RESUMEN
Background: HER2 (ERBB2) gene amplification and its corresponding overexpression are present in 15-30% of invasive breast cancers. While HER2-targeted agents are effective treatments, resistance remains a major cause of death. The American College of Surgeons Oncology Group Z1041 trial (NCT00513292) was designed to compare the pathologic complete response (pCR) rate of distinct regimens of neoadjuvant chemotherapy and trastuzumab, but ultimately identified no difference. Patients and methods: In supplement to tissues from 37 Z1041 cases, 11 similarly treated cases were obtained from a single institution study (NCT00353483). We have extracted genomic DNA from both pre-treatment tumor biopsies and blood of these 48 cases, and performed whole genome (WGS) and exome sequencing. Coincident with these efforts, we have generated RNA-seq profiles from 42 of the tumor biopsies. Among patients in this cohort, 24 (50%) achieved a pCR. Results: We have characterized the genomic landscape of HER2-positive breast cancer and investigated associations between genomic features and pCR. Cases assigned to the HER2-enriched subtype by RNA-seq analysis were more likely to achieve a pCR compared to the luminal, basal-like, or normal-like subtypes (19/27 versus 3/15; P = 0.0032). Mutational events led to the generation of putatively active neoantigens, but were overall not associated with pCR. ERBB2 and GRB7 were the genes most commonly observed in fusion events, and genomic copy number analysis of the ERBB2 locus indicated that cases with either no observable or low-level ERBB2 amplification were less likely to achieve a pCR (7/8 versus 17/40; P = 0.048). Moreover, among cases that achieved a pCR, tumors consistently expressed immune signatures that may contribute to therapeutic response. Conclusion: The identification of these features suggests that it may be possible to predict, at the time of diagnosis, those HER2-positive breast cancer patients who will not respond to treatment with chemotherapy and trastuzumab. ClinicalTrials.gov identifiers: NCT00513292, NCT00353483.
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Antineoplásicos Inmunológicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Trastuzumab/uso terapéutico , Anciano , Neoplasias de la Mama/genética , Quimioterapia Adyuvante , Variaciones en el Número de Copia de ADN , Femenino , Estudios de Asociación Genética , Genoma Humano , Mutación de Línea Germinal , Humanos , Mutación INDEL , Persona de Mediana Edad , Terapia Neoadyuvante , Polimorfismo de Nucleótido Simple , Receptor ErbB-2/metabolismo , Resultado del TratamientoRESUMEN
PURPOSE: We examined acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) events among 9679 women treated for breast cancer on four adjuvant Alliance for Clinical Trials in Oncology trials with >90 months of follow-up in order to better characterize the risk for AML/MDS in older patients receiving anthracyclines. METHODS: We used multivariable Cox regression to examine factors associated with AML/MDS, adjusting for age (≥65 vs. <65 years; separately for ≥70 vs. <70 years), race/ethnicity, insurance, performance status, and anthracycline receipt. We also examined the effect of cyclophosphamide, the interaction of anthracycline and age, and outcomes for those developing AML/MDS. RESULTS: On Cancer and Leukemia Group B (CALGB) 40101, 49907, 9344, and 9741, 7290 received anthracyclines; 15% were in the age ≥65 and 7% were ≥70. Overall, 47 patients developed AML/MDS (30 AML [0.3%], 17 MDS [0.2%]); 83% of events occurred within 5 years of study registration. Among those age ≥65 and ≥70, 0.8 and 1.0% developed AML/MDS (vs. 0.4% for age <65), respectively. In adjusted analyses, older age and anthracycline receipt were significantly associated with AML/MDS (adjusted hazard ratio [HR] for age ≥65 [vs. <65] = 3.13, 95% confidence interval [CI] 1.18-8.33; HR for anthracycline receipt [vs. no anthracycline] = 5.16, 95% CI 1.47-18.19). There was no interaction between age and anthracycline use. Deaths occurred in 70% of those developing AML/MDS. CONCLUSIONS: We observed an increased risk for AML/MDS for older patients and those receiving anthracyclines, though these events were rare. Our results help inform discussions surrounding anticipated toxicities of adjuvant chemotherapy in older patients.
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Neoplasias de la Mama/complicaciones , Neoplasias de la Mama/epidemiología , Leucemia Mieloide Aguda/epidemiología , Leucemia Mieloide Aguda/etiología , Síndromes Mielodisplásicos/epidemiología , Síndromes Mielodisplásicos/etiología , Neoplasias Primarias Secundarias , Factores de Edad , Anciano , Anciano de 80 o más Años , Antraciclinas/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/tratamiento farmacológico , Quimioterapia Adyuvante/efectos adversos , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Humanos , Persona de Mediana Edad , Riesgo , Factores de TiempoRESUMEN
The International Tamoxifen Pharmacogenomics Consortium was established to address the controversy regarding cytochrome P450 2D6 (CYP2D6) status and clinical outcomes in tamoxifen therapy. We performed a meta-analysis on data from 4,973 tamoxifen-treated patients (12 globally distributed sites). Using strict eligibility requirements (postmenopausal women with estrogen receptor-positive breast cancer, receiving 20 mg/day tamoxifen for 5 years, criterion 1); CYP2D6 poor metabolizer status was associated with poorer invasive disease-free survival (IDFS: hazard ratio = 1.25; 95% confidence interval = 1.06, 1.47; P = 0.009). However, CYP2D6 status was not statistically significant when tamoxifen duration, menopausal status, and annual follow-up were not specified (criterion 2, n = 2,443; P = 0.25) or when no exclusions were applied (criterion 3, n = 4,935; P = 0.38). Although CYP2D6 is a strong predictor of IDFS using strict inclusion criteria, because the results are not robust to inclusion criteria (these were not defined a priori), prospective studies are necessary to fully establish the value of CYP2D6 genotyping in tamoxifen therapy.
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Antineoplásicos Hormonales/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Citocromo P-450 CYP2D6/genética , Tamoxifeno/uso terapéutico , Anciano , Antineoplásicos Hormonales/farmacocinética , Neoplasias de la Mama/genética , Femenino , Variación Genética/genética , Genotipo , Humanos , Menopausia , Persona de Mediana Edad , Farmacogenética/métodos , Análisis de Supervivencia , Tamoxifeno/farmacocinética , Resultado del TratamientoRESUMEN
We designed a phase I clinical trial of escalating doses of topotecan with CY and carboplatin in combination with autologous hematopoietic SCT (AHSCT) for the treatment of relapsed or persistent platinum sensitive ovarian or primary peritoneal carcinoma. After stem cell collection, 16 patients received topotecan at 1.5, 2.5, 3.5, 4.5 or 6.0 mg/m(2)/d combined with CY 1.5 g/m(2)/d and carboplatin 200 mg/m(2)/d, all by 4-day continuous infusion. Steady state pharmacokinetics of topotecan and carboplatin were examined. Pre-treatment biopsies were examined for the expression of topoisomerase (topo) I, Ki67 and Bcl-2 family members by immunohistochemistry. One of six patients at a topotecan dose of 4.5 mg/m(2)/d and two of three patients at 6.0 mg/m(2)/d had dose-limiting toxicity of grade 3 stomatitis lasting >2 weeks. There was no treatment-related mortality. As topotecan clearance was constant over the dose range examined, topotecan steady state plasma concentrations increased with dose. Median progression-free survival and overall survival were 6.5 months and 2.7 years, respectively. Shorter progression-free survival was observed in tumors with low topo expression (P=0.04). Topotecan can safely be dose escalated to 4.5 mg/m(2)/d in combination with CY, carboplatin and AHSCT. This trial is registered at ClinicalTrials.gov as NCT00652691.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Trasplante de Células Madre Hematopoyéticas , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/terapia , Neoplasias Peritoneales/tratamiento farmacológico , Neoplasias Peritoneales/terapia , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Carboplatino/administración & dosificación , Carboplatino/farmacocinética , Terapia Combinada , Ciclofosfamida/administración & dosificación , ADN-Topoisomerasas de Tipo I/metabolismo , Supervivencia sin Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Persona de Mediana Edad , Neoplasias Ováricas/metabolismo , Neoplasias Peritoneales/metabolismo , Topotecan/administración & dosificación , Topotecan/efectos adversos , Topotecan/farmacocinéticaRESUMEN
Breast density, a strong risk factor for breast cancer, is reduced by the anti-estrogen, tamoxifen (TAM). We examined whether aromatase inhibitor (AI) therapy results in further reductions in breast density among women completing 5 years of TAM. Among a sample of women with early-onset breast cancer who were randomized to letrozole (LET)(n=56) or placebo (PLAC)(n=48) after 5 years of TAM, we examine the change in percent density at 9-15 months as well as a per-year change in PD by treatment group. There was no difference in the adjusted mean change (-1.0%, LET; -0.3%, PLAC (P=0.58)) or the percentage change (-2.7%, LET; -3.0%, PLAC (P=0.96)) in PD between treatment groups at 9-15 months. Results were similar for longitudinal change (-0.68% per year, LET; -0.12% per year, PLAC (P=0.23)). Breast density does not appear to be a clinically relevant biomarker in women who already have low PD following 5 years of TAM.
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Inhibidores de la Aromatasa/uso terapéutico , Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/tratamiento farmacológico , Nitrilos/uso terapéutico , Moduladores Selectivos de los Receptores de Estrógeno/uso terapéutico , Tamoxifeno/uso terapéutico , Triazoles/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Inhibidores de la Aromatasa/administración & dosificación , Neoplasias de la Mama/patología , Esquema de Medicación , Femenino , Humanos , Letrozol , Mamografía , Persona de Mediana Edad , Nitrilos/administración & dosificación , Proyectos Piloto , Moduladores Selectivos de los Receptores de Estrógeno/administración & dosificación , Tamoxifeno/administración & dosificación , Resultado del Tratamiento , Triazoles/administración & dosificaciónRESUMEN
BACKGROUND: A one-stage phase II trial was conducted to assess the tumor response rate and toxicity profile of single agent oral vinorelbine as first or second-line chemotherapy for women at least 65 years of age with metastatic breast cancer. PATIENTS AND METHODS: Twenty-five patients with metastatic breast cancer aged > or = 65 years of age were enrolled to receive oral vinorelbine on a weekly basis. The oral vinorelbine was given at 60 mg/m2 weekly for the first four doses and was increased to 70 mg/m2 for the subsequent administrations if there was no grade 4 neutropenia or no more than one episode of grade 3 neutropenia. Therapy was continued until progression or intolerable toxicity. RESULTS: Twenty-five patients were included and evaluable for analysis. One patient (4%) achieved a partial response (PR) that lasted for more than 13 months. Two additional patients remained stable for at least 6 months for a clinical benefit rate (PR + stable disease) of 12%. The 1-year survival rate was estimated to be 48% (95% CI 30% to 74.5%). Median time to progression was estimated to be 4.7 months (95% CI 2.0-5.5 months) and the 9-month disease progression-free rate was estimated to be 8% (95% CI 30.9% to 74.5%). The treatment was fairly well tolerated with grade 3 neutropenia in 12.5%, fatigue in 12.5% of the patients, and grade 2 neuromotor and neurosensory toxicities in 12.5% and 8.3%, respectively. CONCLUSION: Oral vinorelbine as a single agent at these dose and schedule in this population of women > or = 65 years is well tolerated but has a low level of objective efficacy for the treatment of metastatic breast cancer.
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Antineoplásicos Fitogénicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Metástasis de la Neoplasia , Vinblastina/análogos & derivados , Administración Oral , Anciano , Anciano de 80 o más Años , Antineoplásicos Fitogénicos/administración & dosificación , Antineoplásicos Fitogénicos/efectos adversos , Neoplasias de la Mama/patología , Progresión de la Enfermedad , Femenino , Humanos , Neutropenia/inducido químicamente , Análisis de Supervivencia , Tasa de Supervivencia , Vinblastina/administración & dosificación , Vinblastina/efectos adversos , Vinblastina/uso terapéutico , VinorelbinaRESUMEN
BACKGROUND: Docetaxel has yielded promising response rates as a component of doxorubicin-based combination schedules in patients with metastatic breast cancer, including docetaxel/doxorubicin and docetaxel/doxorubicin/cyclophosphamide (AC). This randomized two-stage phase II study was conducted to evaluate sequential treatment with docetaxel and AC as first-line treatment in patients with recurrent or metastatic breast cancer previously untreated with chemotherapy for metastatic disease. PATIENTS AND METHODS: Thirty-three patients were randomized to either docetaxel (100 mg/m(2)) on day 1 of a 21-day cycle for three cycles followed by AC (60/600 mg/m(2)) on day 1 of a 21-day cycle for three cycles (n = 17) or vice-versa (n = 16), without prophylactic granulocyte colony-stimulating factor support. In addition, we compared pre-treatment serum sErbB1 and sErbB2 protein concentrations with that of an age- and menopausal status-matched group of healthy women, and examined changes in serum sErbB1 and sErbB2 protein concentrations in these two treatment schedules. Data from each one of the two arms of the trial (docetaxel then AC, or AC and then docetaxel) were analyzed separately. RESULTS: Enrollment was suspended after the first-stage of accrual, based on statistical design. Confirmed objective response rates after six cycles of treatment were 35% [95% confidence interval (CI) 14% to 62%] with docetaxel then AC and 38% (95% CI 15% to 65%) with AC then docetaxel. Dose reductions were frequent and mostly due to grade 4 neutropenia. Median survival time was 2.5 years in the docetaxel then AC group, and 1.1 years in the AC then docetaxel group. Serum sErbB1 concentrations were not significantly different between the study patients and healthy women, and did not change significantly after three and six cycles of treatment. In contrast, serum sErbB2 concentrations were significantly higher in the study patients compared with healthy women and tended to decrease after three and six cycles of treatment. CONCLUSIONS: Response rates at the end of six cycles of treatment, which led to termination of accrual after the first stage using either the sequence of docetaxel first or docetaxel after AC chemotherapy, were lower than anticipated. However, median survival times and median progression-free survival times are similar to those reported in other studies. These data further suggest that additional studies to assess whether serum sErbB2 concentrations are useful predictors of responsiveness to chemotherapy are warranted.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Paclitaxel/análogos & derivados , Taxoides , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/patología , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/patología , Carcinoma Ductal de Mama/tratamiento farmacológico , Carcinoma Ductal de Mama/patología , Carcinoma Lobular/tratamiento farmacológico , Carcinoma Lobular/patología , Estudios de Casos y Controles , Ciclofosfamida/administración & dosificación , Progresión de la Enfermedad , Docetaxel , Doxorrubicina/administración & dosificación , Receptores ErbB/sangre , Femenino , Humanos , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Paclitaxel/administración & dosificación , Receptor ErbB-2/sangre , Inducción de Remisión , Tasa de SupervivenciaRESUMEN
Soluble ErbB (sErbB) growth factor receptors are being investigated as cancer biomarkers. Gonadotropic and steroid hormones have been shown to modulate the expression of ERBB family members in vivo. Accordingly, the range of sErbB1 values and their relationship to gonadotropic and steroid hormones need to be established in healthy subjects to provide a baseline for future clinical studies. We assayed sera from healthy men and women to determine p110 sErbB1 concentrations by acridinium-linked immunosorbent assay (ALISA). Follicle-stimulating hormone (FSH), estradiol, and testosterone concentrations were measured using the ACS:180 Immunoassay Analyzer. Luteinizing hormone (LH) and progesterone concentrations were quantified using the Access Immunoassay System. Unadjusted for age, p110 sErbB1 concentrations in healthy men and women do not differ significantly. However, sErbB1 concentrations show a strong age-gender interaction, increasing with age in men but decreasing with age in women. Consequently, sErbB1 concentrations are significantly higher in premenopausal women compared with either postmenopausal women or age-matched men and in age-matched men compared with postmenopausal women. Serum sErbB1 concentrations show significant negative associations with both FSH and LH concentrations in healthy women and a significant positive association with FSH concentrations in healthy men. Univariate linear regression models show that these respective gonadotropic hormones and age are independent predictors of sErbB1 concentrations in men and women. Multivariate models show that when age and FSH and LH concentrations are mutually adjusted for each other, they account for 22% of the variability observed in sErbB1 concentrations in healthy women. These data support the hypothesis that gonadotropic and steroid hormones may modulate ERBB1 expression in vivo and suggest that age- and gonadotropin-adjusted sErbB1 concentrations may be of clinical utility. Furthermore, these data demonstrate that gender, age, menstrual cycle phase, menopausal status, and exogenous hormone use must be considered when using serum p110 sErbB1 concentrations as cancer biomarkers.
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Receptores ErbB/sangre , Hormonas Esteroides Gonadales/sangre , Gonadotropinas/sangre , Adulto , Factores de Edad , Anciano , Biomarcadores/sangre , Femenino , Humanos , Modelos Lineales , Masculino , Menopausia , Persona de Mediana Edad , Neoplasias/sangre , Neoplasias/epidemiología , Valores de Referencia , Factores de Riesgo , Factores SexualesRESUMEN
Between March 1992 and November 1994, 91 patients with stage III and IV ovarian carcinoma were enrolled in a randomized comparative study of cyclophosphamide 600 mg/m2 plus carboplatin 300 mg/m2 vs. cyclophosphamide 600 mg/m2 plus carboplatin 600 mg/m2, each regimen given monthly for six cycles. Patients on the intensive regimen also received 10 micrograms/kg of granulocyte macrophage colony stimulating factor (GM-CSF) (molgramostim) daily for 14 days following each chemotherapy treatment. The study was closed prematurely because of very poor case accrual following the preliminary announcement (in May 1993) that paclitaxel appeared superior to cyclophosphamide in the platinum-based treatment of ovarian cancer. More than 4 years after our last case entry, we analyzed the survival results for the 44 eligible patients who received the conventional dose of carboplatin and the 43 eligible patients receiving our intensified dose of carboplatin. More than 90% of the treated patients receiving the conventional dose regimen received at least 75% of the planned doses at each of the six treatment intervals, whereas the percentage of treated patients able to receive at least 75% of the assigned intensive dose regimen had declined from 95% in cycle 2 to 53% by cycle 6. Furthermore, although 32 patients received all six planned cycles of treatment in the conventional regimen group, only 15 received all six cycles of the intensified regimen. Patients receiving the intensive regimen had more fever, dermatitis, lethargy, musculoskeletal pain, and pulmonary complications than did the conventional dose patients. Median survival times for the two treatment groups were very similar (38.5 and 38.1 months, respectively, for the conventional and intensive regimens), and we saw no evidence that the distribution of survival times differed between the treatment regimens (p = 0.95).
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carboplatino/administración & dosificación , Factor Estimulante de Colonias de Granulocitos y Macrófagos/uso terapéutico , Neoplasias Ováricas/tratamiento farmacológico , Proteínas Recombinantes/uso terapéutico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Población Negra , Carboplatino/efectos adversos , Terapia Combinada , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Factor Estimulante de Colonias de Granulocitos y Macrófagos/administración & dosificación , Humanos , Persona de Mediana Edad , Medio Oeste de Estados Unidos , Neoplasias Ováricas/mortalidad , Neoplasias Ováricas/patología , Neoplasias Ováricas/cirugía , Proteínas Recombinantes/administración & dosificación , Tasa de Supervivencia , Población BlancaRESUMEN
OBJECTIVE: To measure a 1-day point prevalence of alcohol dependence among hospitalized patients and to assess practices of detection, evaluation, and diagnosis of alcohol problems. PATIENTS AND METHODS: On April 27, 1994, a total of 795 adult inpatients at 2 midwestern teaching hospitals were asked to complete a survey that included the Self-administered Alcoholism Screening Test (SAAST). The records of SAAST-positive patients were reviewed to determine the numbers of patients receiving laboratory screening for alcoholism, addiction consultative services, and a discharge diagnosis of alcoholism. RESULTS: The survey response rate was 84% (667/795). Of the 569 patients who provided SAAST information, 42 (7.4%) had a positive SAAST score and thus were identified as alcohol dependent. Thirteen (31%) of the 42 alcoholic patients received addiction or psychiatric consultative services during their hospitalization. Serum gamma-glutamyltransferase was measured in 4 (11%) of the 38 actively drinking alcoholic patients. Three (7%) of 42 alcoholic patients received a discharge diagnosis of alcohol abuse or dependence. CONCLUSIONS: The alcoholism prevalence rate was lower than those observed in several other US hospitals. Laboratory testing may be underutilized in identifying hospitalized patients who may be addicted to alcohol. Physician use of consultative services and diagnosis of alcohol dependence had not improved from similar observations more than 20 years earlier. These findings may indicate persistent problems in physician detection, assessment, and diagnosis of alcoholism.
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Alcoholismo/diagnóstico , Hospitalización , Adulto , Distribución por Edad , Anciano , Anciano de 80 o más Años , Alanina Transaminasa/sangre , Alcoholismo/epidemiología , Femenino , Humanos , Hígado/enzimología , Masculino , Persona de Mediana Edad , Minnesota/epidemiología , Prevalencia , Distribución por Sexo , Encuestas y Cuestionarios , gamma-Glutamiltransferasa/sangreRESUMEN
While research exists on the well-being of women during a specific phase of breast cancer, little research exists in which researchers utilized the same instruments to examine differences in women's well-being, based on the phase of their breast cancer. Using a trajectory framework, the purpose of this study is to examine the differences in the physical and social well-being of women during the following breast cancer states: newly diagnosed, adjuvant therapy, stable disease and recurrent disease. The convenience sample consisted of 35 women newly diagnosed with breast cancer, 52 women with breast cancer undergoing adjuvant therapy, 84 women whose breast cancer was considered stable and 64 women with recurrent breast cancer. Participants completed a packet of questionnaires which contained a demographic questionnaire, Short Form-36 (SF-36) Health Survey, a researcher designed (RD) questionnaire, Cancer Rehabilitation Evaluation System-Short Form (CARES-SF) and the Brief Symptom Inventory (BSI). Descriptive statistics, analysis of variance, and general linear F-tests were used to analyze the data. Differences were found across phases of disease on various subscales, including those representing perceived health states, overall impact, medical interactions, physical function, role function, fatigue, pain, social function and satisfaction with health. No significant differences were found between groups on the BSI subscales with the exception of somatization, global psychosocial measures, sexual and marital relation subscales. While individuals with recurrent disease often experienced more difficulties with their well-being than women in the other groups, women newly diagnosed and in the adjuvant group experienced more difficulties in select areas of well-being when compared with women in the stable group. Health care professionals need to recognize differences between groups to better meet the needs of patients with a breast cancer diagnosis.
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Adaptación Fisiológica/fisiología , Adaptación Psicológica , Actitud Frente a la Salud , Neoplasias de la Mama/psicología , Ajuste Social , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/terapia , Femenino , Humanos , Matrimonio/psicología , Persona de Mediana Edad , Autoimagen , Disfunciones Sexuales Psicológicas/etiología , Encuestas y CuestionariosRESUMEN
PURPOSE: A prospective randomized phase III clinical trial was conducted to assess whether the addition of tamoxifen (TAM) to the three-agent regimen of cisplatin (CDDP), dacarbazine (DTIC), and carmustine (BCNU) significantly increased the progression-free survival and overall survival of patients with advanced malignant melanoma. PATIENTS AND METHODS: Patients with advanced malignant melanoma were treated with CDDP + DTIC + BCNU (CDB) with or without TAM. The dose schedule was CDDP 25 mg/m(2) given intravenously (IV) for 30 to 45 minutes in 500 mL of dextrose and (1/2) normal saline (NS) on days 1 to 3 of a 3-week cycle; DTIC 220 mg/m(2) IV for 1 hour in 500 mL of dextrose and (1/2) NaCl on days 1 to 3 of a 3-week cycle; BCNU 150 mg/m(2) IV for 2 to 3 hours in 750 to 1,000 mL of dextrose and 5% water on day 1 of every odd 3-week cycle; and TAM 20 mg taken orally every morning. RESULTS: There were 184 eligible patients enrolled. These patients were observed until death or for a minimum of 1.3 years. At last contact, 12 were still alive. The median time to progression was 3.4 months on the CDB arm and 3.1 months on the CDB + TAM arm. The median survival time was 6.8 months with CDB and 6.9 months with CDB + TAM. Progression-free survival (P =.429) and overall survival (P =.545) were not found to differ by treatment. CONCLUSION: The addition of TAM to this three-agent regimen of CDB was not found to provide a meaningful clinical advantage in the treatment of patients with advanced malignant melanoma.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias del Ojo/tratamiento farmacológico , Melanoma/tratamiento farmacológico , Neoplasias Cutáneas/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Carmustina/administración & dosificación , Cisplatino/administración & dosificación , Dacarbazina/administración & dosificación , Supervivencia sin Enfermedad , Neoplasias del Ojo/mortalidad , Femenino , Humanos , Masculino , Melanoma/mortalidad , Persona de Mediana Edad , Estudios Prospectivos , Neoplasias Cutáneas/mortalidad , Tasa de Supervivencia , Tamoxifeno/administración & dosificación , Resultado del TratamientoRESUMEN
The goals of this clinical trial involving postmenopausal women with metastatic breast cancer were to: (a) examine the effects of letrozole on tamoxifen (TAM) pharmacokinetics; (b) examine estrogen suppression in patients receiving TAM plus letrozole; and (c) evaluate tolerability, toxicity, objective response, and time to progression for the combination. Postmenopausal women with measurable or evaluable metastatic breast cancer received TAM (20 mg daily) for 6 weeks, and then letrozole (2.5 mg daily) was added. To examine for any effect of letrozole on the levels of TAM and two metabolites [N-desmethyl-TAM and 4-hydroxy-TAM], serum samples were obtained at 6, 12, 18, and 24 weeks. To examine for aromatase inhibition, serum samples were obtained before treatment and at 6, 12, 18, and 24 weeks for estradiol, estrone (E1) E1 sulfate, and sex hormone-binding globulin. A total of 34 patients were entered on this trial, and 23 patients were still on study at week 24, 18 of whom had blood samples available at both week 6 and week 24. The 95% confidence interval for the mean difference between levels at week 24 and levels at week 6 was -34 to 15 ng/ml for TAM, -35 to 45 ng/ml for N-desmethyl-TAM, and -1 to 2 for 4-hydroxy-TAM. For estradiol, a significant decrease (median, 88.5%; range, 73.7-95.2%) was identified after 6 weeks of letrozole, which was maintained for an additional 12 weeks. Similar significant reductions were identified for E1. E1 sulfate levels increased after 6 weeks of TAM alone but then decreased significantly after the addition of letrozole. Sex hormone-binding globulin levels were significantly elevated after 6 weeks of TAM alone and remained elevated after the addition of letrozole. Six of the 34 patients (17.6%) achieved an objective response (95% confidence interval, 6.8-34.5%), with a median time to disease progression of 7.6 months. There was no indication of a systematic decrease in TAM, N-desmethyl-TAM, or 4-hydroxy-TAM after the additional of letrozole. Estrogen suppression induced by letrozole was substantial despite the concomitant administration of TAM. The antitumor effect of TAM plus letrozole was less than expected.
Asunto(s)
Antineoplásicos Hormonales/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Neoplasias de la Mama/tratamiento farmacológico , Nitrilos/farmacología , Tamoxifeno/farmacocinética , Triazoles/farmacología , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos Hormonales/administración & dosificación , Antineoplásicos Hormonales/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Interacciones Farmacológicas , Endocrinología , Femenino , Humanos , Letrozol , Persona de Mediana Edad , Nitrilos/administración & dosificación , Nitrilos/efectos adversos , Posmenopausia , Tamoxifeno/administración & dosificación , Tamoxifeno/efectos adversos , Resultado del Tratamiento , Triazoles/administración & dosificación , Triazoles/efectos adversosRESUMEN
STUDY DESIGN: Single-group repeated measures for single rater reliability. OBJECTIVES: To describe the intratester reliability for measurements of active lumbar spine mobility and pelvic inclination during standing obtained with the back range-of-motion (BROM) device. BACKGROUND: The BROM device has often been used to quantify lumbar spine active range of motion. No studies have reported the reliability of the BROM device in a clinical setting. METHODS AND MEASURES: One examiner measured all 3 planes of lumbar range of motion in 40 nonimpaired subjects. For each plane of motion, 2 BROM device measurements were made. Intraclass correlation coefficients were calculated to express the intratester reliability for each plane of motion measured. RESULTS: Intraclass correlation coefficients were in the range of 0.67 to 0.94 for lumbar measurements with the BROM device. CONCLUSIONS: Intratester reliability was fair to poor for sagittal plane measurements and pelvic inclination. Measurements obtained by the same examiner for lumbar lateral flexion and rotation with the BROM device, however, were reliable.
Asunto(s)
Dolor de la Región Lumbar , Modalidades de Fisioterapia/instrumentación , Rango del Movimiento Articular , Adulto , Diseño de Equipo , Femenino , Humanos , Región Lumbosacra , Masculino , Variaciones Dependientes del Observador , Valores de ReferenciaRESUMEN
One hundred fifty-one postmenopausal women with progressive metastatic breast cancer and no prior hormonal therapy were treated with either diethylstilbestrol (DES) or tamoxifen (TAM). One hundred forty-three eligible patients were followed until death or for a minimum of 14.1 years on the DES arm or 16.7 years on the TAM arm. The overall objective response was 42% for DES and 33% for TAM (p = 0.31) and the median duration of response was 11.8 months for DES and 9.9 months for TAM (p = 0.38). Duration of response and progression-free survival were not found to be significantly different between DES and TAM (p = 0.32 and 0.65, respectively). The median survival was 3.0 years for DES vs. 2.4 years for TAM. The 5-year survival was 35% for the DES arm and 16% for the TAM arm. Survival was significantly better for women on DES than for women on TAM (adjusted p = 0.039). Review of records did not show any difference in pattern of treatment failure or subsequent treatments in the DES and TAM arms. Treatment with DES was more commonly associated with toxicity such as nausea, edema, vaginal bleeding, and cardiac problems, whereas hot flashes were commonly seen with TAM therapy. The initial treatment with DES is associated with increased survival. The basis of this survival advantage is not known. TAM still is the preferred agent in the treatment of metastatic breast cancer, but this trial underscores the fact that estrogens have activity and remain in the armamentarium for treatment of selected patients with metastatic breast cancer.
Asunto(s)
Antineoplásicos Hormonales/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Dietilestilbestrol/uso terapéutico , Tamoxifeno/uso terapéutico , Anciano , Anciano de 80 o más Años , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/mortalidad , Neoplasias Óseas/secundario , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Dietilestilbestrol/efectos adversos , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Persona de Mediana Edad , Metástasis de la Neoplasia , Posmenopausia , Neoplasias de los Tejidos Blandos/tratamiento farmacológico , Neoplasias de los Tejidos Blandos/mortalidad , Neoplasias de los Tejidos Blandos/secundario , Análisis de Supervivencia , Tamoxifeno/efectos adversosRESUMEN
BACKGROUND: Metaplastic breast cancer is a rare disease with little information available to guide therapy. The goals of this study were to describe the patient characteristics, systemic therapies and clinical outcomes of all patients with primary metaplastic breast cancer treated at Mayo Clinic between 1976 and 1997. PATIENTS AND METHODS: Patients were identified through the medical index of Mayo Clinic. Clinical information was abstracted from the medical record of each patient. A literature search using MEDLINE and CANCERLIT for the years 1966-1997 was performed to identify all previously reported case series in the English language containing 10 or more patients. RESULTS: Twenty-seven patients were identified with a median age at diagnosis of 59 years (range 39-90 years). The median tumor size was 3.4 cm (range 0.5-7.0 cm). One patient had metastatic disease at presentation. Twenty-three patients had information available on nodal status, estrogen receptor (ER) and progesterone receptor (PR) status. Twenty patients (87%) were node-negative and three patients (13%) were both ER and PR positive. Disease-free survival (DFS) and overall survival (OS) were assessed for those who presented with local-regional disease. The three-year DFS was 40% (95% CI: 23%-73%) and the three-year OS was 71% (95% CI: 51%-97%). In univariate analysis, those patients 60 years of age or older at diagnosis were found to have an increased DFS (P = 0.011). Among those with prior estrogen use, both DFS (P = 0.022) and OS (P = 0.003) were decreased. Thirteen patients (50%) developed metastases with a median DFS time of 2.4 years. Ten different chemotherapy regimens were utilized for metastatic disease and one partial response was observed. There were no responses to tamoxifen in four patients with metastatic disease. Median survival after the development of metastases was eight months. CONCLUSIONS: Despite presenting more commonly as node-negative disease, DFS and OS in metaplastic breast cancer is decreased compared to typical adenocarcinomas. Systemic therapy also appears to be less effective. Patients with metaplastic breast cancer, particularly those with metastatic disease could be appropriate candidates for innovative therapeutic regimens.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/patología , Neoplasias de la Mama/terapia , Neoplasias Complejas y Mixtas/secundario , Neoplasias Complejas y Mixtas/terapia , Cuidados Paliativos , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/mortalidad , Carcinoma/mortalidad , Carcinoma/patología , Carcinoma/secundario , Carcinoma/terapia , Carcinoma de Células Escamosas/mortalidad , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/secundario , Carcinoma de Células Escamosas/terapia , Ciclofosfamida/administración & dosificación , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Doxorrubicina/administración & dosificación , Femenino , Fluorouracilo/administración & dosificación , Estudios de Seguimiento , Humanos , Metástasis Linfática , Metaplasia , Metotrexato/administración & dosificación , Persona de Mediana Edad , Neoplasias Complejas y Mixtas/mortalidad , Neoplasias Complejas y Mixtas/patología , Pronóstico , Radioterapia Adyuvante , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Tasa de Supervivencia , Tamoxifeno/administración & dosificación , Resultado del TratamientoRESUMEN
BACKGROUND: Tamoxifen (TAM) is generally considered the hormonal agent of choice for postmenopausal women with hormone receptor positive breast carcinoma. The somatostatin analogues, including octreotide, have demonstrated inhibition of breast carcinoma cell lines and multiple endocrinologic actions, including reduction of insulin-like growth factor I (IGF-I), a potent mitogen for breast carcinoma cells. In an attempt to improve the efficacy of TAM, this randomized trial was performed. METHODS: One hundred thirty-five eligible postmenopausal women with metastatic breast carcinoma were randomized to TAM (10 mg twice daily) alone or combined with octreotide 150 microg (administered subcutaneously thrice daily). The two groups were well balanced, except the TAM group had higher proportions of patients with visceral disease (50% vs. 37%) and a disease free interval longer than 5 years (47% vs. 34%). A cohort of 18 patients was evaluated for the impact of treatment on serum IGF-I, free IGF-I, IGF binding protein 3 levels, and total IGF binding capacity. RESULTS: The median time to progression was estimated to be 14.2 months with TAM and 10.3 months with TAM plus octreotide. The distribution of progression free survival times revealed no significant difference (P = 0.26), and the progression hazard ratio (TAM/TAM + octreotide) was 0.81 (95% confidence interval [CI], 0.56-1.17). The distribution of survival times revealed no significant difference (P = 0.92), and the death hazard ratio was 0.98 (95% CI, 0.62-1.55). When the 106 patients with measurable or evaluable disease were considered, the objective response rate was 49% with TAM alone and 43% with TAM plus octreotide (P = 0.70). Patients who received TAM plus octreotide had higher incidences of nausea, diarrhea, and steatorrhea. The percentage of decline in serum IGF-I, from pretreatment levels to those following 3-6 weeks of treatment, was significantly greater (P < 0.01) with TAM plus octreotide than with TAM alone. CONCLUSIONS: There is no indication that the combination of TAM plus octreotide as administered in this study is substantially more efficacious than TAM alone in the treatment of postmenopausal women with metastatic breast carcinoma. The limited cohort included in IGF-I studies suggests that TAM plus octreotide produces a significantly greater reduction in serum IGF-I levels.
Asunto(s)
Antineoplásicos Hormonales/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Tamoxifeno/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos Hormonales/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/sangre , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Femenino , Humanos , Factor I del Crecimiento Similar a la Insulina/análisis , Persona de Mediana Edad , Metástasis de la Neoplasia , Octreótido/administración & dosificación , Octreótido/efectos adversos , Tasa de Supervivencia , Tamoxifeno/efectos adversosRESUMEN
Epithelial ovarian cancer (EOC) has a high mortality rate, which is due primarily to the fact that early clinical symptoms are vague and nonspecific; hence, this disease often goes undetected and untreated until in its advanced stages. Sensitive and reliable methods for detecting earlier stages of EOC are, therefore, urgently needed. Epidermal growth factor (EGF) is a ligand for EGF receptor (ErbB1); this receptor is the product of the c-erbB1 proto-oncogene. ErbB1 overexpression is common in human ovarian carcinoma-derived cell lines and tumors, in which overexpression is thought to play a critical role in tumor etiology and progression. Furthermore, ErbB1 overexpression is associated with disease recurrence and decreased patient survival. Recently, we have developed an acridinium-linked immunosorbent assay that detects a approximately 110-kDa soluble analogue of ErbB1, ie., sErbB1, in serum samples from healthy men and women (A. T. Baron, et al., J. Immunol. Methods, 219: 23-43, 1998). Here, we demonstrate that serum p110 sErbB1 levels are significantly lower in EOC patients with stage III or IV disease prior to (P < 0.0001) and shortly after (P < 0.0001) cytoreductive staging laparotomy than in healthy women of similar ages, whereas EGF levels are significantly higher than those of age-matched healthy women only in serum samples collected shortly after tumor debulking surgery (P < 0.0001). We observe that the preoperative serum sErbB1 concentration range of advanced stage EOC patients barely overlaps with the serum sErbB1 concentration range of healthy women. In addition, we show that serum sErbB1 and EGF levels changed temporally for some EOC patients who were surgically debulked of tumor and who provided a second serum sample during the course of combination chemotherapy. Finally, we observe a significant positive association between sErbB1 and EGF levels only in serum samples of EOC patients collected prior to cytoreductive surgery (correlation coefficient = 0.61968; P = 0.0027). These data suggest that epithelial ovarian tumors concomitantly affect serum sErbB1 and EGF levels. In conclusion, these data indicate that serum sErbB1 and EGF (postoperative only) levels are significantly different between EOC patients and healthy women and that altered and/or changing serum sErbB1 and EGF levels may provide important diagnostic and/or prognostic information useful for the management of patients with EOC.
Asunto(s)
Biomarcadores de Tumor/sangre , Factor de Crecimiento Epidérmico/sangre , Receptores ErbB/sangre , Neoplasias Glandulares y Epiteliales/sangre , Neoplasias Ováricas/sangre , Acridinas , Adulto , Anciano , Biomarcadores de Tumor/genética , Carcinoma/sangre , Carcinoma/patología , Estudios de Casos y Controles , Quimioterapia Adyuvante , Progresión de la Enfermedad , Factor de Crecimiento Epidérmico/genética , Receptores ErbB/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Técnicas de Inmunoadsorción , Laparotomía , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Neoplasias Glandulares y Epiteliales/patología , Neoplasias Glandulares y Epiteliales/cirugía , Neoplasias Ováricas/patología , Neoplasias Ováricas/cirugía , Pronóstico , Proto-Oncogenes Mas , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Tasa de Supervivencia , Células Tumorales CultivadasRESUMEN
Numerous comparative clinical trials have been conducted evaluating combination hormonal therapy involving the aromatase inhibitor aminoglutethimide, but there is no evidence for any superiority of this approach over single-agent therapy alone. The advent of new aromatase inhibitors with greater potency, selectivity, and better tolerability has prompted a reconsideration of the combined therapy approach, with attention being focused on pharmacologic and endocrinologic clinical research. The value of combining newer aromatase inhibitors with other hormonal agents remains to be established.