RESUMO
In this update of the consensus of the Spanish Society of Medical Oncology (Sociedad Española de Oncología Médica-SEOM) and the Spanish Society of Pathology (Sociedad Española de Anatomía Patológica-SEAP), advances in the analysis of biomarkers in advanced colorectal cancer (CRC) as well as susceptibility markers of hereditary CRC and molecular biomarkers of localized CRC are reviewed. Recently published information on the essential determination of KRAS, NRAS and BRAF mutations and the convenience of determining the amplification of human epidermal growth factor receptor 2 (HER2), the expression of proteins in the DNA repair pathway and the study of NTRK fusions are also evaluated. From the pathological point of view, the importance of analysing the tumour budding and poorly differentiated clusters, and its prognostic value in CRC is reviewed, as well as the impact of molecular lymph node analysis on lymph node staging in CRC. The incorporation of pan-genomic technologies, such as next-generation sequencing (NGS) and liquid biopsy in the clinical management of patients with CRC is also outlined. All these aspects are developed in this guide, which, like the previous one, will remain open to any necessary revision in the future.
Assuntos
Biomarcadores Tumorais/análise , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Consenso , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Biópsia Líquida , Oncologia , Mutação , Patologia , Sociedades Médicas , EspanhaRESUMO
Publication of this consensus statement is a joint initiative of the Spanish Society of Pathology (SEAP) and the Spanish Society of Medical Oncology (SEOM), intended to revise and update the diagnostic and treatment recommendations published 2 years ago on biomarker use and the management of patients with colorectal carcinoma (CRC), thereby providing an opportunity to improve healthcare efficiency and resource use in these patients. This expert group recommends testing for KRAS and NRAS status in all patients with metastatic CRC being considered for anti-epidermal growth factor receptor (anti-EGFR) therapy, as this type of treatment should only be used in patients not harbouring mutations in these genes. In contrast, testing for BRAF, EGFR, PI3K and PTEN mutation status is not necessary for therapeutic decision making, so does not need to be done routinely.
Assuntos
Biomarcadores Tumorais/genética , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/genética , Receptores ErbB/genética , GTP Fosfo-Hidrolases/genética , Humanos , Oncologia/organização & administração , Proteínas de Membrana/genética , Reação em Cadeia da Polimerase/métodos , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas p21(ras) , Sociedades Médicas/organização & administração , Espanha , Proteínas ras/genéticaRESUMO
Breast cancers and most malignant tumors are composed of heterogeneous tumor cells both at genetic and morphological levels; intra-tumor heterogeneity can be one underlying cause of therapeutic resistance. Classical studies have focused on analyses of the relationship between primary tumors and metastatic dissemination, and on subclone evolution. However, it should be noted that tumor heterogeneity at the level of protein expression (proteomics) has not been yet studied in depth. The differences in protein expression also can play an important role in elucidating the relationship between intra-tumor heterogeneity and resistance to systemic therapy. In fact, in human tumors there is not always a homogeneous expression of many of the crucial factors involved in cell signaling, such as pMAPK, pAKt, pMTOR, even with constitutive oncogenic alterations upstream, such as HER2, PI3 K. Conversely, two of these factors, peIF4E and p4E-BP1, which are downstream, and control protein translation, show a diffuse and strong protein expression. In summary, most of cell signaling factors show a heterogeneous expression, regardless of oncogenic alterations. Tissue heterogeneity could be driven by local factors, including hypoxia. The fact that the phosphorylation of crucial proteins such as 4E-BP1 and eIF4E is observed homogeneously throughout most tumors and are druggable opens the chance to get real potential targets in cancer therapy.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Neoplasias da Mama/metabolismo , Fator de Iniciação 4E em Eucariotos/metabolismo , Fosfoproteínas/metabolismo , Transdução de Sinais , Animais , Proteínas de Ciclo Celular , Feminino , Humanos , Fosforilação , Proteômica , Transdução de Sinais/fisiologiaRESUMO
BACKGROUND: BRCA1-associated breast cancers have been associated to a triple-negative phenotype. The prevalence of BRCA1 germline mutations in young onset TNBC based on informativeness of family history has not been reported. PATIENTS AND METHODS: From January 2008 to May 2009 were collected blood and tumor samples from patients with TNBC younger than 50 years and without a family history of breast and ovarian cancer in first- and second-degree relatives. Analysis of BRCA1 germline mutations was made. Age at diagnosis and informativeness of family history (presence of female in first- and second-degree relatives alive until age 45) was collected in all cases. Immunohistochemistry of basal-like features was performed centrally in all available tumors. RESULTS: Seven pathogenic mutations were detected in 92 patients (7.6 %), two of them in patients younger than 35 years (28.6 %) (Fisher's exact test, p = 0.631). Three non-classified variants were detected (3.2 %). Family history was informative in two patients with a pathogenic mutation (28.6 %) and not informative in five (71.4 %) (Fisher's exact test, p = 0.121). Of the seven patients with a pathogenic mutation, four had a basal-like phenotype. CONCLUSION: Patients with apparently sporadic TNBC younger than 50 years and a non-informative family history are candidates for germline genetic testing of BRCA1.
Assuntos
Genes BRCA1 , Mutação em Linhagem Germinativa , Neoplasias de Mama Triplo Negativas/genética , Adulto , Idade de Início , Cromatografia Líquida de Alta Pressão , Análise Mutacional de DNA , Feminino , Predisposição Genética para Doença , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Estudos Retrospectivos , Neoplasias de Mama Triplo Negativas/metabolismoRESUMO
INTRODUCTION: Calretinin and Wilms' tumor gene (WT1) are mesothelial markers routinely used to confirm the diagnosis of malignant pleural mesothelioma (MPM). We investigated the prognostic value of calretinin and WT1 expression in predicting survival in a series of patients diagnosed with MPM in our institution. MATERIALS AND METHODS: Fifty-two patients diagnosed of MPM were retrospectively reviewed. Calretinin and WT1 were stained for IHC analysis in formalin-fixed, paraffin-embedded sections and positivity was considered for tumors with >1 % of tumor cells stained. Survival data were calculated by the Kaplan-Meier method and Cox regression was used to evaluate the prognostic value of the variables. RESULTS: Calretinin IHC expression was positive in 83.7 % of patients and WT1 in 78.1 %. A significant association of calretinin and WT1 expression with epithelial histology was detected (p = 0.030 and p = 0.010). We found a significant increase in OS in patients with epithelial subtype, PS1 and neutrophil-lymphocyte ratio (NLR) ≤5 (p < 0.05). In the IHC markers analysis, we found a significant increase in OS for patients with WT1 positive expression (16.4 vs. 2.3 m, p = 0.013), but not differences for calretinin expression (16.6 vs. 5.0 months, p = 0.37). In the multivariate analysis, epithelial histology and WT1 remained as significant prognostic factors for survival (p = 0.004 and p = 0.010, respectively). CONCLUSION: In our series of 52 MPM patients, epithelial histology, PS, NLR and WT1 expression are significant prognostic factors for survival. We concluded that WT1, but not calretinin, is a useful prognostic factor in MPM. The role of WT1 assessment is worth of prospective validation in future studies on MPM.
Assuntos
Biomarcadores Tumorais/análise , Mesotelioma/patologia , Neoplasias Pleurais/patologia , Proteínas WT1/biossíntese , Adulto , Idoso , Idoso de 80 Anos ou mais , Calbindina 2/análise , Calbindina 2/biossíntese , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Masculino , Mesotelioma/mortalidade , Pessoa de Meia-Idade , Neoplasias Pleurais/mortalidade , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Proteínas WT1/análiseRESUMO
Endometrial carcinoma is the most common gynaecological malignancy in the western world and the most frequent among infiltrating tumours of the female genital tract. Despite the characterisation of molecular events associated with the development of endometrial carcinoma, those associated with the early steps of infiltration and invasion in endometrial cancer are less known. Deep myometrial invasion correlates with more undifferentiated tumours, lymph-vascular invasion, node affectation and decreased global survival. In this review we present an overview of the molecular pathology of myometrial infiltration that defines the initial steps of invasion in endometrial cancer. Down-regulation of E-cadherin as a main player of epithelial to mesenchymal transition, as well as modifications on other molecules involved in cell-cell contacts, render cells with a migratory phenotype. In addition, altered signalling pathways and transcription factors associate with myometrial invasion, histologic grade and metastasis.