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Nielsen K.V.,Dako Denmark | Ejlertsen B.,Copenhagen University | Ejlertsen B.,Danish Breast Cancer Cooperative Group DBCG Registry | Moller S.,Danish Breast Cancer Cooperative Group DBCG Registry | And 6 more authors.
Molecular Oncology | Year: 2012

The clinical benefit of anthracyclines has been connected to HER2 status, TOP2A status and centromere 17 copy numbers (CEN-17). Data from a clinical trial randomizing patients to anthracyclines was used to assess whether the number of CEN-17 in breast cancers may predict incremental responsiveness to anthracyclines besides what is obtained when used relatively to TOP2A and HER2. As cut sections of paraffin-embedded tissue are prone to truncation of nuclei, strict definition of ploidy levels is lacking. We therefore used normal breast tissue to assist define ploidy levels in cut sections. Fluorescence in situ hybridization (FISH) with centromere 17 (CEN-17) and TOP2A was performed on 120 normal breast specimens. The diploid CEN-17 copy number was reduced from the expected two signals in whole nuclei to an average of 1.68 signals per nucleus in cut sections of normal breast. Ploidy levels determined in normal breast were applied to data on 767 patients with known HER2 and TOP2A status randomized to anthracyclines in the DBCG 89D trial. CEN-17 ploidy levels were in cut sections from the 767 breast cancer patients established as: Haploid: ≤1.25 (10%), diploid: 1.26-2.09 (60%), triploid: 2.10-2.93 (21%), tetraploid: 2.94-3.77 (5%) or higher ploidy: ≥3.78 (4%). Amplification of HER2 and deletion of TOP2A were frequently observed in tumors with a high ploidy level. In univariate analyses increasing ploidy was associated with decreased disease-free survival (DFS) (P=0.0001) and overall survival (OS) (P<0.0001). However, in multivariate analysis CEN-17 was not established as an independent prognostic factor and was neither a statistically significant predictor of benefit from CEF (Cyclophosphamide/Epirubicin/5-Fluorouracil) compared to CMF (Cyclophosphamide/Methotrexate/5-Fluorouracil) (P Interaction 0.39 for DFS and 0.67 for OS). In conclusion, CEN-17 levels do not independently from TOP2A/CEN-17 ratio identify breast cancer patients who achieve an incremental benefit from adjuvant anthracyclines. © 2011 Federation of European Biochemical Societies. Source

Nielsen K.V.,Dako Denmark | Muller S.,Dako Denmark | Moller S.,Danish Breast Cancer Cooperative Group DBCG Registry | Schonau A.,Dako Denmark | And 4 more authors.
Molecular Oncology | Year: 2010

Copy number changes in TOP2A have frequently been linked to ERBB2 (HER2) amplified breast cancers. To study this relationship, copy number changes of ERBB2 and TOP2A were investigated by fluorescence in situ hybridization (FISH) in two cell lines; one characterized by having amplification of both genes and the other by having amplification of ERBB2 and deletion of TOP2A. The characteristics are compared to findings on paired ERBB2 and TOP2A data from 649 patients with invasive breast cancer from a previously published biomarker study. The physical localization of FISH signals in metaphase spreads from cell lines showed that simultaneous amplification is not a simple co-amplification of a whole amplicon containing both genes. Most gene signals are translocated to abnormal marker chromosomes. ERBB2 genes but not TOP2A genes are present in tandem amplicons, leading to a higher ERBB2 ratio. This observation was confirmed by patient FISH data: among 276 (43% of all patients) abnormal tumors, 67% had different ERBB2 and TOP2A status. ERBB2 amplification with normal TOP2A status was found in 36% of the abnormal tumors (15% of all patients). Simultaneous amplification of both genes was found in 28% of the abnormal tumors (12% of all patients) while TOP2A deletion and ERBB2 amplification was observed in 16% of the abnormal cases (8% of all patients). A small number of tumors had TOP2A amplification (4%) or deletion (6%) without simultaneous changes of the ERBB2 gene. ERBB2 deletion was also observed (5%) but only in tumors with simultaneous TOP2A deletion. The average gene/reference ratio was significantly different: 5.0 for TOP2A but 7.2 for ERBB2 in the amplified tumors (P < 0.01). Amplification of the two genes may be caused by different mechanisms, leading to higher level of amplification for ERBB2 compared to TOP2A. In the majority of breast cancer patients, simultaneous aberration of ERBB2 and TOP2A is not explained by simple co-amplification. © 2009 Federation of European Biochemical Societies. Source

Jorgensen C.L.T.,Copenhagen University | Ejlertsen B.,Danish Breast Cancer Cooperative Group DBCG Registry | Bjerre K.D.,Danish Breast Cancer Cooperative Group DBCG Registry | Balslev E.,Copenhagen University | And 2 more authors.
BMC Cancer | Year: 2013

Background: The purpose of the present study was to retrospectively evaluate whether copy number changes of the genes encoding the ribonucleotide reductase subunit M1 (RRM1) and/or subunit M2B (RRM2B) predict sensitivity to gemcitabine administered in combination with docetaxel compared to single agent docetaxel in advanced breast cancer patients.Methods: Primary tumor samples from patients randomly assigned to gemcitabine plus docetaxel or docetaxel alone were analyzed for RRM1 and RRM2B copy number changes using Fluorescence In Situ Hybridization (FISH) technology with probes covering respectively RRM1 at 11p15.5 and a reference probe covering the centromere of chromosome 11 (CEN-11), and RRM2B at 8q22.3 and a reference probe covering the centromere of chromosome 8 (CEN-8). The assays were validated in a material of 60 normal breast samples. Time to progression (TTP) was the primary endpoint. Overall survival (OS) and response rate (RR) were secondary endpoints. Associations between RRM1/CEN-11 and/or RRM2B/CEN-8 ratios and time-to-event endpoints were analyzed by unadjusted and adjusted Cox proportional hazards regression models. Heterogeneity of treatment effects on TTP and OS according to gene status were investigated by subgroup analyses, and the Wald test was applied. All statistical tests were two-sided.Results: FISH analysis for both RRM1 and RRM2B was successful in 251 patients. RRM1 and RRM2B aberrations (deletions and amplifications) were observed in 15.9% and 13.6% of patients, respectively. RRM1 aberrations were associated with a decreased OS in the time interval 1.5-7.4 years (hazard ratio = 1.72, 95% confidence interval = 1.05-2.79, P = 0.03). RRM2B aberrations alone or in combination with RRM1 aberrations had no prognostic impact in terms of TTP or OS. RR was not different by gene status. No significant differences were detected in TTP or OS within subgroups according to gene status and chemotherapy regimen.Conclusions: This study demonstrated the presence of RRM1 and RRM2B copy number changes in primary breast tumor specimens. Nevertheless, we found no support of the hypothesis that aberrations of RRM1 or RRM2B, neither individually nor in combination, are associated with an altered clinical outcome following chemotherapy with gemcitabine in combination with docetaxel compared to docetaxel alone in advanced breast cancer patients. © 2013 Jørgensen et al.; licensee BioMed Central Ltd. Source

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