Estrogen receptor alpha/beta ratio and estrogen receptor beta as predictors of endocrine therapy responsiveness-a randomized neoadjuvant trial comparison between anastrozole and tamoxifen for the treatment of postmenopausal breast cancer.

BACKGROUND: The role of estrogen receptor beta (ER-ß) in breast cancer (BC) remains unclear. Some studies have suggested that ER-ß may oppose the actions of estrogen receptor alpha (ER-α), and clinical evidence has indicated that the loss of ER-ß expression is associated with a poor prognosis and resistance to endocrine therapy. The objective of the present study was to determine the role of ER-ß and the ER-α/ER-ß ratio in predicting the response to endocrine therapy and whether different regimens have any effect on ER-ß expression levels. METHODS: Ninety postmenopausal patients with primary BC were recruited for a short-term double-blinded randomized prospective controlled study. To determine tumor cell proliferation, we measured the expression of Ki67 in tumor biopsy samples taken before and after 26 days of treatment with anastrozole 1 mg/day (N = 25), tamoxifen 20 mg/day (N = 24) or placebo (N = 29) of 78 participants. The pre- and post-samples were placed in tissue microarray blocks and submitted for immunohistochemical assay. Biomarker statuses (ER-ß, ER-α and Ki67) were obtained by comparing each immunohistochemical evaluation of the pre- and post-surgery samples using the semi-quantitative Allred's method. Statistical analyses were performed using an ANOVA and Spearman's correlation coefficient tests, with significance at p ≤ 0.05. RESULTS: The frequency of ER-ß expression did not change after treatment (p = 0.33). There were no significant changes in Ki67 levels in ER-ß-negative cases (p = 0.45), but in the ER-ß-positive cases, the anastrozole (p = 0.01) and tamoxifen groups (p = 0.04) presented a significant reduction in post-treatment Ki67 scores. There was a weak but positive correlation between the ER-α and ER-ß expression levels. Only patients with an ER-α/ER-ß expression ratio between 1 and 1.5 demonstrated significant differences in Ki67 levels after treatment with anastrozole (p = 0.005) and tamoxifen (p = 0.026). CONCLUSIONS: Our results provide additional data that indicate that the measurement of ER-ß in BC patients may help predict tamoxifen and anastrozole responsiveness in the neoadjuvant setting. These effects of hormonal treatment appear to be dependent on the ratio of ER-α/ER-ß expression. TRIAL REGISTRATION: Current Controlled Trials ISRCTN89801719.

Expression of BCL-2 and bax proteins in breast cancer after in vivo tamoxifen administration / Expressão das proteínas BCL-2 e BAX no câncer de mama após administração in vivo de tamoxifeno

Apesar de apresentarem receptores estrogênicos nas células tumorais, algumas pacientes com câncer de mama não se beneficiam do tratamento com tamoxifeno, medicamento conhecido por interferir no ciclo celular e promover apoptose. Sabendo-se que as proteínas BCL-2 e BAx estão diretamente relacionadas a este processo, é importante compreender quais os caminhos que levam à morte celular que sofrem interferência do tamoxifeno. Amostras pareadas de câncer de mama foram obtidas antes e após tratamento de pacientes previamente, assim randomizadas: grupo controle e grupo de tratamento com tamoxifeno. O grupo de tratamento recebeu tamoxifeno (20 mg/dia) por 14 dias. A identificação imunoistoquímica da expressão de BAX e BCL-2 foi analizada de forma semiquantitativa, considerando o número de células coradas e a intensidade da coloração. Os escores de cada reação foram comparados pré e pós-tratamento, e também em relação ao grupo controle. Das 25 pacientes estudadas, considerando nenhuma exposição ao medicamento, foram encontradas 36 (9/25) e 72% (18/25) de casos positivos para BCL-2 e Bax, respectivamente. Este estudo não encontrou mudanças significativas sobre a expressão das proteínas BCL-2 e BAX, após 14 dias de tratamento com tamoxifeno (p>0,05), comparado ao grupo controle. A expressão das proteínas BCL-2 e BAX também não sofreu mudanças significativas após 14 dias de exposição ao tamoxifeno. Este é um dos poucos trabalhos prospectivos randomizados de estudo in vivo dos efeitos do tamoxifeno na apoptose.

Despite the presence of estrogen receptor in breast cancer cells, some patients do not show benefits on their treatmentwith tamoxifen, which is a medication that interferes on cell cycle promoting apoptosis. Since BCL-2 and BAX proteins are directly linked to this process, it is important to understand which pathways for cell death are related to and interfered by tamoxifen. Paired samples of breast cancer tumors, which were previously obtained before and after tamoxifen therapy were randomly divided in the Control and Treated Patients Groups. The Treated Group received tamoxifen for 14 days (20 mg/day). The immunohistochemical identification of BAX and BCL-2 expression was analyzed in a semi-quantitative scale consideraing the number of positive cells and intensity of staining. The scores of each reaction were compared pre and post-treatment and to the Control Group. Over the 25 patients studied, considering no exposure to the drug, there were 36 (9/25) and 72% (18/25) of positive cases for BCL-2 and BAX, respectively. This study showed no significant changes over BCL-2 and BAX proteins expressions after 14 days of tretament with tamoxifen (p>0,05) compared to the control patients. Expression of BCL-2 and BAX proteins did not suffer statistically significant changes after a 14-day exposure to tamoxifen. This is one of a few prospective randomized double-blind studies about in vivo effects of tamoxifen in apoptosis.

A case report of male breast cancer in a very young patient: what is changing?

Male breast cancer accounts for 1% of all breast cancer cases, and men tend to be diagnosed at an older age than women (mean age is about 67 years). Several risk factors have been identified, such as genetic and hormonal abnormalities. The present study reported the case of a 25-year-old man who was diagnosed with an advanced invasive ductal carcinoma; however, he did not have any important risk factors. Even though more data is emerging about this disease, more efforts to understand risk factors, treatment options and survival benefits are needed. In this case, we discussed the risk factors as well as the impaired fertility associated with breast cancer therapies.

Importância do atendimento integrado em mastologia para redução da mortalidade por câncer de mama / The role of integrated patient care in mastology to reduce breast cancer mortality rate

Após analisar 39.589 mulheres atendidas de julho de 2005 a maio de 2010 no Centro de Referência da Saúde da Mulher (Hospital Estadual Perola Byington), foi observado que o atendimento resolutivo permitiu concluir o diagnóstico em lesões clínicas em 95,4% das pacientes. Cerca de 34,5% das pacientes encaminhadas não tinham nenhuma patologia mamária; destas, mais de 68% tinham realizado exames por imagem solicitados pelo ginecologista. Apenas 7,1% das pacientes encaminhadas apresentavam carcinoma. A porcentagem de pacientes no estádio I aumentou de 12,7 para 23,4%. Igualmente no estádio II, houve aumento de 40,3 para 54,1% das pacientes diagnosticadas. Ao contrário, houve redução no número de tumores avançados (estádio III) de 40,2 para 15,2%. Os resultados obtidos permitem concluir que, no momento do diagnóstico, os tumores nos estádios I e II representaram 77,5% dos casos. Esses resultados mostram de forma clara que a falta de acesso e resolutividade são as mais importantes causas de progressão da doença, pois certamente em três ou seis meses grande parte das neoplasias das pacientes diagnosticadas e tratadas nos Estádio I e II progrediria. A rápida redução no número de casos avançados permite estimar redução de mortalidade de 19,8% pela doença. O modelo de atendimento mostra uma excelente estratégia de custo efetividade voltado para instituições com grande demanda das grandes cidades brasileiras, que tratam mais de 80% dos casos de câncer de mama, permitindo uma rápida redução da taxa de mortalidade.

After examining 39,589 women attended from July, 2005 to May, 2010 in the Reference Center for Women’s Health (Pérola Byington State Hospital), we concluded the diagnosis in one step consultation in 95.4% of patients. About 34.5% of referred patients had no breast pathology; of these, over 68% had undergone imaging studies requested by the gynecologist. We observed that only 7.1% of referred patients had carcinoma. The percentage of patients in stage I increased from 12.7 to 23.4%. Also, in stage II there was an increase from 40.3 to 54.1 % of those diagnosed. Instead, there was reduction in the number of advanced tumors (stage III) from 40.2 to 15.2%. The results showed that at diagnosis, the tumors in stages I and II accounted for 77.5% of the cases. These results clearly show that the lack of access and biopsy to confirm the diagnosis are the most important causes of disease progression, because certainly in three or six months, most tumors of patients diagnose and treated in Stages I and II would progress. The rapid reduction in the number of cases that we have developed allows us to estimate a mortality reduction of 19.8% by the disease. The service model shows an excellent cost effective strategy aimed at institutions with high demands from Large Brazilian cities, treating more than 80% of cases of breast cancer, allowing a rapid reduction of mortality rate.

Indicações da cirurgia conservadora no câncer de mama / Indications for conservative surgery in breast cancer

O rastreamento mamográfico aumentou o número de pacientes em estádios iniciais do câncer de mama, que propiciaram a realização de estudos randomizados sobre cirurgia conservadora. Esses estudos demonstraram que a cirurgia conservadora associada à radioterapia, indicada em tumores com até 3 cm de diâmetro, não modifica a sobrevida após 25 anos de seguimento, apesar de acarretar um aumento significativo de recidiva local.

Screening mammography has increased the number of patients in early stages of breast cancer, which led to randomized studies on conservative surgery. These studies demonstrate that conservative surgery combined with radiotherapy, indicated in tumors with up to 3 cm, does not after survival after 25 years of follow-up, despite a significant increase of local recurrence.

Estado atual da biópsia do linfonodo sentinela / Sentinel lymph biopsy in breast cancer

A biópsia do linfonodo sentinela (LS) tornou-se procedimento padrão para a avaliação do status axilar nos casos de câncer de mama inicial. Esse procedimento foi validado por vários estudos, com uma acurácia média de 95%. O objetivo deste artigo de atualização foi analisar os resultados mais recentes e as dúvidas que ainda são reportadas na literatura a respeito do uso da biópsia LS no tratamento cirúrgico do câncer de mama.

The sentinel Lymph node biopsy has become the standard procedure to the axiLLary status evaluation in early breast cancer. This procedure has been vaLidated by severaL studies with an accuracy of 95%. The aim of this update article was to analyze the most recently resuLts and open probLems reported inLiterature about the use of sentinel node biopsy in breast cancer surgical treatment.

Correlação entre COX-2 e ciclina D-1 após administração de tamoxifeno neoadjuvante em curto prazo no tratamento de carcinoma de mama / Correlation of COX-2 and ciclyn D-1 after short-time neoadjuvant tamoxifen on breast cancer

Introdução: O tamoxifeno é a droga utilizada há mais tempo na terapia hormonal do câncer de mama. A superexpressão da ciclina D-1 interfere negativamente no tratamento com tamoxifeno e pode contribuir para predição da falha terapêutica observada em algumas pacientes. COX-2 induz a oxidação de estrogênio a dietilestilbestrol e importante ação genotóxica na mama. Ciclina D-1 e COX-2 ainda não foram descritos associados em relação ao tratamento com tamoxifeno em curto período (14 dias). Objetivo: Avaliar os efeitos da administração neoadjuvante de tamoxifeno em curto prazo (14 dias) sobre a expressão de COX-2 e ciclina D -1 no tratamento do câncer de mama. Métodos: Estudo prospectivo randomizado realizado na disciplina de Mastologia da Unifesp. Vinte e cinco pacientes com carcinoma de mama nos estádios II e III, subdivididas em grupos (controle, n=13, e tratamento, n=12). As amostras de ciclina D-1 e COX-2 foram avaliadas antes e após o tratamento. A avaliação imuno-histoquímica foi realizada por meio de anticorpos policlonais para COX-2 (Novo castra - Clone 4H12) e ciclina D-1 (Novocastra - Clone DCS-6). Os resultados foram classificados de acordo com a fração e intensidade de coloração das células marcadas. Resultados: Observou-se positividade da COX-2 em 56% dos tumores, sem diferença significativa nos dois momentos da amostra (p = 0,39 - Mann Whitney test*1). A expressão da COX-2 não apresentou diferença significativa nas amostras pré e pós nos grupos controle e tratamento. Na amostra total do estudo, observou-se alteração da expressão da ciclina D-1 entre os dois momentos da amostra (teste de McNemar - Diferença = 36.00% (p = 0,06). Entre os grupos controle e tratamento, observou-se que a diferença das medianas de ciclina D-1 entre as amostras pós e pré (pós - pré) demonstrou tendência à significância estatística pelo teste de Mann-Whitney (p = 0,08). Conclusão: O tratamento neoadjuvante com tamoxifeno em curto prazo (14 dias) não foi capaz de modificar...

Introduction: Tamoxifen is the most used drug in the hormonal therapy of the breast cancer. Ciclyn D-J, one CCNDJ gene product's (PRADJ), is essential for the normal lobule-alveolar mammary development and acts in the cellular cycle control. Ciclyn D-I superexpression act negatively in tamoxifen treatment, and may contribute to predict the failure observed in some patients. COX-2 activity induces oestrogen oxidation to dietilstilbestrol and promotes genotoxics effects on the breast. Ciclyn D-1 and COX-2 association had not been described yet to short time tamoxifen treatment. Objective: Evaluate short time (14 days) neoadjuvant tamoxifen effects on COX-2 and ciclyn D-1 expression in breast cancer patients. Methods: Randomized prospective study in the Federal University of Sao Paulo. Twenty five patients with stage II and III breast cancer were included. The groups were control (n = 13) and treatment (n = 12). Ciclyn D-1 and COX-2 samples were evaluated before and after treatment. Imunohistochemistry was performed on the tissue sections using a polyclonal antibody to COX-2 (Novocastra - Clone 4H12) and cyclin D-1 (Novocastra - Clone DCS-6). The results were classified according Already score, based on the intensity and fraction marked cells. Results: COX-2 was positive in 56% of tumors. No significant difference was observed between the two groups (p = 0.39 Mann Whitney test). The Difference of cyclin D-1 medium (post - pre) in the control group was 5, while in the tamoxifen group was 0.5. (p=0.08, Mann Whitney test). Correlation between COX-2 and ciclyn D-1 was expressed by Pearson index (r). In treatment group moderate linear and positive correlation was observed (r = 0.51 - Pearson's index) (p = 0.08). It wasn't observed in control group (r = 0.42) (p = 0.12). Conclusion: Tamoxifen treatment in short time period (14 days) wasn't modified significantly COX-2 and ciclyn D-1 expression.