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Dumontet C.,French Institute of Health and Medical Research | Krajewska M.,Sanford Burnham Institute for Medical Research | Treilleux I.,French Institute of Health and Medical Research | Mackey J.R.,Cross Cancer Institute | And 4 more authors.
Clinical Cancer Research | Year: 2010

Purpose: There are currently no validated factors predictive of response to taxanes in patients with breast cancer. We analyzed specimens from patients included in the Breast Cancer International Research Group (BCIRG) 001 trial, a randomized study which showed the superiority of docetaxel/doxorubicin/ cyclophosphamide over fluorouracil/doxorubicin/cyclophosphamide as adjuvant therapy for nodepositive operable breast cancer in terms of disease-free survival (DFS) and overall survival (OS). Experimental Design: Immunohistochemical assessment of biological markers included histologic grade, tumor size, estrogen and progesterone receptors, lymph node status, HER2, MUC1, Ki-67/MIB-1, p53, Bcl-2, Bax, Bcl-XL, BAG-1, β-tubulin isotypes II, III and IV, τ protein, and detyrosinated α tubulin. Associations between selected parameters and survival were tested through univariate analyses, then completed with multivariate analyses and a bootstrap resampling technique. Results: In univariate analysis histologic grade, tumor size, number of involved nodes, estrogen and progesterone receptor status, p53, Ki-67, tubulin III, and τ protein were associated both with DFS and with OS. In multivariate analysis estrogen and progesterone receptors, tumor size, number of involved nodes, and Ki-67 protein were associated both with DFS and with OS, whereas τ protein levels were correlated with DFS and tubulin III and P53 were correlated with OS. No interaction was observed between Ki-67 and treatment allocation. Conclusions: We conclude that the expression in primary tumors of Ki-67 and p53 protein, as well as of the microtubule-related parameters ô protein and tubulin III, are independent prognostic factors in patients receiving adjuvant chemotherapy for node-positive breast cancer but are not predictive of benefit from docetaxel-containing adjuvant chemotherapy. ©2010 AACR.

Martin M.,Grupo Espanol de Investigacion en Cancer de Mama | Roche H.,Institute Claudius Regaud | Pinter T.,Petz Aladar Megyei Oktato Korhaz | Crown J.,Petz Aladar Megyei Oktato Korhaz | And 24 more authors.
The Lancet Oncology | Year: 2011

Background: Vascular endothelial growth factor (VEGF) has a crucial role in angiogenesis, and is a valid target in metastatic breast cancer. Motesanib is an investigational oral inhibitor of VEGF receptors. We aimed to determine whether treatment with motesanib plus paclitaxel is better than placebo plus paclitaxel in patients with HER2-negative locally recurrent or metastatic breast cancer. Methods: Between Dec 1, 2006, and July 4, 2008, patients with untreated HER2-negative metastatic breast cancer were randomly assigned (using a randomisation list created by personnel not associated with the study) in a 1:1:1 ratio to paclitaxel (90 mg/m2 on days 1, 8, and 15 every 3 weeks) plus either masked motesanib 125 mg orally once per day (n=91), masked placebo orally once per day (n=94), or open-label bevacizumab 10 mg/kg intravenously on days 1 and 15 of each 28-day cycle (n=97), after stratification according to adjuvant or neoadjuvant chemotherapy (taxane-containing regimens vs other regimens vs none), number of metastatic sites (<3 vs ≥3), and hormone receptor status (positive vs negative). Placebo was provided as a replica of motesanib 25 mg tablets. The primary endpoint was objective response rate (ORR) based on the population as assigned to treatment. This trial is registered with ClinicalTrials.gov, number NCT00356681. Findings: ORRs for the motesanib group and the placebo group did not differ significantly (49% vs 41%; absolute difference 8% [95% CI -6 to 22]; p=0·31). The ORR in the bevacizumab group (52%) was similar to that in the motesanib group. The most common grade 3 or higher adverse events included diarrhoea (18 of 92 patients in the motesanib group, none of 89 patients in the placebo group, and four of 96 patients in the bevacizumab group), fatigue (11, eight, and six), hypertension (11, one, and seven), and peripheral sensory neuropathy (ten, seven, and 19). More patients in the motesanib group had serious adverse events than did those in the placebo or bevacizumab groups (34, 26, and 21 patients, respectively); the most common of these in the motesanib group were gastrointestinal in nature. Interpretation: Data from this trial do not support the further investigation of motesanib at this dose and schedule in this population. Funding: Amgen. © 2011 Elsevier Ltd.

Eiermann W.,Red Cross | Eiermann W.,All Ireland Co operative Oncology Research Group | Eiermann W.,Hospital Universitario San Carlos | Eiermann W.,Mount Medical Center | And 212 more authors.
Journal of Clinical Oncology | Year: 2011

Purpose: Anthracyclines, taxanes, and alkylating agents are among the most active agents in treatment of adjuvant breast cancer (BC), but the optimal schedule for their administration is unknown. We performed an adjuvant trial to compare the sequential regimen of doxorubicin with cyclophosphamide (AC) followed by docetaxel (ie, AC>T) with the combination regimen of TAC. Patients and Methods: Women with node-positive, human epidermal growth factor receptor 2-nonamplified, operable BC were stratified by number of axillary nodes and hormone receptor status and were randomly assigned to adjuvant chemotherapy with six cycles of TAC (75/50/500 mg/m 2 every 3 weeks) or four cycles of AC (60/600 mg/m 2 every 3 weeks) followed by four doses of docetaxel at 100 mg/m 2 every 3 weeks (AC>T). After completion of chemotherapy, radiation therapy was given as indicated, and patients with hormone receptor (HR) -positive disease received adjuvant hormonal therapy with tamoxifen and/or aromatase inhibitors. Results: In 30 months, 3,298 patients were enrolled (n = 1,649 in each arm). The major baseline characteristics were well balanced between the groups. At a median follow-up of 65 months, estimated 5-year disease-free survival rates were 79% in both groups (log-rank P = .98; hazard ratio [HR], 1.0; 95%CI, 0.86 to 1.16), and 5-year overall survival rates for both arms were 88% and 89%, respectively (log-rank P = .37; HR, 0.91; 95% CI, 0.75 to 1.11). TAC was associated with more febrile neutropenia and thrombocytopenia, and AC>T was associated with more sensory neuropathy, nail changes, and myalgia. The incidence of neutropenic infection was similar in both groups. Conclusion: The sequential and combination regimens incorporating three drugs were equally effective but differed in toxicity profile. © 2011 by American Society of Clinical Oncology.

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