RESUMEN
BACKGROUND: Epidermal growth factor receptor mutations are predictive of the success of EGFR tyrosine kinase inhibitor treatment in patients with advanced non--small-cell lung cancer. As with other solid tumors, lung cancer is thought to be the result of an accumulation of genetic alterations after exposure to carcinogens. The aim of the present study was to clarify the relationship between multistep carcinogenesis and the accumulation of EGFR mutations. PATIENTS AND METHODS: The intratumor heterogeneity of EGFR mutations was analyzed in 38 patients with resected mixed-type lung adenocarcinoma according to histological patterns, and the clinical features of the patients harboring intratumor heterogeneity of EGFR mutations were evaluated. RESULTS: Intratumor heterogeneity of EGFR mutations was detected in 9 of 38 tumors. EGFR mutations were more common in the bronchioloalveolar (lepidic) carcinoma pattern than in the papillary and acinar patterns, although this difference was not significant. However, there was a significant correlation between intratumor heterogeneity of EGFR mutations and smoking history (P < .043). CONCLUSION: Intratumor heterogeneity of EGFR mutations correlates with the distribution of histological subtype in mixed type adenocarcinoma and is associated with smoking history.
Asunto(s)
Adenocarcinoma Bronquioloalveolar/patología , Adenocarcinoma/patología , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma Papilar/patología , Receptores ErbB/genética , Neoplasias Pulmonares/patología , Mutación/genética , Adenocarcinoma/genética , Adenocarcinoma/mortalidad , Adenocarcinoma Bronquioloalveolar/genética , Adenocarcinoma Bronquioloalveolar/mortalidad , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma Papilar/genética , Carcinoma Papilar/mortalidad , ADN de Neoplasias/genética , Femenino , Estudios de Seguimiento , Humanos , Captura por Microdisección con Láser , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidad , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Reacción en Cadena de la Polimerasa , Pronóstico , Fumar/efectos adversos , Tasa de SupervivenciaRESUMEN
BACKGROUND: Epidermal growth factor receptor (EGFR) mutations are predictive of response to EGFR tyrosine kinase inhibitors (TKIs) in NSCLC. Several methods have been used to detect EGFR mutations; however, it is not clear which is the most suitable for use in the clinic. In this study, we directly compare the clinical sensitivity and specificity of 3 PCR methods. PATIENTS AND METHODS: We compared the 3 PCR methods (mutant-enriched PCR, PNA-LNA PCR, and PCR clamp) in patients with advanced NSCLC. A patient who showed sensitive mutations by at least 1 PCR method was treated with gefitinib. A patient who showed no sensitive mutations was treated with chemotherapy with cytotoxic agents. RESULTS: Fifty patients with advanced NSCLC previously untreated with EGFR-TKIs were enrolled in this trial. Seventeen patients were harboring EGFR mutations, 5 of whom showed discrepancies between the results of different PCR methods. All 5 patients responded to gefitinib. All patients harboring EGFR mutations received gefitinib treatment and 21 of 33 EGFR-mutation-negative patients received chemotherapy with cytotoxic agents. Median progression-free survival of the gefitinib group and the chemotherapy group were 8.2 and 5.9 months, respectively. CONCLUSION: We considered that all the discrepancies might be false negatives because the patients responded to gefitinib. To clarify the reason for the false negatives of each PCR method, and establish the clinical sensitivity and specificity of each PCR method, a large prospective clinical trial is warranted.
Asunto(s)
Receptores ErbB/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Mutación/genética , Reacción en Cadena de la Polimerasa/métodos , Inhibidores de Proteínas Quinasas/uso terapéutico , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/patología , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células Grandes/tratamiento farmacológico , Carcinoma de Células Grandes/genética , Carcinoma de Células Grandes/patología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patología , ADN de Neoplasias/genética , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Pronóstico , Estudios Prospectivos , Tasa de SupervivenciaRESUMEN
PURPOSE: Gefitinib is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that has dramatic effects in selective patients with non-small cell lung cancer (NSCLC). A simple non-invasive method for predicting the efficacy of gefitinib is preferable in clinical settings. In this study, we evaluated prospectively whether surfactant protein-A (SP-A) and -D (SP-D) may be new conventional predictors of the efficacy of gefitinib treatment. METHODS: We measured serum SP-A and SP-D levels on days 0 and 29 in 40 patients with advanced NSCLC treated with 250 mg gefitinib daily. Eligibility criteria included performance status ≤3, age ≤80 years, and stage IIIB-IV disease. In addition, EGFR mutations were analyzed in 24 patients. RESULTS: Multivariate analysis showed that favorable progression-free survival (PFS) after gefitinib treatment was associated with adenocarcinoma and high serum SP-D levels before treatment. EGFR mutation analysis of 24 patients showed that 16 patients had exon 19 deletion and/or exon 21 point mutations. EGFR mutations were significantly correlated with response to gefitinib and serum SP-D levels before treatment was significantly high in patients with the EGFR mutations. Serum SP-A levels were not associated with PFS. CONCLUSIONS: The present study showed that measurement of serum SP-D levels before treatment in patients with NSCLC may be a new surrogate marker for predicting the response to gefitinib.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/tratamiento farmacológico , Proteína D Asociada a Surfactante Pulmonar/sangre , Quinazolinas/uso terapéutico , Adenocarcinoma/sangre , Adenocarcinoma/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Biomarcadores Farmacológicos/sangre , Carcinoma de Pulmón de Células no Pequeñas/sangre , Supervivencia sin Enfermedad , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/genética , Femenino , Gefitinib , Humanos , Neoplasias Pulmonares/sangre , Masculino , Persona de Mediana Edad , Polimorfismo Genético/genética , Pronóstico , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteína A Asociada a Surfactante Pulmonar/sangre , Quinazolinas/efectos adversos , Resultado del TratamientoRESUMEN
It has been proposed that stepwise progression occurs from atypical adenomatous hyperplasia (AAH) through bronchioloalveolar carcinoma (BAC) to invasive lung adenocarcinoma. However, the underlying molecular mechanisms have not been identified. We report a patient with a mixed adenocarcinoma of the lung that had different EGFR mutations in the papillary subtype, the acinar subtype, and the surrounding AAH and BAC areas. EGFR mutations may accumulate during tumor progression and lead to heterogeneity of EGFR mutations within the tumor.
Asunto(s)
Adenocarcinoma Bronquioloalveolar/genética , Adenocarcinoma/genética , Receptores ErbB/genética , Neoplasias Pulmonares/genética , Mutación , Nódulo Pulmonar Solitario/genética , Adenocarcinoma/patología , Adenocarcinoma Bronquioloalveolar/patología , Femenino , Humanos , Neoplasias Pulmonares/patología , Persona de Mediana Edad , Nódulo Pulmonar Solitario/patologíaRESUMEN
INTRODUCTION: Vinorelbine alone and irinotecan alone have been shown to have efficacy against non-small cell lung cancer (NSCLC); each drug has different mechanisms of action. A phase I study using a combination of vinorelbine and irinotecan as first-line treatment for advanced NSCLC was done to determine the maximum tolerated dose (MTD) and the dose-limiting toxicity (DLT). METHODS: Previously untreated patients (
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Adulto , Anciano , Antineoplásicos Fitogénicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Recuento de Células Sanguíneas , Camptotecina/administración & dosificación , Camptotecina/análogos & derivados , Carcinoma de Pulmón de Células no Pequeñas/patología , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Irinotecán , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Análisis de Supervivencia , Vinblastina/administración & dosificación , Vinblastina/análogos & derivados , VinorelbinaRESUMEN
The natural history of lung adenocarcinoma with ground-glass opacity (GGO) remains undetermined. We describe a lung adenocarcinoma in which GGO transformed through a scar-like lesion over the long term into a solid nodule of poorly differentiated adenocarcinoma. Whether poorly differentiated lung adenocarcinoma can evolve from GGO-type adenocarcinoma is an important issue that requires clarification.