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Purpose The role of temporary ovarian suppression with gonadotropin-releasing hormone agonists (GnRHa) during chemotherapy as a strategy to preserve ovarian function and fertility in premenopausal women remains controversial. This systematic review and meta-analysis using individual patient-level data was conducted to better assess the efficacy and safety of this strategy in patients with early breast cancer. Methods The trials in which premenopausal women with early breast cancer were randomly assigned to receive (neo)adjuvant chemotherapy alone or with concurrent GnRHa were eligible for inclusion. Primary end points were premature ovarian insufficiency (POI) rate and post-treatment pregnancy rate. Disease-free survival and overall survival were secondary end points. Because each study represents a cluster, statistical analyses were performed using a random effects model. Results A total of 873 patients from five trials were included. POI rate was 14.1% in the GnRHa group and 30.9% in the control group (adjusted odds ratio, 0.38; 95% CI, 0.26 to 0.57; P < .001). A total of 37 (10.3%) patients had at least one post-treatment pregnancy in the GnRHa group and 20 (5.5%) in the control group (incidence rate ratio, 1.83; 95% CI, 1.06 to 3.15; P = .030). No significant differences in disease-free survival (adjusted hazard ratio, 1.01; 95% CI, 0.72 to 1.42; P = .999) and overall survival (adjusted hazard ratio, 0.67; 95% CI, 0.42 to 1.06; P = .083) were observed between groups. Conclusion Our findings provide evidence for the efficacy and safety of temporary ovarian suppression with GnRHa during chemotherapy as an available option to reduce the likelihood of chemotherapy-induced POI and potentially improve future fertility in premenopausal patients with early breast cancer.
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Neoplasias de la Mama/tratamiento farmacológico , Preservación de la Fertilidad/métodos , Hormona Liberadora de Gonadotropina/agonistas , Tratamientos Conservadores del Órgano/métodos , Ovario/efectos de los fármacos , Insuficiencia Ovárica Primaria/prevención & control , Adulto , Supervivencia sin Enfermedad , Femenino , Humanos , Premenopausia , Insuficiencia Ovárica Primaria/inducido químicamente , Ensayos Clínicos Controlados Aleatorios como Asunto , Resultado del TratamientoRESUMEN
PURPOSE: Indoximod is an oral inhibitor of the indoleamine 2,3-dioxygenase pathway, which causes tumor-mediated immunosuppression. Primary endpoints were maximum tolerated dose (MTD) and toxicity for indoximod in patients with advanced solid tumors. Secondary endpoints included response rates, pharmacokinetics, and immune correlates. EXPERIMENTAL DESIGN: Our 3+3 phase I trial comprised 10 dose levels (200, 300, 400, 600, and 800 mg once/day; 600, 800, 1200, 1600, and 2000 mg twice/day). Inclusion criteria were measurable metastatic solid malignancy, age ≥18 years, and adequate organ/marrow function. Exclusion criteria were chemotherapy ≤ 3 weeks prior, untreated brain metastases, autoimmune disease, or malabsorption. RESULTS: In 48 patients, MTD was not reached at 2000 mg twice/day. At 200 mg once/day, 3 patients previously treated with checkpoint inhibitors developed hypophysitis. Five patients showed stable disease >6 months. Indoximod plasma AUC and Cmax plateaued above 1200mg. Cmax (~12 µM at 2000 mg twice/day) occurred at 2.9 hours, and half-life was 10.5 hours. C reactive protein (CRP) levels increased across multiple dose levels. CONCLUSIONS: Indoximod was safe at doses up to 2000 mg orally twice/day. Best response was stable disease >6 months in 5 patients. Induction of hypophysitis, increased tumor antigen autoantibodies and CRP levels were observed.
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Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Neoplasias/tratamiento farmacológico , Triptófano/análogos & derivados , Adulto , Anciano , Anciano de 80 o más Años , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Indolamina-Pirrol 2,3,-Dioxigenasa/antagonistas & inhibidores , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Triptófano/administración & dosificación , Triptófano/efectos adversos , Adulto JovenRESUMEN
Conventional cancer treatment strategies assume that maximum patient benefit is achieved through maximum killing of tumor cells. However, by eliminating the therapy-sensitive population, this strategy accelerates emergence of resistant clones that proliferate unopposed by competitors-an evolutionary phenomenon termed "competitive release." We present an evolution-guided treatment strategy designed to maintain a stable population of chemosensitive cells that limit proliferation of resistant clones by exploiting the fitness cost of the resistant phenotype. We treated MDA-MB-231/luc triple-negative and MCF7 estrogen receptor-positive (ER(+)) breast cancers growing orthotopically in a mouse mammary fat pad with paclitaxel, using algorithms linked to tumor response monitored by magnetic resonance imaging. We found that initial control required more intensive therapy with regular application of drug to deflect the exponential tumor growth curve onto a plateau. Dose-skipping algorithms during this phase were less successful than variable dosing algorithms. However, once initial tumor control was achieved, it was maintained with progressively smaller drug doses. In 60 to 80% of animals, continued decline in tumor size permitted intervals as long as several weeks in which no treatment was necessary. Magnetic resonance images and histological analysis of tumors controlled by adaptive therapy demonstrated increased vascular density and less necrosis, suggesting that vascular normalization resulting from enforced stabilization of tumor volume may contribute to ongoing tumor control with lower drug doses. Our study demonstrates that an evolution-based therapeutic strategy using an available chemotherapeutic drug and conventional clinical imaging can prolong the progression-free survival in different preclinical models of breast cancer.
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Neoplasias de la Mama/tratamiento farmacológico , Animales , Neoplasias de la Mama/patología , Línea Celular Tumoral , Proliferación Celular , Modelos Animales de Enfermedad , Femenino , Humanos , Imagen por Resonancia Magnética , Ratones , Paclitaxel/farmacología , Paclitaxel/uso terapéutico , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
BACKGROUND: MK-5108 is a potent/highly selective Aurora A kinase inhibitor. METHODS: A randomized Phase I study of MK-5108, administered p.o. BID Q12h on days 1-2 in 14-21 day cycles either alone (MT; Panel1/n = 18; 200 to 1800 mg) or in combination (CT; Panel2/n = 17; 100 to 225 mg) with IV docetaxel 60 mg/m(2), determined the maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics (Panel1, only) and tumor response in patients with advanced solid tumors. This study was terminated early due to toxicities in Panel2 at MK-5108 doses below the anticipated PK exposure target. RESULTS: 35 patients enrolled (33 evaluable for tumor response). No dose-limiting toxicities (DLTs) were observed in Panel1; three patients had 3 DLTs in Panel2 (G3 and G4 febrile neutropenia at 200 and 450 mg/day, respectively; G3 infection at 450 mg/day). In Panel1, AUC0-12hr and Cmax increased less than dose proportionally following the first MT dose but increased roughly dose proportionally across 200 to 3600 mg/day after 4th dose. The t1/2 ranged from 6.6 to 13.5 h across both panels. No clear effects on immunohistochemistry markers were observed; however, significant dose-related increases in gene expression were seen pre-/post-treatment. Best responses were 9/17 stable disease (SD) (Panel1) as well as 1/16 PR and 7/16 SD (Panel2) (450 mg/day). CONCLUSIONS: MK-5108 MT was well tolerated at doses up to 3600 mg/day with plasma levels exceeding the minimum daily exposure target (83 µM*hr). The MTD for MK-5108 + docetaxel (CT) was established at 300 mg/day, below the exposure target. Use of pharmacodynamic gene expression assays to determine target engagement was validated.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Aurora Quinasa A/antagonistas & inhibidores , Ácidos Ciclohexanocarboxílicos/administración & dosificación , Neoplasias/tratamiento farmacológico , Tiazoles/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Área Bajo la Curva , Estudios Cruzados , Ácidos Ciclohexanocarboxílicos/efectos adversos , Ácidos Ciclohexanocarboxílicos/farmacocinética , Docetaxel , Relación Dosis-Respuesta a Droga , Femenino , Semivida , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Neoplasias/patología , Inhibidores de Proteínas Quinasas/administración & dosificación , Taxoides/administración & dosificación , Tiazoles/efectos adversos , Tiazoles/farmacocinéticaRESUMEN
The many improvements in breast cancer therapy in recent years have so lowered rates of recurrence that it is now difficult or impossible to conduct adequately powered adjuvant clinical trials. Given the many new drugs and potential synergistic combinations, the neoadjuvant approach has been used to test benefit of drug combinations in clinical trials of primary breast cancer. A recent FDA-led meta-analysis showed that pathologic complete response (pCR) predicts disease-free survival (DFS) within patients who have specific breast cancer subtypes. This meta-analysis motivated the FDA's draft guidance for using pCR as a surrogate endpoint in accelerated drug approval. Using pCR as a registration endpoint was challenged at ASCO 2014 Annual Meeting with the presentation of ALTTO, an adjuvant trial in HER2-positive breast cancer that showed a nonsignificant reduction in DFS hazard rate for adding lapatinib, a HER-family tyrosine kinase inhibitor, to trastuzumab and chemotherapy. This conclusion seemed to be inconsistent with the results of NeoALTTO, a neoadjuvant trial that found a statistical improvement in pCR rate for the identical lapatinib-containing regimen. We address differences in the two trials that may account for discordant conclusions. However, we use the FDA meta-analysis to show that there is no discordance at all between the observed pCR difference in NeoALTTO and the observed HR in ALTTO. This underscores the importance of appropriately modeling the two endpoints when designing clinical trials. The I-SPY 2/3 neoadjuvant trials exemplify this approach.
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Neoplasias de la Mama/tratamiento farmacológico , Quimioterapia Adyuvante , Ensayos Clínicos como Asunto , Descubrimiento de Drogas , Femenino , Humanos , Terapia Neoadyuvante , Resultado del TratamientoAsunto(s)
Inhibidores de la Aromatasa/efectos adversos , Artralgia/inducido químicamente , Artralgia/terapia , Neoplasias de la Mama/tratamiento farmacológico , Yoga , Anciano , Inhibidores de la Aromatasa/uso terapéutico , Femenino , Humanos , Persona de Mediana Edad , Proyectos Piloto , Resultado del TratamientoRESUMEN
ATP-binding cassette (ABC) drug transporters consuming ATPs for drug efflux is a common mechanism by which clinical cancers develop multidrug resistance (MDR). We hypothesized that MDR phenotypes could be suppressed by administration of "ersatzdroges," nonchemotherapy drugs that are, nevertheless, ABC substrates. We reasoned that, through prolonged activation of the ABC pumps, ersatzdroges will force MDR cells to divert limited resources from proliferation and invasion thus delaying disease progression. We evaluated ABC substrates as ersatzdroge by comparing their effects on proliferation and survival of MDR cell lines (MCF-7/Dox and 8226/Dox40) with the effects on the drug-sensitive parental lines (MCF-7 and 8226/s, respectively) in glucose-limited condition. The changes in glucose and energy demands were also examined in vitro and in vivo. MCF-7/Dox showed higher ATP demand and susceptibility to glucose resource limitation. Ersatzdroges significantly decreased proliferation of MCF-7/Dox when the culture media contained physiological glucose concentrations (1.0 g/L) or less, but had no effect on MCF-7. Similar evidence was obtained from 8226/Dox40 and 8226/s comparison. In vivo 18F-FDG-PET imaging demonstrated that glucose uptake was increased by systemic administration of an ersatzdroge in tumors composed of MDR. These results suggest that administration of ersatzdroges, by increasing the metabolic cost of resistance, can suppress proliferation of drug-resistance phenotypes. This provides a novel and relatively simple application model of evolution-based strategy, which can exploit the cost of resistance to delay proliferation of drug-resistant cancer phenotypes. Furthermore, suggested is the potential of ersatzdroges to identify tumors or regions of tumors that express the MDR phenotype.
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Antineoplásicos/farmacología , Proliferación Celular/efectos de los fármacos , Resistencia a Antineoplásicos , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Animales , Antineoplásicos/uso terapéutico , Supervivencia Celular/efectos de los fármacos , Claritromicina/farmacología , Claritromicina/uso terapéutico , Ciclosporina/farmacología , Ciclosporina/uso terapéutico , Resistencia a Múltiples Medicamentos , Eritromicina/farmacología , Eritromicina/uso terapéutico , Femenino , Expresión Génica , Humanos , Células MCF-7 , Neoplasias Mamarias Experimentales/metabolismo , Neoplasias Mamarias Experimentales/patología , Ratones Desnudos , Terapia Molecular Dirigida , Carga Tumoral , Verapamilo/farmacología , Verapamilo/uso terapéutico , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Indoleamine 2,3-dioxygenase (IDO) is an enzyme that tumors use to create a state of immunosuppression. Indoximod is an IDO pathway inhibitor. Preclinical studies demonstrated that indoximod combined with chemotherapy was synergistic in a mouse model of breast cancer. A phase I 3+3 trial was designed to study the combination of docetaxel and indoximod. METHODS: Docetaxel was administered at 60 mg/m2 intravenously every 3 weeks dose levels 1-4 and 75 mg/m2 for dose level 5. Indoximod was given at 300, 600, 1000, 2000, and 1200 mg PO twice daily continuously for levels 1-5, respectively. Serum drug levels were measured. RESULTS: Twenty-seven patients were treated, with 22 evaluable for response. DLTs included grade 3 dehydration (level 1), hypotension(level 4), mucositis (level 4) and grade 5 enterocolitis (level 2). Dose level 5 is the recommended phase II dose. The most frequent adverse events were fatigue (58.6%), anemia (51.7%), hyperglycemia (48.3%), infection (44.8%), and nausea (41.4%). There were 4 partial responses (2 breast, 1 NSCLC, 1 thymic tumor). No drug-drug interactions were noted. CONCLUSIONS: Docetaxel plus indoximod was well tolerated with no increase in expected toxicities or pharmacokinetic interactions. It was active in a pretreated population of patients with metastatic solid tumors.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias/tratamiento farmacológico , Administración Intravenosa , Administración Oral , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/sangre , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Docetaxel , Esquema de Medicación , Monitoreo de Drogas , Femenino , Florida , Humanos , Factores Inmunológicos/administración & dosificación , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Metástasis de la Neoplasia , Neoplasias/patología , Taxoides/administración & dosificación , Factores de Tiempo , Resultado del Tratamiento , Triptófano/administración & dosificación , Triptófano/análogos & derivadosRESUMEN
Conventional systemic therapy for disseminated breast cancer is based on the general assumption that the greatest patient benefit is achieved by killing the maximum number of tumor cells. While this strategy often achieves a significant reduction in tumor burden, most patients with metastatic breast cancer ultimately die from their disease as therapy fails because tumor cells evolve resistance. We propose that the conventional maximum dose/maximum cell kill cancer therapy, when viewed from an evolutionary vantage, is suboptimal and likely even harmful as it accelerates evolution and growth of the resistant phenotypes that ultimately cause patient death. As an alternative, we are investigating evolutionary therapeutic strategies that shift the treatment goal from killing the maximum number of cancer cells to maximizing patient survival. Here we introduce two novel approaches for systemic therapy for metastatic breast cancer, considering the evolutionary nature of tumor progression; adaptive therapy and double-bind therapy.
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Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/fisiopatología , Resistencia a Antineoplásicos/fisiología , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/biosíntesis , Adenosina Trifosfato/metabolismo , Animales , Neoplasias de la Mama/patología , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Metástasis de la Neoplasia , Fenotipo , Receptor ErbB-2/biosíntesis , Moduladores Selectivos de los Receptores de Estrógeno/farmacología , Factores de TiempoRESUMEN
BACKGROUND: Inhibition of AKT with MK-2206 has demonstrated synergism with anticancer agents. This phase 1 study assessed the MTD, DLTs, PK, and efficacy of MK-2206 in combination with cytotoxic and targeted therapies. METHODS: Advanced solid tumor patients received oral MK-2206 45 or 60 mg (QOD) with either carboplatin (AUC 6.0) and paclitaxel 200 mg/m2 (arm 1), docetaxel 75 mg/m2 (arm 2), or erlotinib 100 or 150 mg daily (arm 3); alternative schedules of MK-2206 135-200 mg QW or 90-250 mg Q3W were also tested. RESULTS: MTD of MK-2206 (N = 72) was 45 mg QOD or 200 mg Q3W (arm 1); MAD was 200 mg Q3W (arm 2) and 135 mg QW (arm 3). DLTs included skin rash (arms 1, 3), febrile neutropenia (QOD, arms 1, 2), tinnitus (Q3W, arm 2), and stomatitis (QOD, arm 3). Common drug-related toxicities included fatigue (68%), nausea (49%), and rash (47%). Two patients with squamous cell carcinoma of the head and neck (arm 1; Q3W) demonstrated a complete and partial response (PR); additional PRs were observed in patients (1 each) with melanoma, endometrial, neuroendocrine prostate, NSCLC, and cervical cancers. Six patients had stable disease ≥6 months. CONCLUSION: MK-2206 plus carboplatin and paclitaxel, docetaxel, or erlotinib was well-tolerated, with early evidence of antitumor activity.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Administración Oral , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Área Bajo la Curva , Carboplatino/administración & dosificación , Carboplatino/efectos adversos , Docetaxel , Relación Dosis-Respuesta a Droga , Clorhidrato de Erlotinib , Exantema/inducido químicamente , Fatiga/inducido químicamente , Neutropenia Febril/inducido químicamente , Femenino , Compuestos Heterocíclicos con 3 Anillos/administración & dosificación , Compuestos Heterocíclicos con 3 Anillos/efectos adversos , Compuestos Heterocíclicos con 3 Anillos/farmacocinética , Humanos , Masculino , Persona de Mediana Edad , Náusea/inducido químicamente , Neoplasias/clasificación , Neoplasias/metabolismo , Paclitaxel/administración & dosificación , Paclitaxel/efectos adversos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Quinazolinas/administración & dosificación , Quinazolinas/efectos adversos , Estomatitis/inducido químicamente , Taxoides/administración & dosificación , Taxoides/efectos adversos , Acúfeno/inducido químicamente , Resultado del Tratamiento , Adulto JovenRESUMEN
OBJECTIVE: Although many survivors continue to worry about cancer years after completing treatment, little is known about factors associated with cancer worry. This study examined associations between breast cancer worry and demographic and clinical variables, as well as fatigue, symptom burden, and risk perception in a sample of breast cancer survivors 3 years post-adjuvant treatment. We hypothesized that after controlling for demographic and treatment factors, a significant proportion of variance in cancer worry would be explained by greater fatigue severity, more symptom burden, and greater perceived risk of recurrence. METHODS: Stage 0-II breast cancer patients (N = 202) completed measures of risk perception, cancer worry (modified Lerman's Cancer Worry Scale), symptom burden (Memorial Symptom Assessment Scale), and fatigue severity (Fatigue Symptom Inventory) 3 years after completing adjuvant treatment. Multiple regression analyses were used to determine the proportion of variance in cancer worry accounted for by fatigue, symptom burden, and risk perception after controlling for demographic and clinical variables. RESULTS: Age, fatigue, symptom burden, and risk perception each explained a significant proportion of variance in cancer worry (p < 0.05). Fatigue, symptom burden, and risk perception together accounted for 27% of the variance in cancer worry after controlling for demographic and clinical factors (p < 0.01). CONCLUSIONS: The hypothesis was supported that fatigue, symptom burden, and risk perception are associated with cancer worry among breast cancer survivors. It is possible that lingering fatigue and other symptoms may remind breast cancer survivors of their disease.
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Ansiedad/psicología , Neoplasias de la Mama/psicología , Fatiga/psicología , Sobrevivientes/psicología , Adulto , Anciano , Anciano de 80 o más Años , Ansiedad/etiología , Neoplasias de la Mama/complicaciones , Neoplasias de la Mama/terapia , Quimioterapia Adyuvante , Fatiga/etiología , Femenino , Humanos , Estudios Longitudinales , Persona de Mediana Edad , Estadificación de Neoplasias , Radioterapia Adyuvante , Análisis de Regresión , Factores de Riesgo , Factores Socioeconómicos , Encuestas y Cuestionarios , Factores de Tiempo , Resultado del TratamientoRESUMEN
Many cancers adapt to chemotherapeutic agents by upregulating membrane efflux pumps that export drugs from the cytoplasm, but this response comes at an energetic cost. In breast cancer patients, expression of these pumps is low in tumors before therapy but increases after treatment. While the evolution of therapeutic resistance is virtually inevitable, proliferation of resistant clones is not, suggesting strategies of adaptive therapy. Chemoresistant cells must consume excess resources to maintain resistance mechanisms, so adaptive therapy strategies explicitly aim to maintain a stable population of therapy-sensitive cells to suppress growth of resistant phenotypes through intratumoral competition. We used computational models parameterized by in vitro experiments to illustrate the efficacy of such approaches. Here, we show that low doses of verapamil and 2-deoxyglucose, to accentuate the cost of resistance and to decrease energy production, respectively, could suppress the proliferation of drug-resistant clones in vivo. Compared with standard high-dose-density treatment, the novel treatment we developed achieved a 2-fold to 10-fold increase in time to progression in tumor models. Our findings challenge the existing flawed paradigm of maximum dose treatment, a strategy that inevitably produces drug resistance that can be avoided by the adaptive therapy strategies we describe.
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Neoplasias de la Mama/terapia , Carcinoma/terapia , Oncología Médica/métodos , Oncología Médica/tendencias , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Neoplasias de la Mama/genética , Carcinoma/genética , Línea Celular Tumoral , Proliferación Celular , Supervivencia sin Enfermedad , Resistencia a Antineoplásicos/genética , Resistencia a Antineoplásicos/fisiología , Metabolismo Energético/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Glucosa/metabolismo , Glucólisis/genética , Humanos , Modelos BiológicosRESUMEN
We report a rare finding of two male breast cancer patients with HER2-positive breast cancer who also developed thyroid cancer. We reviewed 45 male breast cancer patients treated in our institution from 2003 to 2008. Only five male breast cancer patients were HER2-positive. In reviewing the published data, we found no cases of thyroid cancer and concurrent breast cancer in men. However, breast cancer and thyroid cancer have shown close association in women. This finding therefore provokes speculation as to whether we should investigate whether women with HER2-positive breast cancer are at a higher risk for thyroid cancer. Although this observation seems to be clinically prevalent, publications are sparse in clinical research areas linking thyroid cancer to breast cancer.
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Academias e Institutos , Neoplasias de la Mama Masculina/complicaciones , Neoplasias de la Mama Masculina/patología , Receptor ErbB-2/metabolismo , Neoplasias de la Tiroides/complicaciones , Neoplasias de la Tiroides/patología , Anciano , Humanos , Hibridación Fluorescente in Situ , Masculino , Persona de Mediana Edad , Coloración y EtiquetadoRESUMEN
PURPOSE: Chemotherapy-induced amenorrhea is a serious concern for women undergoing cancer therapy. This prospective randomized trial evaluated the use of gonadotropin-releasing hormone (GnRH) analog triptorelin to preserve ovarian function in women treated with chemotherapy for early-stage breast cancer. PATIENTS AND METHODS: Premenopausal women age 44 years or younger were randomly assigned to receive either triptorelin or no triptorelin during (neo)adjuvant chemotherapy and were further stratified by age (< 35, 35 to 39, > 39 years), estrogen receptor status, and chemotherapy regimen. Objectives included the resumption of menses and serial monitoring of follicle-stimulating hormone (FSH) and inhibin A and B levels. RESULTS: Targeted for 124 patients with a planned 5-year follow-up, the trial was stopped for futility after 49 patients were enrolled (median age, 39 years; range, 21 to 43 years); 47 patients were treated according to assigned groups with four cycles of adriamycin plus cyclophosphamide alone or followed by four cycles of paclitaxel or six cycles of fluorouracil, epirubicin, and cyclophosphamide. Menstruation resumed in 19 (90%) of 21 patients in the control group and in 23 (88%) of 26 in the triptorelin group (P= .36). Menses returned after a median of 5.8 months (range, 1 to 19 months) after completion of chemotherapy in the triptorelin versus 5.0 months (range, 0 to 28 months) in the control arm (P= .58). Two patients (age 26 and 35 years at random assignment) in the control group had spontaneous pregnancies with term deliveries. FSH and inhibin B levels correlated with menstrual status. CONCLUSION: When stratified for age, estrogen receptor status, and treatment regimen, amenorrhea rates on triptorelin were comparable to those seen in the control group.
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Amenorrea/prevención & control , Antineoplásicos Hormonales/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/tratamiento farmacológico , Fertilidad , Hormona Liberadora de Gonadotropina/agonistas , Terapia Neoadyuvante/métodos , Ovario/efectos de los fármacos , Pamoato de Triptorelina/uso terapéutico , Adulto , Amenorrea/inducido químicamente , Antineoplásicos Hormonales/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Biomarcadores/sangre , Neoplasias de la Mama/patología , Quimioterapia Adyuvante , Ciclofosfamida/efectos adversos , Supervivencia sin Enfermedad , Doxorrubicina/efectos adversos , Esquema de Medicación , Epirrubicina/efectos adversos , Femenino , Fertilidad/efectos de los fármacos , Fluorouracilo/efectos adversos , Hormona Folículo Estimulante/sangre , Estudios de Seguimiento , Hormona Liberadora de Gonadotropina/análogos & derivados , Humanos , Inhibinas/sangre , Menstruación , Estadificación de Neoplasias , Paclitaxel/efectos adversos , Tamoxifeno/efectos adversos , Factores de Tiempo , Resultado del Tratamiento , Pamoato de Triptorelina/administración & dosificaciónRESUMEN
BACKGROUND: Data are scarce about whether past history of major depressive disorder in the absence of current depression places breast cancer patients at risk for worse quality of life. PURPOSE: The current study prospectively examined quality of life during chemotherapy in breast cancer patients with a history of resolved major depressive disorder (n = 29) and no history of depression (n = 144). METHODS: Women with Stages 0-II breast cancer were assessed prior to and at the completion of chemotherapy. Major depressive disorder was assessed via structured interview and quality of life with the SF-36. RESULTS: Patients with past major depressive disorder displayed greater declines in physical functioning relative to patients with no history of depression (p ≤ 0.01). CONCLUSIONS: Findings suggest that breast cancer patients with a history of resolved major depressive disorder are at increased risk for declines in physical functioning during chemotherapy relative to patients with no history of depression.
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Neoplasias de la Mama/psicología , Trastorno Depresivo Mayor/psicología , Calidad de Vida/psicología , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Femenino , Humanos , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Encuestas y CuestionariosRESUMEN
Cytokine and growth factor signaling pathways involving STAT3 are frequently constitutively activated in many human primary tumors, and are known for the transcriptional role they play in controlling cell growth and cell cycle progression. However, the extent of STAT3's reach on transcriptional control of the genome as a whole remains an important question. We predicted that this persistent STAT3 signaling affects a wide variety of cellular functions, many of which still remain to be characterized. We took a broad approach to identify novel STAT3 regulated genes by examining changes in the genome-wide gene expression profile by microarray, using cells expressing constitutively-activated STAT3. Using computational analysis, we were able to define the gene expression profiles of cells containing activated STAT3 and identify candidate target genes with a wide range of biological functions. Among these genes we identified Necdin, a negative growth regulator, as a novel STAT3 target gene, whose expression is down-regulated at the mRNA and protein levels when STAT3 is constitutively active. This repression is STAT3 dependent, since inhibition of STAT3 using siRNA restores Necdin expression. A STAT3 DNA-binding site was identified in the Necdin promoter and both EMSA and chromatin immunoprecipitation confirm binding of STAT3 to this region. Necdin expression has previously been shown to be down-regulated in a melanoma and a drug-resistant ovarian cancer cell line. Further analysis of Necdin expression demonstrated repression in a STAT3-dependent manner in human melanoma, prostate and breast cancer cell lines. These results suggest that STAT3 coordinates expression of genes involved in multiple metabolic and biosynthetic pathways, integrating signals that lead to global transcriptional changes and oncogenesis. STAT3 may exert its oncogenic effect by up-regulating transcription of genes involved in promoting growth and proliferation, but also by down-regulating expression of negative regulators of the same cellular processes, such as Necdin.
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Regulación Neoplásica de la Expresión Génica , Neoplasias/genética , Proteínas del Tejido Nervioso/genética , Proteínas Nucleares/genética , Factor de Transcripción STAT3/genética , Sitios de Unión , Regulación hacia Abajo/genética , Regulación hacia Abajo/fisiología , Perfilación de la Expresión Génica , Genoma Humano , Humanos , Neoplasias/metabolismo , Proteínas del Tejido Nervioso/fisiología , Proteínas Nucleares/fisiología , Análisis de Secuencia por Matrices de Oligonucleótidos , Regiones Promotoras Genéticas , Factor de Transcripción STAT3/fisiología , Transcripción GenéticaRESUMEN
National Comprehensive Cancer Network (NCCN) guidelines for female breast cancer treatment and surveillance are well established, but similar guidelines on male breast cancers are less recognized. As an NCCN institution, our objective was to examine practice patterns and follow-up for male breast cancer compared to established guidelines for female patients. After Institutional Review Board approval, a prospective breast database from 1990 to 2009 was queried for male patients. Medical records were examined for clinico-pathological factors and follow-up. The 5-year survival rates with 95% confidence intervals were estimated using Kaplan-Meier method and Greenwood formula. Of the 19,084 patients in the database, 73 (0.4%) were male patients; 62 had complete data. One patient had bilateral synchronous breast cancer. The median age was 68.8 years (range 29-85 years). The mean/median invasive tumor size was 2.2/1.6 cm (range 0.0-10.0 cm). All cases had mastectomy (29 with axillary node dissection, 23 with sentinel lymph node biopsy only, 11 with sentinel node biopsy followed by completion axillary dissection). Lymph node involvement occurred in 25/63 (39.7%). Based on NCCN guidelines, chemotherapy, hormonal therapy, and radiation are indicated in 34 cases, 62 cases, and 14 cases, respectively. Only 20/34 (59%) received chemotherapy, 51/62 (82%) received hormonal therapy, and 10/14 (71%) received post-mastectomy radiation. Median follow-up was 26.2 months (range: 1.6-230.9 months). The 5-year survival estimates for node positive and negative diseases were 68.5% and 87.5%, respectively (p = 0.3). Despite the rarity of male breast cancer, treatment options based on current female breast tumors produce comparable results to female breast cancer. Increased awareness and a national registry for patients could help improve outcomes and tailor treatment recommendations to the male variant.
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Adenocarcinoma/patología , Adenocarcinoma/terapia , Neoplasias de la Mama Masculina/patología , Neoplasias de la Mama Masculina/terapia , Adhesión a Directriz , Escisión del Ganglio Linfático , Guías de Práctica Clínica como Asunto , Adulto , Anciano , Anciano de 80 o más Años , Axila , Quimioterapia Adyuvante , Humanos , Estimación de Kaplan-Meier , Metástasis Linfática , Masculino , Mastectomía , Persona de Mediana Edad , Radioterapia Adyuvante , Biopsia del Ganglio Linfático CentinelaRESUMEN
INTRODUCTION: A multicenter, open-label phase III study was conducted to test whether sunitinib plus paclitaxel prolongs progression-free survival (PFS) compared with bevacizumab plus paclitaxel as first-line treatment for patients with HER2(-) advanced breast cancer. PATIENTS AND METHODS: Patients with HER2(-) advanced breast cancer who were disease free for ≥ 12 months after adjuvant taxane treatment were randomized (1:1; planned enrollment 740 patients) to receive intravenous (I.V.) paclitaxel 90 mg/m(2) every week for 3 weeks in 4-week cycles plus either sunitinib 25 to 37.5 mg every day or bevacizumab 10 mg/kg I.V. every 2 weeks. [corrected] RESULTS: The trial was terminated early because of futility in reaching the primary endpoint as determined by the independent data monitoring committee during an interim futility analysis. At data cutoff, 242 patients had been randomized to sunitinib-paclitaxel and 243 patients to bevacizumab-paclitaxel. Median PFS was shorter with sunitinib-paclitaxel (7.4 vs. 9.2 months; hazard ratio [HR] 1.63 [95% confidence interval (CI), 1.18-2.25]; 1-sided P = .999). At a median follow-up of 8.1 months, with 79% of sunitinib-paclitaxel and 87% of bevacizumab-paclitaxel patients alive, overall survival analysis favored bevacizumab-paclitaxel (HR 1.82 [95% CI, 1.16-2.86]; 1-sided P = .996). The objective response rate was 32% in both arms, but median duration of response was shorter with sunitinib-paclitaxel (6.3 vs. 14.8 months). Bevacizumab-paclitaxel was better tolerated than sunitinib-paclitaxel. This was primarily due to a high frequency of grade 3/4, treatment-related neutropenia with sunitinib-paclitaxel (52%) precluding delivery of the prescribed doses of both drugs. CONCLUSION: The sunitinib-paclitaxel regimen evaluated in this study was clinically inferior to the bevacizumab-paclitaxel regimen and is not a recommended treatment option for patients with advanced breast cancer.
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Anticuerpos Monoclonales/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Carcinoma/tratamiento farmacológico , Indoles/administración & dosificación , Paclitaxel/administración & dosificación , Pirroles/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Algoritmos , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bevacizumab , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Carcinoma/mortalidad , Carcinoma/patología , Progresión de la Enfermedad , Femenino , Humanos , Indoles/efectos adversos , Persona de Mediana Edad , Terapia Neoadyuvante , Paclitaxel/efectos adversos , Pirroles/efectos adversos , Sunitinib , Análisis de SupervivenciaRESUMEN
CONTEXT: Cancer diagnosis and treatment, particularly chemotherapy, has well-established adverse effects on individuals. Exercise has been found to confer benefits to patients, although the current evidence base is limited primarily to patients assessed during or after treatment. Although exercise has been a target of intervention efforts, its relationship to quality of life in patients about to begin chemotherapy has not fully been examined. OBJECTIVES: To examine the relationship of pre-treatment exercise rates to patient's quality of life. METHODS: One hundred ninety-two adults diagnosed with Stages I-IV cancer and Eastern Cooperative Oncology Group performance status ≤ 2, provided data on exercise, distress (anxiety and depression), and health-related quality of life prior to their initial chemotherapy infusion. RESULTS: As predicted, higher rates of exercise activity were associated with lower levels of anxiety and depression, and better overall mental and physical quality of life. These relationships were independent of demographic variables (i.e., body mass index and age) also associated with quality of life in the present analyses. CONCLUSION: These findings further highlight the importance of assessing exercise before the start of chemotherapy as part of broader efforts to link patients to appropriate interventions aimed at enhancing quality of life. Findings also raise the possibility that assessing exercise rates could be useful in matching patients to the type of intervention most likely to benefit them. Future research should use prospective longitudinal designs to further explore this association.
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Antineoplásicos/uso terapéutico , Terapia por Ejercicio/estadística & datos numéricos , Neoplasias/epidemiología , Neoplasias/terapia , Calidad de Vida , Adulto , Anciano , Anciano de 80 o más Años , Terapia Combinada/estadística & datos numéricos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Prevalencia , Estadística como Asunto , Resultado del Tratamiento , Estados Unidos/epidemiologíaRESUMEN
PURPOSE: The aim was to study the biological and molecular effects of the histone deacetylase (HDAC) inhibitor, valproic acid, in patients with solid tumor malignancies. EXPERIMENTAL DESIGN: A phase I dose escalation of valproic acid given on days 1 to 3 followed by epirubicin (day 3) was followed by a dose expansion of valproic acid combined with 5-fluorouracil, epirubicin, and cyclophosphamide (FEC100). Pharmacodynamic and pharmacokinetic studies entailed valproic acid and epirubicin plasma levels and their interaction, the effects of valproic acid on histone acetylation in peripheral blood mononuclear cells (PBMC) and tumor cells at baseline and day 3, and baseline expression of HDAC2 and HDAC6 as therapeutic targets. RESULTS: Forty-four patients were enrolled in the phase I part, with a disease-specific cohort expansion of 15 breast cancer patients (median age, 55 years; range, 28-66 years) receiving 120 mg/kg/day valproic acid followed by FEC100. Partial responses were seen in 9 of 41 (22%) patients during the phase I part. Objective responses were seen in 9 of 14 (64%) evaluable patients at the dose expansion with a median number of 6 administered cycles. Predominant toxicities were valproic acid-associated somnolence and epirubicin-induced myelosuppression. Valproic acid plasma levels were associated with short-term, reversible depletion of WBC and neutrophils within 48 hours. Histone acetylation in tumor samples and in PBMCs correlated with valproic acid levels and was further linked to baseline HDAC2 but not to HDAC6 expression. CONCLUSION: Valproic acid is a clinically relevant HDAC inhibitor, and PBMCs may serve as a surrogate for tumor histone acetylation in solid tumor malignancies. HDAC2 should be further considered as a relevant therapeutic target.