RESUMO
PURPOSE: Tasquinimod (Active Biotech) is an oral immunomodulatory, anti-angiogenic, and anti-metastatic agent that delayed metastatic disease progression in a randomized placebo-controlled phase II trial in men with metastatic castration-resistant prostate cancer (mCRPC). Here, we report long-term survival with biomarker correlates from this trial. EXPERIMENTAL DESIGN: Two hundred and one (134 tasquinimod and 67 placebo) men with mCRPC were evaluated. Forty-one men randomized to placebo crossed over to tasquinimod. Survival data were collected with a median follow-up time of 37 months. Exploratory biomarker studies at baseline and over time were collected to evaluate potential mechanism-based correlates with tasquinimod efficacy including progression-free survival (PFS) and overall survival (OS). RESULTS: With 111 mortality events, median OS was 33.4 months for tasquinimod versus 30.4 months for placebo overall, and 34.2 versus 27.1 months in men with bone metastases (n = 136), respectively. Multivariable analysis demonstrated an adjusted HR of 0.52 [95% confidence interval (CI), 0.35-0.78; P = 0.001] for PFS and 0.64 (95% CI, 0.42-0.97; P = 0.034) for OS, favoring tasquinimod. Time-to-symptomatic progression was improved with tasquinimod (P = 0.039, HR = 0.42). Toxicities tended to be mild in nature and improved over time. Biomarker analyses suggested a favorable impact on bone alkaline phosphatase and lactate dehydrogenase (LDH) over time and a transient induction of inflammatory biomarkers, VEGF-A, and thrombospondin-1 levels with tasquinimod. Baseline levels of thrombospondin-1 less than the median were predictive of treatment benefit. CONCLUSIONS: The survival observed in this trial of men with minimally symptomatic mCRPC suggests that the prolongation in PFS with tasquinimod may lead to a survival advantage in this setting, particularly among men with skeletal metastases, and has a favorable risk:benefit ratio.
Assuntos
Biomarcadores Tumorais/genética , Intervalo Livre de Doença , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Quinolinas/administração & dosagem , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/secundário , Proteína C-Reativa/genética , Humanos , L-Lactato Desidrogenase/genética , Masculino , Metástase Neoplásica , Neoplasias de Próstata Resistentes à Castração/mortalidade , Neoplasias de Próstata Resistentes à Castração/patologia , Quinolonas , Análise de Sobrevida , Fator A de Crescimento do Endotélio VascularRESUMO
Randomized data from SWOG 8794 and EORTC 22911 confirm the benefit of post-operative radiation therapy (RT) for selected patients with pT3 prostate cancer (CaP) after radical prostatectomy (RP). However, data regarding the potential benefit of RT for patients post-RP with positive lymph node (+LN) involvement are limited. We analyzed the Surveillance Epidemiology End Results (SEER) registry for population-based data on efficacy of post-operative RT for +LN patients after RP. As LN data have only been captured by SEER since 1988, we analyzed data for 1988-1992, with specific attention to 10-year relative survival (defined as observed survival divided by the survival of a gender-, age- and race-matched population cohort without disease). Specifically analyzed were data for 1921 patients with nonmetastatic prostate cancer who underwent surgery alone, or surgery followed by RT, and who had +LNs documented. SEER does not code the interval between surgery and RT, so the ratio of patients receiving salvage versus adjuvant therapy is unknown. Using follow-up data through 2002, post-diagnosis survival was examined by number of +LNs. There was no significant relative survival benefit for +LN patients receiving post-operative RT (chi(2)P=0.270). These data do not support routine use of post-operative RT for patients with +LNs in the surgical specimen.
Assuntos
Metástase Linfática/radioterapia , Neoplasias da Próstata/terapia , Terapia Combinada , Humanos , Masculino , Prostatectomia , Neoplasias da Próstata/radioterapia , Neoplasias da Próstata/cirurgia , Programa de SEER , Análise de SobrevidaRESUMO
BACKGROUND: Tamoxifen has been shown to promote the growth of human endometrial tumors implanted in athymic mice, and it has been associated with a twofold to threefold increase in endometrial cancer. Toremifene, a chlorinated derivative of tamoxifen, and ICI 182,780, a pure antiestrogen, are two new antiestrogens being developed for the treatment of breast cancer. The effects of these drugs on endometrial cancer are currently unknown. Our objective was to evaluate the effects of toremifene and ICI 182,780 on the growth of human endometrial cancer in athymic mice. METHODS: Athymic, ovariectomized mice were implanted with human endometrial tumors and treated with estrogen, tamoxifen, or the new antiestrogens. RESULTS: The effects of tamoxifen and toremifene on the growth of either tamoxifen-stimulated or tamoxifen-naive endometrial tumors in athymic mice were not substantially different. ICI 182,780 inhibited the growth of tamoxifen-stimulated endometrial cancer, in both the presence and the absence of estrogen. CONCLUSIONS: Toremifene and tamoxifen produce identical effects in our endometrial cancer models. Therefore, it is possible that toremifene, like tamoxifen, may be associated with an increased incidence of endometrial cancer. In contrast, ICI 182,780 inhibited tamoxifen-stimulated endometrial cancer, both in the presence and in the absence of estrogen, suggesting that this drug may be safe with regard to the endometrium, even if it is used following tamoxifen, and that it may not result in an increased incidence of endometrial cancer. Indeed, it is even possible that ICI 182,780 may prove useful as an adjuvant agent in early stage endometrial cancer.
Assuntos
Neoplasias do Endométrio/induzido quimicamente , Estradiol/análogos & derivados , Antagonistas de Estrogênios/efeitos adversos , Tamoxifeno/efeitos adversos , Toremifeno/efeitos adversos , Animais , Antineoplásicos Hormonais/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Modelos Animais de Doenças , Estradiol/efeitos adversos , Feminino , Fulvestranto , Camundongos , Camundongos Nus , OvariectomiaRESUMO
It is clear that growth of the MCF-7 breast cancer cell line is stimulated by estrogen and when estrogen is removed, growth slows. We have observed a tumor derived from MCF-7 cells that grows in athymic mice in the absence of estrogen stimulation. We hypothesized that a mutation in the estrogen receptor (ER) could be responsible for this constitutive growth. Using single stranded conformational polymorphism (SSCP) and DNA sequencing analysis, we have identified an ER containing a point mutation at position 415 (gly to val) within the hormone binding domain. The functional activity of this mutant was assessed in vitro and in vivo. Using transient transfection into an ER negative breast cancer cell with an ERE luciferase reporter gene, we found that both the wild-type and mutant receptors have similar efficacy. Additionally, the estrogenic responses were blocked by antiestrogens in a concentration related manner. We also found that tumors with the mutant receptor show similar growth response in athymic mice as wild-type: stimulation with estradiol and inhibition with antiestrogens. We conclude that the point mutation at position 415 (gly to val) is not responsible for constitutive growth.
Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Estradiol/farmacologia , Antagonistas de Estrogênios/farmacologia , Mutação Puntual , Receptores de Estrogênio/genética , Transcrição Gênica/efeitos dos fármacos , Animais , Sítios de Ligação , Divisão Celular/efeitos dos fármacos , Primers do DNA , Estradiol/análogos & derivados , Feminino , Fulvestranto , Glicina , Humanos , Luciferases/biossíntese , Camundongos , Camundongos Nus , Ovariectomia , Reação em Cadeia da Polimerase , Polimorfismo Conformacional de Fita Simples , Receptores de Estrogênio/biossíntese , Receptores de Estrogênio/química , Tamoxifeno/análogos & derivados , Tamoxifeno/farmacologia , Transfecção , Transplante Heterólogo , Células Tumorais Cultivadas , ValinaRESUMO
Tamoxifen is the most widely prescribed endocrine therapy for breast cancer, with more than 7.5 million woman-years of clinical experience. Tamoxifen has both antiestrogenic and estrogenic activity. The antiestrogenic activity accounts for its efficacy against breast cancer, while the estrogenic activity is considered to be associated with positive effects on bone mineral density and lipid profiles and a proliferative effect on the endometrium in some women. Tamoxifen has a good tolerability profile and has demonstrated benefits for breast cancer patients in prolonging overall and disease-free survival and reducing the incidence of contralateral breast cancer. These known benefits of tamoxifen far outweigh the risk of endometrial cancer in tamoxifen-treated patients with breast cancer.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Antagonistas de Estrogênios/uso terapêutico , Tamoxifeno/uso terapêutico , Neoplasias do Endométrio/induzido quimicamente , Feminino , Humanos , Metabolismo dos Lipídeos , Medição de Risco , Tamoxifeno/efeitos adversosRESUMO
We have cloned and characterized a 77-kDa oestrogen receptor (ER) from an oestrogen-independent subclone of the MCF-7 human breast cancer cell line. This receptor contains an in-frame, tandem duplication of exons 6 and 7, located in the steroid-binding domain of the ER. This mutation has abrogated ligand binding, but not DNA binding, in this mutant ER. We previously described the partial structure of a unique oestrogen receptor (ER) that is expressed in an oestrogen-independent MCF-7:2A subclone of the breast cancer cell line MCF-7 (Pink JJ, Wu SQ, Wolf DM, Bilimoria MM, Jordan VC 1996a, Nucleic Acids Res 24 962-969). Sequence analyses determined the molecular weight of this 80-kDa ER to be 77 kDa, and hereafter this protein will be designated as ER77. Examination of the entire coding sequence of the ER77 mRNA indicates that it contains a tandem duplication of exons 6 and 7. Using a coupled transcription/translation system, a 77-kDa ER, which corresponds to the protein observed in the MCF-7:2A cells, was expressed. The ER77 protein does not bind the ligands [3H] oestradiol or [3H]tamoxifen aziridine. In DNA binding gel shift assays, the in vitro synthesized ER77 binds to a consensus vitellogenin A2 oestrogen-response element. In transient transfection experiments, the mutant ER, alone or in combination with the wild-type ER, does not induce expression of an oestrogen-responsive luciferase reporter construct. In fact, expression of the ER77 in the ER-positive T47D:A18 cell line inhibits E2-induced luciferase expression. Overexpression of wild-type ER in T47D:A18 cells leads to elevated constitutive expression of the luciferase reporter, which was inhibited by co-transfection with ER77. These data suggest that the ER77 can interfere with normal ER activity and does not act as a constitutive activator of oestrogen-independent growth in MCF-7:2A cells. Consequently, the constitutive growth observed in MCF-7:2A cells is probably the result of other ER-mediated pathways.
Assuntos
Células Clonais/metabolismo , Receptores de Estrogênio/isolamento & purificação , Sequência de Aminoácidos , Sequência de Bases , Sítios de Ligação/genética , Neoplasias da Mama/química , DNA Complementar/genética , DNA de Neoplasias/química , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/genética , Éxons , Feminino , Humanos , Ligantes , Dados de Sequência Molecular , Reação em Cadeia da Polimerase , Biossíntese de Proteínas , Receptores de Estrogênio/química , Sequências Repetitivas de Ácido Nucleico , Transcrição Gênica , Transfecção , Células Tumorais CultivadasRESUMO
The majority (60-70%) of endometrial cancers express estrogen receptor. Typically, estrogen-receptor-positive endometrial tumors are associated with a more favorable outcome. Despite this, there is often a discrepancy between estrogen receptor expression and clinical outcome of the disease. Although little is known about the exact role of the estrogen receptor in endometrial malignancies, in breast cancer, where such information is abundant, a number of mutations of the estrogen receptor have been identified. To investigate whether mutations of the estrogen receptor gene occur in endometrial cancers we performed single-stranded conformational polymorphism analysis (SSCP) on 35 human endometrial tumors. We detected four point mutations in three different patients. Interestingly, all the mutations were detected in patients who had aggressive endometrial tumors (grade 3). Although we found the incidence of mutations of the estrogen receptor to be low (8.5%) and thus unlikely to be associated with the majority of endometrial cancers, further investigation is needed to elucidate the role of aberrant estrogen receptor expression in the progression of endometrial malignancies.
Assuntos
Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Mutação Puntual , Receptores de Estrogênio/genética , Análise Mutacional de DNA , DNA Complementar/genética , DNA de Neoplasias/genética , Neoplasias do Endométrio/química , Feminino , Humanos , Pessoa de Meia-Idade , Polimorfismo Conformacional de Fita SimplesRESUMO
Tamoxifen has been the endocrine treatment of choice for all stages of breast cancer for nearly a decade. Millions of women are currently receiving tamoxifen worldwide, while large-scale randomised trials have been launched aiming to investigate the drug's merit as a preventive agent. However, there are now concerns about tamoxifen's potential carcinogenicity. The goal of this review is to address these concerns, re-evaluate the available data from laboratory biological models and those from clinical reports and put the whole issue into perspective. Our focus is the association between tamoxifen and the increased frequency of endometrial tumours, while key issues, such as the role of duration of tamoxifen therapy, are also addressed. Finally, we discuss the various monitoring strategies for early detection of endometrial lesions and pertinent problems most likely to be encountered by clinicians taking care of patients who are receiving tamoxifen.
Assuntos
Antineoplásicos Hormonais/efeitos adversos , Neoplasias do Endométrio/induzido quimicamente , Tamoxifeno/efeitos adversos , Animais , Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Testes de Carcinogenicidade , Estudos de Casos e Controles , Cricetinae , Método Duplo-Cego , Neoplasias do Endométrio/patologia , Feminino , Humanos , Neoplasias Hepáticas/induzido quimicamente , Camundongos , Pólipos/induzido quimicamente , Pólipos/patologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Ratos , Tamoxifeno/uso terapêuticoRESUMO
The estrogen receptor (ER) contains two transcriptional activation domains: AF-1 and AF-2. AF-2 is dependent on a highly species-conserved region of the ER. It has been shown that site-directed point mutations of conserved hydrophobic amino acids within this region reduce estrogen-dependent transcriptional activation. In addition, when these mutated ERs are transfected into HeLa cells, both tamoxifen and ICI 164,384 become strong agonists. The implication is that mutations in this region could account for the tamoxifen-stimulated tumors seen clinically. We performed single stranded conformational polymorphism (SSCP) analysis spanning the entire ER along with DNA sequencing of the AF-2 region of the ER isolated from two different tamoxifen-stimulated breast cancers, MCF-7/TAM and MCF-7/MT2, and a tamoxifen-stimulated endometrial cancer, EnCa 101. In addition, a tamoxifen-stimulated endometrial carcinoma cell line, the Ishikawa cell line, was also studied. There were no mutations found by SSCP analysis and sequencing of all four AF-2 regions also revealed no mutations. Mutations within the AF-2 region of the human ER do not appear to account for the growth of human breast and endometrial carcinomas that are used as reproducible laboratory models of tamoxifen-stimulated growth observed clinically.
Assuntos
Carcinoma/genética , Neoplasias do Endométrio/genética , Antagonistas de Estrogênios/administração & dosagem , Neoplasias Ovarianas/genética , Receptores de Estrogênio/genética , Tamoxifeno/administração & dosagem , Carcinoma/metabolismo , Neoplasias do Endométrio/metabolismo , Feminino , Humanos , Mutação/efeitos dos fármacos , Neoplasias Experimentais/genética , Neoplasias Experimentais/metabolismo , Neoplasias Ovarianas/metabolismo , Receptores de Estrogênio/antagonistas & inibidores , Análise de Sequência de DNARESUMO
Toxifen, a nonsteroidal antiestrogen, is currently the most widely used adjuvant therapy for the treatment of breast cancer. Though the efficacy of tamoxifen has been well documented in clinical trials, the certainty over the duration of therapy is less clear. Clinical and laboratory evidence suggests that longer therapy is better; however, whether this means 5 years, 10 years, or indefinite therapy has not been established in clinical trials. Essential to any study of long-term tamoxifen therapy is consideration of its effects not only on breast cancer but also on other estrogen target tissues. The estrogenic effect of tamoxifen that lowers serum lipids results in fewer hospital admissions for heart disease and a reduction in fatal myocardial infarction. Similarly, tamoxifen maintains bone mass that may ultimately result in fewer fractures. The effects of tamoxifen appear to parallel the effects of estrogen, so results from clinical trials of estrogen replacement therapy will provide a useful guide of what to expect with tamoxifen. The negative aspect of the therapy is a modest increase in the incidence of endometrial cancer. However, the incidence of endometrial cancer after stopping either estrogen or tamoxifen remains elevated for at least 5 years after the drug is stopped. Nevertheless, it is important to stress that the overall prognosis remains unaffected. We conclude that it will be difficult to demonstrate survival differences between 5 and 10 years of tamoxifen in clinical trials unless significant tamoxifen-stimulated recurrences occur with continued therapy. The benefits of tamoxifen must be calculated using estimates of the decreased rates of heart disease, contralateral cancers, decreased hospitalizations for fractures, and reduced cancer relapses.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , Tamoxifeno/uso terapêutico , Animais , Osso e Ossos/efeitos dos fármacos , Doenças Cardiovasculares/prevenção & controle , Quimioterapia Adjuvante , Ensaios Clínicos como Assunto , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Lipídeos/sangue , Neoplasias/induzido quimicamente , Osteoporose/prevenção & controle , Medição de Risco , Fatores de TempoAssuntos
Antineoplásicos Hormonais/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Neoplasias do Endométrio/induzido quimicamente , Tamoxifeno/efeitos adversos , Neoplasias da Mama/terapia , Quimioterapia Adjuvante , Neoplasias do Endométrio/patologia , Feminino , Humanos , Fatores de TempoRESUMO
Tamoxifen has been used as an adjuvant therapy for breast cancer for nearly two decades. The benefits of adjuvant tamoxifen therapy in prolonging disease-free and overall survival have been shown in randomized clinical trials. Despite this, some developing evidence suggests that tamoxifen causes a 2- to 3-fold increase in endometrial cancer. This paper reviews the reports of endometrial carcinoma in tamoxifen-treated patients. Two hundred fifty cases of endometrial carcinoma are reported, but only one case is identified in a premenopausal woman. When documented, 77% (n=127) of the cases are good-grade (grade 1 or 2) and 80% (n=125) are stage-I disease. Since the distribution of good grade (79%) and stage I (74%) from the Surveillance, Epidemiology and End Results (SEER) data are comparable, concerns about more aggressive or late-stage disease appear to be unwarranted. The modest increase in the incidence of early-stage, good-grade endometrial carcinoma described during tamoxifen therapy suggests that it would be unreasonable to institute an aggressive detection strategy of endometrial biopsies. This approach would only lead to further detection bias and would not be cost-effective. Physicians should ensure that patients do not have pre-existing endometrial cancer prior to adjuvant tamoxifen therapy for breast cancer and, furthermore, they should educate patients about signs and symptoms of early endometrial carcinoma and when reported these should be followed up with a gynecologic examination.
Assuntos
Antineoplásicos Hormonais/efeitos adversos , Neoplasias do Endométrio/induzido quimicamente , Tamoxifeno/efeitos adversos , Biópsia , Monitoramento de Medicamentos , Neoplasias do Endométrio/epidemiologia , Neoplasias do Endométrio/patologia , Feminino , Humanos , Incidência , Estadiamento de Neoplasias , Educação de Pacientes como Assunto , Programa de SEERRESUMO
During the past 5 years, a number of case reports and clinical trial results have associated tamoxifen therapy with an increased incidence of endometrial carcinoma. A review of the literature shows that there are over 200 cases of endometrial carcinoma reported in tamoxifen-treated women. Most cases are Stage I (82%), grade 1-2 disease (80%), which is consistent with the Surveillance Epidemiology and End Results Reporting data of 74 and 79% for Stage I and grade 1-2 endometrial carcinoma. We conclude that there is a modest increase in endometrial carcinoma incidence during tamoxifen therapy (i.e., 2/1000 tamoxifen treated women per year versus 1/1000 women per year for Surveillance Epidemiology and End Results Reporting), that there is no strong association with duration of therapy, and that tamoxifen is not associated with a high-grade, poor prognosis disease. The benefits of tamoxifen in lives saved exceeds the incidence of endometrial carcinoma.