RESUMEN
The classification of endometrial carcinoma divided into types I and II has shown clinical usefulness. Molecular alterations of PTEN and Wnt/ß-catenin have been identified in this neoplasia. However, the role of mammalian target of rapamycin according to subcellular localization in the pathogenesis of this neoplasia and its prognostic significance are not well defined. We studied the expression of phosphorylated mammalian target of rapamycin, PTEN, and ß-catenin and their relationship with clinicopathologic features, molecular factors (microsatellite instability, mismatch repair, and BRAF genes) and patients' survival in a series of 260 nonconsecutive endometrial carcinomas. Tissue microarrays were manually constructed, and genomic DNA was extracted from paraffin-embedded cylinders (1 mm thick) from preselected tumor areas. The mammalian target of rapamycin in the nuclei (mTORC2; 47%) or cytoplasm (mTORC1; 48%) were seen in type II endometrial carcinoma, the latter also in advanced stages (P ≤ .046). PTEN loss (58%) was detected in type I endometrial carcinoma of grade 1, at early stage, with mismatch repair gene loss (24.4%) and microsatellite instability-positive status (22%; P ≤ .05). Nuclear ß-catenin (16%) was found in type I tumors of younger patients (P ≤ .003). In contrast, BRAF-V600E mutations were not detected (0%). Mammalian target of rapamycin cytoplasmic high expression implied poorer prognosis (P = .02; Kaplan-Meier, log-rank test), but grade 3 tumors, vascular invasion, advanced stage, or PTEN presence correlated independently with a negative impact on survival (all P ≤ .036; Cox analysis). Our results show that mammalian target of rapamycin, PTEN, and ß-catenin are independently involved in different molecular subtypes of endometrial carcinoma with diverse patients' prognosis and support their distinctive treatment based on targeted drugs.
Asunto(s)
Adenocarcinoma/genética , Biomarcadores de Tumor/genética , Carcinoma Endometrioide/genética , Neoplasias Endometriales/genética , Serina-Treonina Quinasas TOR/metabolismo , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/metabolismo , Carcinoma Endometrioide/metabolismo , Carcinoma Endometrioide/patología , Reparación de la Incompatibilidad de ADN , ADN de Neoplasias/genética , Neoplasias Endometriales/metabolismo , Neoplasias Endometriales/patología , Femenino , Estudios de Seguimiento , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Inestabilidad de Microsatélites , Persona de Mediana Edad , Mutación , Fosfohidrolasa PTEN/genética , Fosfohidrolasa PTEN/metabolismo , Fosforilación , Pronóstico , Sirolimus , Serina-Treonina Quinasas TOR/genética , Análisis de Matrices Tisulares , beta Catenina/genética , beta Catenina/metabolismoRESUMEN
Background The predictive value of IGF1R on local recurrence in invasive breast carcinoma (BC) is not well known. Methods In a series of 197 lymph-node negative BC patients treated with breast-conserving surgery and radiation therapy, we performed immunohistochemistry for alpha-IGF1R, beta-IGF1R (phosphorylated/active form) and Estrogen/Progesterone receptors. We further evaluated the IGF1R mRNA expression by quantitative RT-PCR and IGF1R mutations by direct DNA sequencing (exons 19 and 21) in 85 primary BC (42 control cases, 31 with local recurrence and 12 with distant metastasis) and in 31 local recurrences. Unconditional logistic regression analyses were performed to identify risk factors for recurrence. Results Local recurrences were associated with high-grade tumors, PR-negative and low active-IGF1R, which emerged as independent breast relapse predictors by multivariate analysis. Conclusion Patients with early BC treated with lumpectomy and radiation who have low-grade tumors and favorable markers (increased content of active IGF1R and PR-positive) have a low risk of local recurrence. Therefore, do not benefit from a boost dose on the surgical scar.
Asunto(s)
Neoplasias de la Mama/metabolismo , Recurrencia Local de Neoplasia/metabolismo , Receptor IGF Tipo 1/metabolismo , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias de la Mama/patología , Neoplasias de la Mama/terapia , Terapia Combinada , Femenino , Humanos , Inmunohistoquímica , Mastectomía Segmentaria , Persona de Mediana Edad , Mutación , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/terapia , ARN Mensajero/análisis , Radioterapia , Receptor IGF Tipo 1/genética , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de Riesgo , Análisis de Matrices TisularesRESUMEN
Patients with lymph node-negative breast carcinoma (LNNBC) and positive hormone receptor (HR) status during estrogen-based endocrine therapy have different prognoses. The contribution of HER-2 (human epidermal growth factor receptor-2) has not been extensively evaluated. We stained 230 LNNBCs for estrogen and progesterone receptors (ER and PR) and HER-2. HER-2 gene status was studied in 150 randomly selected tumors by chromogenic in situ hybridization and cases with discordant or nondefinitive results by fluorescence in situ hybridization. Patients with ER+ and/or PR+ tumors were treated with tamoxifen. We found positive expression of ER, PR, and HER-2 in 73.7%, 67%, and 27.8%, respectively, and HER-2 amplification in 18.0%. Poorer outcome was seen for patients with ER+ and/or PR+/HER-2 overexpressing tumors and as a trend for patients with HER-2 amplification. ER/PR and HER-2 expression showed an independent prognostic value. In LNNBCs with positive HR status, HER-2 overexpression and/or amplification confer an aggressive tumor phenotype, and this might be related to tamoxifen unresponsiveness.
Asunto(s)
Neoplasias de la Mama/química , Receptor ErbB-2/análisis , Receptores de Estrógenos/análisis , Receptores de Progesterona/análisis , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Femenino , Humanos , Inmunohistoquímica , Metástasis Linfática , Persona de Mediana Edad , Pronóstico , Estudios RetrospectivosAsunto(s)
Queratodermia Palmoplantar/patología , Anciano , Biopsia , Diagnóstico Diferencial , Humanos , Masculino , Piel/patologíaRESUMEN
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