RESUMEN
Overexpression of CD24 is an independent prognostic factor for breast cancer. Recently, two polymorphisms in the CD24 gene were linked to disease risk and progression in autoimmune diseases. Here, we evaluated the clinical relevance of these polymorphisms with respect to their potential to predict a pathologic complete response (pCR) to neoadjuvant chemotherapy (NCT) for primary breast cancer (PBC), one of the strongest prognostic factors in this setting. A total of 257 patients were randomized to either doxorubicin/cyclophosphamide (AC) or doxorubicin/pemetrexed (AP), both followed by docetaxel (Doc) as NCT for T2-4 N0-2 M0 PBC as part of an international, multicenter, randomized phase II trial. CD24 polymorphisms were analyzed on germ line DNA and correlated with clinicopathologic variables and pCR. No significant associations were found between either of the polymorphisms and any of the clinicopathologic variables. In a multivariate analysis, CD24 Val/Val genotype was the only significant predictor of pCR (OR: 4.97; P = 0.003). The predictive potential was significant in both treatment arms and in the hormone receptor-positive subgroup. There was no correlation between CD24 3'UTR (TG/Del) genotype and pCR. We did not observe any association between CD24 genotype and CD24 protein expression or in vitro chemosensitivity, but there was a significant correlation between CD24 Val/Val and intratumoral lymphocyte aggregates. In conclusion, CD24 Ala/Val SNP is a strong and independent predictor of pCR after NCT for PBC and may affect immune functions rather than tumor characteristics. Further evaluation of the CD24 function and validation of its predictive potential are clearly warranted.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Antígeno CD24/genética , Terapia Neoadyuvante , Polimorfismo Genético , Sustitución de Aminoácidos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Antígeno CD24/metabolismo , Línea Celular Tumoral , Ciclofosfamida/administración & dosificación , Docetaxel , Doxorrubicina/administración & dosificación , Femenino , Genotipo , Glutamatos/administración & dosificación , Guanina/administración & dosificación , Guanina/análogos & derivados , Humanos , Antígenos Comunes de Leucocito/metabolismo , Linfocitos/metabolismo , Linfocitos/patología , Persona de Mediana Edad , Invasividad Neoplásica , Pemetrexed , Análisis de Secuencia de ADN , Estadísticas no Paramétricas , Taxoides/administración & dosificación , Resultado del TratamientoRESUMEN
OBJECTIVE: This pilot open-label clinical study evaluated the safety and pharmacokinetics of albumin-bound paclitaxel (nab-paclitaxel) in patients with advanced solid tumors and hepatic dysfunction. RESEARCH DESIGN/METHODS: Dosing was determined according to baseline bilirubin levels as described in the package insert for Taxol((R)) (paclitaxel), and patients received 130, 200 or 260 mg/m(2) nab-paclitaxel every 3 weeks. RESULTS: Thirty patients with elevated baseline bilirubin and aspartate aminotransferase levels received nab-paclitaxel. The most commonly-occurring grade 3/4 adverse events were neutropenia and fatigue. Grade 3/4 neutropenia occurred in 10, 30 and 30% of patients receiving 130, 200 and 260 mg/m(2) nab-paclitaxel, respectively. Grade 3 fatigue presented in 50 and 30% patients receiving 130 and 200 mg/m(2) nab-paclitaxel, respectively (no grade 4 event). Only one (10%) patient had a grade 3 sensory neuropathy in the 260 mg/m(2) nab-paclitaxel arm. Treatment-related grade 3 bilirubinemia and elevated aspartate aminotransferase was observed in patients receiving 130 mg/m(2) (30 and 10%, respectively) and 260 mg/m(2) nab-paclitaxel (20 and 10%, respectively). One patient had a grade 4 bilirubinemia in the 200 mg/m(2) nab-paclitaxel arm. Total bilirubin levels were inversely correlated to paclitaxel clearance (p < 0001). CONCLUSIONS: nab-Paclitaxel has an acceptable tolerability profile in patients with solid tumors and hepatic dysfunction. The safety and pharmacokinetic results support the same dose modification scheme recommended for cremophor-based paclitaxel.
Asunto(s)
Albúminas/uso terapéutico , Antineoplásicos Fitogénicos/uso terapéutico , Hepatopatías/complicaciones , Neoplasias/tratamiento farmacológico , Paclitaxel/uso terapéutico , Adulto , Anciano , Albúminas/administración & dosificación , Albúminas/efectos adversos , Albúminas/farmacocinética , Antineoplásicos Fitogénicos/administración & dosificación , Antineoplásicos Fitogénicos/efectos adversos , Antineoplásicos Fitogénicos/farmacocinética , Femenino , Humanos , Hepatopatías/metabolismo , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Paclitaxel/administración & dosificación , Paclitaxel/efectos adversos , Paclitaxel/farmacocinética , Proyectos PilotoRESUMEN
BACKGROUND: This multicenter, randomized trial compared overall response rate between pemetrexed plus irinotecan (ALIRI) and leucovorin-modulated 5-fluorouracil plus irinotecan (FOLFIRI) in patients with advanced colorectal cancer. Secondary objectives included overall and progression-free survival, duration of response, toxicities, and biomarkers. PATIENTS AND METHODS: ALIRI patients received pemetrexed 500 mg/m(2) and irinotecan 350 mg/m(2) with vitamin supplementation on day 1 of each 21-day cycle. FOLFIRI patients received irinotecan 180 mg/m(2) on days 1, 15, 29; on days 1, 2, 15, 16, 29, 30, patients received leucovorin 200 mg/m(2), bolus 5-fluorouracil 400 mg/m(2), and 5-fluorouracil 600 mg/m(2) as 22-hour infusion. RESULTS: Of 132 patients randomly assigned, 130 patients (64 = ALIRI, 66 = FOLFIRI) received > or =1 dose of treatment. Response rates (ALIRI = 20.0%, FOLFIRI = 33.3%) were not significantly different between arms (p = 0.095). Progression-free survival was 5.7 months for ALIRI and 7.7 months for FOLFIRI (p < 0.001). Neutropenia, fatigue, diarrhea, nausea, and vomiting were the major toxicities. There were 5 drug-related deaths (ALIRI = 4, FOLFIRI = 1). Biomarker analysis failed to reveal that any of the 18 preselected genes were clearly associated with tumor response. CONCLUSIONS: Neither efficacy nor safety improved on the ALIRI arm compared to the FOLFIRI arm. Progression-free survival on FOLFIRI was significantly longer compared to ALIRI. Potential biomarkers capable of predicting response to either regimen in advanced or metastatic colorectal carcinoma need further characterization.