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Nitz U.,Heinrich Heine University Düsseldorf | Nitz U.,West German Study Group | Nitz U.,Ev. Bethesda Hospital | Gluz O.,West German Study Group | And 24 more authors.
Annals of Oncology | Year: 2014

Background: Taxane-based adjuvant chemotherapy is standard in node-positive (N+) early breast cancer (BC). The magnitude of benefit in intermediate-risk N+ early BC is still unclear. WSG-AGO epiribicine and cyclophosphamide (EC)-Doc is a large trial evaluating modern taxane-based chemotherapy in patients with 1-3 positive lymph nodes (LNs) only. Patients and methods: A total of 2011 BC patients (18-65 years, pN1) were entered into a randomized phase III trial comparing 4 × E90C600 q3w followed by 4 × docetaxel100 q3w (n = 1008) with the current standard: 6 × F500E100C500 q3w (n = 828) or C600M40F600 d1, 8× q4w (n = 175). Primary end point was event-free survival (EFS); secondary end points were overall survival (OS), toxicity, translational research, and quality of life. Central tumor bank samples were evaluable in a representative collective (n = 772; 40%). Ki-67 was assessed centrally in hormone receptor-positive disease as a surrogate marker for the distinction of luminal A/B-like tumors. Results: Baseline characteristics were well balanced between study arms in both main study and central tumor bank subset. At 59-month median follow-up, superior efficacy of EC-Doc [versus FEC (a combination of 5-fluorouracil, epirubicin, and cyclophosphamide)] was seen in EFS and OS: 5-year EFS: 89.8% versus 87.3% (P = 0.038); 5-year OS: 94.5% versus 92.8% (P = 0.034); both tests one-tailed. EC-Doc caused more toxicity. In hormone receptor-positive (HR)+ disease, only high-Ki-67 tumors (≥20%) derived significant benefit from taxane-based therapy: hazard ratio = 0.39 (95% CI 0.18-0.82) for EC-Doc versus FEC (test for interaction; P = 0.01). Conclusion: EC-Doc significantly improved EFS and OS versus FEC in intermediate-risk BC (1-3 LNs) within all subgroups as defined by local pathology. In HR+ disease, patients with luminal A-like tumors may be potentially over-treated by taxane-based chemotherapy. Clinical Trial number: ClinicalTrials.gov, NCT02115204. © The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.


Schneeweiss A.,University of Heidelberg | Forster F.,TU Chemnitz | Tesch H.,Center for Hematology and Medical Oncology at Bethanien Hospital | Aktas B.,University of Duisburg - Essen | And 8 more authors.
Anticancer Research | Year: 2016

Aim: The German ML21165 study evaluated bevacizumab-containing therapy for metastatic breast cancer (mBC) in routine oncology practice. Patients and Methods: Patients received bevacizumab with chemotherapy until disease progression, unacceptable toxicity or consent withdrawal. Prespecified end-points were safety and efficacy [response rate, progression-free survival (PFS) and overall survival (OS)]. Results: Between May 2007 and September 2009, 865 patients received first-line bevacizumab plus paclitaxel for mBC, of whom 16% were aged ?70 years and 9% had ECOG performance status of 2 or more. At data cut-off (median of 15.9 months' follow-up), the median PFS was 9.6 months [95% confidence interval (CI)=9.0-10.4 months] and the median OS was 21.6 months (95% CI=19.4-23.5 months). The most common non-haematological adverse drug reactions of grade 3 or more were pain (9%), hypertension (5%), sensory neuropathy (3%) and proteinuria (3%). Prolonged bevacizumab was well-tolerated. Conclusion: The efficacy and safety of first-line bevacizumab-paclitaxel in routine oncology practice is consistent with results from randomized trials.


PubMed | University Hospital Mainz, St Elisabeth Hospital, WiSP Research Institute, University of Heidelberg and 7 more.
Type: Clinical Study | Journal: Anticancer research | Year: 2016

The German ML21165 study evaluated bevacizumab-containing therapy for metastatic breast cancer (mBC) in routine oncology practice.Patients received bevacizumab with chemotherapy until disease progression, unacceptable toxicity or consent withdrawal. Pre-specified end-points were safety and efficacy [response rate, progression-free survival (PFS) and overall survival (OS)].Between May 2007 and September 2009, 865 patients received first-line bevacizumab plus paclitaxel for mBC, of whom 16% were aged 70 years and 9% had ECOG performance status of 2 or more. At data cut-off (median of 15.9 months follow-up), the median PFS was 9.6 months [95% confidence interval (CI)=9.0-10.4 months] and the median OS was 21.6 months (95% CI=19.4-23.5 months). The most common non-haematological adverse drug reactions of grade 3 or more were pain (9%), hypertension (5%), sensory neuropathy (3%) and proteinuria (3%). Prolonged bevacizumab was well-tolerated.The efficacy and safety of first-line bevacizumab-paclitaxel in routine oncology practice is consistent with results from randomized trials.


Rutgers E.,Netherlands Cancer Institute | Piccart-Gebhart M.J.,Institute Jules Bordet | Bogaerts J.,European Organisation for Research and Treatment of Cancer | Delaloge S.,Institute Gustave Roussy | And 12 more authors.
European Journal of Cancer | Year: 2011

Background: The MINDACT (Microarray In Node-negative and 1-3 node positive Disease may Avoid ChemoTherapy) trial investigates the clinical utility of the 70-gene profile (MammaPrint) for the selection of breast cancer patients for adjuvant chemotherapy (CT) together with standard clinicopathological criteria. We present the results of the pilot phase consisting of first 800 patients included. Methods: MINDACT has enrolled 6600 patients, classified into high or low risk by MammaPrint and clinicopathological risk through Adjuvant! Online. Patients with both clinical (C) and genomic (G) high risks are offered adjuvant CT; those with both C and G low risks do not receive CT; patients with discordant risk are randomised for the decision of adjuvant CT based on C or G risk. CT randomisation of anthracycline-based versus docetaxel/capecitabine and endocrine therapy randomisation between letrozole and tamoxifen → letrozole are offered. Results: During the pilot phase 46% of screened patients were enrolled. Main reasons for non-enrolment were node positivity before trial amendment, sample quality problems and failure to meet logistic settings. Among the 800 patients, 386 (48%) were C-low/G-low, 198 (24.8%) as C-high/G-high, 75 (9.4%) as C-low/G-high and 141 (17.6%) as C-high/G-low. In total 216 (27%) cases were discordant. The difference between patients with C-high (42%) and G-high risk (34%) is 8.25% (95% confidence interval (CI), 4.7-11.8%; P <.0001). Compliance with the treatment decision was high (>92%). Conclusions: The logistically complex MINDACT trial is feasible in a multinational setting. The proportion of discordant patients, the potential reduction in CT by using the genomic signature and compliance to treatment assignment are in accordance with the trial hypotheses. © 2011 Elsevier Ltd. All rights reserved.


Background: Adjuvant treatment decision-making based on conventional clinical/pathological and prognostic single molecular markers or genomic signatures is a therapeutic area in which over-/under-treatment are still key clinical problems even though substantial and continuous improvement of outcome has been achieved over the past decades. Response to therapy is currently not considered in the decision-making procedure. ADAPT is one of the first new generation (neo)adjuvant trials dealing with individualization of (neo)adjuvant decision-making in early breast cancer and aims to establish early predictive surrogate markers, e.g., Ki-67, for therapy response under a short induction treatment in order to maximally individualize therapy and avoid unnecessary toxicity by ineffective treatment.Methods/design: The prospective, multi-center, controlled, non-blinded, randomized, investigator initiated phase II/III ADAPT trial has an innovative " umbrella" protocol design. The " umbrella" is common for all patients, consisting of dynamic testing of early therapy response. ADAPT will recruit 4,936 patients according to their respective breast cancer subtype in four distinct sub-trials at 80 trial sites in Germany; 4,000 patients with hormone receptor positive (HR+) and HER2 negative disease will be included in the ADAPT HR+/HER2- sub-trial, where treatment decision is based on risk assessment and therapy response to induction therapy, and 380 patients will be included in ADAPT HER2+/HR+. A further 220 patients will be included in ADAPT HER2+/HR- and 336 patients will be recruited for ADAPT Triple Negative. These three sub-trials focus on identification of early surrogate markers for therapy success in the neoadjuvant setting. Patients will be allocated to the respective sub-trial according to the result of their diagnostic core biopsy, as reported by local/central pathology for HR and HER2 status. Discussion: Recent trials, such as the GeparTrio, have shown that response-guided therapy using clinical response may improve outcome. For chemotherapy or HER2-targeted treatment, pathologic complete response in a neoadjuvant setting is an excellent predictor of outcome. For endocrine therapy, response to short induction treatment - as defined by decrease in tumor cell proliferation - strongly correlates with outcome. ADAPT now aims to combine static prognostic and dynamic predictive markers, focusing not just on single therapeutic targets, but also on general markers of proliferation and cell death. Biomarker analysis will help to optimize selection of subtype-specific treatment.Trial registration: ClinicalTrials.gov: ADAPT Umbrella: NCT01781338; ADAPT HR+/HER2-: NCT01779206; ADAPT HER2+/HR+: NCT01745965; ADAPT HER2+/HR-: NCT01817452; ADAPT TN: NCT01815242. © 2013 Hofmann et al.; licensee BioMed Central Ltd.


Muller P.,University of Basel | Kreuzaler M.,University of Basel | Khan T.,ETH Zurich | Khan T.,Hoffmann-La Roche | And 19 more authors.
Science Translational Medicine | Year: 2015

Targeted drug delivery with antibody-drug conjugates such as the HER2-directed ado-trastuzumab emtansine (T-DM1) has emerged as a powerful strategy for cancer therapy. We show that T-DM1 is particularly effective in eliciting antitumor immunity in patients with early breast cancer (WSG-ADAPT trial) and in a HER2-expressing orthotopic tumor model. In the latter, despite primary resistance to immunotherapy, combined treatment with T-DM1 and anti-CTLA-4/PD-1 (cytotoxic T lymphocyte-associated protein-4/programmed cell death protein-1) was curative because it triggered innate and adaptive immunity. Tumor rejection was accompanied by massive T cell infiltration, TH1 (T helper 1) cell polarization, and, notably, a substantial increase in regulatory T cells. Depletion of regulatory T cells resulted in inflammation and tissue damage, implying their essential role in protecting the host during therapy. This study provides insights into the mechanisms of T-DM1's therapeutic activity and a rationale for potential therapeutic combination strategies with immunotherapy.


Nitz U.,Evangelic Hospital Bethesda | Nitz U.,West German Study Group | Gluz O.,Evangelic Hospital Bethesda | Gluz O.,West German Study Group | And 15 more authors.
Annals of Oncology | Year: 2014

Background: WSG-ARA plus trial evaluated the effect of adjuvant darbepoetin alfa (DA) on outcome in node positive primary breast cancer (BC). Patients and methods: One thousand two hundred thirty-four patients were randomized to chemotherapy either with DA (DA+; n = 615) or without DA (DA-; n = 619). DA (500μg q3w) was started at hemoglobin (Hb) levels <13.0g/dl (<12g/dl after DA label amendment) and stopped at Hb levels ≥14.0g/dl (12g/dl after label amendment). Primary efficacy end point was event-free survival (EFS); secondary end points were toxicity, quality of life (QoL) and overall survival (OS). Results: Venous thrombosis (DA+: 3.0%, DA-: 1.0%; P = 0.013) was significantly higher for DA+, but not pulmonary embolism (0.3% in both arms). Median Hb levels were stable in DA+ (12.6g/dl) and decreased in DA- (11.7g/dl). Hb levels >15g/dl were reported in 0.8% of cycles. QoL parameters did not significantly differ between arms. At 39 months, DA had no significant impact on EFS (DA+: 89.3%, DA-: 87.5%; Plog-rank = 0.55) or OS (DA+: 95.5%, DA-: 95.4%; Plog-rank = 0.77). Conclusions: DA treatment did not impact EFS or OS in routine adjuvant BC treatment. © The Author 2013. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.


Gluz O.,West German Study Group | Wild P.,University of Regensburg | Wild P.,University of Zürich | Liedtke C.,West German Study Group | And 17 more authors.
Breast Cancer Research and Treatment | Year: 2011

The goal of this analysis was to characterize the survival impact of angiogenesis in the patients with high-risk breast cancer, particularly the predictive impact on benefit from dose intensification of adjuvant chemotherapy. Formalin-fixed tissue sample of 152 patients treated as part of the WSG AM-01 trial by either high-dose or conventional dose-dense chemotherapy were analyzed. Angiogenic activity was measured using microvessel count and vascular surface area (VSA) determined by the expression of vascular markers CD31 (n = 128) and CD105/endoglin (n = 130). Protein molecular breast cancer subclasses were analyzed by k-means clustering (k = 5). The univariate impact of factors on event-free (EFS) and overall survival (OS) was tested by log-rank statistics and quantified by univariate Cox analysis. Multivariate survival analysis included factors significant in univariate analysis, as well as interactions was performed for EFS. Both VSA/CD31 (P = 0.004) and VSA/CD105 (P = 0.003) were significantly higher among cases with increased Ki-67. A significant association with molecular subtypes was also found for VSA/CD105: in patients with basal-like/Her-2 subtypes, mean was 1.72 versus 1.24 in patients with other subtypes (P < 0.001). Elevated VSA/CD105 was associated with both significantly decreased EFS (P = 0.01) and OS (P = 0.02). Increased tumor size and positive Her-2 status were also prognostic for poorer EFS. The benefit of dose intensification for EFS was seen in those low-VSA/CD105 patients. The result was evident both in univariate and in multivariate survival analysis including all factors that were significant at the univariate level. Expression of angiogenesis markers may mirror or confer resistance to chemotherapy in the patients with breast cancer, particularly within the context of dose intensified chemotherapy. Highly angiogenic tumors may not derive sufficient benefit from dose intensification of chemotherapy alone. Our findings may serve as a rationale for further exploring antiangiogenic treatment options in the patients with such highly angiogenic tumor subtypes. © Springer Science+Business Media, LLC. 2010.

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