RESUMEN
Docetaxel is one of the most commonly used chemotherapeutic agents in breast cancer. To avert from significant toxicities with no clinical benefit, identification of predictive markers for response is one of the most important unsolved clinical needs. Therefore, the potential associations of RASSF1A hypermethylation and response to docetaxel-based chemotherapy were evaluated, and the underlying mechanism was studied. The expression of RASSF1A in breast cancer cell lines and tissues of normal breast, ductal carcinoma in situ (DCIS), and breast cancer (n=45) was analyzed by immunohistochemistry and western blot analysis. Immunohistochemical staining showed that the expression of RASSF1A was frequently lost in primary breast cancers and human breast cancer cell lines, while normal breast tissues or DCIS displayed moderate to strong expression. Furthermore, quantitative methylation analysis of the RASSF1A promoter region in 45 primary breast cancers revealed that RASSF1A was frequently methylated in primary breast cancers (≥20% methylation in 53% of the patients), and prospective analysis in patients with locally advanced or recurrent breast cancer showed that the mean level of methylation of RASSF1A was significantly higher in patients who did not respond to docetaxel-based chemotherapy (30.6±8.5%) than patients with partial or complete response (20.1±11.2%, p=0.042). Finally, in vitro studies showed that RASSF1A had cooperative activity in suppression of cancer cell growth and proliferation by enhancing docetaxel-induced cell cycle arrest. Our results suggest that hypermethylated RASSF1A is an important modulating factor for the efficacy of docetaxel-based chemotherapy in breast cancer.
Asunto(s)
Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Metilación de ADN , Neoplasias Ductales, Lobulillares y Medulares/tratamiento farmacológico , Regiones Promotoras Genéticas , Taxoides/farmacología , Moduladores de Tubulina/farmacología , Proteínas Supresoras de Tumor/genética , Adulto , Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Secuencia de Bases , Neoplasias de la Mama/metabolismo , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Proliferación Celular , Docetaxel , Regulación hacia Abajo , Epigénesis Genética , Femenino , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica , Humanos , Modelos Logísticos , Análisis Multivariante , Neoplasias Ductales, Lobulillares y Medulares/metabolismo , Análisis de Secuencia de ADN , Taxoides/uso terapéutico , Moduladores de Tubulina/uso terapéutico , Proteínas Supresoras de Tumor/metabolismoRESUMEN
Anti-angiogenic therapies are currently in cancer clinical trials, but to date there are no established tests for evaluating the angiogenic status of a patient. We measured 11 circulating angiogenesis-associated molecules in cancer patients before and after local treatment. The purpose of our study was to screen for possible relationships among the different molecules and between individual molecules and tumor burden. We measured VEGF-A, PlGF, SCF, MMP-9, EDB+ -fibronectin, sVEGFR-2, sVEGFR-1, salphaVbeta3, sTie-2, IL-8 and CRP in the blood of 22 healthy volunteers, 17 early breast, 17 early colorectal, and 8 advanced sarcoma/melanoma cancer patients. Breast cancer patients had elevated levels of VEGF-A and sTie-2, colorectal cancer patients of VEGF-A, MMP-9, sTie-2, IL-8 and CRP, and melanoma/sarcoma patients of sVEGFR-1. salphaVbeta3 was decreased in colorectal cancer patients. A correlation between VEGF-A and MMP-9 was found. After tumor removal, MMP-9 and salphaVbeta3 significantly decreased in breast and CRP in colorectal cancer, whereas sVEGFR-1 increased in colorectal cancer patients. In sarcoma/melanoma patients treated regionally with TNF and chemotherapy we observed a rise in VEGF-A, SCF, VEGFR-2, MMP-9, Tie-2 and CRP, a correlation between CRP and IL-8, and a decreased in sVEGFR-1 levels. In conclusion, among all factors measured, only VEGF-A and MMP-9 consistently correlated to each other, elevated CRP levels were associated with tumor burden, whereas sVEGF-R1 increased after tumor removal in colorectal cancer. Treatment with chemotherapy and TNF induced changes consistent with an angiogenic switch. These results warrant a prospective study to compare the effect of surgical tumor removal vs. chemotherapy on some of these markers and to evaluate their prognostic/predictive value.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/sangre , Neoplasias Colorrectales/sangre , Metaloproteinasa 9 de la Matriz/metabolismo , Neovascularización Patológica , Factor A de Crecimiento Endotelial Vascular/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/cirugía , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/cirugía , Femenino , Humanos , Masculino , Melanoma/sangre , Melanoma/tratamiento farmacológico , Melanoma/cirugía , Invasividad Neoplásica , Neoplasias Ductales, Lobulillares y Medulares/sangre , Neoplasias Ductales, Lobulillares y Medulares/tratamiento farmacológico , Neoplasias Ductales, Lobulillares y Medulares/cirugía , Sarcoma/sangre , Sarcoma/tratamiento farmacológico , Sarcoma/cirugía , Neoplasias Cutáneas/sangre , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/cirugía , Factor de Necrosis Tumoral alfa/uso terapéuticoRESUMEN
OBJECTIVE: We conducted a retrospective analysis of prognosis factors for survival in breast cancer patients with 1-3 axillary lymph node metastases and tried to identify a subset of patients with good prognosis suitable for cyclophosphamide, methotrexate and 5-fluorouracil (CMF) adjuvant chemotherapy. METHODS: A cohort of 446 breast cancer patients received definite surgery and adjuvant chemotherapy with CMF at Chang Gung Memorial Hospital from 1990 to 1998. They were enrolled in the study. The median follow-up time was 69 months. Prognostic factors including age, tumor size, number of involved nodes, steroid receptor status, tumor ploidy, synthetic-phase fraction, histologic grade and administration of tamoxifen were analysed for disease-free survival (DFS) and overall survival (OS) by Cox regression model. RESULTS: The estimated 5 year OS and DFS for all patients were 85.4 and 71.5%, respectively. Multivariate analysis revealed that tumor size, age and estrogen receptor (ER) status were independent prognostic factors for OS, and tumor size, age, ER status and number of involved nodes were independent prognostic factors for DFS. The 5 year OS rates of the low-risk group (age >40, tumor < or =3 cm and positive ER) and average-risk group (either age < or =40, tumor >3 cm or negative ER) were 98.8 and 82.4%, respectively (P = 0.0001). The 5 year DFS of the low-risk and high-risk group were 88.2 and 67.7%, respectively (P = 0.0001). CONCLUSION: Among breast cancer patients with 1-3 positive lymph nodes excellent survival rate was found in those who had favorable prognostic factors, including age >40, tumor size < or =3 cm and positive ER. Adjuvant chemotherapy with CMF regimen is optimal for these low-risk patients.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Metástasis Linfática/prevención & control , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/mortalidad , Adenocarcinoma Mucinoso/tratamiento farmacológico , Adenocarcinoma Mucinoso/mortalidad , Adulto , Anciano , Axila , Neoplasias de la Mama/mortalidad , Quimioterapia Adyuvante , Ciclofosfamida/uso terapéutico , Femenino , Fluorouracilo/uso terapéutico , Humanos , Ganglios Linfáticos/patología , Metástasis Linfática/diagnóstico , Metotrexato/uso terapéutico , Persona de Mediana Edad , Neoplasias Ductales, Lobulillares y Medulares/tratamiento farmacológico , Neoplasias Ductales, Lobulillares y Medulares/mortalidad , Pronóstico , Estudios Prospectivos , Receptores de Estrógenos/metabolismo , Estudios Retrospectivos , Tasa de Supervivencia , Factores de Tiempo , Resultado del TratamientoRESUMEN
OBJECTIVE: The feasibility of dose-dense sequential adjuvant chemotherapy with Adriamycin, paclitaxel and cyclophosphamide was evaluated. METHODS: Fifty-five high-risk breast cancer patients were enrolled. The following chemotherapy schedule was used: 4 x Adriamycin --> 4 x paclitaxel --> 4 x cyclophosphamide, q 2 weeks (Adriamycin, 60 mg/m2; paclitaxel, 200 mg/m2 over 3 h, and cyclophosphamide, 800 mg/m2). RESULTS: The dose intensity was 95.0, 99.8 and 97.4% of that planned for treatment with Adriamycin, paclitaxel and cyclophosphamide, respectively. During treatment with Adriamycin, paclitaxel and cyclophosphamide, 20, 12.7 and 25.5% of the patients, respectively, did not need filgrastim to maintain the dose density. The average number of filgrastim doses per cycle, when necessary, was 3.6. Neutropenia of grade 3-4 was found in 67.3, 13.5 and 10.0% of the patients after treatment with Adriamycin, paclitaxel and cyclophosphamide, respectively. A single case of febrile neutropenia was observed. Anemia occurred in 96.4% of the patients, and was significantly more frequent (p = 0.031) and more severe (p = 0.002) during paclitaxel treatment than in the other chemotherapy cycles. CONCLUSIONS: Dose-dense sequential chemotherapy with Adriamycin, paclitaxel and cyclophosphamide is well tolerated and safe. Individual treatment with granulocyte colony-stimulating factor is needed to maintain the dose density in most patients, but some tolerate this regimen without it, probably due to differences in drug clearances.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Carcinoma Ductal de Mama/tratamiento farmacológico , Neoplasias Ductales, Lobulillares y Medulares/tratamiento farmacológico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/patología , Carcinoma Ductal de Mama/patología , Ciclofosfamida/administración & dosificación , Relación Dosis-Respuesta a Droga , Doxorrubicina/administración & dosificación , Estudios de Factibilidad , Femenino , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Humanos , Dosis Máxima Tolerada , Persona de Mediana Edad , Neoplasias Ductales, Lobulillares y Medulares/patología , Paclitaxel/administración & dosificaciónRESUMEN
The incorporation of a taxane into an anthracycline-containing regimen in the adjuvant treatment of breast cancer is a promising approach. In this study, we aimed to evaluate the safety and efficacy of four cycles of FEC (fluorouracil 500 mg/m2, epirubicin 70 mg/m2, cyclophosphamide 500 mg/m2, every 3 weeks) followed by four cycles of paclitaxel (175 mg/m2 every 3 weeks) in the adjuvant treatment of node-positive and other high-risk breast cancer patients. A total of 88 female patients were enrolled. Mean age (+/- SD) of the patients was 47 +/- 10 (min: 24; max: 71). The patients were followed for a median of 48 months (min: 20; max: 64). The most common side effects were nausea-vomiting (grade I-II: 91%; grade III: 2%), as well as hematological toxicity (grade I-II: 70%; grade III: 3%). Although all patients experienced some degree of toxicity, it was severe enough to be classified as grade III or IV in only 10 (11%) of the cases. Of note, six (8%) patients had grade I and only one (1%) had grade II cardiotoxicity. No grade III or IV cardiotoxicity was observed. The full eight cycles of study treatment could be administered to 75 patients (85%). Side effects necessitated the reduction of the doses of FEC and paclitaxel in one (1%) and three patients (3%), respectively. Median overall (OS) and disease-free survival (DFS) have not yet been reached. Five-year OS and DFS have been estimated to be 78% and 61%, respectively. We conclude that FEC followed by paclitaxel is a well-tolerated and feasible regimen in the adjuvant treatment of early breast cancer. Its efficacity is comparable with other commonly used regimens and merits evaluation in a phase III study.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Adulto , Anciano , Neoplasias de la Mama/patología , Neoplasias de la Mama/cirugía , Quimioterapia Adyuvante , Ciclofosfamida/administración & dosificación , Supervivencia sin Enfermedad , Epirrubicina/administración & dosificación , Femenino , Fluorouracilo/administración & dosificación , Humanos , Metástasis Linfática , Persona de Mediana Edad , Neoplasias Ductales, Lobulillares y Medulares/tratamiento farmacológico , Neoplasias Ductales, Lobulillares y Medulares/patología , Neoplasias Ductales, Lobulillares y Medulares/cirugía , Paclitaxel/administración & dosificación , Seguridad , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
Breast cancer has a significant capacity to metastasize to bone. Bisphosphonates are the standard treatment for hypocalcaemia of malignancy (HCM), which is a common complication of bone metastasis. The combination of bisphosphonates with standard anticancer drugs such as paclitaxel or tamoxifen results in a synergistic apoptotic effect greater than that produced by either single agent alone. Potential antitumour effects in vitro of the two bisphosphonates zoledronic acid (Zol) and ibandronate (Ib) (each at 30 microM) combined with different anticancer drug combinations: cyclophosphamide/metotrexate/5-fluorouracil (CMF), epirubicin/cyclophosphamide (EC), epirubicin/paclitaxel (ET), and epirubicin/docetaxel (EDoc) were investigated using ATP-cell viability assay (ATP-CVA). Twenty cases of female primary, invasive breast cancer were assessed. Ibandronate and zoledronic acid alone showed an inhibitory effect on breast cancer tumour cells in vitro. The breast tumour growth inhibition effect for those two drugs amounted to 22 and 25% respectively. Inhibitory effects were clearly visible for all four combinations of anticancer drugs together with both bisphosphonates. Combinations of anticancer drugs with zoledronic acid seem to be more effective with respect to tumour growth inhibition than combinations with ibandronate.
Asunto(s)
Adenocarcinoma Mucinoso/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias Ductales, Lobulillares y Medulares/tratamiento farmacológico , Adenocarcinoma Mucinoso/patología , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/patología , División Celular/efectos de los fármacos , Ciclofosfamida/administración & dosificación , Difosfonatos/administración & dosificación , Docetaxel , Sinergismo Farmacológico , Epirrubicina/administración & dosificación , Femenino , Fluorouracilo/administración & dosificación , Humanos , Ácido Ibandrónico , Imidazoles/administración & dosificación , Técnicas In Vitro , Metotrexato/administración & dosificación , Persona de Mediana Edad , Invasividad Neoplásica/prevención & control , Neoplasias Ductales, Lobulillares y Medulares/patología , Paclitaxel/administración & dosificación , Taxoides/administración & dosificación , Ácido ZoledrónicoRESUMEN
PURPOSE: The purpose was to evaluate the utility of some bcl-2 family proteins fas and fasL as predictive indicators for chemotherapy response in advanced breast cancer. EXPERIMENTAL DESIGN: Between October 1994 and October 1997, 283 patients with advanced breast cancer were included in a multicenter randomized study comparing docetaxel (D) to sequential methotrexate and 5-fluorouracil (MF) after anthracycline failure. The response rates (complete response + partial response) were 42 and 21% in the D and MF arms, respectively (P < 0.001). In 126 patients, histological blocks of primary tumors were available for immunohistochemical analysis of bax, bcl-2, bcl-xL, bag-1, fas and fasL. RESULTS: Of the investigated factors, bag-1 correlated positively with bax, bcl-2, and fasL, and fasL correlated positively with fas and bax. None of these apoptosis-related factors was associated with a response to chemotherapy either in the whole patient population or in the D or MF arms. Interestingly, low bcl-2 expression was associated with shorter time to progression (P = 0.02) and shorter overall survival (OS; P = 0.001). High fasL expression showed a trend toward shorter OS. In multivariate backwards stepwise Cox analysis, in which histological grade and estrogen receptor status (ER) were also included, bcl-2 (P = 0.01) and fasL (P = 0.005) remained highly significantly associated with OS, whereas histological grade and ER lost their significance. CONCLUSIONS: None of the investigated apoptosis-related factors of primary tumor could predict the later response to either D or MF treatment. However, fasL and bcl-2 were strong prognostic factors. Patients who had tumors with high fasL and low bcl-2 expression had the shortest OS.