Prognostic impact of macrometastasis linear size in sentinel node biopsy for breast carcinoma.

AIM: The aim of the present study was to evaluate the risk of axillary non-sentinel lymph-node metastases (ALN) in breast cancer patients presenting macrometastasis (Mac-m) in the sentinel lymph node (SN). MATERIALS AND METHODS: A retrospective series of 1464 breast cancers from patients who underwent ALN dissection following the diagnosis of Mac-m in the sentinel node (SN) was studied. In all the cases the MAC-m linear size was evaluated and correlated with presence or absence of non-SN ALN metastases. RESULTS: Non-SN metastases were detected in 644∖1464 cases (43.98%). The risk of further axillary metastases ranged from 20.2% (37/183) in cases with Mac-m between 2 and 2.9 mm, to 65.3% (262/401) in cases with Mac-m measuring > 10 mm. The risk of non-SN ALN metastases showed a 3% increase, parallel to each mm increment in SN metastasis size. The data evaluated with the receiver operating characteristic (ROC) curve showed that the Mac-m could be subdivided according to a new cut-off of 7 mm. pT1 tumours, with Mac-m < 7 mm had a risk of non-SN ALN metastases of <30%. Furthermore 109/127 of these (85.8%) had 3 or less non-SN ALN -metastases. CONCLUSIONS: The present data give a detailed description on the risk of non-SN ALN involvement, that may be useful in the evaluation of breast cancer patients. It is suggested that a Mac-m size of <7 mm is related to a low residual axillary disease burden in breast cancer patients with small (pT1) tumours.

Combination of microvascular medial femoral condyle and iliac crest flap for hemi-midface reconstruction.

In midface defects including the orbit (Brown class III and IV), no single flap can provide adequate reconstruction. In this technical note, the combination of vascularized iliac crest flap and vascularized medial femoral condyle flap (MFC) is described. The vascularized iliac crest flap is reported to be the gold standard for maxilla reconstruction. There is, however, no consensus on the best method for orbital and nasal wall reconstruction. The MFC flap can be harvested as a thin corticoperiosteal flap or as an osteomyocutaneous flap. Due to the periosteal blood supply, this flap can be customized for an individual defect of the upper hemi-midface. It is therefore of great benefit in orbital and nasal wall reconstruction. By combining the deep circumflex iliac artery (DCIA) bone flap and the MFC flap, the best standard reconstruction technique of the hemi-maxilla can be combined with a new anatomical precise microvascular reconstruction technique of the orbit. A nearly symmetric midface appearance can be achieved.

Comparative study of the osseous healing process following three different techniques of bone augmentation in the mandible: an experimental study.

The aim of this study was to evaluate the osseointegration of three different bone grafting techniques. Forty-eight mature New Zealand rabbits were divided randomly into three groups of 16 each. Horizontal augmentation was performed on the corpus of the mandible using three different techniques: free bone graft (FBG), free periosteal bone graft (PBG), pedicled bone flap (BF). The animals were sacrificed at postoperative weeks 1, 3, or 8. Specimens were decalcified for histological examination, and histomorphometric measurements were performed. The histological evaluation demonstrated bony fusion between the grafts and the augmented mandibular bone after 8 weeks in all groups. At week 8, the bone volume was significantly greater in the BF group than in the FBG (P<0.001) and PBG (P=0.001) groups, and also the trabecular thickness was significantly greater than in the FBG (P=0.015) and PBG (P=0.015) groups. Trabecular separation was significantly lower in the BF group than in the FBG group at week 8 (P=0.015). BF demonstrated greater osseous healing capacity compared to FBG and PBG. The preserved vascularization in BF improves the bone quality in mandibular bone augmentations.

The genomic profile of HER2-amplified breast cancers: the influence of ER status.

Expression profiling studies have suggested that HER2-amplified breast cancers constitute a heterogeneous group that may be subdivided according to their ER status: HER2-amplified ER-positive breast carcinomas that fall into the luminal B cluster; and HER2-amplified ER-negative cancers which form a distinct molecular subgroup, known as the erbB2 or HER2 subgroup. ER-negative breast cancer differs significantly from ER-positive disease in the pattern, type, and complexity of genetic aberrations. Here we have compared the genomic profiles of ER-positive and ER-negative HER2-amplified cancers using tiling path microarray-based comparative genomic hybridization (aCGH). Validation of the differentially amplified regions was performed in an independent series of 70 HER2-amplified breast cancers. Although HER2-amplified cancers had remarkably complex patterns of molecular genetic aberrations, ER-positive and ER-negative HER2-amplified breast carcinomas shared most molecular genetic features as defined by aCGH. Genome-wide Fisher's exact test analysis revealed that less than 1.5% of the genome was significantly differentially gained or lost in ER-positive versus ER-negative HER2-amplified cancers. However, two regions of amplification were significantly associated with ER-positive carcinomas, one of which mapped to 17q21.2 and encompassed GJC1, IGFBP4, TNS4, and TOP2A. Chromogenic in situ hybridization analysis of an independent validation series confirmed the association between ER status and TOP2A amplification. In conclusion, although hormone receptor status does not determine the overall genetic profile of HER2-amplified breast cancers, specific genetic aberrations may be characteristic of subgroups of HER2 breast cancers.

Squalene epoxidase, located on chromosome 8q24.1, is upregulated in 8q+ breast cancer and indicates poor clinical outcome in stage I and II disease.

Gains of chromosomes 7p and 8q are associated with poor prognosis among oestrogen receptor-positive (ER+) stage I/II breast cancer. To identify transcriptional changes associated with this breast cancer subtype, we applied suppression subtractive hybridisation method to analyse differentially expressed genes among six breast tumours with and without chromosomal 7p and 8q gains. Identified mRNAs were validated by real-time RT-PCR in tissue samples obtained from 186 patients with stage I/II breast cancer. Advanced statistical methods were applied to identify associations of mRNA expression with distant metastasis-free survival (DMFS). mRNA expression of the key enzyme of cholesterol biosynthesis, squalene epoxidase (SQLE, chromosomal location 8q24.1), was associated with ER+ 7p+/8q+ breast cancer. Distant metastasis-free survival in stage I/II breast cancer cases was significantly inversely related to SQLE mRNA in multivariate Cox analysis (P<0.001) in two independent patient cohorts of 160 patients each. The clinically favourable group associated with a low SQLE mRNA expression could be further divided by mRNA expression levels of the oestrogen-regulated zinc transporter LIV-1. The data strongly support that SQLE mRNA expression might indicate high-risk ER+ stage I/II breast cancers. Further studies on tumour tissue from standardised treated patients, for example with tamoxifen, may validate the role of SQLE as a novel diagnostic parameter for ER+ early stage breast cancers.

[Different coexisting genotypes in the breast cancer cell line MDA-MB-468]. / Unterschiedliche koexistierende Genotypen in der Brustkrebszelllinie MDA-MB-468.

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.

Allelic imbalances of the egfr gene as key events in breast cancer progression--the concept of committed progenitor cells.

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.

Basal carcinoma of the breast revisited: an old entity with new interpretations.

The introduction of global gene expression analysis in breast cancer research has focused attention onto a repeatedly described subgroup of invasive breast cancer, the basal-like carcinomas. This subgroup is characterised by the expression of high-molecular weight cytokeratins 5, 14 and 17; using immunohistochemical diagnosis, it represents approximately 7-20% of invasive breast cancers. Some of these tumours fulfil the criteria of grade 3 invasive ductal carcinoma, the so-called triple negative carcinomas. However, other rare subgroups of metaplastic, medullary and myoepithelial carcinomas also belong to this entity. Even though the initial clinical prognostic relevance of basal-like breast cancers may have been overestimated, its distinctive biology generates many questions regarding the pathogenesis, chemosensitivity and optimal clinical management of this subgroup. Physiological progenitor cells within the normal female breast share essential immunohistochemical features with basal-like breast cancers. Although the exact relationship between subgroups of normal breast cells and their respective malignant counterparts is still under investigation, the major hallmarks of physiological progenitor cells are either maintained or reactivated by distinct genetic changes in basal breast cancer cells. This review will discuss the impact of these findings on our global understanding of breast cancer pathogenesis, especially from the perspective of its potential histogenesis. Clinical consequences and potential future research directions driven by the definition of basal breast cancers will also be discussed.

[Retroperitoneoscopic excision of an adrenal cyst]. / Die retroperitoneoskopische exzision einer nebennierenzyste.

INTRODUCTION: Laparoscopic management of adrenal benign cysts is the method of choice today. In contrast to the transabdominal laparoscopic approach, retroperitoneoscopy is rarely performed, although it seems to be a comparable method and alternative technique for cyst resection. CASE REPORT: A thin 27-year-old woman in good condition presented with epigastric and left flank pain as well as reflux of gastric acid. A large adrenal cystic lesion was detected on ultrasonography and computed tomography of the abdomen. The question of whether the cyst arose from the upper pole of the left kidney or from the adrenal gland could not be answered. Retroperitoneoscopic excision of the cystic lesion was performed. The histopathological work-up revealed the finding of an adrenal pseudocyst. Symptoms of epigastric and left flank pain as well as reflux of gastric acid resolved after pseudocyst removal. CONCLUSIONS: The retroperitoneoscopic approach for symptomatic adrenal cyst resection represents an effective, cost-reducing and durable treatment.

Expression of beta-catenin and p53 are prognostic factors in deep aggressive fibromatosis.

AIMS: To determine the prognostic significance of beta-catenin in aggressive fibromatosis and to identify potential molecular markers for new targeted therapies. METHODS AND RESULTS: A tissue microarray of 37 cases of deep aggressive fibromatosis was constructed and subjected to immunohistochemical analysis for beta-catenin, p53, smooth muscle actin (SMA), desmin, Ki67, c-erbB2, epidermal growth factor receptor (EGFR), c-kit, CD34 and S100. Complete clinical follow-up was available for 23 patients. Nuclear beta-catenin expression was associated with an increased rate of local tumour recurrence (60.0% 1-year and 0% 5-year event-free survival; P < 0.05). Furthermore, p53 expression was associated with an increased risk of tumour recurrence (50% 1-year event-free survival rate and 0% 5-years event-free survival rate, P < 0.05). The coexpression of p53 and beta-catenin was significantly correlated (P < 0.05). No statistically significant association was seen between MIB1 and p53 or beta-catenin expression, respectively. No expression of EGFR, c-erbB2 or c-kit was seen. CONCLUSIONS: The overexpression of beta-catenin and p53 is associated with a decreased event-free survival in deep aggressive fibromatosis. Further studies are required to establish whether these findings can lead to an improvement in the treatment of this rare neoplasm.

Pitfalls in immunohistochemical assessment of EGFR expression in soft tissue sarcomas.

BACKGROUND: 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. OBJECTIVE: To test and compare different EGFR antibodies to determine the frequency of EGFR expression in STS. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Expression of early placenta insulin-like growth factor in breast cancer cells provides an autocrine loop that predominantly enhances invasiveness and motility.

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.

Cytogenetic differences in breast cancer samples between German and Japanese patients.

BACKGROUND: Japanese and German breast cancer cases differ substantially in the frequency of egfr amplification. AIMS: To unravel further the cytogenetic differences between Japanese and German breast cancer cases. METHODS: 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. RESULTS: 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. CONCLUSIONS: The interethnic differences of invasive breast cancer are reflected by cytogenetic aberrations, which are also associated with the differential expression of the ER.

[Salivary duct carcinoma]. / Speichelgangkarzinome.

This tutorial focuses on salivary duct carcinoma (SDC), a rare, high grade neoplasm mainly of major salivary glands. The clinical course of these tumors is characterised by extended local disease, early distant metastasis, and poor outcome. The morphology of SDC is reminiscent of breast ductal carcinomas and may occasionally cause diagnostic problems. In spite of mimicry with ductal carcinoma in situ of the breast and an in situ component, that is evident in most tumors by immunohistology with antibodies directed against high molecular weight cytokeratins (Ck), SDC is always an invasive carcinoma. By immunohistology, most tumors show reactivity with antibodies directed against Ck 7, Ck 8/18 and Ck 19 whereas a morphologically indistinguishable subgroup expresses Ck 5/6 in tumor cells in addition to residual basal epithelia. Carcinoembryonic antigen, GCDFP-15 and androgen receptor are other helpful markers in routine diagnosis of SDC. Prostate-specific antigen is detectable in some cases. Abnormal p53 expression seems to indicate an adverse prognosis. Expression of c-erbB2, the over-expression of which is associated with a poor prognosis, may form the basis for a targeted therapeutic approach for selected cases of SDC.

[Myoepthelial tumors of salivary glands]. / Myoepitheliale Tumoren der Kopfspeicheldrüsen.

This tutorial focuses on myoepithelial tumors of salivary glands, an entity with heterogeneous cytomorphology and inconsistent immunophenotype. Moreover, the clinical course cannot be predicted reliably from cytomorphological and immunophenotypic analysis. This heterogeneity causes problems in routine diagnostic, so that diagnosis ultimately rests on conventional histology. In a representative series of myoepitheliomas and malignant myoepitheliomas, antibodies against cytokeratins 5/6, S 100 protein and vimentin produced the most consistent reactivity profile. Staining for cytokeratins 5/6 is a useful addition to the established immunohistologic marker panel in the work-up of myoepitheliomas, because of its reliable expression in most cases and because it may underline the epithelial nature of the lesion. Comparative genomic hybridisation (CGH) profiles of myoepitheliomas and myoepithelial carcinomas showed no chromosomal aberration in less than 50% of myoepithelial carcinomas, so that CGH is of limited help in a given case. In a case that was represented in three separately localized manifestations of the disease that differed in their CGH profiles, gross genetic aberrations suggest to be acquired during tumor progression and should raise the suspicion of malignancy. Thus, diagnosis of myoepithelial tumors of salivary glands has to rest on morphological grounds with support of a restricted panel of immunohistologic markers.

Catenin expression in T1/2 carcinomas of the floor of the mouth.

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.

Expression patterns of angiogenic and lymphangiogenic factors in ductal breast carcinoma in situ.

The objective of this study was to investigate expression of various growth factors associated with angiogenesis and lymphangiogenesis and of their receptors in ductal carcinomas in situ of the breast (DCIS). We studied protein expression of basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF)-A, endothelin (ET)-1, and VEGF-C, and their receptors bFGF-R1, Flt-1, KDR, ET(A)R, ET(B)R, and Flt-4 immunohistochemically in 200 DCIS (pure DCIS: n=96; DCIS adjacent to an invasive component: n=104) using self-constructed tissue microarrays. Basic fibroblast growth factor-R1, VEGF-C, Flt-4, and ET(A)R were expressed in the tumour cells in the majority of cases, whereas bFGF and Flt-1 expression was rarely observed. VEGF-A, KDR, ET-1, and ET(B)R were variably expressed. The findings of VEGF-C and its receptor Flt-4 as lymphangiogenic factors being expressed in tumour cells of nearly all DCIS lesions and the observed expression of various angiogenic growth factors in most DCIS suggest that in situ carcinomas are capable of inducing angiogenesis and lymphangiogenesis. Moreover, we found a higher angiogenic activity in pure DCIS as compared to DCIS with concomitant invasive carcinoma. This association of angiogenic factors with pure DCIS was considerably more pronounced in the subgroup of non-high-grade DCIS (n=103) as compared with high-grade DCIS (n=94). Determination of these angiogenic markers may therefore facilitate discrimination between biologically different subgroups of DCIS and could help to identify a particularly angiogenic subset with a potentially higher probability of recurrence or of progression to invasiveness. For these DCIS, targeting angiogenesis may represent a feasible therapeutic approach for prevention of progression of DCIS to invasion.

Primary multifocal osseous Hodgkin disease: a case report and review of the literature.

PURPOSE: Hodgkin disease (HD) typically involves the lymphatic system at one or more sites. Rarely, Hodgkin disease presents as an osseous lesion without involvement of lymph nodes. Therefore, the histologic diagnosis of osseous HD can be problematic. We present a rare case of multifocal osseous HD and a review the literature with special emphasis on treatment and prognosis. METHODS: Osteomyelitis and lymphoma are the main differential diagnoses and can only be excluded histologically by the presence of Sternberg Reed cells or by immunohistochemical examinations. This case reports a 21-year old man with a Hodgkin lymphoma located at the proximal femur and the proximal tibia. RESULTS: Staging studies revealed no other tumor manifestations. Regarding the Ann Arbor classification, the presented case should be a stage IV disease. The patient is without evidence of disease 4 years after curettage, local radiation therapy, and systemic chemotherapy despite the poor prognosis considering the Ann Arbor classification. CONCLUSION: Reviewing the few reported cases, osseous HD must be distinguished from systemic HD with diffuse bone marrow involvement and from osseous metastases in advanced stage of disease because it seems to have a better prognosis.

Expression of endothelin-A-receptor predicts unfavourable response to neoadjuvant chemotherapy in locally advanced breast cancer.

Endothelin-1 (ET-1) and its receptors (ETAR and ETBR), referred to as the endothelin (ET) axis, are overexpressed in breast carcinomas and appear to influence tumour growth and progression. The objective of this study was to determine the effect of expression of the ET axis in breast carcinomas on response to cytotoxic chemotherapy. The study included 44 patients with locally advanced breast cancer participating in a prospective phase III study evaluating high-dose neoadjuvant chemotherapy of epirubicin and cyclophosphamide. Expression of ET-1, ETAR and ETBR was determined by semiquantitative immunohistochemical analysis of breast cancer tissue from prechemotherapy tru-cut biopsies. Immunohistochemical staining was positive for ET-1 in 61.5%, for ETAR in 35% and for ETBR in 35.9% of breast carcinomas. Pathological response to chemotherapy was significantly decreased in ETAR-positive patients (P=0.002). In total, 50% of ETAR-positive patients as compared to 7.7% of ETAR-negative patients attained pathologically 'no change'. Logistic regression confirmed ETAR as an independent predictive marker for pathological response (P=0.009). These data indicate that increased expression of ETAR in breast carcinomas is associated with resistance to chemotherapy. Determination of ETAR status may serve as a predictive marker for identifying patients less likely to be responsive to conventional chemotherapy.