Biomedical subjects

Hans Bojar

Publications and source records attributed to Hans Bojar.

17 recordsLinked to original sources

PubMed2006

Gene expression in acute Stanford type A dissection: a comparative microarray study.

BACKGROUND: We compared gene expression profiles in acutely dissected aorta with those in normal control aorta. MATERIALS AND METHODS: Ascending aorta specimen from patients with an acute Stanford A-dissection were taken during surgery and compared with those from normal ascending aorta from multiorgan donors using the BD Atlas Human1.2 Array I, BD Atlas Human Cardiovascular Array and the Affymetrix HG-U133A GeneChip. For analysis only genes with strong signals of more than 70 percent of the mean signal of all spots on the array were accepted as being expressed. Quantitative real-time polymerase chain reaction (RT-PCR) was used to confirm regulation of expression of a subset of 24 genes known to be involved in aortic structure and function. RESULTS: According to our definition expression profiling of aorta tissue specimens revealed an expression of 19.1% to 23.5% of the genes listed on the arrays. Of those 15.7% to 28.9% were differently expressed in dissected and control aorta specimens. Several genes that encode for extracellular matrix components such as collagen IV alpha2 and -alpha5, collagen VI alpha3, collagen XIV alpha1, collagen XVIII alpha1 and elastin were down-regulated in aortic dissection, whereas levels of matrix metalloproteinases-11, -14 and -19 were increased. Some genes coding for cell to cell adhesion, cell to matrix signaling (e.g., polycystin1 and -2), cytoskeleton, as well as several myofibrillar genes (e.g., alpha-actinin, tropomyosin, gelsolin) were found to be down-regulated. Not surprisingly, some genes associated with chronic inflammation such as interleukin -2, -6 and -8, were up-regulated in dissection. CONCLUSION: Our results demonstrate the complexity of the dissecting process on a molecular level. Genes coding for the integrity and strength of the aortic wall were down-regulated whereas components of inflammatory response were up-regulated. Altered patterns of gene expression indicate a pre-existing structural failure, which is probably a consequence of insufficient remodeling of the aortic wall resulting in further aortic dissection.

Journal Article↗

PubMed2006

STAT5 phosphorylation in malignant melanoma is important for survival and is mediated through SRC and JAK1 kinases.

Altered signaling pathways are key regulators of cellular functions in tumor cells. Constitutive activation of signal transducer and activator of transcription (STAT)3 and -5 may be involved in tumor formation and progression. We have investigated the role of STAT5 in cutaneous melanoma metastases using various RNA and protein techniques. In melanoma specimens, Stat5b transcripts were upregulated approximately 3.8-fold. In 13 of 21 (62%) human melanoma metastases, STAT5 was phosphorylated in comparison to normal human melanocytes and benign nevi. The STAT5 target gene Bcl-2 was frequently upregulated. The investigation of the underlying mechanism revealed specific STAT5 activation by recombinant human epidermal growth factor (rEGF). rEGF-induced activation of STAT5 occurred in vitro through the non-receptor tyrosine kinases transforming gene (src) of Rous Sarcoma virus and Janus kinase 1. Inhibition of Stat5b expression by small interfering RNA strongly reduced the expression of Bcl-2 and led to decreased cell viability and increased apoptosis in the melanoma cell lines A375 and BLM. Transfection with dominant-negative Stat5b caused enhanced cell death and G1 arrest in A375 cells. Our study identifies phosphorylated STAT5 in melanoma and shows regulation through rEGF; STAT5 may thus act as a survival factor for growth of human melanoma and may represent a potential target for molecular therapy.

Aged↗

PubMed2006

Breast cancer expression profiling: the impact of microarray testing on clinical decision making.

The available clinical prognostic tools show an obvious limitation in predicting the outcome of breast cancer patients, and pathological features cannot classify tumours accurately. Microarray-based molecular classification of breast tumours or selection of gene expression panels to improve risk prediction or treatment outcomes are thought to be theoretically superior to established clinical and pathological criteria, based on guidelines such as the St Gallen and National Institute of Health consensus, or which use specific prognostic tools, such as the Nottingham Prognostic Index or Adjuvant-Online algorithm. Although two diagnostic tests based on gene expression profiling of breast cancer are commercially available, a new molecular classification and molecular forecasting of breast cancer based on expression profiling cannot outperform the standard tumour diagnostic at present. This review focuses on some important problems in the practical application of molecular profiling of breast cancer for clinical purposes.

Breast Neoplasms↗

PubMed2005

Predictors of primary breast cancers responsiveness to preoperative epirubicin/cyclophosphamide-based chemotherapy: translation of microarray data into clinically useful predictive signatures.

BACKGROUND: Our goal was to identify gene signatures predictive of response to preoperative systemic chemotherapy (PST) with epirubicin/cyclophosphamide (EC) in patients with primary breast cancer. METHODS: Needle biopsies were obtained pre-treatment from 83 patients with breast cancer and mRNA was profiled on Affymetrix HG-U133A arrays. Response ranged from pathologically confirmed complete remission (pCR), to partial remission (PR), to stable or progressive disease, "No Change" (NC). A primary analysis was performed in breast tissue samples from 56 patients and 5 normal healthy individuals as a training cohort for predictive marker identification. Gene signatures identifying individuals most likely to respond completely to PST-EC were extracted by combining several statistical methods and filtering criteria. In order to optimize prediction of non responding tumors Student's t-test and Wilcoxon test were also applied. An independent cohort of 27 patients was used to challenge the predictive signatures. A k-Nearest neighbor algorithm as well as two independent linear partial least squares determinant analysis (PLS-DA) models based on the training cohort were selected for classification of the test samples. The average specificity of these predictions was greater than 74% for pCR, 100% for PR and greater than 62% for NC. All three classification models could identify all pCR cases. RESULTS: The differential expression of 59 genes in the training and the test cohort demonstrated capability to predict response to PST-EC treatment. Based on the training cohort a classifier was constructed following a decision tree. First, a transcriptional profile capable to distinguish cancerous from normal tissue was identified. Then, a "favorable outcome signature" (31 genes) and a "poor outcome signature" (26 genes) were extracted from the cancer specific signatures. This stepwise implementation could predict pCR and distinguish between NC and PR in a subsequent set of patients. Both PLS-DA models were implemented to discriminate all three response classes in one step. CONCLUSION: In this study signatures were identified capable to predict clinical outcome in an independent set of primary breast cancer patients undergoing PST-EC.

Journal Article↗

PubMed2004

Immediate gene expression changes after the first course of neoadjuvant chemotherapy in patients with primary breast cancer disease.

PURPOSE: Our goal was to identify genes undergoing expressional changes shortly after the beginning of neoadjuvant chemotherapy for primary breast cancer. EXPERIMENTAL DESIGN: The biopsies were taken from patients with primary breast cancer prior to any treatment and 24 hours after the beginning of the neoadjuvant chemotherapy. Expression analyses from matched pair samples representing 25 patients were carried out with Clontech filter arrays. A subcohort of those 25 paired samples were additionally analyzed with the Affymetrix GeneChip platform. All of the transcripts from both platforms were queried for expressional changes. RESULTS: Performing hierarchical cluster analysis, we clustered pre- and posttreatment samples from individual patients more closely to each other than the samples taken from different patients. This reflects the rather low number of transcripts responding directly to the drugs used. Although transcriptional drug response occurring during therapy differed between individual patients, two genes (p21(WAF1/CIP1) and MIC-1) were up-regulated in posttreatment samples. This could be validated by semiquantitative and real-time reverse transcription-PCR. Partial least- discriminant analysis based on approximately 25 genes independently identified by either Clontech or Affymetrix platforms could clearly discriminate pre- and posttreatment samples. However, correlation of certain gene expression levels as well as of differential patterns and clusters as determined by a different platform was not always satisfying. CONCLUSIONS: This study has demonstrated the potential of monitoring posttreatment changes in gene expression as a measure of the pharmacodynamics of drugs. As a clinical laboratory model, it can be useful to identify patients with sensitive and reactive tumors and to help for optimized choice for sequential therapy and obviously improve relapse- free and overall survival.

Adult↗

PubMed2004

Identifying superficial, muscle-invasive, and metastasizing transitional cell carcinoma of the bladder: use of cDNA array analysis of gene expression profiles.

PURPOSE: Expression profiling by DNA microarray technology permits the identification of genes underlying clinical heterogeneity of bladder cancer and which might contribute to disease progression, thereby improving assessment of treatment and prediction of patient outcome. EXPERIMENTAL DESIGN: Invasive (20) and superficial (22) human bladder tumors from 34 patients with known outcome regarding disease recurrence and progression were analyzed by filter-based cDNA arrays (Atlas Human Cancer 1.2; BD Biosciences Clontech) containing 1185 genes. For 9 genes, array data were confirmed using real-time reverse transcription-PCR. Additionally, Atlas array data were validated using Affymetrix GeneChip oligonucleotide arrays with 22,283 human gene fragments and expressed sequence tags sequences in a subset of three superficial and six invasive bladder tumors. RESULTS: A two-way clustering algorithm using different subsets of gene expression data, including a subset of 41 genes validated by the oligonucleotide array (Affymetrix), classified tumor samples according to clinical outcome as superficial, invasive, or metastasizing. Furthermore, (a) a clonal origin of superficial tumors, (b) highly similar gene expression patterns in different areas of invasive tumors, and (c) an invasive-like pattern was observed in bladder mucosas derived from patients with locally advanced disease. Several gene clusters that characterized invasive or superficial tumors were identified. In superficial bladder tumors, increased mRNA levels of genes encoding transcription factors, molecules involved in protein synthesis and metabolism, and some proteins involved into cell cycle progression and differentiation were observed, whereas transcripts for immune, extracellular matrix, adhesion, peritumoral stroma and muscle tissue components, proliferation, and cell cycle controllers were up-regulated in invasive tumors. CONCLUSIONS: Gene expression profiling of human bladder cancers provides insight into the biology of bladder cancer progression and identifies patients with distinct clinical phenotypes.

Algorithms↗

PubMed2003

Non-small lung cancer cells are prime targets for p53 gene transfer mediated by a recombinant adeno-associated virus type-2 vector.

In this study, we elucidated the potential of recombinant adeno-associated virus type-2 (rAAV-2) vectors for lung cancer gene therapy. Cell lines of the three major histological subtypes of non-small cell lung cancer (NSCLC) were highly susceptible for rAAV-2 showing transduction rates between 63.4 and 98.9%. In contrast, cell lines of small cell carcinomas were resistant to rAAV-2 infection. For restoration of p53 function in p53 deficient NSCLC, a rAAV-2 vector was constructed containing wt p53 cDNA. Following transduction with rAAV-p53, cell growth of all NSCLC cell lines was significantly reduced in a dose-dependent manner between 44 and 71.7% in comparison with rAAV-GFP transduced cells. The reduction of tumor cell growth was associated with increased apoptosis. Adding cisplatin to rAAV-p53-infected cells led to a significant growth inhibition between 81 and 91% indicating a synergistic effect between cisplatin and rAAV-p53. Interestingly, the tumor cells surviving cisplatin and rAAV-p53 treatment were inhibited in their ability to form colonies as reflected by a reduction of colony growth between 57 and 90.4%. In conclusion, rAAV-2 vectors exhibit a strong tropism for NSCLC. Successful inhibition of tumor cell growth following transduction with a rAAV-p53 vector underlines the potential role of rAAV-2 in cancer gene therapy.

Adenoviridae↗

PubMed2002

Analysis of BRCA1, TP53, and TSG101 germline mutations in German breast and/or ovarian cancer families.

About 5%-10% of breast cancers are considered to be hereditary and associated with germline mutations of specific genes. As yet, the most frequently affected genes identified are BRCA1 and BRCA2, but also other genes such as TP53 are supposed to influence the predisposition toward breast cancer. In the present study, we analyzed patients of 19 German families with early onset breast cancer and/or a family history of breast and/or ovarian cancer for the presence of mutations in BRCA1 and TP53. In addition, we screened for germline mutations in the putative tumor suppressor gene TSG101. For this purpose we used direct sequence analysis of the entire coding regions for all three genes and, in the case of BRCA1, single-strand conformation polymorphism analysis and protein transcription-translation assays. We identified eight previously described polymorphisms and several aberrations in BRCA1: 1 unclassified missense mutation, 3 small protein truncating mutations, 1 novel pseudoexon, and 5 splicing variants. No mutation was detected in TP53. Analysis of TSG101 transcripts revealed an aberrant transcript in two breast cancer patients belonging to the same family, suggesting TSG101 as a predisposing gene in hereditary breast cancer.

Adult↗

PubMed2002

Gene expression profiling identifies significant differences between the molecular phenotypes of bone marrow-derived and circulating human CD34+ hematopoietic stem cells.

CD34+ hematopoietic stem cells are used clinically to support cytotoxic therapy, and recent studies raised hope that they could even serve as a cellular source for nonhematopoietic tissue engineering. Here, we examined in 18 volunteers the gene expressions of 1185 genes in highly enriched bone marrow CD34+ (BM-CD34+) or granulocyte-colony-stimulating factor-mobilized peripheral blood CD34+ (PB-CD34+) cells by means of cDNA array technology to identify molecular causes underlying the functional differences between circulating and sedentary hematopoietic stem and progenitor cells. In total, 65 genes were significantly differentially expressed. Greater cell cycle and DNA synthesis activity of BM-CD34+ than PB-CD34+ cells were reflected by the 2- to 5-fold higher expression of 9 genes involved in cell cycle progression, 11 genes regulating DNA synthesis, and cell cycle-initiating transcription factor E2F-1. Conversely, 9 other transcription factors, including the differentiation blocking GATA2 and N-myc, were expressed 2 to 3 times higher in PB-CD34+ cells than in BM-CD34+ cells. Expression of 5 apoptosis driving genes was also 2 to 3 times greater in PB-CD34+ cells, reflecting a higher apoptotic activity. In summary, our study provides a gene expression profile of primary human CD34+ hematopoietic cells of the blood and marrow. Our data molecularly confirm and explain the finding that CD34+ cells residing in the bone marrow cycle more rapidly, whereas circulating CD34+ cells consist of a higher number of quiescent stem and progenitor cells. Moreover, our data provide novel molecular insight into stem cell physiology.

Antigens, CD34↗

PubMed2002

Gene expression profiling of advanced head and neck squamous cell carcinomas and two squamous cell carcinoma cell lines under radio/chemotherapy using cDNA arrays.

BACKGROUND AND PURPOSE: The response of squamous cell carcinomas of the head and neck (HNSCC) to radio/chemotherapy is accompanied by complex changes in patterns of gene expression. It is highly probable that a better understanding of molecular and genetic changes can help to optimize the treatment of HNSCC. cDNA arrays provide a powerful tool for high-throughput monitoring of gene expression in small clinical specimens. MATERIALS AND METHODS: We used tumour biopsies from four patients with HNSCC which have been taken prior to and during radio/chemotherapy. The patterns of gene expression obtained from clinical samples were compared with gene expression profiles of two squamous cell carcinoma cell lines (FaDU and UD-7A). RESULTS: The experimental data analysis revealed changes in expression levels of several genes during radio/chemotherapy. Despite treatment, independent samples taken from the same cell line or tumour in situ were more similar to each other than either was to other specimens. The data indicate a high gene heterogeneity of HNSCC that is preserved during treatment. CONCLUSIONS: From our preliminary results we conclude that the cDNA array experimental approach can detect differences in gene expression between treated and untreated small tumour biopsies, as well as inter-individual differences in expression profiles between HNSCC tumours. The examination of a greater sample size will be needed to make this preliminary evaluation useful to elucidate the functional significance of individual genes which exhibit altered levels of expression under radiation therapy.

Carcinoma, Squamous Cell↗

PubMed2002

Interleukin-12 and interleukin-18 change ICAM-I expression, and enhance natural killer cell mediated cytolysis of human osteosarcoma cells.

Cytokines play important roles in the expression of adhesion molecules and the function of anti-tumor effector cells in the immune system. In this study, the influence of interleukin-12 (IL-12) and IL-18 on the expression of ICAM-1 and natural killer (NK)-cell mediated lysis in a human osteosarcoma cell line (HOS) was evaluated. ICAM-I expression of HOS cells were analyzed by flow cytometry following treatment with IL-12, IL-18 or both, and in co-cultures with peripheral lymphocytes. NK-cell activation in response to IL-12 and IL-18 was investigated by selective flow cytometry using propidium iodide. ICAM-1 expression on HOS cells was significantly enhanced by IL-12, but only when co-cultured in cell-to-cell contact with peripheral lymphocytes. Antibodies to interferon-gamma abrogated this effect. If HOS cells and peripheral lymphocytes were separated in co-cultures, IL-18 could substitute for cell-to-cell contact, facilitating IL-12-mediated enhancement of ICAM-1. Addition of IL-18 also enhanced NK-mediated cytolysis of HOS cells. These findings demonstrate that IL-12 can enhance the expression of ICAM-1 in the presence of IFN-gamma and, with IL-18, enhances NK anti-tumor activity. Immunomodulation via cytokine therapy may lead to improved eradication of chemotherapy-resistant osteosarcomas.

Cell Line, Tumor↗

PubMed2002

Effects of tamoxifen on human squamous cell carcinoma lines of the head and neck.

Tamoxifen (TAM) is a well-tolerated compound in the treatment of breast cancer and is primarily considered to act by competition with estrogen receptors (ER). Here we investigated the in vitro efficacy and potentially underlying mechanisms of TAM in established cell lines of squamous cell carcinomas of the head and neck (SCCHN). Using proliferation and apoptosis assays the antitumor activity of TAM in five SCCHN and the breast carcinoma line MCF-7 (positive control) was determined. MCF-7 was more sensitive to low-dose TAM (below 1 microM), whereas SCCHN showed significant growth inhibition at higher TAM concentrations (5-10 microM). Growth curve analysis and apoptosis assays were indicative for a cytostatic effect of low-dose TAM and high-dose TAM led to cell loss by apoptosis in sensitive SCCHN. In order to further characterize the observed antitumor effects we determined the amount of steroid hormone receptors with the dextran-coated charcoal method and immunocytochemistry. In addition, production of transforming growth factor (TGF-)-alpha, -beta1 and -beta2 was measured by ELISA, and protein kinase C (PKC) activity was assessed with a radioligand assay. Except MCF-7, none of the SCCHN lines was positive for ER. TAM caused decreased TGF-alpha and increased TGF-beta levels in MCF-7, but not in SCCHN supernatants. Furthermore, the antiestrogen reduced PKC activity in MCF-7, but not in SCCHN. In the present in vitro system, the observed antitumor activity of high-dose TAM in SCCHN cannot be explained by estrogen antagonism, alterations of TGF-alpha/beta levels or decreased PKC activity.

Antineoplastic Agents, Hormonal↗

PubMed2000

The Estrogen Receptor Paradox in Breast Cancer: Association of High Receptor Concentrations with Reduced Overall Survival.

Occasional reports have suggested an unfavorable effect of high estrogen receptor (ER) concentrations in primary breast cancer. In a population-based study we identified a subgroup explicitly exhibiting this seemingly paradoxical effect. ER concentrations were prospectively measured in a single laboratory by multipoint DCC assay. The relative risk of death in relation to the concentration of the interval-scaled variables ER and PgR was continually estimated by serial Cox regression analyses. Thus we circumvented loss of information due to primary categorization and avoided assumptions about relations between factor and risk. Based on 2,735 consecutively accrued primary breast cancer cases (median follow-up 56 months) we identified node-negative patients up to 60 years of age as the relevant subpopulation. High (>/=300 fmol/mg protein) ER concentrations exhibited an even more unfavorable impact (p < 0.03) on overall survival than ER concentrations of less than 10 fmol/mg protein. The well-known association of age and ER concentration was definitely excluded as an underlying biological cause for the increased risk. Differences in the distribution of other prognostic factors (HER-2/neu, Ki-67, DNA ploidy) were also excluded. As we observed a preponderance of pT2 tumors in the high ER group, we repeated the analysis, selectively focusing on pT2 tumors in the relevant subgroup, but the effect remained unchanged. In contrast, node-positive patients adjusted for age significantly (p = 0.02) profited from high ER concentrations as compared to the ER-negative group. As the phenomenon did not occur in node-positive patients, receptor defects in the high-ER group seem unlikely. To the contrary, we suspect that ER overexpressing cells are hypersensitive even to low levels of estrogens. Once they have sneaked past local barriers prior to primary surgery, they may cause early death in the absence of appropriate adjuvant endocrine therapy.

Journal Article↗

PubMedDate not supplied

Interleukin-12 and interleukin-18 induce indoleamine 2,3-dioxygenase (IDO) activity in human osteosarcoma cell lines independently from interferon-gamma.

PURPOSE: In this study we evaluated the ability of inducing activation of the enzyme indoleamine 2,3-dioxygenase (IDO) for the development of a new adjuvant therapy of osteosarcomas. The pathway that has described in the literature states that IDO activity is elevated by IFN-gamma. This mechanism is important because the increased IDO activation induces an intracellular degradation of the essential amino acid tryptophan and thereby activates apoptosis in human osteosarcoma cells. MATERIALS AND METHODS: Four different well-established human osteosarcoma cell lines (MNNG/HOS, KHOS-240, HOS and MG-63) were investigated in vitro. Several cytokines were tested for their ability to induce IDO activity. However special emphasis was placed to evaluate the synergistic effects of Interleukin-12 (IL-12) in combination with Interleukin-18 (IL-18). In the first series of experiments IDO induction was investigated by direct application of the cytokines IFN-gamma, TNF-alpha, IL-12 and IL-18 in different concentrations. Secondly, the increase of IDO expression from osteosarcoma cell lines was analysed in the presence of activated lymphocytes with or without cytokine application. RESULTS: Our results demonstrated that the combined application of IL-12 and IL-18 enhanced IDO activity in the human osteosarcoma cell lines HOS and MG-63, in the presence of activated lymphocytes. In the absence of activated lymphocytes, no significant enhancement could be detected. In all our experiments the increase in IDO expression was only partly inhibited by blocking INF-gamma. CONCLUSION: The presented study demonstrates that IL-12 and IL-18, or even more a combined application of both cytokines, induce IDO expression besides the known pathway via IFN-gamma. These mechanisms have been shown herein for the first time in human osteosacoma cell lines. Since IDO expression could still be shown after complete blocking of IFN-gamma, we conclude that at least a second pathway is responsible for inducing IDO activity. This is in contrast to the present knowledge about IDO activation.

Bone Neoplasms↗

PubMedDate not supplied

rIL-18 triggered gene therapy based on a transduction with the IL-12 plasmid: a new option as immuno-therapy for osteosarcoma?

Gene therapy is a promising new method to treat tumors locally. Immuno-therapy for treatment of osteosarcomas is one option for hopefully improving the survival rate of patients with this tumor. Transduction of OS cells with the pCMV-IL-12neo plasmid induced a significant increase in IFN-gamma expression by mononuclear cells. This is known to induce antitumor effects mediated by the immune system. In combination with an administration of rIL-18, the IFN-gamma increase was multiplied in a dose-dependent manner. This study demonstrated that osteosarcoma cells can be targeted effectively in vitro by plasmids encoding the IL-12 gene. Considering the synergistic pathways it is reasonable to combine a local, gene transfer based on IL-12 with a rIL-18 administration to trigger the potentially promising immuno-effects for adjuvant treatment of osteosarcomas.

Animals↗

PubMedDate not supplied

Immunotherapy by gene transfer with plasmids encoding IL-12/IL-18 is superior to IL-23/IL-18 gene transfer in a rat osteosarcoma model.

BACKGROUND: Osteosarcomas are primary malignant tumors of bone or soft parts arising from bone-forming mesenchymal cells. Despite dramatic therapeutic advances, namely neo-adjuvant and adjuvant chemotherapy, progress is at a plateau. Cytokine-mediated gene therapy might represent a further advance in the therapy of the osteosarcoma. MATERIALS AND METHODS: We transfected UMR 108 osteosarcoma cells with different plasmids encoding IL-12, IL-23, proIL-18 and ICE (Interleukin-converting enzyme). IFN-gamma induction, which is known to induce antitumor effects mediated by the immune system, and cytotoxic effects of various cytokine combination were investigated. RESULTS: Our results show that local secretion of IL-12 by UMR 108 cells led to an induction of cytotoxic effects mediated by mononuclear cells, which were enhanced by additional administration of recombinant IL-18. In contrast to IL-18, IL-23 showed a moderate increase of IFN-gamma induction when transfected alone and could only slightly increase the IFN-gamma induction mediated by IL-12. IL-18 enhanced IFN-gamma induction when applied alone and was able to increase the IFN-gamma production that was induced by IL-12. CONCLUSION: IL-23 seems to be a less effective immuno-therapeutic for adjuvant treatment of osteosarcomas than IL-12 and IL-18, when taking only IFN-gamma induction into consideration.

Animals↗

PubMedDate not supplied

Predictive biological markers for response of invasive breast cancer to anthracycline/cyclophosphamide-based primary (radio-)chemotherapy.

BACKGROUND: The role of biological markers for the prediction of neoadjuvant chemotherapy and radio-chemotherapy may be evaluated using pathological complete response [pCR] in patients with invasive breast cancer. MATERIALS AND METHODS: To investigate this, pre-treatment biopsies from 517 patients with locally advanced breast cancer were analyzed for expression of estrogen receptor [ER], progesterone receptor [PgR], Her-2/neu, epidermal growth factor receptor [EGF-R], p53, Bcl-2 and MIB-1 by immunohistochemistry [IHC], and these data were compared to the pathological response after preoperative epirubicine/cyclophosphamide [EC] chemotherapy (+/- radiotherapy). RESULTS: pCR was more frequent (28.30%, 56/198) in tumors that received radio-chemotherapy compared to chemotherapy alone (11.9%, 38/319, p < 0.0001). Patients with high grading, lower ER, PgR, Bcl-2 or a higher proliferation had a significantly greater benefit from chemotherapy. The overexpressions of Her2/neu or EGF-R were weakly correlated to pCR, while p53 staining did not have any predictive value. Younger patients, with negative PgR and high proliferation index, had the highest benefit from EC therapy (56% pCR). The different multivariate indices of binary regression, PLS-DA and SIMCA, had similar predictive quality and were slightly superior to univariate factors. CONCLUSION: This study emphasizes the value of traditional biological markers and Bcl-2 for use in the individual selection of a primary therapy regimen.

Adult↗