RESUMEN
PURPOSE: Epidermal growth factor receptor (EGFR) is a targetable receptor frequently overexpressed in basal-like breast cancer, which comprises most triple-negative breast cancers (TNBCs), the only subtype without established targeted therapy. PATIENTS AND METHODS: In this randomized phase II trial, patients with metastatic TNBC received anti-EGFR antibody cetuximab (400 mg/m(2) load then 250 mg/m(2) per week intravenously [IV]) alone, with carboplatin (area under the curve of 2, once per week IV) added after progression or as concomitant therapy from the beginning. Response rate (RR) was the primary end point; others included time to progression (TTP), overall survival (OS), and toxicity. Embedded correlative studies included molecular subtyping on archival tissue. Fresh tumor tissue before and after 7 to 14 days of therapy was used for microarray analyses exploring EGFR pathway activity and inhibition. RESULTS: In 102 patients with TNBC, RRs were 6% (two of 31) to cetuximab and 16% (four of 25) to cetuximab plus carboplatin after progression. RR to those treated from the beginning with cetuximab plus carboplatin was 17% (12 of 71); 31% of patients responded or had prolonged disease stabilization. The cetuximab plus carboplatin regimen was well tolerated, but both TTP and OS were short at 2.1 months (95% CI, 1.8 to 5.5 months) and 10.4 months (95% CI, 7.7 to 13.1 months), respectively. Of 73 patients with archival tissue for analysis, 74% had basal-like molecular subtype. Sixteen patients had tumor biopsies before and 1 week after therapy; genomic patterns of the EGFR pathway showed activation in 13 and inhibition by therapy in five. CONCLUSION: Despite strong preclinical data, combination cetuximab plus carboplatin in metastatic TNBC produced responses in fewer than 20% of patients. EGFR pathway analysis showed that most TNBCs involved activation. However, cetuximab blocked expression of the EGFR pathway in only a minority, suggesting that most had alternate mechanisms for pathway activation.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/análisis , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Receptor ErbB-2/antagonistas & inhibidores , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales Humanizados , Neoplasias de la Mama/química , Carboplatino/administración & dosificación , Cetuximab , Progresión de la Enfermedad , Femenino , Humanos , Persona de Mediana Edad , Estadificación de Neoplasias , Receptor ErbB-2/análisis , Receptores de Estrógenos/análisis , Receptores de Progesterona/análisis , Transducción de Señal , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
Proteasome inhibitors may inhibit DNA repair of radiation-induced strand breaks and adducts thereby making the combination of radioimmunotherapy and bortezomib a promising approach. Preclinical models demonstrate additive/synergistic effects from combining DNA damaging agents with proteasome inhibitors. This phase I trial combines ibritumomab tiuxetan with bortezomib. Twelve patients with relapsed/refractory mantle cell and low grade B-cell non-Hodgkin lymphoma were enrolled. Patients with prior radioimmunotherapy were prohibited. The maximum tolerated dose (MTD) was not reached. No dose limiting toxicities (DLTs) occurred in cohort 1 or 2. One of six patients on cohort 3 had DLTs of asthenia, dizziness and neuropathy. Grade 3/4 thrombocytopenia occurred in two patients (16%) and grade 3/4 neutropenia in three patients (25%). Five subjects (41.7%) had complete responses (CRs) and one patient had a partial response (8.3%) for an overall response rate (ORR) of 50%. The combination of standard dose ibritumomab tiuxetan and bortezomib at 1.5 mg/m(2) is well tolerated with a promising response rate.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Ácidos Borónicos/uso terapéutico , Resistencia a Antineoplásicos , Linfoma de Células B/tratamiento farmacológico , Linfoma de Células del Manto/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Pirazinas/uso terapéutico , Terapia Recuperativa , Anciano , Anciano de 80 o más Años , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica , Bortezomib , Femenino , Estudios de Seguimiento , Humanos , Linfoma de Células B/mortalidad , Linfoma de Células B/patología , Linfoma de Células del Manto/mortalidad , Linfoma de Células del Manto/patología , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Clasificación del Tumor , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/patología , Pronóstico , Radioinmunoterapia , Tasa de SupervivenciaRESUMEN
PURPOSE: Trastuzumab (Herceptin), an anti-human epidermal growth factor receptor 2 (HER2) antibody, has been shown to be an effective radiosensitizer in preclinical studies. The present Phase II trial evaluated trastuzumab plus radiotherapy in patients with HER2-positive, chemotherapy-refractory, locally advanced or locoregionally recurrent breast cancer. METHODS AND MATERIALS: Eligible patients had measurable disease, normal cardiac function, and biopsy-confirmed residual HER2-positive disease. Patients received weekly trastuzumab (2 mg/kg intravenously), concurrent with radiotherapy (50 Gy) to the breast and regional lymph nodes for 5 weeks. If feasible, surgery followed radiotherapy. The primary endpoint was safety, and the secondary endpoint was efficacy (pathologic response and interval to symptomatic local progression). RESULTS: Of the 19 patients enrolled, 7 were ineligible and received radiotherapy alone and 12 received therapy per protocol. Of these 12 patients, 11 had a Stage T4 diagnosis. Grade 3 toxicities included skin (n = 2) and lymphopenia (n = 1). One patient experienced delayed wound healing after surgery. No patients developed symptomatic cardiac dysfunction. Of the 7 patients who had undergone mastectomy, 3 (43%) had a substantial pathologic response (complete response or microscopic residual disease), significantly more than a comparison cohort (2 of 38 or 5%, p = .02). The median interval to symptomatic local progression was not reached. The median overall survival was 39 months. CONCLUSION: This is the first prospective trial providing evidence for a radiosensitizing effect of trastuzumab in breast cancer. The combination of trastuzumab and radiotherapy was well tolerated.