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Background: Endocrine therapy is recommended for the treatment of postmenopausal women with hormone receptor-positive (HR+) advanced breast cancer (ABC). Methods: ACT-FASTER was a German prospective non-interventional cohort study in postmenopausal women with HR+ ABC receiving fulvestrant 500 mg as first line (1 L), second line (2 L) or third line (3 L), or exemestane (any line) in the real-world palliative setting. Primary study objectives included the effectiveness of fulvestrant according to line of palliative treatment measured by time to progression (TTP), and real-life data on the epidemiology and management of these patients. Results: Of 498 evaluable patients (mean age 67.5 years), 99% were estrogen receptor-positive. On study, 86.7% of patients received fulvestrant 500 mg and 13.3% exemestane. Median TTP was 9.7 months in patients receiving fulvestrant 1 L; 6.8 months for 2 L; and 6.7 months for 3 L. The comparison between fulvestrant 1 L palliative treatment and 2 L or 3 L showed that early initiation of treatment prolonged TTP (hazard ratio 1.26; 95% confidence interval 1.08-1.48). Treatments were well tolerated. Conclusion: Fulvestrant 500 mg was administered successfully to patients under daily practice conditions, and both medications were well tolerated. TTP was longest in patients treated with fulvestrant 500 mg 1 L compared with 2 L and 3 L in the palliative care setting.

The present study aimed to investigate the effects of bone marrow-derived mesenchymal stem cells (BMSCs) that had been pretreated with pioglitazone and/or rosiglitazone on the growth and proliferation rate of MCF-7 cells. The adhesive interaction between the BMSCs and the MCF-7 cancer cells revealed that the pretreatment of BMSCs with a combination of two types of thiazolidinedione drug reduced the growth and proliferation rate of the MCF-7 cells. The proliferation rate of the MCF-7 cells could also be reduced by the non-adhesive interaction of the cancer cells with BMSCs pretreated with pioglitazone and/or rosiglitazone. The growth and proliferation rate reduction effects on the MCF-7 cells may be attributed to the reduction in the protein level of fibroblast growth factor 4 (FGF4) in the conditioned medium of the pretreated BMSCs. The evidence that the low protein level of FGF4 in the conditioned medium of the pretreated BMSCs perturbed the proliferation rate of the MCF-7 cells by reducing the levels of Ki-67 and proliferating cell nuclear antigen transcripts in the cancer cells was also demonstrated in the present study using a FGF4-neutralizing antibody. All the above findings demonstrate that future studies on the correlation between FGF4 and pretreated BMSCs would be beneficial.

Background/aim One of the major problems in breast cancer treatment is pharmacoresistance. Therefore, exploration of treatment alternatives is of clinical relevance. The present work focused on tumor cell-inhibiting effects of a combination of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and all trans retinoic acid (ATRA) in breast cancer cells. Materials and methods Breast cancer cell lines (BT-20, BT-474, MDA-MB-231, MDA-MB-436, MDA-MB-453, MCF-7, SKBR3, T47D, ZR-75-1) and the mammary epithelial cell line MCF-10A were treated with TRAIL and ATRA alone and in combination. Cell viability was assessed via 3-(4,5)-dimethylthiahiazo(-z-yl)-3,5-di-phenytetrazoliumromide (MTT) assay, the potential of cell colony formation via clonogenic assay, cell death induction via cell-cycle analysis by fluorescence-activated cell sorting (FACS), terminal deoxynucleotidyltransferase-mediated UTP nick end labeling (TUNEL) assay and Cell death detection ELISAPLUS, expression of apoptosis and TRAIL pathway proteins via western blot and cell surface expression of TRAIL receptor 1 (DR4) via FACS analysis. Results TRAIL and ATRA evoked synergistic inhibition of breast cancer cell viability based on cytostatic and cytotoxic mechanisms. This correlated with augmented fragmentation of nuclear DNA, up-regulation of TRAIL receptor, down-regulation of cyclin D1 and enhancement of caspase activity. MCF-10A cells were merely slightly susceptible to TRAIL and ATRA. Conclusion The cytostatic and cytotoxic effects of the combination of TRAIL and ATRA are tumor cell-selective.

The prognosis of metastatic breast cancer (MBC) is extremely heterogeneous. Although patients with MBC will uniformly die to their disease, survival may range from a few months to several years. This underscores the importance of defining prognostic factors to develop risk-adopted treatment strategies. Our aim has been to use simple measures to judge a patient's prognosis when metastatic disease is diagnosed.We retrospectively analyzed 2269 patients from four clinical cancer registries. The prognostic score was calculated from the regression coefficients found in the Cox regression analysis. Based on the score, patients were classified into high-, intermediate-, and low-risk groups. Bootstrapping and time-dependent receiver operating characteristic curves were used for internal validation. Two independent datasets were used for external validation.Metastatic-free interval, localization of metastases, and hormone receptor status were identified as significant prognostic factors in the multivariate analysis. The three prognostic groups showed highly significant differences regarding overall survival from the time of metastasis [intermediate compared with low risk: hazard ratio (HR) 1.76, 95% confidence interval (CI) 1.36-2.27, P0.001; high compared with low risk: HR 3.54, 95% CI 2.81-4.45, P0.001). The median overall survival in these three groups were 61, 38, and 22 months, respectively. The external validation showed congruent results.We developed a prognostic score, based on routine parameters easily accessible in daily clinical care. Although major progress has been made, the optimal therapeutic management of the individual patient is still unknown. Besides elaborative molecular classification of tumors, simple clinical measures such as our model may be helpful to further individualize optimal breast cancer care.

BACKGROUND Early detection and improved (neo)-adjuvant treatment has extended survival of breast cancer over the last decades. It remains controversial whether a survival benefit is achieved once metastases have occurred. This study investigates survival trends in metastatic breast cancer (MBC) looking at the distribution of prognostic factors and the time period of the diagnosis of the primary and metastatic disease. PATIENTS AND METHODS In this retrospective study, 1635 patients, diagnosed with MBC and treated at three German cancer centers, were included. For the survival analysis, patients were grouped into three time periods [1980-1994 (a), 1995-1999 (b) and 2000-2009 (c)], which were chosen according to the availability of new antineoplastic drugs for the treatment of MBC. Additionally, patients were divided into three risk groups using the simultaneously published prognostic score. RESULTS The analysis of overall survival according to the date of primary diagnosis demonstrated a significant decline compared with the reference (a): (a versus b) hazard ratio (HR) = 1.37; P < 0.001; (a versus c) HR = 2.45; P < 0.001. Considering the time of first occurrence of metastasis, survival remains unchanged over the three periods (a versus b): HR = 0.94 P = 0.436; (a versus c): HR = 0.95; P = 0.435. However, a significant shift towards more unfavorable risk factors was seen. CONCLUSIONS Although survival in MBC remains unchanged over time, patients developing metastatic disease have a more aggressive disease that is presumably compensated by more effective treatment. This alteration of tumor biology in MBC may be explained by a negative selection of patients with adverse risk profiles due to the advantages of the adjuvant therapy.

BACKGROUND: Marginal zone lymphoma (MZL) is a non-Hodgkin lymphoma that occurs as extra nodal, nodal, or splenic. While MZL is generally considered an indolent disease, a substantial percentage of patients follow an unfavorable course. The objective of this retrospective analysis was to identify predictors for a reduced overall survival (OS), or conversely an increased OS. PATIENTS AND METHODS: One hundred and ninety-seven MZL patients were analyzed. Apart from assessing previously published risk factors, concomitant morbidity at diagnosis, transformation into aggressive lymphoma, and occurrence of additional malignancies were evaluated. RESULTS: Next to the known risk factors, i.e. above 60 years of age and elevated serum lactate dehydrogenase (LDH), we demonstrate that transformation into aggressive lymphoma, as well as additional malignancies, are important independent risk factors for a shortened OS in a multivariate analysis, irrespective of the MZL localization. Impressively, in the group of patients lacking LDH elevation, transformation, and/or additional malignancies, only 1 of 63 patients died during follow-up compared with 37 of 87 patients in the high-risk group (HR = 22.8; 95% confidence interval 3.1-167.0; P = 0.002). CONCLUSIONS: Our analysis proposes novel risk factors and warrants for a continuous follow-up to detect the occurrence of transformation and additional malignancies early on.

The influence of CYP2D6 genotype on the efficacy of tamoxifen (Tam) has been extensively analyzed in early breast cancer with conflicting results. However, there is only scarce data regarding this potential influence in advanced breast cancer (ABC). We hypothesize that Tam is more effective in patients with a functional CYP2D6 allele than in patients with impaired CYP2D6 activity. ABC patients with prior or ongoing palliative Tam treatment (20 mg/d) were eligible. Genomic DNA was extracted from blood (n = 51) and formalin-fixed, paraffin-embedded tissue (n = 43). CYP2D6*2, *3, *4, *5, *6, *10, *17, *29, *41, CYP2D6 duplication and multiplication were determined in blood and CYP2D6*4 in tissue samples. Primary endpoint was progression free survival (PFS); secondary endpoints included clinical benefit (CB), and overall survival (OS). The clinical charts were retrospectively analyzed regarding survival and treatment effects. Genotyping was performed blinded and clinical data were analyzed separately. 94 patients were identified with a median age of 59 years (29-90 years). In 6 patients genotyping did not show conclusive results, therefore these patients were excluded from further analysis. Genotyping results were as follows: 1.1 % ultrarapid, 84.1 % extensive, 3.4 % intermediate, and 11.4 % poor metabolizers. Patients without any fully functional allele (IM/IM, IM/PM, PM/PM) had a significant shorter PFS and OS compared to patients with at least one functional allele (EM/EM, EM/IM, EM/PM) (PFS: p = 0.017; HR = 2.19; 95 % CI 1.15-4.18; OS: p = 0.028; HR = 2.79; 95 % CI 1.12-6.99). The CB rate was 73 % for EM-group and 38.5 % for IM + PM-group (p = 0.019). Our results show a significant influence of the CYP2D6 genotype on the efficacy of Tam in the treatment of ABC. In contrast to the adjuvant setting, the evidence in the palliative setting is congruent. CYP2D6 testing in ABC should be considered.

Depression and anxiety are the core disorders causing emotional distress in patients (pts) with metastatic breast cancer. The aim of our study was to screen metastatic breast cancer outpatients for anxiety and depression, and to investigate the influence of age, Karnofsky Performance Status (KPS), cancer activity, and inflammation as represented by IL-6 levels on these two mood disorders. Pts treated with chemotherapy for metastatic breast cancer (n = 70) were assessed using the Hospital Anxiety and Depression Scale (HADS) for symptoms (scores 0–21) and caseness (score ≥11) of clinical depression and anxiety. Blood samples for IL-6 concentrations were collected at 10:00 a.m. A total of 22 (31.4 %) pts were diagnosed with caseness of clinical depression and 23 (32.9 %) pts with clinical anxiety, while 12 pts were diagnosed positive for both mood disorders. Depression and anxiety were positively but moderately correlated (Spearman’s r 2 = 0.24, p < 0.001). IL-6 was significantly correlated with symptoms of depression (r 2 = 0.42, p < 0.001) and to a lesser extent to symptoms of anxiety (r 2 = 0.16, p = 0.001). In addition, IL-6 was positively associated with tumor progression (p < 0.001). Multiple linear regression analysis showed that tumor progression (standardized b = 0.226, p = 0.047), symptoms of anxiety (b = 0.292, p = 0.016), and IL-6 (b = 0.314, p = 0.007) were independently associated with clinical depression, whereas anxiety was linked to tumor progression (b = 0.238, p = 0.030), symptoms of depression (b = 0.407, p < 0.001) and age (b = −0.381, p < 0.001), but not to IL-6 (b = 0.168, p = 0.134). Even though a positive correlation between depression and anxiety exists, clinical parameters like age, cancer activity, KPS, and IL-6 do influence depression and anxiety differently. Unlike clinical depression, anxiety is not associated with increased IL-6 levels, however, shows a reciprocal correlation with age.

Die medikamentose Systemtherapie ist wichtiger Bestandteil eines multimodalen Therapiekonzeptes beim primaren Mammakarzinom. Sie wird als Chemotherapie, endokrine Therapie, Anti-HER2-Antikorpertherapie oder als Kombination bzw. Sequenz dieser Therapieformen vor (neoadjuvant) oder nach (adjuvant) der Operation durchgefuhrt. Die Systemtherapie reduziert nachweislich Rezidivrate und Mortalitat. Dies gilt fur die Polychemotherapie (Gabe von Anthrazyklinen und Taxanen), fur die medikamentose Ausschaltung der Ovarialfunktion, fur Tamoxifen, Aromatasehemmer und Trastuzumab. Das absolute Ausmas dieser Effekte ist abhangig vom individuellen Rezidivrisiko. Altere Patientinnen sollten eine Systemtherapie erhalten, die der fur jungere Patientinnen vergleichbar ist. Bei Indikationsstellung und Durchfuhrung sind veranderte Organfunktionen und Komorbiditaten zu berucksichtigen. Eine optimale supportive Therapie (z. B. Myelopoesestimulation, Antiemese, Versorgung mit Perucken etc.) ist integraler Bestandteil aller systemischen Therapien. Alle Patientinnen mussen uber mogliche Nebenwirkungen und Spatfolgen aufgeklart werden und Prophylaxemasnahmen angeboten bekommen. Im Beitrag werden die aktuellen S3-Leitlinienempfehlungen 2012 fur die adjuvante, d. h. die postoperative Systemtherapie zusammengefasst.

Die Auswahl der systemischen Therapie des Mammakarzinoms wird zunehmend durch eine molekulare Klassifikation in 5 Subtypen beeinflusst. So werden Luminal A-Tumore (ER/PgR positiv, HER2 negativ, Ki-67 niedrig), Luminal B/HER2 negativ (ER/PgR positiv, HER2 negativ, Ki-67 hoch), Luminal B/HER2 positiv (ER/PgR positiv, HER2 positiv, jedes Ki-67), HER2 positiv und Basal-like (ER/PgR negativ, HER2 negativ) Tumoren unterschieden, die jeweils verschiedene therapeutische Ansatze verlangen. Eine Vielzahl neuer Substanzen ist zurzeit in der klinischen Erprobung, so zeigen z. B. mTOR-Inhibitoren in der Kombination mit endokrinen Substanzen eine grose Wirksamkeit. Auch bei der anti-HER2-Therapie sind mit neuen Antikorpern wie Pertuzumab oder der Kopplung zytotoxischer Substanzen an Trastuzumab (T-DM1) neue Wege vielversprechend. Die zunehmende Individualisierung der systemischen Therapie birgt die Chance auf eine weitere Verbesserung der Wirksamkeit sowie die Moglichkeit Patientengruppen zu identifizieren, die bestimmte Therapiemodalitaten nicht bedurfen, was wiederum hilft, unnotige Toxizitaten einzusparen.

Background: Clinical trials under-represent patients (pts) >65 years. Non-interventional studies (NISs) help to evaluate therapies in daily practice. This NIS evaluates efficacy and safety of cetuximab in combination with chemotherapy in metastatic colorectal cancer (mCRC) pts aged >65 years vs ⩽65 years. Methods: A total of 657 pts were recruited into the NIS and analysed applying descriptive statistics and χ2 or Fisher's exact test. Results: A total of 309 and 305 pts aged ⩽65 and >65 years, respectively, were documented; 80% showing a reduced ECOG status of 1–2 and 95% having received at least one palliative treatment. Cetuximab was combined with irinotecan according to approval status. Grade III/IV toxicities occurred in 20% of pts without any difference between age groups although the older pts had significantly more pre-existing comorbidities (P=0.001). A total of 64.2% of the pts developed skin rash, which was strongly related to response (P65 years. Progression-free survival (PFS) did not differ between pts 18–65 years old (6.5 months) in comparison with pts >65 years (7.0 months). In a multivariate analysis only ECOG status had a negative impact on PFS (HR: 0,675; 95% Cl, 0.53–0.87; P=0.0019). Conclusion: This NIS reports one of the largest mCRC collectives >65 years and reduced performance status. Cetuximab has a similar efficacy and safety profile for pts aged ⩽65 and >65 years.

The surface receptor CUB domain-containing protein 1 (CDCP1) is highly expressed in several adenocarcinomas and speculated to participate in anchorage-independent cell survival and cell motility. Tyrosine kinase phosphorylation seems to be crucial for intracellular signaling of CDCP1. Lapatinib, a tyrosine kinase inhibitor (TKI), is approved for treatment of HER-2/neu overexpressing metastatic breast cancer and functions by preventing autophosphorylation following HER-2/neu receptor activation. This study aimed to investigate the effect of CDCP1 expression on anchorage-independent growth and cell motility of breast cancer cells. Moreover, studies were performed to examine if lapatinib provided any beneficial effect on HER-2/neu((+)/-)/CDCP1(+) breast cancer cell lines. In our studies, we affirmed that CDCP1 prevents cells from undergoing apoptosis when cultured in the absence of cell-substratum anchorage and that migratory and invasive properties of these cells were decreased when CDCP1 was down-regulated. However, only HER-2/neu(+), but not HER-2/neu((+)/-) cells showed decreased proliferation and invasion and an enhanced level of apoptosis towards loss of anchorage when treated with lapatinib. Therefore, we conclude that CDCP1 might be involved in regulating adhesion and motility of breast cancer cells but that lapatinib has no effect on tyrosine kinases regulating CDCP1. Nonetheless, other TKIs might offer therapeutic approaches for CDCP1-targeted breast cancer therapy and should be studied considering this aspect.

Aufgrund mangelnder Evidenz existiert fur > 65-jahrige Brustkrebspatientinnen keine Standardtherapie, und die Therapieempfehlungen basieren v.a. auf der Datenlage jungerer postmenopausaler Patientinnen. Es besteht fur alle Therapiemodalitaten eine Fehlversorgung, die einen negativen Effekt auf das rezidivfreie Uberleben und das Gesamtuberleben hat. Alter an sich sollte kein Faktor sein, der die Therapiewahl bestimmt, sondern der erwartete individuelle Nutzen einer Therapie sollte mit ihren Risiken unter Berucksichtigung der Komorbiditaten und der weiteren Lebenserwartung abgewogen werden. Bei nach geriatrischem Assessment als ”fit“ eingestuften alteren Patientinnen sollte eine Therapie gemas den aktuellen Leitlinien gewahlt werden. Eine adjuvante Chemotherapie sollte insbesondere bei Hormonrezeptor-negativen Karzinomen haufiger eingesetzt werden. Eine endokrine Therapie sollte allen Hormonrezeptor-positiven Patientinnen angeboten werden.

Background: Despite advances in the first- and secondline treatment of advanced breast cancer, optimal therapy thereafter remains controversial. Treatment of heavily pretreated patients is not standardized, often of low efficacy, and limited by comorbidity. In these patients, an effective treatment with low toxicity is needed. Patients and Methods: We retrospectively analyzed all metastatic breast cancer patients treated with 5-fluorouracil as continuous infusion (CI-5FU) with daily doses of 150–300 mg/m2. Results: 43 patients were treated with CI-5FU until disease progression. The median number of metastatic sites was 3. Most patients were heavily pretreated with a median of 3 palliative chemotherapies (range 1–11). 42 patients were evaluable for objective response; among them 5 (12%) showed a partial response (PR) and 6 (15%) showed stable disease (SD) lasting at least 6 months, leading to a clinical benefit (CB) rate (complete response + PR + SD ≧ 6 months) of 27%. The median time to progression of patients with CB was 10 months (range 3–22). Overall survival of all patients from the start of CI-5FU was 8 months (range 1–75) and from the time of first metastases 42 months (range 9–281). Toxicity was low even in patients with hepatic insufficiency. Conclusion: CI-5FU showed a positive efficacy/toxicity ratio. Taking into account the high number of previous treatments, it results in a remarkable CB rate of 27%.

Background: The orphan surface receptor CDCP1 is over-expressed in various cancers and signals via Src family kinases (SFKs). It has been shown to be involved in anchorage independency of distinct tumors [Uekita et al. 2007; Moasser 2009]. Since CDCP1 is also speculated to be involved in tumor cell migration and invasion, the following study investigated the in vitro migration and invasion of breast cancer cell lines. In order to prove if lapatinib treatment might benefit CDCP1-positive but HER2/neu-negative breast cancer patients, we investigated the level of apoptosis after lapatinib application to different cell lines. Material and Methods: Four breast cancer cell lines were selected according to their CDCP1/HER-2/neu receptor expression (MDA-MB-231high/high; T47Dhigh/low; SKBR3low/high; MCF7neg./high). CDCP1 knock-down was achieved via nucleofection of Stealth™ RNAi (Invitrogen) against CDCP1. In vitro migration and invasion were analyzed for 48hs using trans-well assays (Merck). Migrated cells were labeled with Calcein AM and relative fluorescence units (RFU) were measured at 485/520nm. To investigate the effect of lapatinib, cells were cultured for 48hs in the presence of lapatinib (0,75 µM) as attached cells or as suspension culture on ultra-low adhesion plates, respectively. The enrichment of free nucleosomes was measured and compared between CDCP1-RNAi transfected and parental cells. Results: When transfected with CDCP1-RNAi, migration of SKBR-3 cells was not affected (96.2% migrating cells compared to control). However, CDCP1-RNAi-transfected MDA-MB-231 cells showed a strong reduction in migration (70.2% (± 21.5%)) compared to mock-transfected cells and the observed effect was even more impressive in T47D cells (58.3± 16.1% migration compared to control; P=0,011)). Invasion of CDCP1- silenced MDA-MB-231 was reduced to 71.4% (± 5.9%) of the mock-transfected control cells. Again, T47D cells also were severely impaired by CDCP1-knock-down (0.32 ± 0.02% of invasive cells compared to control; P Conclusions: The migratory activity of breast cancer cell lines did not strictly correlate with the degree in CDCP1 expression. However, CDCP1- knock down yielded in a clearly reduced migration and invasion of MDA-MB-231 cells and was even more impressive in T47D cell line. However, no effect was observed in SKBR3 cells. Thus, CDCP1 might represent one of a panel of surface receptors that participate in cell movement. However, Lapatinib was shown to have no effect on the viability of CDCP1pos./Her2/neuneg./low cells. Nonetheless, our study reveals that CDCP1 might have a strong impact on migration and invasive capacities of breast cancer cell lines and thus represents a potential target in more individualized breast cancer therapies. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-06-21.

Background: Sagopilone (ZK-EPO) is a fully synthetic microtubule-stabilizing agent that has demonstrated high antitumor activity in preclinical models. This first-in-human phase I study aimed to determine the maximum tolerated dose (MTD) and dose-limiting toxic effects (DLTs) of 3-weekly sagopilone treatment. Patients and methods: A total of 52 patients with advanced solid tumors received a 30-min infusion of escalating doses of sagopilone (0.6-29.4 mg/m(2)) every 3 weeks. Nine additional patients were recruited to a 3-h infusion arm (16.53-or 22.0-mg/m(2) dose) to assess the incidence of neuropathy with prolonged infusion. Results: The MTD was established as 22.0 mg/m(2). DLTs comprised peripheral sensory neuropathy (PNP), infection, hyponatremia, diarrhea, and central ataxia. PNP was the most common grade 3 event, with a similar incidence in the 30-min and 3-h arms. Hematologic adverse events were rare and of low intensity. One confirmed partial response (PR) and one unconfirmed PR were reported in the 30-min arm, and a further unconfirmed PR was observed in the 3-h arm. Eleven patients achieved disease stabilization. Sagopilone showed high levels of tissue binding and no obvious serum accumulation in both arms. Conclusions: These data demonstrate that sagopilone therapy is feasible and well tolerated. The recommended dose for phase II studies is 16.53 mg/m(2), once every 3 weeks.

Background: In the ‘Arimidex’, Tamoxifen Alone or in Combination (ATAC) trial, the aromatase inhibitor (AI) anastrozole had a ignificantly better efficacy and safety profile than tamoxifen as initial adjuvant therapy for hormone receptor-positive (HR+) early breast cancer (EBC) in postmenopausal patients. To compare the combined long-term clinical and economic benefits, we carried out a cost-effectiveness analysis (CEA) of anastrozole versus tamoxifen based on the data of the 100- month analysis of the ATAC trial from the perspective of the German public health insurance. Patients and Methods: A Markov model with a 25-year time horizon was developed using the 100-month analysis of the ATAC trial as well as data obtained from published literature and expert opinion. Results: Adjuvant treatment of EBC with anastrozole achieved an additional 0.32 quality-adjusted life-years (QALYs) gained per patient compared with tamoxifen, at an additional cost of D 6819 per patient. Thus, the incremental cost effectiveness of anastrozole versus tamoxifen at 25 years was D 21,069 ($ 30,717) per QALY gained. Conclusions: This is the first CEA of an AI that is based on extended follow-up data, taking into account the carryover effect of anastrozole, which maintains the efficacy benefits beyond therapy completion after 5 years. Adjuvant treatment with anastrozole for postmenopausal women with HR+ EBC is a cost-effective alternative to tamoxifen. Hintergrund: Bei der adjuvanten Therapie von postmenopausalen Patientinnen mit Hormonrezeptor-positivem (HR+) Mammakarzinom belegen die ATAC-100-Monatsdaten (ATAC-Studie: ‘Arimidex’, Tamoxifen Alone or in Combination) einen signifikanten Vorteil von Anastrozol gegenüber Tamoxifen in Bezug auf Rezidivrisiko und Verträglichkeit. Es wurde eine Kosten-Nutzwert-Analyse von Anastrozol im Vergleich zu Tamoxifen aus der Sicht des deutschen Gesundheitssystems durchgeführt. Material und Methoden: Als Berechnungsbasis wurde ein Markov- Modell zur Abschätzung der Kosteneffektivität entwickelt. Der Modellierungszeitraum umfasste 25 Jahre. Die Daten wurden anhand der ATAC-100-Monatsdaten, vorliegender Literatur und durch ein interdisziplinäres Expertenteam ermittelt. Ergebnisse: Eine adjuvante Therapie mit Anastrozol erzielte 0,32 quality-adjusted life-years (QALYs) pro Patientin mehr, verglichen mit einer adjuvanten Tamoxifentherapie. Die zusätzlichen Kosten der Therapie mit Anastrozol lagen bei 6819 D pro Patientin. Im Vergleich mit Tamoxifen erzielte Anastrozol einen ICER (Incremental Cost-Effectiveness Ratio) von 21 069 D (30 717 $)/QALY über den gesamten Modellierungszeitraum. Schlussfolgerung: Diese Kosten- Nutzwert-Analyse eines Aromatasehemmers basiert erstmals auf einer Datenanalyse, die auch das Follow-Up und den sogenannten Carryover- Effekt nach einer abgeschlossenen 5-Jahres-Therapie beinhaltet. Anastrozol ist auch nach dieser Analyse aus der Sicht des deutschen Gesundheitssystems eine kosteneffektive Therapieoption für postmenopausale Patientinnen mit einem HR+ frühen Mammakarzinom. Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Previously we reported that the peroxisome proliferator-activated receptor α/γ dual ligand TZD18 inhibited growth and induced apoptosis of leukemia and glioblastoma cells. Now we show that TZD18 also has the same effects against six human breast cancer cell lines. To obtain insights into the mechanism involved in TZD18-induced growth inhibition and apoptosis in breast cancer, the gene expression profiles of TZD18-treated and untreated MCF-7 and MDA-MB-231 cells were compared by microarray analysis. Results reveal that many genes implicated in endoplasmic reticulum stress signaling, such as CHOP (also known as DDIT3 or GADD153), GRP78 (HSPA5), and ATF4, are highly up-regulated, suggesting endoplasmic reticulum stress is induced. This is supported by our data that treatment of MCF-7 and MDA-MB-231 cells with TZD18 induces phosphorylation of PERK and the α subunit of eukaryotic initiation factor 2 (eIF2α), as well as an up-regulation of GRP78 and an activation of ATF6, all of which are specific markers for endoplasmic reticulum stress. Furthermore, this ligand increases the endoplasmic reticulum stress–related cell death–regulators such as CHOP, DR5, GADD34, Bax, and Bak in these cells. Importantly, knockdown of CHOP by small interference RNA antagonizes the TZD18-induced apoptosis, indicating a crucial role of CHOP in the apoptotic process triggered by TZD18. In addition, TZD18 also activates stress-sensitive mitogen-activated protein kinase (MAPK) pathways including p38, ERK, and JNK. The specific inhibitors of these MAPKs attenuated the TZD18-induced growth inhibition in these cells. These results clearly show that activation of these MAPKs is important for TZD18-induced growth inhibition. In summary, TZD18-treatment leads to the activation of endoplasmic reticulum stress response and, subsequently, growth arrest and apoptosis in breast cancer cells. [Mol Cancer Ther 2009;8(8):2296–307]

Bronchoalveolar lavage (BAL) is a practicable procedure establishing the etiology of pneumonia. In patients with neutropenia, empirical antimicrobial treatment is mandatory immediately after diagnosis of infection, usually before results of BAL are available. We evaluated the impact of BAL on treatment and outcome of pneumonia in immunocompromised patients with a special regard to neutropenia. Bronchoscopy with BAL was performed in 58 episodes of clinical documented pneumonia in patients with hematological malignancies (88%) or solid tumors (12%), in 30 cases patients had neutropenia, in 28 cases patients had no neutropenia. In 93% of cases, BAL was performed under empirical antimicrobial treatment. BAL fluid was cultivated for bacteria, fungi, and tested for Pneumocystis jirovecii and cytomegalovirus (CMV). BAL revealed positive bacterial results in 67% of cases. Gram-positive microorganisms were detected in 95% of positive BAL results, gram-negative microorganisms in 23%, mixed bacterial cultures occurred in 41%. Positive fungi cultures were found in 59%. P. jirovecii was detected in 5% of cases tested and CMV in 8%. There was no significant difference between neutropenic and non-neutropenic patients. BAL results directed a change of therapy in only six of 58 episodes (5%). Overall mortality related to pneumonia was 16%. In this patient setting, the yield of BAL rarely has a significant influence on treatment and outcome of pneumonia. The early beginning of antimicrobial treatment reduces the diagnostic yield of BAL. In patients with pneumonia during neutropenia, its use should be well considered.

Honokiol, an active component isolated and purified from Chinese traditional herb magnolia, was demonstrated to inhibit growth and induce apoptosis of different cancer cell lines such as human leukaemia, colon, and lung cancer cell lines; to attenuate the angiogenic activities of human endothelial cells in vitro; and to efficiently suppress the growth of angiosarcoma in nude mice. In this study, we have demonstrated that treatment of different human breast cancer cell lines with honokiol resulted in a time- and concentration-dependent growth inhibition in both estrogen receptor-positive and -negative breast cancer cell lines, as well as in drug-resistant breast cancer cell lines such as adriamycin-resistant and tamoxifen-resistant cell lines. The inhibition of growth was associated with a G1-phase cell cycle arrest and induction of caspase-dependent apoptosis. The effects of honokiol might be reversely related to the expression level of human epidermal growth receptor 2, (HER-2, also known as erbB2, c-erbB2) since knockdown of her-2 expression by siRNA significantly enhanced the sensitivity of the her-2 over-expressed BT-474 cells to the honokiol-induced apoptosis. Furthermore, inhibition of HER-2 signalling by specific human epidermal growth receptor 1/HER-2 (EGFR/HER-2) kinase inhibitor lapatinib synergistically enhanced the anti-cancer effects of honokiol in her-2 over-expressed breast cancer cells. Finally, we showed that honokiol was able to attenuate the PI3K/Akt/mTOR (Phosphoinositide 3-kinases/Akt/mammalian target of rapamycin) signalling by down-regulation of Akt phosphorylation and upregulation of PTEN (Phosphatase and Tensin homolog deleted on chromosome Ten) expression. Combination of honokiol with the mTOR inhibitor rapamycin presented synergistic effects on induction of apoptosis of breast cancer cells. In conclusion, honokiol, either alone or in combination with other therapeutics, could serve as a new, promising approach for breast cancer treatment.

In sequence to our first survey in 2004 on antihormonal therapy with aromatase inhibitors (AIs), we conducted a second survey on the prescription practice in 2005.We distributed the anonymous questionnaires amongst the participants of the 2005 congresses of the German Society of Senology and German Society of Haematology and Oncology.The surveys were mostly completed by gynaecologists (46%) and medical oncologists (46%). According to the responses given, over 31,000 breast cancer patients were treated in these institutions in 2004, over 18,000 of whom received AIs. 37/30% of doctors prescribed AIs for national/private health insurance patients depending on the known risks of tamoxifen treatment (50% of cases). Whilst only 6/10% of doctors prescribed AIs for more than 50% of patients with either national/private health insurance in 2004, this figure reached 49% in 2005, independent of the type of medical insurance. Assuming unrestricted approval, 68/65% of doctors would treat over 50% of their patients with an AI.The rate of treatment with AIs has increased dramatically. The previous gold standard, tamoxifen, was by and large replaced by AIs in 2004/2005. We may assume that almost all receptor- positive breast cancer patients will receive an AI in the course of their adjuvant therapy in the very near future.

Die meisten klinischen Studien setzen fur die Rekrutierung von Patientinnen mit Mammakarzinom eine Altergrenze zwischen 60 und 70 Jahren fest. Es gibt nur wenige valide Daten zur Therapie des Mammakarzinoms bei alten Patientinnen. Aufgrund der geringen Reprasentanz alter Patientinnen in klinischen Studien ist der Onkologe weiterhin gezwungen, die Ergebnisse, die an jungeren postmenopausalen Patientinnen erhoben wurden, auf diese Altersgruppe zu ubertragen und anhand individueller Uberlegung unter Berucksichtigung der altersspezifischen Besonderheiten zu adaptieren. Analysen der Datenbanken zeigen jedoch, dass diesen Patientinnen haufig sinnvolle Therapien auf dem Boden dieser Uberlegungen vorenthalten werden. Eine adjuvante Chemotherapie bei nodalnegativem Mammakarzinom und positiven Hormonrezeptoren erscheint keinen Benefit zu erbringen. Die Chemotherapie sollte dagegen im Alter viel haufiger als bisher bei Patientinnen mit nodalpositivem und hormonrezeptornegativem Mammakarzinom zum Einsatz kommen. Auf eine adjuvante Bestrahlung kann bei „Low-Risk-Tumoren“ (T1/2 N0) bei uber 70-jahrigen Patientinnen verzichtet werden. Bei den Hochrisikopatientinnen (T3/4 oder N+) ist prinzipiell auch bei uber 70-jahrigen Patientinnen von einem Vorteil auszugehen, wenn nicht ein schlechter Allgemeinzustand oder Komorbiditaten die Prognose bestimmen.