Challenges in the endocrine management of breast cancer
ABSTRACT The goal of endocrine therapy in breast cancer is to block the action of estrogen on the tumor cells either by inhibiting estrogen from binding to the specific estrogen receptor or by inhibiting its synthesis. Tamoxifen, a selective estrogen receptor modulator, is the standard endocrine treatment for hormone receptor-positive breast cancer, both in the adjuvant and metastatic settings. Tamoxifen inhibits the binding of estrogen to the receptor, resulting in inhibition of hormone action. However, as tamoxifen is also weakly estrogenic, it may not be optimally effective and increases the risk of endometrial cancer and stroke. Furthermore, patients may be refractory or may become resistant to tamoxifen treatment. Since aromatase inhibitors (AI) block the synthesis of estrogen and have no intrinsic estrogenic activity, they have the potential to be more effective than tamoxifen. Their different mechanism of action and chemical structures may also circumvent tamoxifen resistance. Consequently, AIs are currently being evaluated as an alternative to tamoxifen treatment. A preclinical model has recently been developed to compare the efficacy of AIs and antiestrogens in different treatment schemes and to assist in the design of clinical trials. Current studies with the MCF-7Ca xenograft model are exploring the effects of combination and sequential therapy on tumor growth. The efficacy of AIs in the treatment of hormone receptor-positive breast cancer was first demonstrated in five multicenter second-line trials enrolling several hundreds of postmenopausal patients with metastatic breast cancer who had failed tamoxifen treatment. More recently, anastrozole demonstrated efficacy at least equivalent to that of tamoxifen in first-line randomized, phase III clinical trials in postmenopausal women with hormone receptor-positive or unknown metastatic breast cancer, whereas letrozole demonstrated superiority. The steroidal AI exemestane is currently under evaluation. Letrozole is the only AI to have been studied in a randomized, phase III trial in the neoadjuvant setting. In this trial, more patients underwent breast-conserving surgery with letrozole than with tamoxifen. Smaller phase II studies also suggest that both anastrozole and exemestane are active in the neoadjuvant setting. Because neoadjuvant trials permit temporal sampling of breast tissue, substudies in the phase III trial with letrozole have examined the impact of such biomarkers as estrogen receptor, progesterone receptor and epidermal growth factor receptor family members, HER-1 and HER-2, on patient response. AIs are currently under evaluation in the adjuvant setting, and preliminary results of the Arimidex, Tamoxifen Alone or in Combination (ATAC) trial have been reported. AIs have proven as safe as tamoxifen in trials in patients with metastatic breast cancer. Ongoing clinical trials in the adjuvant setting include companion studies of end-organ effects, particularly bone metabolism and lipid metabolism evaluations. Quality-of-life assessments are also parts of major clinical trials. A head-to-head quality-of-life assessment of anastrozole compared with letrozole demonstrated patient preference for letrozole. These assessments also clearly indicated the eagerness of patients to participate actively in treatment decisions
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ABSTRACT: The search for improved molecular cancer diagnostics is a challenge for which systems approaches show great promise. As is becoming increasingly clear, cancer is a perpetually-evolving, highly multi-factorial disease. With next generation sequencing providing an ever-increasing amount of high-throughput data, the need for analytical tools that can provide meaningful context is critical. Systems approaches have demonstrated an ability to separate meaningful signal from noise that arises from population heterogeneity, heterogeneity within and across tumors, and multiple sources of technical variation when sufficient sample sizes are obtained and standardized measurement technologies are used. The ability to develop clinically useful molecular cancer diagnostics will be predicated on advancements on two major fronts: 1) more comprehensive and accurate measurements of multiple endpoints, and 2) more sophisticated analytical tools that synthesize high-throughput data into meaningful reflections of cellular states. To this end, systems approaches that have integrated transcriptomic data onto biomolecular networks have shown promise in their ability to classify tumor subtypes, predict clinical progression, and inform treatment options. Ultimately, the success of systems approaches will be measured by their ability to develop molecular cancer diagnostics through distilling complex, systems-wide information into actionable information in the clinic.Discovery medicine 12/2010; 10(55):531-42. · 3.50 Impact Factor
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ABSTRACT: A part of breast cancers depend on stimulus from estrogen for their growth. In such cases, once we can block the effect from estrogen, we can effectively inhibit the growth and recur- rence of breast cancers. Only hormone receptor, especially estrogen receptor (ER) positive cancer cells can be stimulated by estrogen. There are about 2/3 postmenopausal patients' breast cancers are ER positive; on the contrast, only 1/3 premenopausal patients' breast cancers are ER positive. Hormone therapy, in such cases, can work at 3 different mechanisms. The first mecha- nism is to decrease estrogen production. Drugs of this kind include gonadotropin releasing hor- mone agonist (GnRH agonist) for premenopausal women and aromatase inhibitors (AIs) for postmenopausal women. The secondary mechanism is to competitively inhibit estrogen binding to ER, the most important drug is tamoxifen. The third mechanism is to destroy ER directly, such as Fulvestrant. These drugs work through different mechanisms and on different patient population whose cancer cells must be ER positive. They can be used as adjuvant therapies af- ter surgery, in order to decrease disease recurrence. They also can be used as palliative therapies in order to delay disease progression then to prolong life. Although tamoxifen is now the gold standard for premenopausal women, most of recent studies and reports focused on AIs as adju- vant therapies for postmenopausal women. It is now widely accepted that AIs, either upfront use for 5 years, or sequential use with tamoxifen for total 5 to 10 years, are more effective than tamoxifen alone on disease recurrence and even overall survival. Since there is so much infor- mation, clinicians should be familiar with all these drugs' indication, effects and especially, the diagnosis and managements of side effects which might happen after long-term use, so that we can really decrease disease recurrence, delay disease progression and improve quality of life for our patients.
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ABSTRACT: Resumen • E L CÁNCER DE MAMA constituye la neoplasia más frecuente de la mujer en el mundo. La hormonoterapia es una de las principales armas del tratamiento médico que se basa en el bloqueo de la acción hormonal para evitar el crecimiento celular. La terapia endocrina constituye parte esencial del tratamiento tanto en el escenario adyuvante como en la enfermedad metastásica y es determinada por la expresión de los receptores de estrógeno (RE) y/o los receptores de progesterona (PgR). Tamoxifén (TAM) adyuvante por 5 años es el tra-tamiento estándar para mujeres premenopáusicas que expresen RE y/o RPg. En las mujeres pos-menopáusicas los inhibidores de aromatasa con o sin TAM son el nuevo estándar de manejo adyuvante. En la mujeres premenopáusicas y en el escenario adyuvante, la castración médica gracias a los análogos LH-RH más Tamoxifén en adición a la quimioterapia mejora el pronóstico. Todos estos datos emergen de los sucesivos meta-análisis realizados que son consistentes en con-firmar el beneficio de la hormonoterapia en las pacientes con receptores hormonales positivos en términos de sobrevida, sobrevida libre de enfermedad, índice de recurrencia locorregio-nal y a distancia. En la enfermedad metastásica, la posición de Tamoxifén es de franca competen-cia con los inhibidores de aromatasa ya que estos son tan activos e incluso mejores que el Tamoxifén. Este trabajo revisa los paradigmas actuales en la hormonoterapia en los escenarios adyuvante, neoadyuvante, enfermedad metastásica y quimio-prevención, los datos publicados que han afectado los patrones de nuestra práctica oncológica y las controversias actuales. Palabras Clave: Hormonoterapia, Tamoxifén, inhibidores de aromatasa.