Loss of PTEN expression and AKT activation in HER2-positive breast carcinomas.

PURPOSE: To examine the expression of AKT and PTEN in a series of HER2-positive primary invasive breast tumors using immunohistochemistry, and to associate these expression profiles with classic pathologic features such as tumor grade, hormone receptor expression, lymphatic vascular invasion, and proliferation. METHODS: A total of 104 HER2-positive breast carcinoma specimens were prepared in tissue microarrays blocks for immunohistochemical detection of PTEN and phosphorylated AKT (pAKT). Original histologic sections were reviewed to assess pathological features, including HER2 status and Ki-67 index values. The associations between categorical and numeric variables were identified using Pearson's chi-square test and the Mann-Whitney, respectively. RESULTS: Co-expression of pAKT and PTEN was presented in 59 (56.7%) cases. Reduced levels of PTEN expression were detected in 20 (19.2%) cases, and these 20 tumors had a lower Ki-67 index value. In contrast, tumors positive for pAKT expression [71 (68.3%)] were associated with a higher Ki-67 index value. CONCLUSION: A role for AKT in the proliferation of HER2-positive breast cancers was confirmed. However, immunohistochemical detection of PTEN expression did not correlate with an inhibition of cellular proliferation or control of AKT phosphorylation, suggesting other pathways in these mechanisms of control.

Loss of PTEN expression and AKT activation in HER2-positive breast carcinomas / Perda da expressão do PTEN e ativação da AKT em carcinomas mamários HER2-positivos

PURPOSE: To examine the expression of AKT and PTEN in a series of HER2-positive primary invasive breast tumors using immunohistochemistry, and to associate these expression profiles with classic pathologic features such as tumor grade, hormone receptor expression, lymphatic vascular invasion, and proliferation. METHODS: A total of 104 HER2-positive breast carcinoma specimens were prepared in tissue microarrays blocks for immunohistochemical detection of PTEN and phosphorylated AKT (pAKT). Original histologic sections were reviewed to assess pathological features, including HER2 status and Ki-67 index values. The associations between categorical and numeric variables were identified using Pearson's chi-square test and the Mann-Whitney, respectively. RESULTS: Co-expression of pAKT and PTEN was presented in 59 (56.7%) cases. Reduced levels of PTEN expression were detected in 20 (19.2%) cases, and these 20 tumors had a lower Ki-67 index value. In contrast, tumors positive for pAKT expression [71 (68.3%)] were associated with a higher Ki-67 index value. CONCLUSION: A role for AKT in the proliferation of HER2-positive breast cancers was confirmed. However, immunohistochemical detection of PTEN expression did not correlate with an inhibition of cellular proliferation or control of AKT phosphorylation, suggesting other pathways in these mechanisms of control. .

OBJETIVOS: Avaliar a expressão imuno-histoquímica de AKT e PTEN em uma série de carcinomas mamários invasivos HER2-positivos, e associar seus padrões de expressão com variáveis anatomopatológicas clássicas, como grau histológico, expressão de receptores hormonais, embolização vascular linfática e atividade proliferativa. MÉTODOS: Um total de 104 amostras de carcinomas mamários invasivos HER2-positivos foram preparadas em blocos de microarranjos de tecido para detecção imuno-histoquímica de PTEN e AKT fosforilada (pAKT). Cortes histológicos originais foram revistos para avaliação das características anatomopatológicas, incluindo o estado do HER2 e a avaliação da expressão de Ki-67. As associações entre as variáveis categóricas e as numéricas foram feitas com o uso dos testes do chi-quadrado de Pearson e Mann-Whitney, respectivamente. RESULTADOS: Co-expressão de pAKT e PTEN foi identificada em 59 (56,7%) casos. Expressão reduzida de PTEN foi detectada em 20 (19,2%) casos, e esses 20 tumores mostraram menores valores de Ki-67. Por outro lado, tumores positivos para pAKT [71 (68,3%)] apresentaram células positivas para valores mais altos de Ki-67. CONCLUSÕES: O papel de AKT na proliferação de carcinomas mamários HER-2 positiva foi confirmada. Entretanto, a detecção imuno-histoquímica de PTEN não se correlacionou com inibição da proliferação celular ou controle da fosforilação de AKT, sugerindo outras vias nesses mecanismos de controle. .

Coordinated expression of oestrogen and androgen receptors in HER2-positive breast carcinomas: impact on proliferative activity.

AIMS: Human epidermal growth factor receptor 2 (HER2)-positive breast cancers are aggressive neoplasms associated with a variable response to systemic therapies. Therefore, the identification of biomarkers to better characterise this heterogeneity would improve treatment efficacy. The aim of this study was to evaluate the influence of androgen receptor (AR) and oestrogen receptor (ER) on clinicopathological features in a series of HER2-positive breast carcinomas. METHODS: A total of 104 carcinomas were selected and reviewed. Immunohistochemical studies for ER, progesterone receptor and Ki-67 were analysed on tumour whole histological sections. AR expression was analysed on samples represented on tissue microarrays. According to steroid receptor expression, cases were classified into three groups: AR positive/ER positive (48 cases), AR positive/ER negative (41 cases) and AR negative/ER negative (13 cases). RESULTS: AR-positive tumours corresponded to 89 (85.6%) of 104 carcinomas. AR-positive carcinomas were associated with a higher frequency of ER and progesterone receptor co-expression and lower proliferative activity determined by the expression of Ki-67. AR-negative carcinomas were more often high grade. The group of AR-positive/ER-negative carcinomas was associated with the highest frequency of apocrine morphological features. The group of AR-negative/ER-negative carcinomas was associated with the highest proliferative activity and the highest frequency of high histological and nuclear grade. The lowest frequency of high-grade tumours and the lowest proliferative activity were seen among tumours with expression of both receptors. CONCLUSIONS: These results suggest that co-expression of AR and ER can provide a protective effect based on phenotypical presentation of HER2-positive carcinomas. Furthermore, lack of both steroid hormone receptors characterises the most aggressive phenotype.

MammaGene: ensaio quantitativo de 21 genes para prognóstico do câncer de mama receptor de estrogênio positivo / MammaGene®: a quantitative 21-gene assay for prognostic of breast cancer estrogen receptor-positive

Objetivos: Padronizar em nosso meio um ensaio que analisa, por RT-PCR, 21 genes e descrever a experiência inicial com 95 casos consecutivos de carcinoma inicial de mama receptor de estrogênio positivo. Métodos: O teste foi desenvolvido a partir dos relatos publicados por Cronin et al. (2004) e Paik et al. (2004) para a avaliação da expressão de genes em tecido fixado em formalina e incluído em parafina. O teste foi aplicado em uma coorte consecutiva de 95 amostras de câncer de mama receptor de estrogênio positivo e os escores finais foram comparados com a idade da paciente, O tamanho do tumor, o tipo e o grau histológico, expressão imunoistoquímica do receptor de estrogênio, índice de Ki67 e subtipo molecular. Resultados: Os escores finais variaram de 3 a 90 e as categorias de risco de recorrência em dez anos foram: baixa (34 casos), intermediária (38 casos) e alta (23 casos). Não houve associação das categorias de risco com idade, comprometimento linfonodal e tipo histológico. A media do tamanho dos tumores foi maior no grupo de alto escore (2,0 versus 1,2 cm). Observou-se associação entre o escore obtido pelo teste e grau histológico, Ki-67, nível de expressão de receptor de estrogênio e subtipo molecular. Conclusão: A realização do teste de 21 genes foi factível em nosso meio. Alem disso, os dados preliminares, aliados aos dados da literatura, sugerem que tal teste pode ser uma ferramenta útil na avaliação do risco de recorrência a distância em câncer de mama receptor de estrogênio positivo. No entanto, estudos adicionais são necessários para comparar os resultados deste trabalho com séries amplas publicadas na literatura.

Objectives: To standardize a homemade RT-PCR-based 21-gene assay and to describe the preliminary experience with 95 early positive estrogen receptor breast cancer consecutive cases. Methods: The test was developed using the reports described by Cronin et al. (2004) and Paik et al. (2004) for the evaluation of gene expression in fixed, paraffin-embedded tumor tissue. The test was performed in a consecutive cohort of 95 positive estrogen receptor breast carcinomas, and the final scores were compared with the patient's age, tumor size, histological type, histological degree, estrogen receptor immunohistochemical expression, Ki-67 expression, and molecular luminal subtype. Results: Final scores ranged from 3 to 90 and risk categories of recurrence in ten years were: low (34 cases), intermediate (38 cases), and high (23 cases). There was no association between score categorical distribution and age, lymph node status, or histological type. Mean tumor size was higher in the high score group (2.0 versus 1.2 cm). We have observed an overall concordance between the score obtained by the test, and the histological degree, Ki-67, estrogen receptor level, and molecular subtype. Conclusion: The developed 21-gene assay is a feasible test to be performed in a homemade setting. Besides, the preliminary data from this study suggest, in comparison with data from the literature, that this test has the potential to be a useful tool to evaluate the risk of breast cancer distant recurrence. However, further data are necessary in order to compare this paper's results with larger series published in the literature.