HER2 and ESR1 mRNA expression levels and response to neoadjuvant trastuzumab plus chemotherapy in patients with primary breast cancer

Introduction: Recent data suggest that benefit from trastuzumab and chemotherapy might be related to expression of HER2 and estrogen receptor (ESR1). Therefore, we investigated HER2 and ESR1 mRNA levels in core biopsies of HER2-positive breast carcinomas from patients treated within the neoadjuvant GeparQuattro trial. Methods: HER2 levels were centrally analyzed by immunohistochemistry (IHC), silver in-situ hybridization (SISH) and qRT-PCR in 217 pretherapeutic formalin-fixed, paraffin-embedded (FFPE) core biopsies. All tumors had been HER2-positive by local pathology and had been treated with neoadjuvant trastuzumab/ chemotherapy in GeparQuattro. Results: Only 73% of the tumors (158 of 217) were centrally HER2-positive (cHER2-positive) by IHC/SISH, with cHER2-positive tumors showing a significantly higher pCR rate (46.8% vs. 20.3%, p<0.0005). HER2 status by qRT-PCR showed a concordance of 88.5% with the central IHC/SISH status, with a low pCR rate in those tumors that were HER2-negative by mRNA analysis (21.1% vs. 49.6%, p<0.0005). The level of HER2 mRNA expression was linked to response rate in ESR1-positive tumors, but not in ESR1-negative tumors. HER2 mRNA expression was significantly associated with pCR in the HER2-positive/ESR1-positive tumors (p=0.004), but not in HER2-positive/ESR1-negative tumors. Conclusions: Only patients with cHER2-positive tumors - irrespective of the method used - have an increased pCR rate with trastuzumab plus chemotherapy. In patients with cHER2-negative tumors the pCR rate is comparable to the pCR rate in the non-trastuzumab treated HER-negative population. Response to trastuzumab is correlated to HER2 mRNA levels only in ESR1-positive tumors. This study adds further evidence to the different biology of both subsets within the HER2-positive group

KIF2A silencing inhibits the proliferation and migration of breast cancer cells and correlates with unfavorable prognosis in breast cancer

Background; Kinesin family member 2a (KIF2A), a type of motor protein found in eukaryotic cells, is associated with development and progression of various human cancers. The role of KIF2A during breast cancer tumorigenesis and progression was studied. Methods; Immunohistochemical staining, real time RT-PCR and western blot were used to examine the expression of KIF2A in cancer tissues and adjacent normal tissues from breast cancer patients. Patients’ survival in relation to KIF2A expression was estimated using the Kaplan–Meier survival and multivariate analysis. Breast cancer cell line, MDA-MB-231 was used to study the proliferation, migration and invasion of cells following KIF2A-siRNA transfection. Results; The expression of KIF2A in cancer tissues was higher than that in normal adjacent tissues from the same patient (P < 0.05). KIF2A expression in cancer tissue with lymph node metastasis and HER2 positive cancer were higher than that in cancer tissue without (P < 0.05). A negative correlation was found between KIF2A expression levels in breast cancer and the survival time of breast cancer patients (P < 0.05). In addition, multivariate analysis indicated that KIF2A was an independent prognostic for outcome in breast cancer (OR: 16.55, 95% CI: 2.216-123.631, P = 0.006). The proliferation, migration and invasion of cancer cells in vitro were suppressed by KIF2A gene silencing (P < 0.05). Conclusions; KIF2A may play an important role in breast cancer progression and is potentially a novel predictive and prognostic marker for breast cancer

HER2 induced EMT and tumorigenicity in breast epithelial progenitor cells is inhibited by coexpression of EGFR.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access.The members of the epidermal growth factor receptor (EGFR) kinase family are important players in breast morphogenesis and cancer. EGFR2/HER2 and EGFR expression have a prognostic value in certain subtypes of breast cancer such as HER2-amplified, basal-like and luminal type B. Many clinically approved small molecular inhibitors and monoclonal antibodies have been designed to target HER2, EGFR or both. There is, however, still limited knowledge on how the two receptors are expressed in normal breast epithelium, what effects they have on cellular differentiation and how they participate in neoplastic transformation. D492 is a breast epithelial cell line with stem cell properties that can undergo epithelial to mesenchyme transition (EMT), generate luminal- and myoepithelial cells and form complex branching structures in three-dimensional (3D) culture. Here, we show that overexpression of HER2 in D492 (D492(HER2)) resulted in EMT, loss of contact growth inhibition and increased oncogenic potential in vivo. HER2 overexpression, furthermore, inhibited endogenous EGFR expression. Re-introducing EGFR in D492(HER2) (D492(HER2/EGFR)) partially reversed the mesenchymal state of the cells, as an epithelial phenotype reappeared both in 3D cultures and in vivo. The D492(HER2/EGFR) xenografts grow slower than the D492(HER2) tumors, while overexpression of EGFR alone (D492(EGFR)) was not oncogenic in vivo. Consistent with the EGFR-mediated epithelial phenotype, overexpression of EGFR drove the cells toward a myoepithelial phenotype in 3D culture. The effect of two clinically approved anti-HER2 and EGFR therapies, trastuzumab and cetuximab, was tested alone and in combination on D492(HER2) xenografts. While trastuzumab had a growth inhibitory effect compared with untreated control, the effect of cetuximab was limited. When administered in combination, the growth inhibitory effect of trastuzumab was less pronounced. Collectively, our data indicate that in HER2-overexpressing D492 cells, EGFR can behave as a tumor suppressor, by pushing the cells towards epithelial differentiation.Landspitali University Hospital Science Fund, University of Iceland Research Fund, Science and Technology Policy Council Research Fund and Grant of Excellence, ‘Göngum saman’, a supporting group for breast cancer research in Iceland

Grupo de familiares na prática de ensino de graduação em enfermagem

Atualmente, os Centros de Atenção Psicossocial (CAPS) são dispositivos estratégicos para assistência em saúde mental no Brasil. Os enfermeiros são profissionais exigidos na equipe mínima deste dispositivo, que valoriza as atividades grupais na abordagem dos usuários. Relato de experiência de alunos do Curso de Graduação em Enfermagem da UFMT, na realização de grupo de sala de espera com familiares de usuários de um CAPS de Cuiabá-MT. Justifica-se em virtude das poucas oportunidades que alunos de enfermagem têm para desenvolver habilidades de abordagem grupal na sua formação, voltada prioritariamente para o cuidado clínico individual. O objetivo da experiência foi proporcionar aprendizado teórico-prático de todas as etapas do trabalho com grupos: reconhecimento da necessidade e possibilidade da atividade, planejamento, coordenação e avaliação do grupo. Os resultados confirmam a necessidade e possibilidade da realização de experiências grupais na assistência em saúde mental e no ensino de enfermagem.Los Centros de Atención Psicosocial (CAPS) son dispositivos estratégicos para la asistencia a la salud mental en Brasil en la actualidad. Los enfermeros son profesionales exigidos en el mínimo equipo de este dispositivo que valoriza las actividades grupales en el abordaje de los usuarios. Relato de experiencia de alumnos del Curso de Graduación en Enfermería de la UFMT en la realización de grupo de sala de espera con familiares de usuarios de un CAPS de Cuiabá, MT, Brasil. Se justifica en virtud de las pocas oportunidades que tienen los estudiantes de enfermería en el desarrollo de competencias de abordaje grupal en su formación, focalizada principalmente para la atención clínica individual. El objetivo de la experiencia era proporcionar aprendizaje teórico-práctico de todas las etapas del trabajo con grupos: reconocimiento de la necesidad y posibilidad de la actividad, planificación, coordinación y evaluación del grupo. Los resultados confirman la necesidad y la viabilidad de la realización de experiencias de grupo en el cuidado de la salud mental y la educación de enfermería.The Centers of Psychosocial Care (CAPS, acronym in Portuguese) are strategic devices for mental health care currently available in Brazil. Nurses are professionals required to compose the minimum staff of this device, which values the group activities involving users. This study presents a r report of the experience of nursing undergraduates from Universidade Federal do Mato Grosso(UFMT) on their conducting waiting-room group sessions with relatives of users of a CAPS from Cuiabá, Mato Grosso state. This experience is justified by the fact that nursing students have few opportunities to develop group approach abilities during their graduation course, which focuses mainly on clinical individual care. The aim of the experience was to provide theoretical-practical learning of all the work stages of group work: recognizing the need and possibility of conducting the activity, planning, coordination and group evaluation. The results confirm the need and possibility of performing group experiences in mental health care and in nursing education

Extended genetic analysis of Brazilian isolates of Bacillus cereus and Bacillus thuringiensis

Multiple locus sequence typing (MLST) was undertaken to extend the genetic characterization of 29 isolates of Bacillus cereus and Bacillus thuringiensis previously characterized in terms of presence/absence of sequences encoding virulence factors and via variable number tandem repeat (VNTR). Additional analysis involved polymerase chain reaction for the presence of sequences (be, cytK, inA, pag, lef, cya and cap), encoding putative virulence factors, not investigated in the earlier study. MLST analysis ascribed novel and unique sequence types to each of the isolates. A phylogenetic tree was constructed from a single sequence of 2,838 bp of concatenated loci sequences. The strains were not monophyletic by analysis of any specific housekeeping gene or virulence characteristic. No clear association in relation to source of isolation or to genotypic profile based on the presence or absence of putative virulence genes could be identified. Comparison of VNTR profiling with MLST data suggested a correlation between these two methods of genetic analysis. In common with the majority of previous studies, MLST was unable to provide clarification of the basis for pathogenicity among members of the B. cereus complex. Nevertheless, our application of MLST served to reinforce the notion that B. cereus and B. thuringiensis should be considered as the same species

ER and HER2 Expression Are POSITIVELY Correlated in HER2 Non-Over Expressing Breast Cancer.

Abstract Aim: To determine the relationship between ER and HER2 expression according to HER2 amplification status.Background: ER and HER2 are the most commonly measured biomarkers in breast cancer and are important targets for therapy. It is known that ER and HER2 positivity are inversely correlated and that among ER+ tumours ER expression is higher in HER2 non-overexpressing (−ve) than HER2 overexpressing (+ve) disease (Konecny et al, JNCI 2003, 95: 142-53). There are however, very few data on the quantitative relationship between ER and HER2 expression in HER2−ve tumours. We therefore measured the expression of ER and HER2 at both the mRNA and protein level in HER2 +ve and −ve breast carcinomas.Methods: ER and HER2 levels were assessed by IHC (6F11 antibody and HercepTest, respectively) on tissue microarrays and q-RT-PCR in formalin-fixed primary breast cancers from 429 patients in the tamoxifen arm of the ABC Trial (ABC Trialists, JNCI 2007, 99: 506-15). HER2 amplification status was assessed with the PathVysion 2-probe FISH test. ER IHC was H-scored. Transcript levels for ER and HER2 from 1139 HER2−ve TransATAC tumours were available from the Oncotype DX test (Dowsett et al, Cancer Res 2009, 69suppl: 75s).Results: Matched results were available from all analyses for 257 ABC patients except for 25 cases where HER2 was by IHC or FISH. HER2 was amplified in 14.4% and equivocal in 1.3% of cases. ER was +ve in 67% of cases. The expected negative correlation between levels of ER and HER2 expression was found in HER2 +ve tumours (r=-0.45, p=0.0028). In contrast in HER2-ve tumours (ER+ve and ER-ve combined) there was a significant POSITIVE correlation between ER and HER2 mRNA levels (r=0.43, p&amp;lt;0.0001). As a result in HER2−ve tumours the quantitative level of HER2 was higher in ER+ve than ER−ve tumours (mean fold difference 1.74, p&amp;lt;0.0001). There was a mean 5.8-fold higher HER2 transcript levels in HER2+ve vs HER2−ve tumours in ER+ve disease and 12.9-fold higher in ER−ve disease. The positive correlation though weaker was maintained in the ER+ve HER2−ve group (r=0.24, p=0.0023) and was present to a similar extent in that subgroup in TransATAC (r=0.25, p&amp;lt;0.00001). The positive association was also significant in ER IHC analyses in ABC: mean±95%CI H-scores were 90±19 and 134±19 in the 0 and 1+ HER2 IHC categories, respectively (p=0.0013).Conclusions: ER and HER2 expression are positively correlated at both protein and transcript levels in HER2−ve breast cancer in contrast to their negative correlation in HER2+ve disease. The distinction between HER2+ve and HER2−ve is greater in ER−ve than ER+ve disease and this may lead to greater diagnostic uncertainties in ER+ve patients. These findings may also have importance for signaling pathways and application of targeted therapy in HER2−ve disease.*Acknowledgement: We are grateful to the ABC Trial Working and Biological Studies Groups, the ATAC Trialists and Cancer Research UK for funding. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 703.</jats:p