The role of topoisomerase IIalpha and HER-2 in predicting sensitivity to anthracyclines in breast cancer patients.
ABSTRACT Human epidermal growth factor receptor-2 (HER-2) and topoisomerase IIalpha (topo IIalpha) co-inhabit chromosome 17. In the search for predictive biomarkers to refine clinical prescription of cytotoxic agents, both HER-2 and topo IIalpha are under exploration for their potential role in identifying individuals with early breast cancer who may benefit from anthracycline therapy. Whilst recent meta-analyses support a predictive role for HER-2 amplification, it remains unclear whether HER-2 is the critical biomarker or whether it is a surrogate marker for topo IIalpha alteration, a known drug target of anthracyclines. The major limitation in considering HER-2 as a single marker is heterogeneity within the subgroups of HER-2 positive and HER-2 negative disease. For topo IIalpha, current data is inconclusive. Issues plaguing this field are technical variability in marker definition, complex regulation pathway of topo IIalpha and lack of prospective, adequately powered studies. With current evidence, neither HER-2 nor topo IIalpha gene status can be considered clinically valuable markers for anthracycline benefit. This paper will focus on issues relating to reliable detection and predictive analyses of HER-2 and topo IIalpha, and highlight potential developments in improving individualized approach to anthracycline use in early breast cancer patients.
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ABSTRACT: Background The combination of trastuzumab and chemotherapy is currently considered the standard of care for locally advanced/operable HER2-positive breast cancer patients. Herein, the potential correlation between pathological complete response (pCR) and the overexpression of Hsp90, Ki67, and the amplification of Topoisomerase II-α(TOPO2A) were investigated in a series of patients undergone neoadjuvant treatment. Methods HER2–amplified patients undergone neoadjuvant trastuzumab-docetaxel were gathered. Baseline and post-surgical Hsp90 immuno-score, Ki67 proliferation index and TOPO2A amplification were determined together with classical clinical-pathological predictors and correlated with pCR and imaging data. Results Twenty-four patients were evaluated for response; pCR, clinical and radiological response, were found in 4 (16.7%; 95% CI 1.7-31.5), 9 (37.5%; 95% CI 18.1-56.8), and 6 (25.0%; 95% CI 7.6-42.3) patients, respectively. pCR was significantly higher in premenopausal (60.0% versus 5.3%, p=0.02) or negative hormonal receptors patients (50.0% versus 5.6%, p=0.03). A trend for patients with high Ki67 and TOPO2A/HER2 co-amplification were found (21.1% versus none, p=0.54; 50.0% versus 12%, p=0.16). pCR was significantly higher in patients with Hsp90 score 3+, in comparison with score 2+ and score 1+ patients (50.0% versus 14.3% versus none, p=0.05). After treatment, a statistically significant lower Ki67 staining (30.0% versus 17.5%, p=0.005), and a trend for the decreased expression of high (score 3+) and moderate (score 2+) Hsp90 immunostaining (McNemar p=0.25, Wilcoxon-Mann-Whitney p=0.08) were found. Conclusions Although underpowered, our data suggest that HER2-positive breast cancer patients overexpressing Hsp90 should be investigated as a ‘newer’ molecular subtype with significantly higher chance of pCR when receiving anti-Her2 agents.Clinical Breast Cancer 06/2014; 15(1). · 2.63 Impact Factor
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ABSTRACT: Introduction. Circulating tumor cells (CTCs) detection prior to and during therapy is considered as an independent and strong prognostic marker. The present study was designed to isolate and characterize CTCs in peripheral blood of an early breast cancer (BC) patient as a biomarker for monitoring treatments efficacy. Materials and methods. In total, 54 early breast cancer patients undergoing neoadjuvant and/or adjuvant chemotherapy regimens were enrolled into a prospective study. CTC detection in blood was performed by AdnaTest BreastCancer(™) (AdnaGen AG, Germany), which is based on the detection of EpCAM, HER2 and MUC1 specific transcripts in enriched CTC-lysates. Additionally, cDNA from isolated CTCs and PBMC was used for qPCR gene expression analysis of TOP1, TOP2A, CTSD, ST6, CK19 and reference gene actin. Results. We found that CTCs can be detected in the peripheral blood of approximately 31% of early stage breast cancer patients. The presence of CTCs was detected in 36% ER positive, 32% PR positive and 30% HER2 positive patients. We found no correlation between CTCs and tumor size, tumor grade, histological grade and receptor status. Only 7% of all patients remained CTCs positive after adjuvant therapy. Gene expression analysis revealed a particular heterogeneity of the studied genes. Conclusions. In conclusion, CTC detection may be a promising early marker of disease progression potentially enhancing the difficult therapeutic decisions. Further studies should, however, clearly demonstrate its utility for both the prediction of outcome and monitoring the effect of treatment.Scandinavian journal of clinical and laboratory investigation 12/2013; · 1.38 Impact Factor
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ABSTRACT: DNA topoisomerases are essential enzymes that control the topological state of DNA replication during mitosis. These enzymes are classified based on their mechanisms and physical properties. During mitosis, superhelical DNA must be unwound or relaxed by DNA topoisomerases prior to a decoding step by DNA processing enzymes, such as DNA polymerase and RNA polymerase. By blocking the reaction of resealing the breaks in the DNA ultimately can result in cellular death. Compounds that inhibit the catalytic function of these enzymes can serve as potential anticancer agents. DNA topoisomerases are found in nature and used as high quality and well-validated targets for the screening of potential anticancer agents. Our current work focuses on determining potential anticancer agents from natural resources using DNA topoisomerases as the screening targets. Large scale production of these enzymes using recombinant DNA technology in our academic laboratory is utilised to avoid dependence on expensive commercially available enzymes. The in-house produced enzymes can also be used to enhance our research in the field of molecular medicine by providing an enzyme source that can be used to screen potential anticancer agents, and for other newly developed diagnostic and medical research projects in the near future as well as a step in moving our efforts into the industrial sector.Electronic Journal of Biotechnology 11/2013; 16(6):18-18. · 0.65 Impact Factor