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Offenbach-Hundheim, Germany

Von Minckwitz G.,German Breast Group | Eidtmann H.,Universitats Frauenklinik | Rezai M.,Luisenkrankenhaus | Fasching P.A.,Friedrich - Alexander - University, Erlangen - Nuremberg | And 19 more authors.
New England Journal of Medicine | Year: 2012

BACKGROUND: Bevacizumab, a monoclonal antibody against vascular endothelial growth factor A, has shown clinical efficacy in patients with human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer. We evaluated the efficacy, measured according to the rate of pathological complete response (absence of invasive and intraductal disease in the breast and the axillary lymph nodes), and the safety of adding bevacizumab to neoadjuvant chemotherapy in patients with early-stage breast cancer. METHODS: We randomly assigned 1948 patients with a median tumor size of 40 mm on palpation to receive neoadjuvant epirubicin and cyclophosphamide followed by docetaxel, with or without concomitant bevacizumab. Patients with untreated HER2-negative breast cancer were eligible if they had large tumors, hormone-receptor-negative disease, or hormone-receptor-positive disease with palpable nodes or positive findings on sentinel-node biopsy, and no increased cardiovascular or bleeding risk. RESULTS: Overall, the rates of pathological complete response were 14.9% with epirubicin and cyclophosphamide followed by docetaxel and 18.4% with epirubicin and cyclophosphamide followed by docetaxel plus bevacizumab (odds ratio with addition of bevacizumab, 1.29; 95% confidence interval, 1.02 to 1.65; P = 0.04); the corresponding rates of pathological complete response were 27.9% and 39.3% among 663 patients with triple-negative tumors (P = 0.003) and 7.8% and 7.7% among 1262 patients with hormone-receptor-positive tumors (P = 1.00). Breast-conserving surgery was possible in 66.6% of the patients in both groups. The addition of bevacizumab, as compared with neoadjuvant therapy alone, was associated with a higher incidence of grade 3 or 4 toxic effects (febrile neutropenia, mucositis, the hand-foot syndrome, infection, and hypertension) but with a similar incidence of surgical complications. CONCLUSIONS: The addition of bevacizumab to neoadjuvant chemotherapy significantly increased the rate of pathological complete response among patients with HER2-negative early-stage breast cancer. Efficacy was restricted primarily to patients with triple-negative tumors, in whom the pathological complete response is considered to be a reliable predictor of long-term outcome. (Funded by Sanofi-Aventis and Roche, Germany; ClinicalTrials.gov number, NCT00567554.) Copyright © 2012 Massachusetts Medical Society. Source

Von Minckwitz G.,C o GBG Forschungs GmbH | Untch M.,HELIOS Klinikum | Blohmer J.-U.,St. Gertrauden Krankenhaus | Costa S.D.,Universitats Frauenklinik | And 13 more authors.
Journal of Clinical Oncology | Year: 2012

Purpose: The exact definition of pathologic complete response (pCR) and its prognostic impact on survival in intrinsic breast cancer subtypes is uncertain. Methods: Tumor response at surgery and its association with long-term outcome of 6,377 patients with primary breast cancer receiving neoadjuvant anthracycline-taxane-based chemotherapy in seven randomized trials were analyzed. Results: Disease-free survival (DFS) was significantly superior in patients with no invasive and no in situ residuals in breast or nodes (n = 955) compared with patients with residual ductal carcinoma in situ only (n = 309), no invasive residuals in breast but involved nodes (n = 186), only focal-invasive disease in the breast (n = 478), and gross invasive residual disease (n = 4,449; P < .001). Hazard ratios for DFS comparing patients with or without pCR were lowest when defined as no invasive and no in situ residuals (0.446) and increased monotonously when in situ residuals (0.523), no invasive breast residuals but involved nodes (0.623), and focal-invasive disease (0.727) were included in the definition. pCR was associated with improved DFS in luminal B/human epidermal growth factor receptor 2 (HER2) -negative (P = .005), HER2-positive/nonluminal (P < .001), and triple-negative (P < .001) tumors but not in luminal A (P = .39) or luminal B/HER2-positive (P < .45) breast cancer. pCR in HER2-positive (nonluminal) and triple-negative tumors was associated with excellent prognosis. Conclusion: pCR defined as no invasive and no in situ residuals in breast and nodes can best discriminate between patients with favorable and unfavorable outcomes. Patients with noninvasive or focal-invasive residues or involved lymph nodes should not be considered as having achieved pCR. pCR is a suitable surrogate end point for patients with luminal B/HER2-negative, HER2-positive (nonluminal), and triple-negative disease but not for those with luminal B/HER2-positive or luminal A tumors. © 2012 by American Society of Clinical Oncology. Source

Von Minckwitz G.,C o GBG Forschungs GmbH | Untch M.,HELIOS Klinikum | Nuesch E.,University of Bern | Loibl S.,C o GBG Forschungs GmbH | And 19 more authors.
Breast Cancer Research and Treatment | Year: 2011

Pathological complete response (pCR) to neoadjuvant treatment correlates with outcome in breast cancer. We determined whether characteristics of neoadjuvant therapy are associated with pCR. We used multi-level models, which accounted for heterogeneity in pCR across trials and trial arms, to analyze individual patient data from 3332 women included in 7 German neoadjuvant trials with uniform protocols. PCR was associated with an increase in number of chemotherapy cycles (odds ratio [OR] 1.2 for every two additional cycles; P = 0.009), with higher cumulative anthracycline doses (OR 1.6; P = 0.002), higher cumulative taxane doses (OR 1.6; P = 0.009), and with capecitabine containing regimens (OR 1.62; P = 0.022). Association of pCR with increase in number of cycles appeared more pronounced in hormone receptor (HR)-positive tumors (OR 1.35) than in HR-negative tumors (OR 1.04; P for interaction = 0.046). Effect of anthracycline dose was particularly pronounced in HER2-negative tumors (OR 1.61), compared to HER2-positive tumors (OR 0.83; P for interaction = 0.14). Simultaneous trastuzumab treatment in HER2-positive tumors increased odds of pCR 3.2-fold (P < 0.001). No association of pCR and number of trastuzumab cycles was found (OR 1.20, P = 0.39). Dosing characteristics appear important for successful treatment of breast cancer. Longer treatment, higher cumulative doses of anthracyclines and taxanes, and the addition of capecitabine and trastuzumab are associated with better response. Tailoring according to breast cancer phenotype might be possible: longer treatment in HR-positive tumors, higher cumulative anthracycline doses for HER2-negative tumors, shorter treatment at higher cumulative doses for triple-negative tumors, and limited number of preoperative trastuzumab cycles in HER2-positive tumors. © 2010 Springer Science+Business Media, LLC. Source

Vajda P.,Surgical Unit | Kereskai L.,University of Pecs | Czauderna P.,Medical University of Gdansk | Schaarschmidt K.,HELIOS Kliniken Berlin Buch | And 9 more authors.
European Journal of Gastroenterology and Hepatology | Year: 2012

Objective: The pathogenesis of nonparasitic splenic cysts (NPSCs) has not been clarified completely. The aim of this multinational and multicentre retrospective study was to further elucidate the origin of NPSCs. Methods: From 1980 to 2006, 50 children and adolescents were surgically treated for NPSC at six paediatric surgical centres in four European countries. The initial histology report of 35 NPSCs, 22 epidermoid cysts, 11 pseudocysts or post-traumatic cysts and two mesothelial cysts was available. Additional re-evaluation, including immunohistochemistry, to detect cytokeratin, carcino-embrionic antigen and mesothelioma antibody in the inner surface of the cysts was carried out. Special attention was given to the possibility of preceding trauma to the splenic area and whether it played a role in the genesis of NPSC. Results: The pathological re-evaluation showed 30 epidermoid cysts, four mesothelial cysts and one pseudocyst. Immunohistology revealed eight epidermoid and two mesothelial linings of the cysts in those 11 patients in whom pseudocyst was diagnosed originally. No pseudocyst was documented in those patients who had a history of previous blunt abdominal trauma but was not proved by ultrasound and computed tomography scan. Conclusion: In contrast with the prevailing belief, it has been demonstrated that NPSCs are congenital in origin, and there is no clinically proven evidence that trauma does play a role in their genesis. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins. Source

Muller-Tidow C.,Martin Luther University of Halle Wittenberg | Muller-Tidow C.,University of Munster | Tschanter P.,Martin Luther University of Halle Wittenberg | Tschanter P.,University of Munster | And 41 more authors.
Leukemia | Year: 2016

DNA methylation changes are a constant feature of acute myeloid leukemia. Hypomethylating drugs such as azacitidine are active in acute myeloid leukemia (AML) as monotherapy. Azacitidine monotherapy is not curative. The AML-AZA trial tested the hypothesis that DNA methyltransferase inhibitors such as azacitidine can improve chemotherapy outcome in AML. This randomized, controlled trial compared the efficacy of azacitidine applied before each cycle of intensive chemotherapy with chemotherapy alone in older patients with untreated AML. Event-free survival (EFS) was the primary end point. In total, 214 patients with a median age of 70 years were randomized to azacitidine/chemotherapy (arm-A) or chemotherapy (arm-B). More arm-A patients (39/105; 37%) than arm-B (25/109; 23%) showed adverse cytogenetics (P=0.057). Adverse events were more frequent in arm-A (15.44) versus 13.52 in arm-B, (P=0.26), but early death rates did not differ significantly (30-day mortality: 6% versus 5%, P=0.76). Median EFS was 6 months in both arms (P=0.96). Median overall survival was 15 months for patients in arm-A compared with 21 months in arm-B (P=0.35). Azacitidine added to standard chemotherapy increases toxicity in older patients with AML, but provides no additional benefit for unselected patients. © 2016 Macmillan Publishers Limited. Source

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