RESUMEN
BACKGROUND: As age advances breast cancer appears to change its biological characteristics, however, very limited data are available to define the precise differences between older and younger patients. METHODS: Over 36 years (1973-2009), 1758 older (≥70 years) women with early operable primary breast cancer were managed in a dedicated clinic. In all, 813 underwent primary surgery and 575 good quality tumour samples were available for biological analysis. The pattern of biomarkers was analysed using indirect immunohistochemistry on tissue microarrays. Comparison was made with a previously characterised series of younger (<70 years) patients. RESULTS: There was high expression of oestrogen receptor (ER), PgR, Bcl2, Muc1, BRCA1 and 2, E-cadherin, luminal cytokeratins, HER3, HER4, MDM2 and 4 and low expression of human epidermal growth factor receptor (HER)-2, Ki67, p53, EGFR and CK17. Oestrogen receptor and axillary stage appeared as independent prognostic factors. Unsupervised partitional clustering showed six biological clusters in older patients, five of which were common in the younger patients, whereas the low ER luminal cluster was distinct in the older series. The luminal phenotype showed better breast cancer-specific survival, whereas basal and HER2-overexpressing tumours were associated with poor outcome. CONCLUSION: Early operable primary breast cancer in older women appears as a distinct biological entity, with existence of a novel cluster. Overall older women showed less aggressive tumour biology and ER appeared as an independent prognostic factor alongside the time-dependent axillary stage. These biological characteristics may explain the differences in clinical outcome and should be considered in making therapeutic decisions.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/cirugía , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Supervivencia sin Enfermedad , Femenino , Humanos , Persona de Mediana Edad , Pronóstico , Resultado del TratamientoRESUMEN
Although the favourable role of T lymphocyte populations in different tumour types is established, that of B cells is still a matter of debate and needs further clarification. The presence of tumour-infiltrating B cells may represent an antibody response against breast tumour antigens. We used immunohistochemistry to investigate the density and localisation of B lymphocytes infiltrating 1470 breast tumours and to identify any prognostic significance and relationship to various clinicopathological factors. Higher numbers of CD20(+) cells were found in the stroma away from the carcinoma (mean 12 cells) compared with either intratumoural or adjacent stromal compartments (mean 1 cell). The majority of tumours showed a diffuse pattern of B cells rather than aggregates. There was a positive correlation between higher numbers of total CD20(+) B cells and higher tumour grade (r (s) = 0.20, P < 0.001), ER and PgR negativity (P < 0.001), and basal phenotype (P < 0.001) subclass. In univariate survival analysis, higher total number of infiltrating CD20(+) cells, irrespective of location, was associated with significantly better BCSS (P = 0.037) and longer DFI (P = 0.001). In multivariate analysis, total CD20(+) B cell count (HR = 0.75, 95% CI = 0.58-0.96 for BCSS and HR = 0.72, 95% CI = 0.58-0.89, for DFI), tumour size, nodal stage, grade, vascular invasion, HER-2 status, and total CD8(+) T cell count were independently associated with outcome. This suggests that humoral immunity, in addition to the cell mediated immunity, may be important in breast cancer. This should be considered in breast cancer immunotherapy and vaccine strategies.
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Linfocitos B/inmunología , Neoplasias de la Mama/inmunología , Carcinoma/inmunología , Inmunidad Humoral , Linfocitos Infiltrantes de Tumor/inmunología , Adulto , Antígenos CD20/análisis , Biomarcadores de Tumor/análisis , Neoplasias de la Mama/química , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Carcinoma/química , Carcinoma/mortalidad , Carcinoma/patología , Supervivencia sin Enfermedad , Inglaterra , Femenino , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Recuento de Linfocitos , Persona de Mediana Edad , Análisis Multivariante , Clasificación del Tumor , Invasividad Neoplásica , Estadificación de Neoplasias , Fenotipo , Pronóstico , Modelos de Riesgos Proporcionales , Receptores de Estrógenos/análisis , Receptores de Progesterona/análisis , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Factores de TiempoRESUMEN
The basal-like or basal phenotype (BP) class of breast cancers have recently attracted attention as a poor prognostic form of breast cancer. However, BP appears to encompass biologically and clinically heterogeneous tumours, resulting in a lack of consensus definition of BP. We analysed 48,000 gene transcripts in 132 invasive breast carcinomas to identify two novel genes (OATP2 and FABP7) significantly associated with BP [defined by cytokeratin (CK)5/6 and/or CK14 positivity]. Using a series of invasive breast carcinoma cases (n = 899), prepared as tissue microarrays, we assessed OATP2 and FABP7 protein expression using immunohistochemistry to investigate associations with clinicopathological variables, patients' outcome and ability to refine BP classification. A total of 7.9 and 15.6% cases were OATP2 and FABP7 positive, respectively. OATP2 was associated with tumours of high histological grade (p < 0.01), ER and PgR negativity (p < 0.01) and shorter breast cancer-specific survival (p = 0.04). FABP7 expression was associated with lower lymph node stage (p < 0.01), ER and PgR negativity (p < 0.01). BP tumours which were FABP7 positive had a significantly longer BCSS (p = 0.05) and disease-free survival (p = 0.01) compared with FABP7 negative basal tumours (p < 0.01). OATP2 positive tumours were associated with adverse survival and increased risk of early recurrence. This study confirms the biological and clinical heterogeneity of the BP in breast cancer. We have identified a novel subgroup of basal tumours showing FABP7 expression that have significantly better clinical outcome. Further studies analysing the role of FABP7 are therefore warranted.
Asunto(s)
Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Proteínas Portadoras/biosíntesis , Transportador 1 de Anión Orgánico Específico del Hígado/biosíntesis , Proteínas Supresoras de Tumor/biosíntesis , Adulto , Biomarcadores de Tumor/análisis , Neoplasias de la Mama/genética , Proteínas Portadoras/genética , Supervivencia sin Enfermedad , Proteína de Unión a los Ácidos Grasos 7 , Femenino , Expresión Génica , Perfilación de la Expresión Génica , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Transportador 1 de Anión Orgánico Específico del Hígado/genética , Persona de Mediana Edad , Estadificación de Neoplasias , Fenotipo , Pronóstico , Análisis de Matrices Tisulares , Resultado del Tratamiento , Proteínas Supresoras de Tumor/genéticaRESUMEN
Gene expression microarrays allow for the high throughput analysis of huge numbers of gene transcripts and this technology has been widely applied to the molecular and biological classification of cancer patients and in predicting clinical outcome. A potential handicap of such data intensive molecular technologies is the translation to clinical application in routine practice. In using an artificial neural network bioinformatic approach, we have reduced a 70 gene signature to just 9 genes capable of accurately predicting distant metastases in the original dataset. Upon validation in a follow-up cohort, this signature was an independent predictor of metastases free and overall survival in the presence of the 70 gene signature and other factors. Interestingly, the ANN signature and CA9 expression also split the groups defined by the 70 gene signature into prognostically distinct groups. Subsequently, the presence of protein for the principal prognosticator gene was categorically assessed in breast cancer tissue of an experimental and independent validation patient cohort, using immunohistochemistry. Importantly our principal prognosticator, CA9, showed that it is capable of selecting an aggressive subgroup of patients who are known to have poor prognosis.
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Biomarcadores de Tumor/genética , Neoplasias de la Mama/genética , Perfilación de la Expresión Génica , Metástasis de la Neoplasia/genética , Redes Neurales de la Computación , Adulto , Anciano , Antígenos de Neoplasias/biosíntesis , Área Bajo la Curva , Neoplasias de la Mama/patología , Anhidrasa Carbónica IX , Anhidrasas Carbónicas/biosíntesis , Biología Computacional/métodos , Femenino , Humanos , Inmunohistoquímica , Persona de Mediana Edad , Pronóstico , Curva ROC , Sensibilidad y Especificidad , Análisis de Matrices TisularesRESUMEN
AIMS: To establish a three dimensional reconstruction of an invasive breast carcinoma using basic laboratory equipment to evaluate and characterise the spatial arrangement of the parenchymal cells of the breast. METHODS: One hundred and twenty eight sequential 4 microm sections (20 microm apart) of the tumour were stained immunohistochemically with an epithelial specific marker (AE1/AE3) or tumour specific marker (c-erbB-2) to reconstruct two different three dimensional images of the normal and malignant parenchymal cells. Sections were digitally imaged using a microscope, scanner, and digital camera linked to a conventional personal computer. Accurate alignment of the digitalised images was carried out using a semiautomatic graphical method of manual interaction, using the cross correlation coefficient as a goodness of fit measure, and an automatic search algorithm using the Fibonacci search algorithm for automatic alignment. The volume was reconstructed using maximum, minimum point projection and "back to front" opacity blending. RESULTS: The quality of the reconstructed images was distinct and perfect, providing a comprehensive and explicit view of the normal and malignant parenchymal tissues of the breast that is not possible by viewing two dimensional histological sections. Specifically, this approach showed the spatial arrangement of the tumour cells and their relation to the surrounding tissues at a high resolution. CONCLUSION: This simple and reproducible approach enables the spread and infiltration of invasive carcinoma to be understood and could also be used to analyse the spatial relation between atypical hyperplastic and malignant in situ lesions of the breast.
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Neoplasias de la Mama/patología , Carcinoma Ductal de Mama/patología , Imagenología Tridimensional/métodos , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/metabolismo , Carcinoma Ductal de Mama/metabolismo , Femenino , Humanos , Técnicas para Inmunoenzimas , Invasividad Neoplásica , Receptor ErbB-2/metabolismo , Reproducibilidad de los ResultadosRESUMEN
BACKGROUND: Macrophages constitute a major component of the leucocytic infiltrate of tumours. Human studies show an association between tumour-associated macrophages and tumours with poor prognostic features. In breast cancer, the presence of macrophages has been correlated with increased angiogenesis and poor prognosis but little information is available about the independent prognostic role of macrophages infiltrating breast carcinomas. AIMS AND METHODS: This study used immunohistochemistry and tissue microarrays to assess the density and localisation of CD68 macrophages infiltrating 1322 breast tumours and to identify any relationship with clinicopathological factors and patient outcome. RESULTS: Tumour-infiltrating macrophages were present in the majority of tumours with a predominantly diffuse pattern. The density of distant stromal macrophages (infiltrating stroma away from the carcinoma, median count 14 cells) was higher than intratumoural (median zero cells) and adjacent stromal macrophages (median three cells). Higher total macrophage number was associated with higher tumour grade (r(s)=0.39, p<0.001), ER and PgR negativity, HER-2 positivity and basal phenotype (p<0.001). In univariate survival analysis, higher numbers of CD68 macrophages were significantly associated with worse breast cancer-specific survival (p<0.001) and shorter disease-free interval (p=0.004). However in multivariate model analysis, the CD68 macrophage count was not an independent prognostic marker. CONCLUSIONS: Macrophages are heterogeneous with different subsets having different functions. The present study suggests that overall macrophage numbers are not related to prognosis in breast cancer. However, further studies are needed to investigate the potential role of different subsets of macrophages.
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Neoplasias de la Mama/patología , Macrófagos/metabolismo , Adulto , Anciano , Antígenos CD/metabolismo , Antígenos de Diferenciación Mielomonocítica/metabolismo , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/mortalidad , Recuento de Células , Femenino , Estudios de Seguimiento , Humanos , Macrófagos/patología , Persona de Mediana Edad , Clasificación del Tumor , Pronóstico , Estudios Retrospectivos , Análisis de Supervivencia , Análisis de Matrices TisularesRESUMEN
AIM: A better understanding of the biology of nodal metastatic disease is of indisputable value. Three-dimensional (3D) serial section alignment and reconstruction techniques can be used for visualisation of nodal metastasis and could provide better understanding of disease growth patterns. METHODS: 19 tumour-involved sentinel nodes (SLNs) from breast cancer patients were serially sectioned, immunohistochemically stained, and digitally scanned. Digital image alignment and voxel-based rendering was used to construct informative 3D visual representations of metastatic tumour distribution within involved nodes. RESULTS: The 3D reconstruction technique was successful and informative. The reconstructions of all 19 SLNs enabled the metastatic tumour cells to be viewed infiltrating normal SLN tissue from all angles. Metastases were present at the afferent lymphatic pole in 17/19 cases, confined to the afferent pole only in 7 cases, located at the efferent pole in 12/19 cases, and efferent pole only in just 2 cases. Finally, this study made the novel observation that metastatic growth occurs in three distinct patterns: sinusoidal, nodular and diffuse. CONCLUSIONS: This methodology provides improved understanding of metastatic disease development and potentially could be used to develop strategies to improve techniques for its routine detection. Further studies are required in order to evaluate the prognostic and biological significance of the growth patterns identified.
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Neoplasias de la Mama/patología , Metástasis Linfática/patología , Axila , Vasos Sanguíneos/patología , Femenino , Humanos , Imagenología Tridimensional/métodos , Metástasis Linfática/diagnóstico por imagen , Invasividad Neoplásica , Estudios Prospectivos , Cintigrafía , Radiofármacos , Biopsia del Ganglio Linfático Centinela , Agregado de Albúmina Marcado con Tecnecio Tc 99mRESUMEN
Aromatase inhibitors have been shown to be superior to Tamoxifen in several settings. It is unclear whether this superiority extends to their use as primary endocrine therapy in elderly patients with early operable primary breast cancer. Biological characteristics of the tumours may aid in selecting the most suitable agent. Primary endocrine therapy with Anastrozole in 64 women >70 years with oestrogen receptor alpha-positive (ERalpha+) breast cancer was compared to that in 84 treated with Tamoxifen during the same period. Biomarkers were assessed by immunohistochemistry on diagnostic core biopsies. There was no significant difference between the two groups (Anastrozole vs Tamoxifen) in terms of clinical benefit rates at 6 months (97% vs 100%) or median progression free survival (16.5 vs 22.5 months). There were no withdrawals due to adverse events from Anastrozole, compared to four with Tamoxifen. 46%, 99%, 8% and 5% of all patients were positive for progesterone receptor, ERbeta2, HER2 and EGFR, respectively, and 64% of patients had a moderate Ki-67 index. Positive HER2 status (18 vs 21 months, p=0.003) and moderate Ki-67 index (17.5 vs 23 months, p=0.042) were associated with significantly shorter progression free survival. Results thus far show that primary endocrine therapy with Anastrozole in elderly patients with early operable ERalpha+ breast cancer is similar to Tamoxifen in terms of efficacy, but appears to be associated with less adverse events leading to withdrawals. In this population, ERalpha+ breast cancer also appears to have a less aggressive biological profile favouring better hormone sensitivity.
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Antineoplásicos Hormonales/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Nitrilos/uso terapéutico , Tamoxifeno/uso terapéutico , Triazoles/uso terapéutico , Anciano , Anciano de 80 o más Años , Anastrozol , Biomarcadores de Tumor/análisis , Neoplasias de la Mama/mortalidad , Supervivencia sin Enfermedad , Femenino , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Receptores de Estrógenos/metabolismoRESUMEN
AIM: Metastases from ovarian serous papillary carcinoma to the breast and primary invasive micropapillary carcinoma of the breast are histologically similar. The distinction is clinically important to ensure appropriate management. Wilms' tumour-1 (WT1) and Ca125 are frequently expressed in serous papillary carcinomas, and uncommonly in unselected mammary carcinomas. One previous study found Ca125 expression in 69% of invasive micropapillary carcinomas. The aim was to assess the frequency of expression of WT1 and Ca125 in invasive micropapillary carcinoma. METHODS AND RESULTS: Twenty-five of 34 invasive micropapillary carcinomas showed no nuclear expression of WT1. The remaining nine tumours showed weak to moderate immunoreactivity in 1-10% of nuclei. Six of these nine tumours also contained ductal carcinoma in situ, which expressed WT1 in five of the six. Membranous or cytoplasmic expression of Ca125 was found in seven tumours. CONCLUSION: Nuclear WT1 expression is present in a minority of invasive micropapillary carcinomas and, when present, expression is focal. The frequency of expression of Ca125 was similar to the results in unselected mammary carcinoma. Thus, these markers are useful members of the immunohistochemical panel for the distinction of mammary invasive micropapillary carcinoma from ovarian serous papillary carcinoma.
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Biomarcadores de Tumor/análisis , Neoplasias de la Mama/metabolismo , Antígeno Ca-125/biosíntesis , Carcinoma Papilar/metabolismo , Proteínas WT1/biosíntesis , Neoplasias de la Mama/patología , Carcinoma Papilar/patología , Cistadenocarcinoma Papilar/secundario , Cistadenocarcinoma Seroso/secundario , Diagnóstico Diferencial , Femenino , Humanos , Inmunohistoquímica , Neoplasias Ováricas/patologíaRESUMEN
Vascular endothelial cell growth factors (VEGF)-A, -C and -D have potent angio and lymphangiogenic functions in experimental models, although their role in the progression of human breast cancer is unclear. The aims of the current study were to examine the relationship between the expression of the aforementioned growth factors with the angio and lymphangiogenic characteristics of breast cancer, and to assess their suitability as potential prognostic factors. Paraffin-embedded sections of 177 primary invasive breast cancer, with complete clinical follow-up information for 10 years, were stained for VEGF-A, -C, -D, podoplanin and CD34 using standard immunohistochemical approaches. The expression of the growth factors was correlated with clinicopathological criteria and patients' survival. Lymph vessel density (LVD) and microvessel density (MVD) were assessed and correlated with expression of the growth factors. Vascular endothelial cell growth factor-A, -C and -D were highly expressed in 40, 37 and 42% of specimens, respectively. High expression of VEGF-A and - C, but not of -D, was associated with a higher LVD (P=0.013 and P=0.014, respectively), a higher MVD (P<0.001 and P=0.002, respectively), the presence of lymph node metastasis (P<0.001 and P<0.001, respectively), distant metastasis (P=0.010 and P=0.008, respectively) and a shorter Overall Survival (P=0.029 and 0.028, respectively). In conclusion, breast cancers that express high levels of VEGF-A and -C are characterised by a poor prognosis, likely through the induction of angio and lymphangiogenesis. Examination of expression of VEGF-A and -C in breast cancer may be beneficial in the identification of a subset of tumours that have a higher probability of recurrence and metastatic spread.
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Neoplasias de la Mama/metabolismo , Linfangiogénesis , Neovascularización Patológica/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Factor C de Crecimiento Endotelial Vascular/metabolismo , Factor D de Crecimiento Endotelial Vascular/metabolismo , Adulto , Anciano , Neoplasias de la Mama/patología , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Técnicas para Inmunoenzimas , Persona de Mediana Edad , Neovascularización Patológica/patología , Pronóstico , Tasa de SupervivenciaRESUMEN
AIM: To assess the expression and coexpression of a range of different biomarkers that have been used to define breast carcinomas with a basal phenotype (BP) and their relationship with prognosis in an attempt to refine the definition of BP and to evaluate the reliability of using a single biomarker to identify these tumours. METHODS AND RESULTS: The expression pattern of basal cytokeratins (CK5/6 and CK14), oestrogen, progesterone and androgen receptors, epidermal growth factor receptor, HER2, BRCA1, P-cadherin and myoepithelial markers (smooth muscle actin and p63) were studied in a well-characterized series of invasive breast carcinoma (1872 cases) with long-term follow-up using immunohistochemistry and tissue microarray. Although the additional markers were associated with basal CK expression, they did not serve to improve recognition of cases with differing outcome when compared with basal CKs alone and, if used to define cases, reduced considerably the proportion of cases allocated to this poor prognostic type of breast cancer. CONCLUSION: BP can be defined based on the expression of basal CKs regardless of the expression of other markers.
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Biomarcadores de Tumor/biosíntesis , Neoplasias de la Mama/metabolismo , Queratina-14/biosíntesis , Queratina-5/biosíntesis , Queratina-6/biosíntesis , Anciano , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/patología , Diferenciación Celular , Femenino , Estudios de Seguimiento , Humanos , Inmunohistoquímica , Invasividad Neoplásica , Fenotipo , Análisis de Matrices TisularesRESUMEN
p27kip1 is a member of the KIP/CIP family of cyclin-dependent kinase inhibitors and is a negative cell-cycle regulator that is thought to play a role in tumour suppression. Reduced levels of this protein have been observed in a number of human cancers. However, evidence is conflicting as to whether p27kip1 has a role to play in breast cancer, including predicting behaviour and prognosis. The present investigation aimed to provide a definitive study of 830 breast cancer cases with median patient follow-up of 104 months to determine the true prognostic significance, if any. Immunohistochemical analysis of tissue microarrays and three scoring methods were used to assess p27kip1 expression. Univariate analysis showed a significant relationship between reduced p27kip1 expression and increasing tumour grade, nuclear pleomorphism, mitosis, and decreasing tubule formation (all p<0.001). Significant associations between reduced p27, negative oestrogen receptor status, and ductal/no special type tumours were also observed. Survival analysis demonstrated that patients with tumours with high p27kip1 levels had an improved survival compared with those with cancers with low expression. On multivariate analysis, when compared with existing factors, p27kip1 was not, however, an independent prognostic factor. It is concluded that the inverse relationship between p27kip1 levels and histological grade and individual grade components suggests a role for p27kip1 in both cell proliferation and differentiation, but is not clinically useful.
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Neoplasias de la Mama/enzimología , Proteínas de Ciclo Celular/análisis , Inhibidores Enzimáticos/análisis , Proteínas de Neoplasias/análisis , Proteínas Supresoras de Tumor/análisis , Adulto , Anciano , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Recuento de Células , Núcleo Celular/patología , Inhibidor p27 de las Quinasas Dependientes de la Ciclina , ADN de Neoplasias/análisis , Femenino , Humanos , Inmunohistoquímica/métodos , Persona de Mediana Edad , Mitosis , Invasividad Neoplásica/patología , Estadificación de Neoplasias , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Pronóstico , Receptores de Estrógenos/análisis , Reproducibilidad de los ResultadosRESUMEN
PTEN is a novel tumour suppressor gene located on chromosome 10. PTEN mutations are believed to exert their effects through the putative PI3K-AKT-mTOR signalling pathway. Specifically, loss of PTEN leads to activation of AKT, which in turn promotes anti-apoptotic and pro-cell cycle entry pathways believed to be essential in tumourigenesis. Whilst PTEN mutations are frequent in a variety of sporadic cancers and inherited cancer syndromes, it is not clear how frequently PTEN mutations and immunohistochemical loss of PTEN expression occur in sporadic breast cancer. This study used tissue microarrays (TMAs) to assess wild-type PTEN and pAKT immunohistochemical staining in 670 and 691 cases, respectively, of primary operable breast cancer. Scores of 0, 1, and 2 were given for negative, weakly positive, and strongly positive degrees of immunoreactivity, respectively. In addition, immunohistochemical assessment of epidermal growth factor receptor (EGFR), Her2, and proliferation by MIB1 expression was performed on the same TMAs and the scores were compared with those of PTEN and pAKT. Eight per cent of cases did not express wild-type PTEN. No correlation was observed between patient, tumour and outcome variables and PTEN. pAKT expression correlated inversely with adverse tumour variables such as tumour grade (p< 0.001) and correlated positively with ER status (p< 0.001). No correlation was seen between either PTEN or AKT and EGFR, Her2 or MIB1. No association of PTEN or pAKT was seen in Kaplan-Meier or multivariate analysis for overall survival. The results indicate that loss of PTEN expression is infrequent in breast cancer. PTEN and AKT do not appear to be prognostic markers. The study argues against the current model of a simple linear tumourigenic PTEN-PI3K-AKT-mTOR pathway in breast cancer. It also suggests that, in this group of breast cancers, the most common upstream regulator of AKT may be ER rather than PTEN, EGFR or Her2.
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Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/metabolismo , Proteínas de Neoplasias/metabolismo , Monoéster Fosfórico Hidrolasas/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Adulto , Anciano , Transformación Celular Neoplásica , Femenino , Humanos , Técnicas para Inmunoenzimas , Persona de Mediana Edad , Fosfohidrolasa PTEN , Pronóstico , Proteínas Proto-Oncogénicas c-akt , Transducción de Señal , Análisis de SupervivenciaRESUMEN
BRCA1 is a tumour suppresser gene frequently mutated in familial breast cancer and thought to influence the progression of sporadic breast cancer. Decreased BRCA1 mRNA and protein expression has been identified in breast cancer cell lines and sporadic breast tumours. Here the prognostic significance of reduced BRCA1 protein expression is investigated in primary operable breast cancer. Immunohistochemical analysis was used to determine the level of BRCA1 protein expression in 100 breast cancers. BRCA1 expression was compared with known prognostic factors and survival to investigate its prognostic significance. BRCA1 nuclear expression was reduced by varying amounts in breast carcinomas. A progressive loss of BRCA1 expression correlated well with higher histological grade (p = 0.002) and an excess of medullary/atypical medullary/grade 3 ductal carcinomas (p = 0.0001). When adjusted for grade, patients with loss of BRCA1 expression had a significantly longer disease-free survival time. Loss of BRCA1 expression associated with high-grade breast tumours suggests that BRCA1 may play an important role in the pathogenesis of sporadic breast cancer.
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Proteína BRCA1/metabolismo , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/metabolismo , Adulto , Anciano , Neoplasias de la Mama/patología , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Persona de Mediana Edad , Proteínas de Neoplasias/metabolismo , Pronóstico , Análisis de SupervivenciaRESUMEN
AIMS: Neuroendocrine differentiation has been detected, and its prognostic value studied, in a number of common human carcinomas. To date there are few detailed studies examining its relevance in breast carcinoma. In this study we evaluate the frequency and prognostic importance of neuroendocrine differentiation in breast adenocarcinoma. METHODS AND RESULTS: The presence of neuroendocrine differentiation, defined as positive reactivity for three markers, neuron-specific enolase (NSE), chromogranin A and/or synaptophysin, has been evaluated in 99 patients with primary operable breast cancer using standard immunocytochemical techniques. A consecutive cohort of patients were selected from the Nottingham/Tenovus series. Comprehensive patient and tumour records have been maintained, and patients were followed up according to a defined protocol. Eighteen cases were positive for NSE, 10 for chromogranin A and 13 for synaptophysin. Eleven percent were positive with more than one neuroendocrine marker. No significant association was found between neuroendocrine differentiation and tumour size, grade, stage or the prevalence of vascular invasion. There was no significant difference in either overall or disease-free survival between patients with or without neuroendocrine differentiation. CONCLUSIONS: In this study we confirm that neuroendocrine differentiation can be identified in a subset (10-18%) of human breast carcinomas. This phenomenon appears to have no relationship to established prognostic factors or patient outcome.