BDNF/TrkB são descritos em diversas neoplasias onde iniciam sinais mitogênicos, facilitam o crescimento tumoral, previnem apoptose e regulam angiogênese e metástase. Outros fatores de crescimento também são importantes para tumorigênese, como GRP/GRPR e EGF/EGFR. O objetivo geral deste trabalho foi investigar o papel de BDNF/TrkB em câncer colorretal avaliando possíveis interações com GRPR e EGFR. Verificamos que BDNF e seu receptor, TrkB, estão presentes em amostras de pacientes com câncer colorretal esporádico, e os níveis de BDNF encontram-se mais elevados no tecido neoplásico que no tecido adjacente ao tumor. O tratamento com RC- 3095, um antagonista de GRPR, na linhagem celular de câncer colorretal humana, HT-29, causa diminuição nos níveis de NGF secretados pelas células e aumento de BDNF em relação ao controle não tratado. RC-3095 inibe a proliferação e viabilidade celular das linhagens HT-29 (EGFR positiva) e SW-620 (EGFR negativa), embora apenas em HT-29 ocorra um aumento significativo na expressão de mRNA de BDNF. Por isso, um anticorpo monoclonal anti-EGFR, cetuximabe, foi combinado a RC-3095, nas células HT-29, sendo capaz de prevenir tal aumento, sugerindo que este efeito seja mediado por EGFR. Os tratamentos com um inibidor de Trks, K252a (1000 nM) ou com cetuximabe (10 nM) também inibem a proliferação celular. Entretanto, a combinação de BDNF a cetuximabe previne este efeito, enquanto que a combinação de doses não efetivas de K252a (10 nM) à cetuximabe (1 nM) inibe a proliferação celular de HT- 29. Além disso, cetuximabe também causa aumento na expressão de mRNA de TrkB e BDNF, após 600 minutos de tratamento. Nossos resultados sugerem que a inibição da proliferação celular in vitro ou do crescimento tumoral in vivo devem acontecer através do bloqueio combinado entre GRPR e TrkB em células de câncer colorretal EGFR positivas, e que BDNF também esteja envolvido em mecanismos de resistência a fármacos. Por isso, o bloqueio de BDNF / TrkB pode emergir como potencial alvo antitumoral. / BDNF / TrkB are described in various cancers where they participate in tumor growth, apoptosis, angiogenesis and metastasis. Furthermore, other growth factors are also important to tumorigenesis as GRP/GRPR and EGF/EGFR. Therefore, the aim of this study was to investigate the role of BDNF/TrkB in colorectal cancer evaluating the interactions with GRPR and EGFR. We found that BDNF and its receptor, TrkB, are present in samples from patients diagnosed with sporadic colorectal cancer, and BDNF levels were higher in tumor tissue compared to adjacent tumor tissue. Treatment with RC-3095, GRPR antagonist, in human colorectal cancer cell line, HT-29 caused a decrease in NGF levels secreted by cells, and generated increase of BDNF when compared to untreated control. RC-3095 inhibited the proliferation and cell viability in HT-29 (EGFR positive) and SW-620 (EGFR negative), but only HT-29 cells showed a significant increase in BDNF mRNA expression. Therefore, a monoclonal anti-EGFR antibody, cetuximab was combined with RC-3095 in HT-29 cells, and was able to prevent such an increase, suggesting that this effect is mediated by EGFR. The treatment with a Trk inhibitor, K252a (1000 nM) or cetuximab (10 nM), inhibited cell proliferation. However, the combination of BDNF with cetuximab prevented this effect, whereas the combination of ineffective doses of K252a (10 nM) with cetuximab (1 nM) still inhibited cell proliferation of HT-29. Furthermore, cetuximab also caused an increase in BDNF and TrkB mRNA expression, 600 minutes after treatment. In summary, our results suggest that inhibition of cell proliferation in vitro or tumor growth in vivo must occur between the combination of GRPR and TrkB in EGFR positive colorectal cancer cells, and that BDNF is also involved in drug resistance mechanisms. Therefore, blockage of BDNF / TrkB may emerge as potential antitumor target.

Estudos caracterizaram o envolvimento da PDI na modulação da geração de EROs pela Nox1 como moduladores da migração de células do músculo liso vascular (VSMC) mediados por fatores de crescimento derivados de plaqueta (PDGF). Outros estudos vêm demonstrando o envolvimento do fator de crescimento epidermal (EGFR) no remodelamento vascular, após a transativação via Angiotensina II. Entretanto o papel da PDI na ativação do EGFR via Nox1 na hipertensão arterial ainda permanece desconhecido. Objetivo foi caracterizar o papel da PDI na expressão de Nox1 dependente do EGFR durante o desenvolvimento da hipertensão arterial. Resultados demonstram um aumento da expressão de HB-EGF e ativação de ERK 1/2 na aorta de animais SHR com 8 semanas e 12 semanas de idade, e no plasma de animais SHR com 12 semanas. Ainda, a OvxPDI acarretou em um aumento na expressão gênica de Nox-1 tanto na OVXPDI quanto na forma OvxPDIMUT. Resultados mostram um novo papel da PDI na expressão gênica de Nox-1 via EGFR e a participação desta tiol oxido redutase na gênese da hipertensão arterial. / Studies characterizing the involvement of PDI in the modulation of ROS by Nox1 as modulators of cell migration of vascular smooth muscle (VSMC) mediated by growth factors derived from platelets (PDGF). Other studies have demonstrated the involvement of the epidermal growth factor receptor (EGFR) on vascular remodeling after transactivation via Angiotensin II. However the role of PDI in the activation of EGFR via Nox1 in hypertension remains unknown. Objective was to characterize the role of PDI in Nox1 dependent EGFR expression during the development of hypertension. Results show an increase of HB-EGF expression and ERK 1/2 activation in the aortic SHR at 8 weeks and 12 weeks of age, and plasma SHR at 12 weeks. Still, the OvxPDI resulted in an increase in gene expression of Nox-1 both in OVXPDI and in OvxPDIMUT way. Results show a new role of PDI in gene expression of Nox-1 via EGFR and the participation of this thiol reductase oxide in the pathogenesis of hypertension.

Leucoplasia oral (LO) é uma lesão potencialmente maligna, definida como uma placa branca que não pode ser caracterizada como outra doença da mucosa oral. Dentro de certo consenso, as LOs devem ser tratadas, mas nenhum tratamento disponível tem a capacidade de prevenir a transformação maligna. Este trabalho teve como objetivo avaliar a eficácia do tratamento cirúrgico das LOs por lasers de CO2 e diodo e verificar a ocorrência de desfechos clínicos de recidivas, desenvolvimento de novas lesões ou transformação maligna após o tratamento. Adicionalmente foi realizado estudo imunohistoquímico em material biopsiado das lesões e em tecido normal gengival (grupo controle). Fatores reconhecidamente de risco como hábitos nocivos (álcool e tabagismo), características clínicas das lesões, grau de displasia, bem como a expressão dos anticorpos investigados, foram analisados e relacionados com a ocorrência de desfechos clínicos em 40 pacientes atendidos no ambulatório de Estomatologia Clínica. Os cortes histológicos das lesões foram classificados de acordo com o grau de displasia e com um sistema binário, e subsequentemente foram testados para os anticorpos anti-p53, anti-COX-2 e anti- EGFR através de reação imuno-histoquímica. Análise de Kaplan-Meier, seguida do teste de log-rank e análise de regressão de Cox avaliaram a ocorrência de recorrência, desenvolvimento de novas lesões e transformação maligna e possíveis fatores relacionados com esses desfechos clínicos. Teste de odds ratio e de x2 avaliaram a expressão dos anticorpos investigados em LOs e grupo controle. Pacientes com LO apresentaram idade média de 60,5 anos e a relação homem/mulher foi de 1,35:1. Hábitos de tabagismo e etilismo foram prevalentes em homens. A maior parte das lesões era < 2 cm (57,1%), tinha aspecto homogêneo (67,3%) e displasia epitelial (61,2%); apenas 7 lesões eram de alto risco (sistema binário). Desfechos clínicos de recorrência, desenvolvimento de novas lesões ou transformação maligna foram observados em 37,5% dos pacientes; 2 pacientes desenvolveram malignidade em sítios distintos da LO inicial. Análise estatística mostrou associação entre desfecho de recorrência e lesões de alto risco, e entre desfecho de desenvolvimento de novas lesões e mulheres acima de 60 anos. Os anticorpos p53 e COX-2 foram mais expressos em LOs que no grupo controle, mas a expressão de nenhum anticorpo foi relacionada com os desfechos clínicos avaliados. O tratamento por lasers de alta potência (CO2 e diodo) mostrou-se eficiente na remoção das lesões, embora não tenha evitado desfechos clínicos de recorrência, desenvolvimento de novas lesões e transformação maligna. Lesões de alto risco e mulheres acima de 60 anos constituíram fatores de risco aos desfechos clínicos, enquanto os anticorpos analisados não foram eficientes para prognosticar a evolução das LOs. / Oral leukoplakia (OL) is a potentially malignant lesion, defined as a white patch that cannot be characterized as any other disease of the oral mucosa. In general, OL should be treated; however no treatment available has been able to prevent malignant transformation. The aim of this study was to evaluate the efficacy of surgical treatment with CO2 and diode lasers in 40 patients with OL and the occurrence of clinical outcomes of recurrence, development of new lesions or malignant transformation, after treatment. Additionally, an immunohistochemistry study was performed in OL biopsy-specimen and in gingival normal tissue (control group). Recognized risk factors such as habits (alcohol and tobacco), clinical characteristics of lesions, grade of dysplasia, as well as the expression of immunohistochemistry reaction were analyzed. Histological slides of lesions were classified according to the grade of dysplasia and a binary system, and subsequently tested for the anti-p53, anti-COX-2 and anti-EGFR antibodies by immunohistochemistry assay. Kaplan-Meier analysis along with log-rank test and Cox regression analysis were used to assess the occurrence of clinical outcomes and the association with risk factors. Odds ratio and x2 tests evaluated the expression of the investigated antibodies in OLs and in the control group. Patients with OL had a mean age of 60.5 years and the men/women ratio was of 1.35:1. Smoking and alcohol habits were more prevalent among men than in women. Lesions were clinically characterized as measuring less than 2 cm (57.1%), with a homogenous aspect (67.3%) and histologically with epithelial dysplasia (61.2%); only 7 lesions were classified as of high-risk (binary system). Clinical outcomes (recurrence, development of new lesions and malignant transformation) were observed in 37.5% patients; 2 patients developed malignancy in areas distant from the initial OL site. Statistical analysis showed association between recurrence and high-risk lesions, and between development of new lesions and women over 60 years old. Anti-P53 and anti-COX-2 antibodies were more expressed among OL than in the control group, but no antibody expression was related to the clinical outcomes analyzed. Surgical treatment with high-power lasers (CO2 and diode) showed to be efficient in the removal of OL lesions, but it did not avoid clinical outcomes of recurrence, development of new lesions and malignant transformation. High-risk lesions and women over 60 years old constituted risk factors for the clinical outcomes, while the analized antibodies were not usefull markers to characterize OL lesions with higher risk of malignancy.

O presente estudo comparou os efeitos da ativação e inibição do EGFR em duas linhagens de câncer de pulmão, cultivadas em monocamada ou esferoides. Os esferoides foram cultivados sem elementos de matriz extracelular. As células A549 e HK2 apresentaram, respectivamente, 3 e 6 cópias do gene ErbB1 por núcleo, embora a expressão de EGFR seja menor nas células HK2. A ativação de EGFR por EGF ou inibição por AG1478 não promoveu mudanças na proliferação celular. Entretanto, as células cultivadas em monocamada, estimuladas com EGF, exibiram alterações na disposição dos microfilamentos de actina e aumento na velocidade de migração celular. UO126 e LY294002 foram adicionados às culturas para inibir, respectivamente, as vias ERK e Akt. A linhagem A549, cultivada em monocamada, não apresentou envolvimento das vias de sinalização de ERK e Akt na migração celular induzida por EGF, mas foi observado o envolvimento dessas vias nos esferoides. Já a linhagem HK2 apresentou o envolvimento de Akt para promover a migração celular após estímulo com EGF nas duas formas de cultivo. / This study compared the effects of activation and inhibition of EGFR in two cell lines of lung cancer, grown in monolayer or spheroids. Spheroids were cultured without extracellular matrix components. HK2 and A549 cells showed, respectively, 3 and 6 ErbB1 gene copies per nucleus, while EGFR expression is lower in the HK2 cells. The activation by EGF or EGFR inhibition by AG1478 did not cause changes in cell proliferation. However, cells cultured in monolayers stimulated with EGF, showed changes in the arrangement of actin microfilaments and increased the speed of cell migration. UO126 and LY294002 were added to the cultures to inhibit, respectively, the ERK and Akt pathways. A549 cells grown in monolayer did not show involvement of ERK and Akt signaling pathways in the cell migration induced by EGF, but was observed involvement of such pathways in the spheroids. HK2 cells showed involvement of Akt to promote cell migration after EGF stimulation in monolayers and in spheroids.

A superexpressão de receptores HER-2 é anormalidade celular de grande relevância clínica no câncer de mama. Ela ocorre em aproximadamente 30% de carcinomas de mama incluindo lesões pré-neoplásicas e malignas, e está associada a prognóstico desfavorável. A hiperativação dos receptores HER-2, consequência natural de sua superexpressão, promove proliferação celular aberrante e tumorigênese. Admite-se que a ativação e envio de sinais via HER-2 possa acontecer quando estes receptores se encontram em compartimentos específicos da membrana celular, os lipid rafts. Assim, um número maior de HER-2 poderia implicar em maior quantidade de lipis rafts. Para testar essa hipótese, usamos modelo de transformação oncogênica que nos permitiu avaliar, especificamente, os efeitos da superexpressão de HER-2 e identificar a quantidade de lipid rafts. Para isso utilizamos a linhagem celular HB4a, derivada de célula epitelial luminal do tecido mamário humano normal com baixa expressão de HER-2; e a linhagem HB4aC5.2, um clone derivado da HB4a, que superexpressa receptores HER-2. Nas células HB4aC5.2, a superexpressão de HER-2 foi acompanhada pelo aumento dos lipid rafts na membrana celular, bem como, hiperativação de sinais de sobrevivência, proliferação (aumento da ativação de proteínas Akt e Erk1/2, respectivamente), e taxa de proliferação celular duas vezes mais rápida que a linhagem normal HB4a. Adicionalmente, a superexpressão de HER-2 foi associada com aumento da lipogênese celular (fenótipo lipogênico), dependente do aumento de ativação da enzima FASN e da superexpressão de DEPTOR. A FASN é responsável pela síntese de palmitato, utilizado para formação de lipid rafts. A superexpressão de DEPTOR, por modular a atividade transcricional de PPAR?, pode evitar a lipotoxicidade do excesso de palmitato. Além disso, DEPTOR, por sua capacidade em reduzir atividade do complexo mTORC1, contribui para sobrevivência celular dependente da proteína Akt. Em continuidade, consideramos, como segunda hipótese, que a desestruturação de lipid rafts poderia influenciar negativamente a ativação dos receptores HER-2. Para isso tratamos, as mesmas linhagens celulares anteriormente descritas, com ácido docosaexaenoico (DHA), um tipo de ácido graxo ômega-3. Nossos resultados mostraram que, nas células HB4aC5.2, o tratamento com DHA desestruturou os lipid rafts, inibiu a sinalização iniciada pelos receptores HER-2 ( diminuição da ativação das proteínas Akt, Erk1/2, FASN, atividade transcricional de PPAR? e expressão de DEPTOR) e reverteu o fenótipo lipogênico. Adiciona-se que essas modificações celulares e moleculares foram acompanhadas por indução significativa de morte e apoptose. As mesmas alterações não foram observadas nas células normais HB4a. Em conclusão, o presente estudo reforça a associação entre a presença de HER-2 e lipid rafts. Adicionalmente aponta que a desestruturação de lipid rafts por DHA reduz a sinalização de HER-2. Por fim, sugere que distúrbios em lipid rafts, induzidos por DHA, possam representar ferramenta útil no controle da sinalização aberrante deflagrada pelos receptores HER-2, e aponta potencial terapêutico na suplementação de DHA para quimioprevenção e tratamento do câncer de mama HER-2 positivo. / HER-2 receptor overexpression is a cellular abnormality of great clinical significance in breast cancer. It is described in approximately 30% of breast carcinomas, including preneoplasic and malignant lesions, and is associated with poor prognosis. Hyperactivation of HER-2 receptors, a natural consequence of its overexpression, promotes aberrant cell proliferation and tumorigenesis. For signal activation and transduction to occur, HER-2 must be localized in specific compartments in the cell membrane: the lipid rafts. Therefore, we hypothesize that a greater number of HER-2 receptors could indicate a greater quantity of lipid rafts. To test this, we used an oncogenic transformation model that specifically allowed assessment of the effects of HER-2 overexpression and identification of the quantity of lipid rafts: an HB4a cell line derived from normal human breast tissue luminal epithelial cells with low HER-2 expression, and an HB4aC5.2 cell line, a clone derived from HB4a that overexpresses HER-2 receptors. In the HB4aC5.2 cells, HER-2 overexpression was accompanied by an increase in lipid rafts in cell membranes as well as hyperactivation of survival signals, proliferation (increased activation of the proteins Akt and ERK1/2, respectively), and an increased rate of proliferation, compared to the normal HB4a line. In addition, HER-2 overexpression was associated with increased cellular lipogenesis (lipogenic phenotype), dependent on the increased activation of the FASN enzyme and the overexpression of DEPTOR. FASN is responsible for the synthesis of palmitate, used to synthesize lipid rafts. Overexpression of DEPTOR by modulating PPAR? transcriptional activity, may avoid lipotoxicity from excess palmitate. Moreover, DEPTOR, with its ability to reduce mTORC1 complex activity, contributes to cell survival dependent on Akt. To continue, we considered as a second hypothesis that the disruption of lipid rafts could negatively influence HER-2 receptor activation. For this, we treated the same cell lines described above with docosahexaenoic acid (DHA), a omega-3 fatty acid. Our results showed that in HB4aC5.2 cells DHA treatment disrupted the lipid rafts, inhibited signaling initiated by HER-2 receptors (reduced activation of Akt, ERK1/2, and FASN proteins, PPAR? transcriptional activity, and DEPTOR expression) and reversed the lipogenic phenotype. In addition, these cellular and molecular changes were accompanied by a significant induction of apoptosis and death. The same changes were not observed in normal HB4a cells. In conclusion, the present study reinforces the association between HER-2 presence and lipid rafts. It also indicates that the disruption of lipid rafts by DHA reduces HER-2 signaling. Finally, it suggests that DHA-induced disturbances in lipid rafts may represent a useful tool in controlling aberrant signaling triggered by HER-2 receptors, and indicate therapeutic potential in DHA supplementation for chemoprevention and treatment of HER-2 positive breast cancer.

Le glioblastome (GBM), tumeur de plus haut grade du système nerveux central (OMS grade 4) a un pronostic très sombre, quelque soit le traitement, lié à une résistance à l’apoptose. L’erlotinib (Tarceva®, OSI 774) est un inhibiteur de la tyrosine kinase du récepteur au facteur de croissance épithélial (EGFR). L’hyper-expression et l’amplification du gène de l’EGFR dans 40 à 60% des GBM, fourni un rationnel pour utiliser l’erlotinib. Nous avons montré sur U87-MG et DBTRG-05MG, deux lignées de GBM, l’absence d’apoptose avec l’erlotinib, liée soit à un déficit en pro-caspase 3, soit à une accumulation d’αB-crystalline bloquant l’activation de la caspase-3. L’absence d’apoptose dévie alors la cellule vers l’autophagie. L’inhibition de l’autophagie par ARN interférents ou par la chloroquine permet d’obtenir une synergie avec l’erlotinib en induisant la mort des cellules tumorales à des doses acceptables.Les GBM ont composition cellulaire hétérogène, avec un petit nombre d’éléments appelés cellules souches cancéreuses (CSC). Douées d’auto-renouvellement, elles participent à la propagation tumorale et à la résistance aux traitements. Nous avons testé l’erlotinib sur trois lignées issues de GBM humains, ayant deux modes de croissance distincts selon les conditions de milieu: en neurosphères (NS) et de type adhérent. Erlotinib a un effet inhibiteur minime sur les trois lignées adhérentes, alors que l’effet est significatif sur les lignées NS, traduisant l’importance de la voie d’EGFR pour les NS. Dans les lignées en NS, l’erlotinib est efficace sur les cellules progénitrices, mais n’a pas d’action ni sur les cellules initiatrices de NS, ni sur les cellules différenciées. L’auto-renouvellement des NS n’est pas non plus altéré. L’association cyclopamine, inhibiteur pharmacologique de la voie de Hedgehog, -erlotinib est synergique en bloquant la croissance et l’initiation des NS, laissant présager une efficacité sur les CSC. Les résultats obtenus sur ces différents modèles permettent d’une part de préciser certains mécanismes de résistance des cellules de GBM, et aussi d’orienter les indications et le choix des traitements susceptibles d’être les plus efficaces. / Glioblastoma (GBM) is the most common primary central nervous system tumor in adults and the prognosis remains dismal, any treatment used. Epidermal Growth Factor Receptor (EGFR) is amplified, overexpressed, and/or mutated in GBM, making it a rational for therapy. Erlotinib, an EGFR kinase inhibitor is strongly associated with clinical response in several cancers. We showed for U87-MG and DBTRG-05MG, two human GBM cell lines, that erlotinib can’t trigger apoptosis, related either to accumulation of αB-crystallin capable to impair caspase 3 cleavage, or to constitutive deficit for procaspase 3 in DBTRG-05MG. Apoptosis deficit switches the cell to autophagic process. Inhibition of autophagy with RNA interference or chloroquine resulted in sensitization of U87 and allowed a synergistic effect with erlotinib at therapeutic doses.Moreover, GBM showed a heterogeneous cell composition with cancer stem cells, progenitors and more differentiated cells. In this study, we test erlotinib in vitro on other GBM models: three cell lines established from surgically resected GBM specimens, grown along two features adherent and neurospheres. On the three differentiated adhering cell lines, erlotinib had only a moderate activity. Conversely, on neurosphere forming cell lines, erlotinib induced a strong inhibition of cell growth related to the EGFR amplification and EGFR expression. A short erlotinib exposure induced cell death primarily in nestin-positive cells; however it was found without effect on neurosphere initiating activity and self renewal. These results suggest that EGFR pathway activation is essential for the proliferation of GBM progenitor cells but dispensable for stem-like cancer cells self–renewal. As Hedgehog pathway is known to be activated in neural stem cells, we assayed the Hedgehog pathway inhibitor cyclopamine in association with erlotinib. While each drug separately was without effect on sphere initiation, their combination led to a 25 fold decrease in the sphere number (p=0.0004).These in vitro models are convenient to investigate resistance mechanisms in GBM. Furthermore, they focus on the necessity to exploit drug combinations for greatest efficiency.

The rationale behind targeted molecular therapy in cancer, oncogene addiction, is that tumors rely on driver oncogenes to control their proliferation and survival. Therefore, an efficacious targeted therapy should induce a dual, detrimental response to the tumor. While there have been clinical success stories using targeted therapies, even tumors that are initially sensitive invariably develop resistance. In the case of triple negative breast cancer (TNBC), despite extensive evidence pointing to its driver oncogene status, inhibitors of the Epidermal Growth Factor Receptor (EGFR) are considered clinically inefficacious. Resistance to EGFR inhibition has been predominantly described as due to genetic alterations. Yet it remains unclear why patients exhibiting the same dysregulated status of a driver oncogene react to targeted therapy, as in the case of EGFR-mutant non-small cell lung cancer, while others do not at all (i.e., TNBC). Furthermore, not all of resistance can be described by genetic alterations to EGFR, to its pathway effectors, or to compensatory pathways. Emerging data reveals that drugs can induce resistance by rewiring epigenomic, transcriptional, and translational regulatory mechanisms. Unfortunately, a major limitation in designing efficacious treatments is our inability to predict whether cell types can rewire in response to drug exposure. Therefore, it is necessary to elucidate mechanisms of growth and survival in cells that have undergone rewiring. This study characterized intrinsic resistance to EGFR inhibition in TNBC. We found that EGFR inhibition induces rewiring, which results in a resistant growth state that bypasses the EGFR-MAPK pathway as a whole. Additionally, we found that a tRNA-modifying complex masks the oncogene addiction status of EGFR in TNBC by stabilizing the protein abundance of a pro-survival protein. Importantly, this happens solely in the context of EGFR inhibition. Taken together, this study highlights potential therapeutic strategies for TNBC and strategies that can be used to improve our understanding of targeted therapy resistance, especially intrinsic resistance.

In breast cancer therapeutic decisions are based on the expression of estrogen (ER), progesterone (PR), the human epidermal growth factor 2 (HER2) receptors and the proliferation marker Ki67. However, only little is known concerning heterogeneity between the primary tumor and axillary lymph node metastases (LNM) in the primary site. We retrospectively analyzed receptor profiles of 215 early breast cancer patients with axillary synchronous LNM. Of our cohort, 69% were therapy naive and did not receive neoadjuvant treatment. Using immunohistochemistry, receptor status and Ki67 were compared between core needle biopsy of the tumor (t-CNB) and axillary LNM obtained during surgery. The discordance rates between t-CNB and axillary LNM were 12% for HER2, 6% for ER and 20% for PR. Receptor discordance appears to already occur at the primary site. Receptor losses might play a role concerning overtreatment concomitant with adverse drug effects, while receptor gains might be an option for additional targeted or endocrine therapy. Hence, not only receptor profiles of the tumor tissue but also of the synchronous axillary LNM should be considered in the choice of treatment.

No description available.

No description available.