RESUMO
CONTEXT: Among cancer-free women aged 35 years or older, tamoxifen reduced the incidence of estrogen receptor (ER)-positive but not ER-negative breast cancer. The effect of tamoxifen on breast cancer incidence among women at extremely high risk due to inherited BRCA1 or BRCA2 mutations is unknown. OBJECTIVE: To evaluate the effect of tamoxifen on incidence of breast cancer among cancer-free women with inherited BRCA1 or BRCA2 mutations. DESIGN, SETTING, AND PARTICIPANTS: Genomic analysis of BRCA1 and BRCA2 for 288 women who developed breast cancer after entry into the randomized, double-blind Breast Cancer Prevention Trial of the National Surgical Adjuvant Breast and Bowel Project (between April 1, 1992, and September 30, 1999). MAIN OUTCOME MEASURE: Among women with BRCA1 or BRCA2 mutations, incidence of breast cancer among those who were receiving tamoxifen vs incidence of breast cancer among those receiving placebo. RESULTS: Of the 288 breast cancer cases, 19 (6.6%) inherited disease-predisposing BRCA1 or BRCA2 mutations. Of 8 patients with BRCA1 mutations, 5 received tamoxifen and 3 received placebo (risk ratio, 1.67; 95% confidence interval, 0.32-10.70). Of 11 patients with BRCA2 mutations, 3 received tamoxifen and 8 received placebo (risk ratio, 0.38; 95% confidence interval, 0.06-1.56). From 10 studies, including this one, 83% of BRCA1 breast tumors were ER-negative, whereas 76% of BRCA2 breast tumors were ER-positive. CONCLUSION: Tamoxifen reduced breast cancer incidence among healthy BRCA2 carriers by 62%, similar to the reduction in incidence of ER-positive breast cancer among all women in the Breast Cancer Prevention Trial. In contrast, tamoxifen use beginning at age 35 years or older did not reduce breast cancer incidence among healthy women with inherited BRCA1 mutations. Whether tamoxifen use at a younger age would reduce breast cancer incidence among healthy women with BRCA1 mutations remains unknown.
Assuntos
Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/genética , Neoplasias da Mama/prevenção & controle , Genes BRCA1 , Genes BRCA2 , Tamoxifeno/uso terapêutico , Adulto , Idoso , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/metabolismo , Análise Mutacional de DNA , Método Duplo-Cego , Feminino , Predisposição Genética para Doença , Humanos , Incidência , Pessoa de Meia-Idade , Mutação , Receptores de Estrogênio , Fatores de RiscoRESUMO
The continued widespread prevalence of breast cancer supports placing a high priority on research aimed at its primary prevention, particularly among women who are at increased risk for developing this disease. The suggestion of potential agents for the primary chemoprevention of breast cancer evolved out of the treatment setting. Extensive experience with tamoxifen, a first-generation selective estrogen receptor modulator (SERM) showing efficacy, first, in the treatment of advanced breast cancer and, subsequently, as adjuvant therapy for early stage disease established the safety of this agent. Cumulative data from multiple adjuvant studies documented the efficacy of tamoxifen in reducing second primary breast cancers in the contralateral breast, supporting its potential as a chemopreventive agent for breast cancer. The safety and second primary data on tamoxifen, together with extensive information on its pharmacokinetics, metabolism, and antitumor effects, as well as its potentially beneficial effects on lipid metabolism and osteoporosis, led the National Surgical Adjuvant Breast and Bowel Project (NSABP) to select tamoxifen for testing in the first prospective randomized phase III trial of the efficacy of a chemopreventive agent for preventing breast cancer in women at increased risk of the disease. Accordingly, in 1992 the NSABP started the Breast Cancer Prevention Trial (P-1) in which 13,388 women > or = 35 years of age who were at increased risk of breast cancer according to Gail model risk factors [family history, age, and personal history (i.e., age at first birth, age at menarche, previous breast biopsies)] were randomized to tamoxifen 20 mg/day or placebo for 5 years. Through 69 months of follow-up tamoxifen reduced the risk of invasive breast cancer, primarily estrogen receptor-positive tumors, by 49% (two-sided p < 0.00001). Tamoxifen reduced the risk of noninvasive breast cancer by 50% (two-sided p < 0.002). In addition, tamoxifen reduced fractures of the hip, radius, and spine, but it had no effect on the rate of ischemic heart disease. As previously shown, the rates of endometrial cancer and vascular events increased with tamoxifen. With the P-1 results establishing tamoxifen as the standard of care for the primary chemoprevention of breast cancer in high-risk women, concern over the side effects of tamoxifen has prompted a continuing search for an agent that displays a more desirable efficacy/toxicity profile. Raloxifene, a second-generation SERM approved for the prevention of osteoporosis in postmenopausal women, displays antiestrogenic properties in the breast and possibly the endometrium, and estrogenic effects in the bone and on the lipid profile, suggesting it as a candidate for comparison with the chemopreventive standard, tamoxifen. Raloxifene will be compared to tamoxifen in an equivalency trial, the Study of Tamoxifen and Raloxifene (STAR) NSABP P-2, which began in July 1999 at almost 500 centers in North America. The plan is to randomize 22,000 postmenopausal women > or = 35 years of age at increased risk of breast cancer by Gail criteria to tamoxifen 20 mg/day or raloxifene 60 mg/day for 5 years. Study endpoints include invasive and noninvasive breast cancer, cardiovascular disease, endometrial cancer, bone fractures, and vascular events.
Assuntos
Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/prevenção & controle , Cloridrato de Raloxifeno/uso terapêutico , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , Tamoxifeno/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Quimioterapia Adjuvante , Feminino , Humanos , Prevalência , Prevenção Primária , Ensaios Clínicos Controlados Aleatórios como Assunto , Medição de Risco , Resultado do TratamentoRESUMO
Selective estrogen receptor modulators (SERMs) are drugs that bind to the estrogen receptor (ER); in some tissues they act like estrogen (agonists), while in other tissues they oppose the action of estrogen (antagonists). The SERM tamoxifen acts as an estrogen antagonist in the breast in that it prevents and treats breast cancer, but it acts as an estrogen agonist in the endometrium, where it can induce cancer. Estrogen, and to a lesser extent SERMs, are effective in preventing and treating osteoporosis. Contrary to the prevalent hypothesis that estrogen provides benefit to women with regard to secondary prevention of coronary heart disease (CHD), randomized clinical trials have demonstrated that estrogen is associated with an increased risk of CHD in this population of women. Conflicting results have been reported on the effect of estrogens on cognitive function. The latest and largest randomized clinical trials have demonstrated a beneficial role in short-term memory in nondemented women, in contrast to the absence of such benefit in improving symptoms in women with Alzheimer's disease. Although estrogens have been used successfully to treat some menopausal symptoms such as hot flashes, the SERMs tamoxifen and raloxifene actually induce or increase hot flashes. Data on the beneficial and adverse effects of estrogen and SERMs are reported along with an elaboration of the constellation of properties that would characterize an ideal SERM working through the ER.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Doenças Cardiovasculares/tratamento farmacológico , Osteoporose/prevenção & controle , Moduladores Seletivos de Receptor Estrogênico/efeitos adversos , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , Cognição/efeitos dos fármacos , Doença das Coronárias/prevenção & controle , Terapia de Reposição de Estrogênios , Feminino , Fraturas Ósseas/etiologia , Fraturas Ósseas/prevenção & controle , Humanos , Menopausa , Osteoporose/complicações , Pós-Menopausa , Medição de Risco , Tamoxifeno/efeitos adversos , Tamoxifeno/uso terapêuticoRESUMO
Differences between clinical trials and clinical practice with respect to defining benefits and benefit/risk ratios for SERMs are discussed. These differences stem from the perception that there is discordance between the statistical significance and the "clinical meaningfulness" of research data in the minds of the practitioner and patient. One way that we can obtain data that are more clinically meaningful is to solicit input in the planning stages of clinical trials from practicing community clinicians and their patients. However, there are drawbacks to community input, such as potentially unrealistic expectations. A further issue is the need to characterize clinically meaningful drug benefits and acceptable benefit/risk ratios for a drug. Individual patients have differences regarding their views of optimal benefits and acceptable risks, so a method or tool for determining what is clinically meaningful would be helpful in presenting comprehensive information to the patient. To present useful information to clinicians, head-to-head comparisons of a new drug with a standard agent should be undertaken. NIH's support in this area of comparator trials is critical to their implementation. Estrogen has been considered the standard for comparison of agents for conditions associated with menopause in clinical trials. Estrogen has been the "gold standard" in clinical practice as well. In fact, challenging the position of estrogen, even where scientifically supported, has proven to be an uphill battle. In the practice setting, we elaborate the challenges of keeping up with the scientific literature and of then communicating this information in a fashion that is relevant to the individual patient.
Assuntos
Ensaios Clínicos como Assunto/normas , Padrões de Prática Médica/normas , Moduladores Seletivos de Receptor Estrogênico/efeitos adversos , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , Ensaios Clínicos Controlados como Assunto/normas , Feminino , Humanos , Relações Médico-Paciente , Projetos de Pesquisa , Medição de RiscoRESUMO
The "considerations" addressed in this section consist of a number of thought-provoking issues and unresolved questions that emerge from the papers in this volume. The evidence for tamoxifen carcinogenicity in animal models and, to a more restricted extent, in humans has led some investigators to question whether SERMs are ready or appropriate for clinical testing--specifically, in a disease prevention setting involving healthy but high-risk individuals. There is, however, inconsistency in both efficacy and toxicity--specifically, carcinogenicity--between animal models and humans, leading others to question the value of basing the decision to proceed with clinical studies on preclinical results in animals. Although the molecular basis for SERM action is rapidly being clarified, the cellular activity of these agents is still elusive. We discuss the view that the efficacy of tamoxifen in breast cancer is based on its treatment of "occult cancers," or small collections of cancer cells that are not clinically apparent, not only in the context of prevention but also in the treatment setting. As part of our approach that assumes estrogen activity to be the foundation upon which SERM development is being modeled, we discuss the inconsistency between the epidemiologic data and prospective randomized data with respect to the relationship between estrogen use and cardiovascular disease. The need to validate surrogate markers of SERM action is discussed in relation to bone but is clearly relevant to all disease sites. The semantics used in describing SERM action as agonistic or antagonistic in relation to estrogen at various target sites has been inconsistent, especially in the clinical context. We attempt to dissect out some of the inconsistencies in semantics in the hope that this will contribute to improved communication of data resulting from SERM research. In the clinical arena, we begin with the premise that the large, simple randomized trial offers the optimal design for the testing of SERMs. In view of limited resources, however, we counter this position with alternative, if less desirable, approaches to the clinical format for SERM testing. Finally, we explore the process by which statistically meaningful results from clinical trials are extrapolated into the specific drug indications that apply to clinical practice.
Assuntos
Moduladores Seletivos de Receptor Estrogênico/normas , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , Animais , Ensaios Clínicos como Assunto/normas , Humanos , Modelos Animais , Neoplasias/classificação , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Osteoporose/classificação , Osteoporose/prevenção & controle , Projetos de Pesquisa , Moduladores Seletivos de Receptor Estrogênico/efeitos adversosRESUMO
Remarkable progress has been made in SERM development. Profiles of new SERMs indicate great potential for efficacy in the prevention and treatment settings, in more than one physiological system, and with improved risk/benefit ratios. The concept of what is achievable with respect to broad-spectrum disease prevention and what constitutes an "ideal" SERM is likely to undergo considerable reevaluation over time. The development of new, more broadly efficacious SERMs will require continued exploration of the effects of estrogen at the cellular and molecular level in tissues and physiologic systems throughout the body. A better understanding is needed of the mechanisms of the biological actions that are mediated through major forms of the estrogen receptor. High priority must be placed on elucidation of the role of the coregulators of estrogen receptor (ER) action. The quest for a SERM(s) with the "optimal clinical profile" also constitutes a major research challenge with respect to designing clinical trials that are simultaneously parsimonious with respect to time, monetary, and human resources and yet capable of delivering unequivocal outcomes with respect to primary end points. A vigorous research effort is needed to identify highly sensitive and specific surrogate measures to facilitate future clinical studies. Research to identify and validate relevant measures of safety is also essential to inform the risk/benefit balance and, thus, the ultimate usefulness of SERMs and their potential for long-term use. Future advances in the modulation of ER action are likely to have profound effects--not only on diseases and conditions known (or later discovered) to be related to estrogen action, but on the development of paradigms for understanding and modifying the action of other nuclear hormone receptors in the prevention and treatment of additional age- and disease-related pathologies.
Assuntos
Qualidade de Vida , Pesquisa/tendências , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , Doença de Alzheimer/prevenção & controle , Ensaios Clínicos como Assunto/normas , Humanos , Pesquisa/normas , Projetos de Pesquisa/normas , Moduladores Seletivos de Receptor Estrogênico/efeitos adversos , Moduladores Seletivos de Receptor Estrogênico/farmacologiaRESUMO
The Breast Cancer Prevention Trial (P-1: BCPT) of the National Surgical Adjuvant Breast and Bowel Project (NSABP) randomized 13,388 women, > or = 35 years of age, at increased risk for breast cancer [> or = 1.66% by Gail model criteria or with a history of lobular carcinoma in situ (LCIS)] to 5 years of tamoxifen or placebo. A 49% reduction (P < 0.00001) in invasive breast cancers occurred, 175 with placebo versus 89 with tamoxifen, mainly among estrogen receptor (ER)-positive tumors (130 with placebo vs. 41 with tamoxifen). The major toxicities of tamoxifen were endometrial cancer (15 with placebo vs. 36 with tamoxifen) and thromboembolic disease, both predominantly in women who were > or = 50 years old. Ramifications emerging from the P-1 results regarding the efficacy and toxicities of preventive tamoxifen include the following: (1) Does tamoxifen induce more virulent breast cancers? (2) Does tamoxifen induce more virulent endometrial cancers? (3) Tamoxifen is especially efficacious in reducing breast cancer risk in LCIS (18 invasive breast cancers with placebo vs. 8 with tamoxifen group) and atypical ductal hyperplasia (AH) (23 invasive breast cancers with placebo vs. 3 with tamoxifen). (4) Does tamoxifen reduce breast cancer risk in women at increased risk due to genetic mutations? (5) How can we prevent tamoxifen-resistant breast cancers? (6) What do the BCPT results tell us about who should take preventive tamoxifen? In its ongoing effort to lower the incidence of breast cancer, the NSABP is now implementing its second breast cancer prevention trial, the Study of Tamoxifen and Raloxifene (STAR), which is comparing the two agents with regard to efficacy and toxicity.
Assuntos
Neoplasias da Mama/prevenção & controle , Moduladores de Receptor Estrogênico/uso terapêutico , Tamoxifeno/uso terapêutico , Neoplasias da Mama/patologia , Carcinoma in Situ/prevenção & controle , Resistência a Medicamentos , Feminino , Humanos , Cloridrato de Raloxifeno/uso terapêutico , Estados UnidosRESUMO
Dendritic cells (DCs) initiate primary and stimulate secondary T-cell responses. We conducted a phase I trial of tumor necrosis factor (TNF-alpha) and granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients with cancer to increase DCs in peripheral blood or skin based on in vitro data that showed that CD34(+) hematopoietic precursors require these cytokines to mature into functional antigen-presenting DCs. Eleven patients were treated for 7 days with GM-CSF, 125 microg/m(2) twice daily as subcutaneous injections, and TNF-alpha as a continuous infusion at dose levels of 25, 50, or 100 microg/m(2)/day. The maximum tolerated dose of TNF-alpha was 50 microg/m(2)/day with this dose of GM-CSF; dose-limiting toxicities occurred in both patients treated with 100 microg/m(2)/day. One became thrombocytopenic and the other had transient confusion. Epidermal Langerhans' cells were quantitated by S100 staining of skin biopsies and DC precursors in peripheral blood by colony-forming unit dendritic (CFU-dendritic) assays. S100-positive cells in the epidermis doubled after treatment (2.55 S100(+) cells/high-power field before treatment to 6.05 after treatment, p = 0.029). CFU-dendritic in peripheral blood increased after treatment in 3 colorectal cancer patients but not in 3 patients with melanoma. CD11c(+) or CD123(+), HLA-DR(bright), lineage-negative dendritic cell precursors were not increased in peripheral blood mononuclear cells. This trial demonstrates that treatment with TNF-alpha and GM-CSF can increase the number of DCs in the skin and the number of dendritic cell precursors in the blood of some patients with cancer. This approach may increase the efficacy of vaccination to tumor antigens in cancer patients.
Assuntos
Fator Estimulador de Colônias de Granulócitos e Macrófagos/uso terapêutico , Células de Langerhans/efeitos dos fármacos , Neoplasias/patologia , Fator de Necrose Tumoral alfa/uso terapêutico , Adulto , Biópsia , Antígeno Carcinoembrionário/sangue , Contagem de Células , Neoplasias do Colo/sangue , Ensaio de Unidades Formadoras de Colônias , Quimioterapia Combinada , Feminino , Citometria de Fluxo , Humanos , Contagem de Leucócitos , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/fisiologia , Masculino , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Proteínas Recombinantes/uso terapêutico , Pele/patologia , Trombocitopenia/induzido quimicamenteRESUMO
Clinical trials to evaluate interventions for cancer prevention are designed as early (phase I, IIa, and IIb) or late-phase studies. Whereas the former are small and generally rely on intermediate endpoint biomarkers of carcinogenesis, the latter are large-scale, long-term, randomized, phase III studies that address endpoints such as cancer incidence. The Breast Cancer Prevention Trial, P-1, conducted by the National Surgical Adjuvant Breast and Bowel Project (NSABP), is discussed as an example of a large, extended, phase III trial designed to answer the question of whether tamoxifen reduces the incidence of breast cancer in women who are at increased risk for the disease.
Assuntos
Ensaios Clínicos Fase III como Assunto/métodos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/prevenção & controle , Quimioprevenção , Feminino , Humanos , National Institutes of Health (U.S.) , Tamoxifeno/uso terapêutico , Estados UnidosRESUMO
Max is a basic region-helix-loop-helix-leucine zipper protein that consists of two major isoforms, p22 (long form, Max-L) and p21 (short form, Max-S). These proteins are encoded by two [the 1.9- and the predominant 2.3-kilobase (kb) forms] of the five alternatively spliced max mRNA species. We now demonstrate that N,N'-hexamethylene bisacetamide-mediated differentiation of murine erythroleukemia cells leads to a pattern of biphasic down-regulation of the 1.9- and the 2.3-kb myn (murine max) mRNAs that closely parallels that which occurs for myc mRNA. In contrast, the p22/Myn-L and p21/Myn-S protein isoforms down-regulate in monophasic fashion. Unlike the short-lived myc mRNA, the myn message is quite stable. However, its half-life of 3-6 h is still consistent with the biphasic down-regulation that accompanies differentiation. Furthermore, unlike myc, the overexpression of which prevents differentiation, elevated max levels merely delay differentiation. Coincident with this is a delay in the second decline of c-myc mRNA. In N,N'-hexamethylene bisacetamide-induced cells blocked from differentiating by overexpression of c-, N- or L-myc, myn mRNA expression is constitutive. These findings suggest that myn may also be involved in differentiation.
Assuntos
Regulação Neoplásica da Expressão Gênica/fisiologia , Genes myc , Leucemia Eritroblástica Aguda/genética , Animais , Diferenciação Celular/genética , Regulação para Baixo/genética , Leucemia Eritroblástica Aguda/patologia , Camundongos , Proteínas Proto-Oncogênicas c-myc/fisiologia , RNA Mensageiro/biossíntese , Transfecção , Células Tumorais CultivadasRESUMO
Max protein forms specific DNA-binding dimeric complexes with itself and with proteins of the c-myc gene family. A large volume of data has accumulated on the role of the c-myc proto-oncogene in cell proliferation, differentiation and tumorigenesis. To elucidate the role of max in regulating c-myc functions and the effect of both proteins on cell proliferation and differentiation, we transfected murine erythroleukemia (MEL) cells with a full-length wild-type (wt) human max gene and a mutant containing a double point mutation in the basic region (bm), which abolishes specific DNA binding. All clones expressing wt-max grow slowly, and the process of inducer-mediated differentiation is delayed. Furthermore, cells transfected with the mutated max exhibit growth retardation, accumulation in the G0/G1 phase of the cell cycle and spontaneous differentiation. Our findings are consistent with a model in which a large excess of wt-Max in the cells enhances the formation of Max-Max growth-suppressor complexes, while elevated bm-Max deprives the cell of growth-promoting Myc-Max heterodimers in a dominant-negative manner, presumably by inactivating endogenous Myc and Max.