RESUMEN
UNLABELLED: Molecular mechanisms of lapatinib resistance in breast cancer are not well understood. The aim of this study was to correlate expression of selected proteins involved in ErbB family signaling pathways with clinical efficacy of lapatinib. Study group included 270 HER2-positive advanced breast cancer patients treated with lapatinib and capecitabine. Immunohistochemical expression of phosphorylated adenosine monophosphate-activated protein (p-AMPK), mitogen-activated protein kinase (p-MAPK), phospho (p)-p70S6K, cyclin E, phosphatase and tensin homolog were analyzed in primary breast cancer samples. The best discriminative value for progression-free survival (PFS) was established for each biomarker and subjected to multivariate analysis. At least one biomarker was determined in 199 patients. Expression of p-p70S6K was independently associated with longer (HR 0.45; 95% CI: 0.25-0.81; p = 0.009), and cyclin E with shorter PFS (HR 1.83; 95% CI: 1.06-3.14; p = 0.029). Expression of p-MAPK (HR 1.61; 95% CI 1.13-2.29; p = 0.009) and cyclin E (HR 2.99; 95% CI: 1.29-6.94; p = 0.011) was correlated with shorter, and expression of estrogen receptor (HR 0.65; 95% CI 0.43-0.98; p = 0.041) with longer overall survival. Expression of p-AMPK negatively impacted response to treatment (HR 3.31; 95% CI 1.48-7.44; p = 0.004) and disease control (HR 3.07; 95% CI 1.25-7.58; p = 0.015). IN CONCLUSION: the efficacy of lapatinib seems to be associated with the activity of downstream signaling pathways - AMPK/mTOR and Ras/Raf/MAPK. Further research is warranted to assess the clinical utility of these data and to determine a potential role of combining lapatinib with MAPK pathway inhibitors.
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Neoplasias de la Mama/tratamiento farmacológico , Inmunohistoquímica/métodos , Quinazolinas/uso terapéutico , Receptor ErbB-2/antagonistas & inhibidores , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Ciclina E/metabolismo , Femenino , Humanos , Estimación de Kaplan-Meier , Lapatinib , Persona de Mediana Edad , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Evaluación de Resultado en la Atención de Salud/métodos , Evaluación de Resultado en la Atención de Salud/estadística & datos numéricos , Fosforilación/efectos de los fármacos , Valor Predictivo de las Pruebas , Pronóstico , Modelos de Riesgos Proporcionales , Inhibidores de Proteínas Quinasas/farmacología , Receptor ErbB-2/metabolismo , Receptores de Estrógenos/metabolismo , Proteínas Quinasas S6 Ribosómicas 70-kDa/metabolismo , Adulto JovenRESUMEN
BACKGROUND: The knowledge of the epidemiology of left ventricular systolic dysfunction (LVSD) in relationship with cardiovascular diseases, their risk factors and history of previous anticancer therapy may lead to development of safer and more effective therapeutic strategies in patients with breast cancer (BC). PATIENTS AND METHODS: Oncologists from various Polish Centers reported 299 new cases of metastatic BC requiring chemotherapy. All registered previous cardiological and oncological therapies should be conducted in accordance with the mandatory guidelines. RESULTS: Twelve new cases (4%) of LVSD were recognized in echocardiography before current chemotherapy. Multivariate logistic regression analysis revealed a significant association of LVSD with hypercholesterolemia (odds ratio (OR)=8.83; 95% confidence interval (CI)=1.44-54.16; p<0.02), prior myocardial infarction (OR=26.81; 95%CI=2.26-318.43; p<0.01), prior antracycline-based therapy either neoadjuvant (OR=13.21; 95%CI=2.18-80.12, p=0.005) or adjuvant (OR=6.94; 95%CI=1.003-47.985, p<0.05). CONCLUSION: LVSD in metastatic BC reflects common negative effects of hypercholesterolemia, coronary events and neoadjuvant/adjuvant chemotherapy with anthracyclines.
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Neoplasias de la Mama/fisiopatología , Metástasis de la Neoplasia/fisiopatología , Sistema de Registros , Sístole , Disfunción Ventricular Izquierda , Anciano , Femenino , Humanos , Persona de Mediana Edad , PoloniaRESUMEN
PURPOSE: P95HER2 (p95) is a truncated form of the HER2, which lacks the trastuzumab-binding site and contains a hyperactive kinase domain. Previously, an optimal clinical cutoff of p95 expression for progression-free survival (PFS) and overall survival (OS) was defined using a quantitative VeraTag assay (Monogram Biosciences) in a training set of trastuzumab-treated metastatic breast cancer (MBC) patients. EXPERIMENTAL DESIGN: In the current study, the predictive value of the p95 VeraTag assay cutoff established in the training set was retrospectively validated for PFS and OS in an independent series of 240 trastuzumab-treated MBC patients from multiple institutions. RESULTS: In the subset of 190 tumors assessed as HER2-total (H2T)-positive using the quantitative HERmark assay (Monogram Biosciences), p95 VeraTag values above the predefined cutoff correlated with shorter PFS (HR = 1.43; P = 0.039) and shorter OS (HR = 1.94; P = 0.0055) where both outcomes were stratified by hormone receptor status and tumor grade. High p95 expression correlated with shorter PFS (HR = 2.41; P = 0.0003) and OS (HR = 2.57; P = 0.0025) in the hormone receptor-positive subgroup of patients (N = 78), but not in the hormone receptor-negative group. In contrast with the quantitative p95 VeraTag measurements, p95 immunohistochemical expression using the same antibody was not significantly correlated with outcomes. CONCLUSIONS: The consistency in the p95 VeraTag cutoff across different cohorts of patients with MBC treated with trastuzumab justifies additional studies using blinded analyses in larger series of patients.
Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Receptor ErbB-2/metabolismo , Anticuerpos Monoclonales Humanizados/inmunología , Antineoplásicos/inmunología , Antineoplásicos/uso terapéutico , Neoplasias de la Mama/genética , Supervivencia sin Enfermedad , Receptor alfa de Estrógeno/metabolismo , Femenino , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Estimación de Kaplan-Meier , Persona de Mediana Edad , Metástasis de la Neoplasia , Valor Predictivo de las Pruebas , Pronóstico , Receptor ErbB-2/genética , Receptor ErbB-2/inmunología , Receptores de Progesterona/metabolismo , Reproducibilidad de los Resultados , Estudios Retrospectivos , Trastuzumab , Resultado del TratamientoRESUMEN
PURPOSE: To present an interim analysis of the trial comparing two neoadjuvant therapies for unresectable rectal cancer. METHODS: Patients with fixed cT3 or cT4 or locally recurrent rectal cancer without distant metastases were randomized to either 5 × 5 Gy and 3 courses of FOLFOX4 (schedule I) or 50.4 Gy delivered in 28 fractions given simultaneously with 5-Fu, leucovorin and oxaliplatin (schedule II). Surgery in both groups was performed 12 weeks after the beginning of radiation and 6 weeks after neoadjuvant treatment. RESULTS: 49 patients were treated according to schedule I and 48 according to schedule II. Grade III+ acute toxicity was observed in 26% of patients in group I and in 25% in group II. There were two toxic deaths, both in group II. The microscopically radical resection (primary endpoint) rate was 73% in group I and 71% in group II. Overall and severe postoperative complications were recorded in 27% and 9% of patients vs. 16% and 7%, respectively. Pathological complete response was observed in 21% of the patients in group I and in 9% in group II. CONCLUSIONS: The interim analysis revealed no major differences in acute toxicity and local efficacy between the two evaluated strategies.