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ABSTRACT: The introduction of concepts proposing multiple cellular subgroups in the normal female breast leads to the hypothesis that distinct cellular phenotypes in the female breast give rise to different subtypes of breast carcinomas e.g. expressing ER, HER2 and EGFR differentially. Therefore, origin of breast carcinoma types may be based on the formation of a cancer prone field in which the committed progenitor cells pass mutations to their progenies, glandular as well as myoepithelial cells. The existence of such field within the human breast was inferred from the results on primary breast cancer obtained by PCR-based microsatellite analysis of allelic imbalance (AI) of the EGF receptor gene. Here, normal breast tissue shows egfr AI adjacent to breast cancer tissue also harboring egfr gene AI. The therapeutic implications of such a model are fundamental, as tumors may display different phenotypes which arise from transformation of different progenitor cells as well as from transformation of more differentiated progenies within a cancer prone field. Thereby they may show up with different clinical courses of the disease, higher rates of metastases and responses to therapy. In this review, we discuss this mechanism focusing on the EGF receptor as an example for regulators of progenitor cell growth in many tissues. Phylloides tumors serve as a putative model for embryonic differentiation stage ruled by EGFR signaling and give insights into the tumor-host-interaction. The inhibition of the EGF receptor by specific monoclonal antibodies (e.g. Erbitux) will give an answer in as far EGFR-signaling is decisive for the development of an invasive breast cancer. For this purpose new models have been inaugurated which vary in the EGF receptor gene dosage and protein expression. Moreover, we discuss the EGF receptor as a target for the treatment of pre-malignant lesions with a high risk for malignant growth, e.g. DCIS, which certainly will be detected more frequently by mammography screening programs soon.
Current cancer drug targets 09/2008; 8(5):431-45. · 5.13 Impact Factor
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ABSTRACT: Intratumor genetic heterogeneity, a well-known characteristic of numerous cancers, often confounds a precise diagnosis and leads to therapy resistance. This study deals with such chromosomal variability, which may be due to an inherent genetic instability affecting heterogeneity and clonal effects. Subpopulations of the breast cancer cell line MDA-MB-468 were isolated according to epidermal growth factor receptor (EGFR) expression by FACS. Whole genome profiling (CGH; mapping arrays) and determination of egfr gene amplification (fluorescence in situ hybridisation, FISH; qPCR) were done directly after sorting or after several passages of cell culture. Subpopulations differed in the amplification of the egfr-locus 7p11-14 showing egfr gene amplification rates of up to 60-fold in high-level expressing populations and less than 2-fold in low-level expressing populations. However, after several passages the original low-level cells showed a new amplification of the egfr gene, which was as heterogeneous as the original amplification detected in MDA-MB-468. Additional, spontaneously expressed fragile sites could be shown in FISH analyses which may affect cell culture heterogeneity. Understanding the precise chromosomal process would clarify mechanisms in vivo and improve both diagnosis and therapy of corresponding cancers.
Der Pathologe 09/2008; 29 Suppl 2:333-7. · 0.67 Impact Factor
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Annals of Oncology 08/2008; 19 Suppl 5:v44-7. · 6.43 Impact Factor
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ABSTRACT: Starke genomische Heterogenität von Tumoren erschwert nicht nur eine Diagnose, sondern könnte auch häufig zum Versagen von
Therapien führen. Ziel dieser Studie war es, chromosomale Veränderungen zu untersuchen, die eine solche Heterogenität bewirken.
Hierzu wurden Klone der Brustkrebszelllinie MDA-MB-468 isoliert, die sich in der Expression des epidermalen Wachstumsfaktor-Rezeptors
(EGFR, „Epidermal Growth Factor Receptor“) unterscheiden. Genomische Veränderungen dieser Klone wurden über CGH und Mapping-Arrays
dargestellt, die Amplifikationen des egfr-Gens mittels Fluoreszenz-in-situ-Hybridisierung (FISH) und qPCR. Die Klone zeigten direkt nach der Isolierung deutliche Unterschiede
im Grad der egfr-Amplifikation. Dabei fanden sich bis zu 60fache Amplifikationen bei den EGFR hoch exprimierenden Klonen und weniger als Verdoppelungen
bei schwach exprimierenden Zellen. Diese Unterschiede waren jedoch nach zahlreichen Zellkulturpassagen nicht mehr so deutlich,
da die schwach exprimierenden Klone eine neue Amplifikation des egfr-Gens zeigten. Diese Amplifikation war genauso heterogen wie die ursprüngliche. Ein genaueres Verständnis der Prozesse, die
hierzu führen, könnte auch die Mechanismen klären, die in vivo eine Rolle spielen und somit nicht nur die Diagnose, sondern auch die Therapie der entsprechenden Tumoren verbessern.
Intratumor genetic heterogeneity, a well-known characteristic of numerous cancers, often confounds a precise diagnosis and
leads to therapy resistance. This study deals with such chromosomal variability, which may be due to an inherent genetic instability
affecting heterogeneity and clonal effects. Subpopulations of the breast cancer cell line MDA-MB-468 were isolated according
to epidermal growth factor receptor (EGFR) expression by FACS. Whole genome profiling (CGH; mapping arrays) and determination
of egfr gene amplification (fluorescence in situ hybridisation, FISH; qPCR) were done directly after sorting or after several passages
of cell culture. Subpopulations differed in the amplification of the egfr-locus 7p11-14 showing egfr gene amplification rates of up to 60-fold in high-level expressing populations and less than 2-fold in low-level expressing
populations. However, after several passages the original low-level cells showed a new amplification of the egfr gene, which was as heterogeneous as the original amplification detected in MDA-MB-468. Additional, spontaneously expressed
fragile sites could be shown in FISH analyses which may affect cell culture heterogeneity. Understanding the precise chromosomal
process would clarify mechanisms in vivo and improve both diagnosis and therapy of corresponding cancers.
Der Pathologe 01/2008; 29:333-337. · 0.67 Impact Factor
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ABSTRACT: Various microsatellite and CGH studies in prostate cancer identify deletions on the short arm of chromosome 8 especially at band 8p21-22 searching for unknown putative tumor suppressor genes. By means of microsatellite markers several candidate genes were detected which may play different roles in early prostate cancer progression. We established a quantitative gene dosage PCR based on the real time PCR method serving the purpose of genomic fine mapping. Therefore we used 10 Assays-on Demand (ABI) for the detection of deletions located between and nearby the microsatellite markers D8S258 and NEFL spanning a genomic region of approximate 7 mbp. Comparative immunohistochemical analysis from tissue micro arrays (TMA) of 1122 independent cases followed. We were able to detect three clearly separated deletion intervals on 8p21-22. One on LZTS1, second on NEFL and third a deletion hot spot on LOXL2, which was affected in 72% of all investigated cases. Our comparative immunohistochemical TMA based studies demonstrate that LOXL2 is nearly lost in most prostate cancer tissues. LOXL2 catalyze the crosslinking of collagen and elastin in the extracellular matrix and it has been assumed that it is involved in tumor suppression and cell adhesion. LOXL2 is frequently expressed in proliferating tissues and shows a high expression in benign prostate tissue too. In prostate cancer the expression is positive correlated with the MIB1-score.
Verhandlungen der Deutschen Gesellschaft für Pathologie 02/2007; 91:302-7.
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ABSTRACT: New targeted cancer treatments acting against growth factor receptors such as the epidermal growth factor receptor (EGFR) necessitate selecting patients for treatment with these drugs. Besides carcinomas, soft tissue sarcomas (STS) express EGFR and might thereby be a promising target for this new therapeutic strategy.
To test and compare different EGFR antibodies to determine the frequency of EGFR expression in STS.
302 consecutive specimens of STS were examined using the tissue microarray technique. EGFR expression levels were assessed by immunohistochemistry using five different commercially available antibodies. Gene amplification status was measured by fluorescence in situ hybridisation (FISH). Immunoreactivity and amplification status were correlated with clinicopathological features and follow up data available in 163 cases.
EGFR expression frequency ranged between 0.3% and 52.9%, depending on the antibody and scoring method used. In all, 3.5% of the tumours showed egfr gene amplification by FISH, which correlated with EGFR expression for three antibodies. Only one antibody had independent prognostic value in multivariate analysis and correlated with an unfavourable outcome; egfr gene amplification status showed no correlation with clinical features.
Frequency of EGFR immunopositivity in STS strongly depends on the antibody used, and only one of five antibodies tested predicted an unfavourable clinical outcome. This indicates that choice of primary antibody and scoring system have a substantial impact on the determination of EGFR immunoreactivity.
Journal of Clinical Pathology 07/2006; 59(6):585-90. · 2.31 Impact Factor
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D Kemming,
U Vogt,
N Tidow,
C M Schlotter,
H Bürger,
M W Helms,
E Korsching,
A Granetzny,
A Boseila,
L Hillejan,
A Marra,
Y Ergönenc,
H Adigüzel, B Brandt
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ABSTRACT: Using semi-quantitative microarray technology, almost every one of the approximately 30 000 human genes can be analyzed simultaneously with a low rate of false-positives, a high specificity, and a high quantification accuracy. This is supported by data from comparative studies of microarrays and reverse-transcription PCR for established cancer genes including those for epidermal growth factor receptor (EGFR), human epidermal growth factor receptor-2 (HER2/ERBB2), estrogen receptor (ESR1), progesterone receptor (PGR), urokinase-type plasminogen activator (PLAU), and plasminogen activator inhibitor-1 (SERPINE1). As such, semi-quantitative expression data provide an almost completely comprehensive background of biological knowledge that can be applied to cancer diagnostics. In clinical terms, expression profiling may be able to provide significant information regarding (i) the identification of high-risk patients requiring aggressive chemotherapy; (ii) the pathway control of therapy predictive parameters (e.g. ESR1 and HER2); (iii) the discovery of targets for biologically rational therapeutics (e.g. capecitabine and trastuzumab); (iv) additional support for decisions about switching therapy; (v) target discovery; and (vi) the prediction of the course of new therapies in clinical trials. In conclusion, whole genome expression analysis might be able to determine important genes related to cancer progression and adjuvant chemotherapy resistance, especially in the context of new approaches involving primary systemic chemotherapy. In this review, we will survey the current progress in whole genome expression analyses for cancer prognosis and prediction. Special emphasis is given to the approach of combining biostatistical analysis of expression data with knowledge of biochemical and genetic pathways.
Molecular diagnosis & therapy 02/2006; 10(5):271-80. · 1.71 Impact Factor
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ABSTRACT: Reduction of the expression of catenin is a crucial step in the pathogenesis, progression and prognosis of many epithelial cancers including squamous cell carcinomas (SCCs). Catenin expression in oral carcinomas was evaluated in relation to clinico-pathological features in order to determine its value as a prognostic marker. Eighty-five patients with histologically proven T1/2 squamous cell carcinoma of the oral floor who underwent surgical treatment were eligible for the study. A tissue microarray consisting of multiple representative tissue cores of each carcinoma was composed. The expression levels of alpha, beta and gamma-catenins were determined immunohistologically. Correlation between clinical features and the expression of catenin proteins was evaluated statistically using Kaplan-Meier curves, log-rank tests and chi(2)-tests. Loss of alpha-catenin expression in carcinoma of the floor of the mouth correlated significantly with poor prognosis (P=0.05). Conversely, significantly reduced rates of lymph-node metastases were observed in alpha- and beta-catenin-positive T1 and T2 SCCs. Loss of gamma-catenin expression indicated a reduced survival rate in nodal-negative tumours (P=0.02). Catenin expression in carcinomas of the floor of the mouth seems to be a predictive parameter in the prognosis of T1 and T2 SSCs.
International Journal of Oral and Maxillofacial Surgery 01/2006; 34(8):907-11. · 1.51 Impact Factor
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B Brandt,
D Kemming,
J Packeisen,
R Simon,
M Helms,
U Feldmann,
A Matuschek,
C Kersting,
B Hinrichs,
J-M Bidart,
D Bellet,
K Bartkowiak,
N Dankbar,
T Dittmar,
G Sauter,
W Boecker,
H Buerger
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ABSTRACT: Early placenta insulin-like growth factor (EPIL) is expressed by a subpopulation of the Her2-positive SKBR3 breast cancer cell line displaying high motility and transendothelial invasiveness in vitro, as recently shown by our group. As a consequence of this, we established cellular models by generating an EPIL-overexpressing SKBR3 cell line, knocked down EPIL by adding specific small interfering RNA (siRNA) to those cells and produced EPIL-enriched and depleted serum-free culture media. EPIL-expressing cells as well as EPIL-induced SKBR3 cells acquired a high capacity for transendothelial invasiveness. We observed a thin and outspread morphology caused by enhanced formation of lamellipodia, i.e. protrusions in the initial phase of motility. In parallel, Her2-positive MDAHer2 breast cancer cells also showed increased invasiveness when induced by EPIL-conditioned medium. A downstream signaling impact of EPIL could be observed in the form of reduced phosphorylation of Her2, erk1/2 and akt, while phospholipase Cgamma1 phophorylation remained unaffected. As an in vivo model for highly motile tumor cells, Paget's disease of the nipple showed simultaneous EPIL and Her2 expression upon immunohistochemical examination using specific antibodies. Such experimental data have been translated to a clinical setting by using a prognostic tissue microarray established from 603 breast cancer cases. Survival data analysis found a significant association between expression levels of EPIL and 5-year overall survival that was dose dependent: EPIL (negative) 84%, EPIL (moderately positive) 77%, EPIL (strongly positive) 48% (P < 0.005). One particular subgroup (7.6% of the cases with full clinical records) that comprised tumors simultaneously expressing EPIL and Her2 represented patients with the poorest 5-year overall survival. The results suggested that EPIL might be a cancer cell-produced growth factor that influences lateral Her2 signaling. Moreover, EPIL may be induced by factors apart from Her2 and may independently provide signaling for cancer invasion and motility.
Endocrine Related Cancer 12/2005; 12(4):823-37. · 4.36 Impact Factor
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ABSTRACT: Japanese and German breast cancer cases differ substantially in the frequency of egfr amplification.
To unravel further the cytogenetic differences between Japanese and German breast cancer cases.
Forty one Japanese breast cancer cases were evaluated by means of comparative genomic hybridisation (CGH). The results were compared with the CGH results from 161 German breast cancer cases.
The mean number of genetic alterations/case was significantly higher in German premenopausal patients with breast cancer than in their Japanese counterparts. Japanese breast cancer cases revealed a higher number of chromosome 17p losses. Losses of 8p were associated with oestrogen receptor (ER) negativity in Japanese patients with breast cancer, whereas in the German patients gains of 3q and 6q were associated with the lack of ER expression.
The interethnic differences of invasive breast cancer are reflected by cytogenetic aberrations, which are also associated with the differential expression of the ER.
Journal of Clinical Pathology 11/2005; 58(10):1101-3. · 2.31 Impact Factor
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ABSTRACT: Recently, we were able to show that the expression of early placenta insulin like growth factor (EPIL) is expressed by highly motile HER-2-positive breast cancer cells in vitro (Brandt et al., Cancer Res. 2002) in Paget cells in vivo and indicates a poor clinical prognosis, irrespectively of other prognostic factors.
In order to demonstrate the interplay between HER-2 and Epil we established a cellular model for high simultaneous Epil and HER-2 expression. The HER-2-positive breast cancer cell line SKBR3 was modified with an EPIL expression vector. In addition, an assay for the knockdown of EPIL-expression via siRNA was established. Erk1/2 expression was measured via Western Blot. The phenotype of the viable cells was determined by laser scan microscopy.
Epil overexpression in SKBR3 cells resulted in fast and frequent protrusion formation of the cells shown by laser scan microscopy. The cells were further characterized by a significantly increased invasiveness, which could be reversed by Epil specific siRNA treatment. Increased invasiveness and morphological changes were associated with a decreased erk1/2 phosphorylation.
These data further supports the assumption that EPIL might provide an autocrine loop in HER-2-positive breast cancer cells that enforce metastasis, conceivably escape from adjuvant therapy and in consequence poor clinical outcome. A tight interaction between HER-2 and EPIL in invasive breast cancer cells is therefore likely. The exact mechanims remain to be elucidated.
Verhandlungen der Deutschen Gesellschaft für Pathologie 02/2005; 89:201-6.
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ABSTRACT: Distinct parallel cytogenetic pathways in breast carcinogenesis could be identified in recent years. Nevertheless, it remained unclear as to which tumours may have progressed in grade or which patterns of cytogenetic alteration may define the switch from an in situ towards an invasive lesion. In order to gain more detailed insights into cytogenetic mechanisms of the pathogenesis of breast cancer, the chromosomal imbalances of 206 invasive breast cancer cases were characterised by means of comparative genomic hybridisation (CGH). CGH data were subjected to hierarchical cluster analysis and the results were further compared with immunohistochemical findings on tissue arrays from the same breast cancer cases. The combined analysis of immunohistochemical and cytogenetic data provided evidence that carcinomas with gains of 7p, and to a lesser extent losses of 9q and gains of 5p, are a distinct subgroup within the spectrum of ductal invasive grade 3 breast carcinomas. These aberrations were associated with a high degree of cytogenetic instability (16.6 alterations per case on average), 16q-losses in over 70% of these cases, strong oestrogen receptor expression and absence of strong expression of p53, c-erbB2 and Ck 5. These characteristics provide strong support for the hypothesis that these tumours may develop through stages of well- and perhaps intermediately differentiated breast cancers. Our results therefore underline the existence of several parallel and also stepwise progression pathways towards breast cancer.
British Journal of Cancer 05/2004; 90(7):1422-8. · 5.04 Impact Factor
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ABSTRACT: Bilaterality in breast cancer is a rare event and together with an early onset of disease points towards inheritance of the disease. However, most cases seem to occur sporadically, either in a synchronous or metachronous manner.
Thirty two invasive carcinomas and one in situ carcinoma from 16 patients with synchronous, bilateral breast cancer were investigated by means of comparative genomic hybridisation (CGH) and polymerase chain reaction based multiplex microsatellite analysis. The results were analysed conventionally and were also subjected to a biomathematical cluster analysis.
On average, bilateral breast cancer cases showed a low number of genetic alterations, a low frequency of genetic amplifications, and a high rate of chromosomal 16q losses. A distinct, characteristic genetic alteration associated with bilateral breast disease could not be found. Although two tumour pairs appeared to be related using biomathematical processing for microsatellite analysis, this result was reproduced by CGH data processing in one patient only.
Most synchronous, bilateral breast cancer cases seem to represent independent tumours rather than metastatic events. Nevertheless, the possibility of a specific susceptibility remains.
Journal of Clinical Pathology 10/2003; 56(9):660-5. · 2.31 Impact Factor
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ABSTRACT: Patients with extensive, long-standing ulcerative colitis have increased risk of colorectal cancer.
To improve the detection of high-risk patients, using a combination of colonic cytology, histology, and DNA image cytometry after segmental colonic lavage.
A series of 16 patients (8 high-risk patients) with ulcerative colitis were investigated.
After segmental lavage step, biopsies were obtained. Gradient centrifugation of the colonic fluid was performed for isolation and purification of epithelial cells. The smears and biopsy specimens obtained were stained for routine interpretation and for DNA image cytometry.
Segmental lavage could be performed in all patients. Specimens from two high-risk patients showed low grade dysplasia and atypia by means of histology and cytology, respectively. In one patient, without increased colorectal cancer risk, atypia was detected. Three patients in the high-risk group, two of those diagnosed as positive for dysplasia and atypia, showed aneuploidy histologically and cytologically. DNA aneuploidy, in cytological material, was found exclusively in three low-risk patients, one of those had atypia cytologically.
Isolation and purification of epithelial cells after segmental colonic lavage using density gradient centrifugation can be performed as part of routine endoscopy. It provides information about atypical cells and DNA aneuploidy as additional markers of malignant transformation. The combination of cytologic examination and DNA image cytometry might improve the detection of high-risk ulcerative colitis patients.
Digestive and Liver Disease 02/2003; 35(1):24-31. · 3.05 Impact Factor
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ABSTRACT: Comparative genomic hybridisation (CGH) is a reliable tool to gain an overview of all unbalanced chromosomal alterations within a tumour. Nevertheless, the high numbers of tumour cells required and the comparatively low resolution are drawbacks of this technique. Polymerase chain reaction (PCR) based multiplex microsatellite analysis represents a semi-automated, highly reproducible method, which requires small amounts of tumour cells. This is a comparative study of CGH and microsatellite analysis.
Eighty one samples of invasive breast cancer were investigated by two sensitive multiplex PCRs containing three microsatellites each of six markers (D6S261, D11S907, D6S300, D11S927, D8S272, and D11S925), and two additional microsatellite markers located within intron 1 of the epidermal growth factor receptor gene (egfr) and p53 (p53CA).
At least one example of loss of heterozygosity was detectable in all breast cancer tissues. However, the overall rate of accordance between the two methods tested was only 61%. An increasing rate of the number of genetic alterations in each case was mirrored by a constantly increasing fractional allelic loss index.
PCR based multiplex microsatellite analysis using this panel of eight microsatellite markers not only enables the characterisation of cells that have malignant potential in a high frequency of patients with breast cancer, but can also give an estimate of the degree of genetic progression.
Journal of Clinical Pathology 12/2001; 54(11):836-40. · 2.31 Impact Factor
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A Semjonow,
F Oberpenning,
C Weining,
M Schön, B Brandt,
G De Angelis,
A Heinecke,
M Hamm,
P Stieber,
L Hertle,
H P Schmid
Clinical Chemistry 09/2001; 47(8):1472-5. · 7.91 Impact Factor
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ABSTRACT: This meeting report summarizes the presentations of three different groups that are active in the field of flow cytometry (FCM) in relation to diagnosing and classification of proliferative disorders. The report starts with the contribution from Regensburg about the developments in DNA FCM, the progression to dual parameter determinations, and combination of immunophenotyping in combination with DNA. In the second part, the use of FCM for the detection of isolated tumor cells in the peripheral blood from patients with prostate or breast cancer is discussed in a contribution from Münster. In the third part, from Heerlen, the use of multi-parameter FCM on formalin-fixed paraffin-embedded tissues from solid tumors is discussed as a new development and application in routine surgical pathology.
Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 06/2001; 438(5):425-32. · 2.49 Impact Factor
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ABSTRACT: An association of a loss of DNA replication control and the activation of erbB oncogenes can be deduced from studies with different cancers (1-5). In the first study on ovarian cancer 26% of the tumors had c-erbB-2 amplifications (6). The correlation between c-erbB-2 amplification and expression on mRNA and protein level was perfect. The median survival time of patients with ovarian cancers was negatively correlated to the degree of amplification. The association of egfr (c-erbB-1) amplification and overexpression with ovarian cancer prognosis has not been investigated as extensively as for c-erbB-2. EGF-R is expressed in normal ovarian epithelium and patients whose ovarian cancer continues to express EGF-R have a worse prognosis (7). Rearrangements of the egfr gene in ovarian cancer were also described, as identified by Southern blot analysis (8). Bauknecht submitted that a failure of chemotherapy was seen for ovarian cancers with low EGF-R expression (8).
Methods in molecular medicine 01/2001; 39:347-56.
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ABSTRACT: This study was performed to test the validity of different methods for determining the status of the erbB-2/HER-2 oncogene in breast cancer tissues for diagnostic use.
Forty formalin-fixed, paraffin-embedded breast carcinomas were investigated by fluorescence in situ and comparative genomic hybridization (FISH, CGH) as well as by immunohistochemistry (IHC) using Dako-HercepTest and CB11 antibody (Ventana). Additionally, competitive-differential polymerase chain reaction (cdPCR) was performed on frozen samples to estimate gene dosage alterations of erbB-2/HER-2. Amplification was detected in 12-23% and protein overexpression in 16-68% of the cases, depending on the methodology and/or the reagent used. Perfect concordance (100%) was found between the results of cdPCR and CB11-IHC, and a 97% concordance between FISH and CB11-IHC. The concordance between Dako-HercepTest and CB11-IHC was 78%: seven of eight 2+ carcinomas with the Dako-HercepTest were classified as nonamplified using FISH.
Our results indicate that high-level expression as well as normal erbB-2/HER-2 status of breast carcinomas can be detected reliably both by IHC and gene dosage assessment in paraffin material for diagnostic use. However, borderline results, especially those with 2 + immunopositivity, should be interpreted with caution and increased emphasis should be given to other clinical and prognostic information available.
Histopathology 12/2000; 37(5):411-9. · 3.08 Impact Factor
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BJU International 10/2000; 86(5):590-7. · 2.84 Impact Factor
