Chemother Pharmacol. · Pubmed #19104816 No free full text.

Abstract: BACKGROUND: Non-pegylated liposomal doxorubicin (NPLD) has demonstrated equivalent antitumor activity to conventional doxorubicin and a significantly lower risk of cardiotoxicity when given as single agent or in combination with cyclophosphamide, but there is limited experience with the combination of NPLD and taxanes. This phase II study was performed to evaluate the efficacy and safety of the NPLD and docetaxel in patients with metastatic breast cancer. PATIENTS AND METHODS: A total of 51 patients were treated with NPLD (60 mg/m(2)) and docetaxel (75 mg/m(2)) in 3-weeks intervals for up to eight cycles. RESULTS: The overall response rate was 50% and 78% of patients derived a clinical benefit. Median time to progression and overall survival were 10.0 months (95% CI, 6.9-13.1 months) and 25 months (95% CI, 22.1-29.8 months), respectively. Median duration of response was 12.0 months (95% CI 7.1-16.9). The treatment was generally well tolerated and associated with toxicities that were consistent with the known side-effects of the individual agents and of anthracycline/taxane combinations. There were no symptomatic cardiac averse events and mild asymptomatic LVEF changes were reported in five patients. CONCLUSIONS: The combination of NPLD and docetaxel is well tolerated and has high antitumour activity in MBC patients.

Kümmel S, Eggemann H, Lüftner D, Gebauer N, Bühler H, Schaller G, Schmid P, Kreienberg R, Emons G, Kriner M, Elling D, Blohmer JU, Thomas A. · Department of Obstetrics and Gynecology, University of Duisburg-Essen, Hufelandstrasse 55, 45122 Essen, Germany. · Int J Biol Markers. · Pubmed #17922461 No free full text.

Abstract: The insulin-like growth factor 1 (IGF1) and its binding protein IGFBP3 (insulin-like growth factor binding protein 3) play a pivotal role during the growth and development of tissues. The purpose of this study was to evaluate the influence of anthracycline- and taxane-containing adjuvant chemotherapy in breast cancer patients on the circulating plasma levels of IGF1 and its main binding protein, IGFBP3. This investigation was part of a prospective randomized phase III study in which breast cancer patients were treated with either conventional or dose-intensified adjuvant chemotherapy. The factors were quantified in the plasma of 151 patients with a commercially available sandwich enzyme immunoassay. Before therapy, both parameters were within the normal range in most patients (n=145 and n=144). After therapy, both factors had increased significantly by 29% (IGF1) and 19% (IGFBP3), with the highest increase being observed in the dose-intensified group. Correlations with patient and tumor characteristics revealed a relatively higher increase in both parameters in premenopausal patients, patients with lower-grade tumors, more positive lymph nodes, larger tumor volume, and positive hormone receptor status. No correlation was found with the HER2 expression of the tumors.

Hermelink K, Untch M, Lux MP, Kreienberg R, Beck T, Bauerfeind I, Münzel K. · Department of Gynecology and Obstetrics, Ludwig Maximilian University, Munich, Germany. · Cancer. · Pubmed #17351951 links to  free full text

Abstract: BACKGROUND: It is believed widely that chemotherapy-induced cognitive impairment occurs in a subgroup of patients with breast cancer. However, recent reports have provided no evidence that chemotherapy affects cognition. In this study, the authors questioned whether cognitive compromise in patients with breast cancer is attributable to chemotherapy. In addition, the effects of therapy-induced menopause and of the erythropoiesis-stimulating factor darbepoetin alpha on cognitive performance were assessed. METHODS: A battery of neuropsychological tests was used to assess cognitive performance in 101 patients with breast cancer before neoadjuvant chemotherapy (T1) and toward the end of neoadjuvant chemotherapy (T2) with combined epirubicin, paclitaxel, and cyclophosphamide with concomitant darbepoetin alpha. Repeated-measures multiple analyses of variance and a reliable-change approach were used for statistical analyses. RESULTS: At T1, the group means ranged below the test norms in 5 of 12 cognitive tests. At T2, multiple analyses of variance (MANOVA) indicated a significant overall improvement in the test results (P<.001). After correcting for practice effects, cognitive decline predominated in 27% of patients, whereas improvement predominated in 28% of patients. Cognitive performance was not related significantly to self-reported cognitive problems, anxiety and depression, menopause, or darbepoetin alpha administration. CONCLUSIONS: Even before chemotherapy, a subgroup of patients with breast cancer showed cognitive compromise that was unrelated to anxiety or depression. During chemotherapy, cognitive function remained stable in most patients, improved in a subgroup, and deteriorated in another subgroup. The deterioration may have been caused by side effects of chemotherapy, but it also may have been related to currently unidentified factors that cause prechemotherapy cognitive compromise. Therapy-induced menopause and darbepoetin alpha did not appear to influence cognition.

Schmid P, Flath B, Akrivakis K, Heilmann V, Mergenthaler HG, Sezer O, Kreienberg R, Possinger K. · Berlin Breast Cancer Research Group, Medizinische Klinik mit Schwerpunkt Onkologie und Hämatologie, Charité Campus Mitte, Humboldt Universität zu Berlin, Berlin, Germany. · Invest New Drugs. · Pubmed #16012794 No free full text.

Abstract: BACKGROUND: Gemcitabine and mitoxantrone are active agents for the treatment of metastatic breast cancer. Due to different modes of action and a favorable toxicity profile they are suitable for combination therapy. This phase I trial was initiated to determine the optimal doses for the combination in patients with metastatic breast cancer. Secondary objectives included the evaluation of the safety and efficacy of the regimen. PATIENTS AND METHODS: Patients with metastatic breast cancer were treated with gemcitabine (1000-1400 mg/m(2)) on days 1, 8 and 15 and mitoxantrone (10-14 mg/m(2)) on day 8. Treatment was repeated every 4 weeks for a maximum of 8 cycles. Doses were assigned at registration according to the escalation scheme. RESULTS: Twenty-six patients received a total of 93 cycles at 5 different dose levels. The maximum tolerated doses were 1200 mg/m(2) gemcitabine and 14 mg/m(2) mitoxantrone with grade 4 neutropenia being the dose limiting toxicity. Recommended phase II doses, however, are gemcitabine 1200 mg/m(2) and mitoxantrone 12 mg/m(2) based on a similar median dose intensity and a more favorable toxicity profile. Predominant toxicity was myelosuppression. Most common non-hematological toxicities were nausea, vomiting, alopecia and elevation of liver enzymes. Twenty-one patients were assessable for response. Four patients achieved a partial response accounting for an overall response rate of 19%. In addition, 12 patients (57%) had stable disease and 5 patients (24%) failed to response to the treatment. Median duration of response and duration of clinical benefit were 14 and 9 months, respectively. CONCLUSION: In this phase I study of gemcitabine and mitoxantrone, the DLT was neutropenia. Recommended phase II doses are gemcitabine 1200 mg/m(2) and mitoxantrone 12 mg/m(2).

Untch M, Himsl I, Kahlert S, Lueck HJ, Eidtmann H, Du Bois A, Meerpohl HG, Thomssen C, Harbeck N, Jackisch C, Kreienberg R, Emons G, Wallwiener D, Wiese W, Schaller G, Kuhn W, Muscholl M, Pauschinger M, Langer B. · Klinikum Grosshadern, Frauenklinik München, Ludwig-Maximilians-Universität, München, Germany. · Oncology (Williston Park). · Pubmed #15685838 No free full text.

Abstract: This study was designed to evaluate the cardiac safety of the combined treatment of HER2-positive metastatic breast cancer patients with trastuzumab (Herceptin) plus epirubicin and cyclophosphamide (EC) in comparison with EC alone in HER2-negative metastatic breast cancer patients. Patients included those with metastatic breast cancer without any prior anti-HER2 treatment, anthracycline therapy, or any other chemotherapy for metastatic disease. This was a nonrandomized, prospective, dose-escalating, multicenter, open-label, phase I study in Germany. A control group of 23 patients received EC 90/600 mg/m2 3-weekly for six cycles (EC90 alone). A total of 26 HER2-positive patients were treated with trastuzumab, or H (2 mg/kg weekly after an initial loading dose of 4 mg/kg), and EC 60/600 mg/m2 3-weekly for six cycles (EC60+H); another 25 HER2-positive patients received H and EC 90/600 mg/m2 3-weekly for six cycles. Asymptomatic reductions in left ventricular ejection fraction (LVEF) of more than 10% points were detected in 12 patients (48%) treated with EC60+H and in 14 patients (56%) treated with EC90+H vs 6 patients (26%) in the EC90 alone cohort. LVEF decreases to <50% occurred in one patient in the EC60+H cohort and in two patients in the EC90+H cohort during the H monotherapy. No cardiac event occurred in the cohort with EC90 alone. The overall response rates for EC60+H and EC90+H were >60%, vs 26% for EC90 alone. The interim results of this study approve the cardiac safety of the combination of H with EC, with low risk of cardiac toxicity. The combination regimen revealed promising efficacy.

Zander AR, Kröger N, Schmoor C, Krüger W, Möbus V, Frickhofen N, Metzner B, Schultze W, Berdel WE, Koenigsmann M, Thiel E, Wandt H, Possinger K, Trümper L, Kreienberg R, Carstensen M, Schmidt EH, Jänicke F, Schumacher M, Jonat W. · Transplant Center, University Hospital Hamburg-Eppendorf, Hamburg, Germany. · J Clin Oncol. · Pubmed #15111618 No free full text.

Abstract: PURPOSE: Investigation of high-dose chemotherapy (HD-CT) followed by autologous hematopoietic stem-cell support compared with standard-dose chemotherapy (SD-CT) as adjuvant treatment in patients with primary breast cancer and 10 or more positive axillary lymph nodes. PATIENTS AND METHODS: Between November 1993 and September 2000, 307 patients were randomized to receive (following four cycles of epirubicin 90 mg/m(2) and cyclophosphamide 600 mg/m(2), intravenously every 21 days) either HD-CT of cyclophosphamide 1500 mg/m(2), thiotepa 150 mg/m(2), and mitoxantrone 10 mg/m(2), intravenously for 4 consecutive days followed by stem-cell support; or SD-CT in three cycles of cyclophosphamide 500 mg/m(2), methotrexate 40 mg/m(2), and fluorouracil 600 mg/m(2) intravenously on days 1 and 8, every 28 days. The primary end point was event-free survival. RESULTS: After a median follow-up of 3.8 years, 144 events with respect to event-free survival have been observed (HD-CT: 63 events; SD-CT: 81 events). The first event of failure (HD-CT v SD-CT) was an isolated locoregional recurrence (nine v 11), a distant failure (52 v 68), and death without recurrence (two v two). The estimated relative risk of HD-CT versus SD-CT was 0.75 (95% CI, 0.54 to 1.06; P =.095). Overall survival showed no difference (HD-CT: 40 deaths; SD-CT: 49 deaths). CONCLUSION: There was a trend in favor of HD-CT with respect to event-free survival, but without statistical significance. Further follow-up and a meta-analysis of all randomized studies will reveal the effect of HD-CT as compared with SD-CT as adjuvant treatment in high-risk primary breast cancer.

Schirrmeister H, Kühn T, Guhlmann A, Santjohanser C, Hörster T, Nüssle K, Koretz K, Glatting G, Rieber A, Kreienberg R, Buck AC, Reske SN. · Department of Nuclear Medicine, University Hospital, 89070 Ulm, Germany. · Eur J Nucl Med. · Pubmed #11315604 No free full text.

Abstract: The present study compared the diagnostic accuracy of fluorine-18 2-deoxy-2-fluoro-D-glucose positron emission tomography (FDG-PET) with conventional staging techniques. The differentiation between malignant and benign lesions and the detection of multifocal disease, axillary and internal lymph node involvement, and distant metastases were evaluated. One hundred and seventeen female patients were prospectively examined using FDG-PET and conventional staging methods such as chest X-ray, ultrasonography of the breast and liver, mammography and bone scintigraphy. All patients were examined on a modern full-ring PET scanner. Histopathological analysis of resected specimens was employed as the reference method. The readers of FDG-PET were blinded to the results of the other imaging methods and to the site of the breast tumour. The sensitivity and specificity of FDG-PET in detecting malignant breast lesions were 93% and 75% respectively. FDG-PET was twofold more sensitive (sensitivity 63%, specificity 95%) in detecting multifocal lesions than the combination of mammography and ultrasonography (sensitivity 32%, specificity 93%). Sensitivity and specificity of FDG-PET in detecting axillary lymph node metastases were 79% and 92% (41% and 96% for clinical evaluation). FDG-PET correctly indicated distant metastases in seven patients. False-positive or false-negative findings were not encountered with FDG-PET. Chest X-ray was false-negative in three of five patients with lung metastases. Bone scintigraphy was false-positive in four patients. Three patients were upstaged since FDG-PET detected distant metastases missed with the standard staging procedure. It is concluded that, compared with the imaging methods currently employed for initial staging, FDG-PET is as accurate in interpreting the primary tumour and more accurate in screening for lymph node metastases and distant metastases. Due to a false-negative rate of 20% in detecting axillary lymph node metastases, FDG-PET cannot replace histological evaluation of axillary status.

Kühn T, Santjohanser C, Koretz K, Böhm W, Kreienberg R. · Department of Gynecology and Obstetrics, University of Ulm, Prittwitzstrasse 43, 89079 Ulm, Germany. · Surg Endosc. · Pubmed #10890968 No free full text.

Abstract: BACKGROUND: Sentinel node biopsy is a promising technique that allows the axillary status of breast cancer patients to be predicted with high accuracy. Reducing false negative results remains a major challenge for the improvement of this procedure. Furthermore, new techniques are required to achieve axillary clearing with less morbidity in cases of unsuccessful mapping or multicentric carcinoma. We analyzed whether axilloscopy and endoscopic sentinel node biopsy is a feasible procedure for visualization of the axillary space and resection of the sentinel node using endoscopic techniques. METHODS: Following blue dye-guided lymphography and liposuction of the axillary fat, endoscopic axillary sentinel node biopsy was performed in 35 breast cancer patients. We then assessed the exposure of anatomical landmarks, the detection rate of the sentinel node, the false negative rate, and the accuracy of consecutive axillary clearing. RESULTS: In almost every case, an excellent anatomical orientation was achieved. The detection rate for the sentinel node was 83.3%. In one case, the sentinel node did not reflect the status of the residual axilla. A mean number of 17.1 lymph nodes was harvested at consecutive axillary clearing. CONCLUSIONS: Axilloscopy and endoscopic sentinel node biopsy, following liposuction of the axillary fat, is a feasible procedure that allows identification and minimally invasive resection of the sentinel node with high accuracy. The endoscopic approach might help to minimize the pitfalls of sentinel node biopsy by visualizing the axillary space. In future, it may become a technique that enables minimally invasive axillary clearing when complete lymphadenectomy is required.

Helms G, Kühn T, Moser L, Remmel E, Kreienberg R. · Universitätsfrauenklinik, Prittwitzstrasse 43, D-89075 Ulm, Germany. · Eur J Surg Oncol. · Pubmed #18838245 No free full text.

Abstract: BACKGROUND: Axillary lymph node dissection (ALND) as part of surgical treatment in breast cancer has been the standard procedure for many decades. However, patients frequently develop shoulder-arm morbidity postoperatively. Recently, sentinel node (SN) biopsy has been established as a new standard of care for axillary staging in breast cancer. This study compares postoperative morbidity between ALND and SN biopsy. The results are compared with the existing literature. METHOD: Between November 2000 and September 2002, 181 women with early stage breast cancer underwent primary surgery following preoperative randomisation into two groups, a "standard group" (SN biopsy was followed by ALND) and a study group (surgical procedure consisting of only SN biopsy when histologically metastasis-free SN was present). Follow-up data (362 sessions; 6 months to 3 years after primary surgery) were available from 150 patients. A summary morbidity score was calculated from four subjective (arm-strength, arm-mobility, arm swelling, pain) and four objective (arm-strength, arm-mobility, lymphedema, sensitivity) criteria. RESULTS: Fifty seven patients underwent SN biopsy only. Ninety three patients underwent ALND, 57 of which had lymph nodes free of metastasis and 36 had lymph nodes with metastasis and axillary clearing. Shoulder-arm morbidity was significantly different between the groups. Patients treated with SN biopsy only scored better on subjective and objective criteria. SUMMARY: Postsurgical shoulder-arm morbidity is a major long-term problem in patients undergoing surgical treatment for breast cancer. This prospective study showed significantly less severe shoulder-arm morbidity following SN biopsy compared to patients undergoing ALND.

Sauer G, Schneiderhan-Marra N, Kazmaier C, Hutzel K, Koretz K, Muche R, Kreienberg R, Joos T, Deissler H. · Department of Obstetrics and Gynaecology, University of Ulm, Germany. · Clin Cancer Res. · Pubmed #18519762 links to  free full text

Abstract: PURPOSE: Identification of molecular characteristics that are useful to define subgroups of patients fitting into differential treatment schemes is considered a most promising approach in cancer research. In this first study of such type, we therefore investigated the potential of multiplexed sandwich immunoassays to define protein expression profiles indicative of clinically relevant properties of malignant tumors. EXPERIMENTAL DESIGN: Lysates prepared from large core needle biopsies of 113 invasive breast carcinomas were analyzed with bead-based miniaturized sandwich immunoassays specific for 54 preselected proteins. RESULTS: Five protein concentrations [fibroblast growth factor-2 (FGF-2), Fas, Fas ligand, tissue inhibitor of metalloproteinase-1, and RANTES] were significantly different in the groups of patients with or without axillary lymph node metastasis. All 15 protein parameters that resulted in P values <0.2 and other diagnostic information [estrogen receptor (ER) status, tumor size, and histologic grading] were analyzed together by multivariate logistic regression. This yielded sets of five (FGF-2, Fas, Fas ligand, IP10, and PDGF-AB/BB) or six (ER staining intensity, FGF-2, Fas ligand, matrix metalloproteinase-13, PDGF-AB/BB, and IP10) parameters for which receiver-operator characteristic analyses revealed high sensitivities and specificities [area under curve (AUC) = 0.75 and AUC = 0.83] to predict the nodal status. A similar analysis including all identified parameters of potential value (15 proteins, ER staining intensity, T) without selection resulted in a receiver-operator characteristic curve with an AUC of 0.87. CONCLUSION: We clearly showed that this approach can be used to quantify numerous proteins from breast biopsies accurately in parallel and define sets of proteins whose combined analyses allow the prediction of nodal involvement with high specificity and sensitivity.

Keimling M, Kaur J, Bagadi SA, Kreienberg R, Wiesmüller L, Ralhan R. · Department of Obstetrics and Gynaecology, University of Ulm, Prittwitzstrasse 43, D-89075 Ulm, Germany. · Int J Cancer. · Pubmed #18491400 No free full text.

Abstract: Increasing evidence indicates that breast cancer pathogenesis is linked with DNA double-strand break (DSB) repair dysfunction. This conclusion is based on advances in the study of functions of breast cancer susceptibility genes such as BRCA1 and BRCA2, on the identification of breast cancer-associated changes regarding the genetics, expression, and localization of multiple DSB repair factors, and on observations indicating enhanced radiation-induced chromosomal damage in cells from predisposed individuals and sporadic breast cancer patients. In this pilot study, we describe a sensitive method for the analysis of DSB repair functions in mammary carcinomas. Using this method we firstly document alterations in pathway-specific DSB repair activities in primary cells originating from familial as well as sporadic breast cancer. In particular, we identified increases in the mutagenic nonhomologous end joining and single-strand annealing mechanisms in sporadic breast cancers with wild-type BRCA1 and BRCA2, and, thus, similar phenotypes to tumors with mutant alleles of BRCA1 and BRCA2. This suggests that detection of error-prone DSB repair activities may be useful to extend the limits of genotypic characterization of high-risk susceptibility genes. This method may, therefore, serve as a marker for breast cancer risk assessment and, even more importantly, for the prediction of responsiveness to targeted therapies such as to inhibitors of poly(ADP-ribose)polymerase (PARP1).