Advances in endocrine therapy for breast cancer: considering efficacy, safety, and quality of life

Breast cancer is the most common cancer found in women in the United States. Endocrine therapy is the standard of care for most women with hormone receptor-positive tumors in adjuvant and metastatic settings. The selective estrogen response modifier tamoxifen has been the standard treatment for postmenopausal patients for many years. Numerous new endocrine therapy agents provide women with novel treatment options, including the nonsteroidal aromatase inhibitors anastrozole and letrozole, the steroidal aromatase inhibitor exemestane, and the estrogen receptor antagonist fulvestrant. Clinical trials have begun to define the role of these agents and their unique side-effect profiles. Nurses are vital in supporting patients in the decision-making process, managing side effects of treatment, and making observations to enhance understanding of the patient experience with new treatments. This article will assist nurses in educating patients about endocrine therapy options and their associated potential short- and long-term side effects, as well as treatment demands.     

Historical perspective on hormonal therapy of advanced breast cancer

Background: Endocrine therapy is the preferred first-line therapy in patients with nonaggressive, receptor-positive, metastatic breast cancer. Endocrine therapies in these patients are as effective as chemotherapy in terms of survival and tumor response. In addition, hormonal therapies produce fewer and less severe adverse effects than does chemotherapy. Classes of endocrine therapy currently on the market include selective estrogen receptor modulators (SERMs), aromatase inhibitors, and progestins. For several decades, tamoxifen has been considered the gold standard of therapy. However, despite its proven efficacy, a high proportion of patients do not respond. Therefore, a need exists for alternative therapies or for agents to use following tamoxifen failure.Objective: This review article highlights the various endocrine options available for patients with advanced breast cancer and discusses new agents on the horizon.Conclusions: Although more studies are needed to determine the optimal sequence of hormonal therapy and the ideal agent within each class, the availability of new and multiple options is encouraging for women with advanced breast cancer.     

Endocrine therapy in cancer.

A proportion of cancers in endocrine target tissues can show the presence of specific receptors for either steroid or polypetide hormones. Manipulation of the controlling hormones does not guarantee regression. A third of cancers in endocrine target organs (breast, uterine endometrium, and prostate) show a 50% reduction in size of lesions after hormonal therapy. If regression resulting from an aggressive form of therapy lasts a short while and the tumor reactivates by the time the unpleasant effects of the therapy wear off, the treatment is not palliative. Endocrine therapy in prostatic cancer is palliative but there is no evidence that is increases survival. 11 different progestational agents in endometrial cancer therapy in the past 25 years resulted in a 30-35% response. Response must be maintained by continual treatment and may last from 12 months to 7-8 years. In breast cancer, tumors with a significant level of estrogen receptor (ER+) have about a 60% chance of regression vs. tumors without estrogen receptors (ER-), 10%. Advanced cancers of the thyroid of the papillary or follicular type regress when the patient is treated by thyroxine, .3 mg daily. Leukemia and lymphoma are frequently treated, with varying degrees of success with corticosteroid therapy, which may also predispose the patient to intercurrent infection. Renal cancer has been often treated by medroxyprogesterone acetate or testosterone propionate, with little success.     

男性乳腺癌54例临床分析

目的探讨男性乳腺癌的临床特点、诊断、治疗及预后情况。方法回顾性分析本院收治的54例男性乳腺癌的临床资料。结果病理类型、肿瘤分期及ER表达为影响男性乳腺癌预后的重要因素。结论早期诊断和治疗是提高男性乳腺癌生存率的关键。治疗上应以手术为主的综合治疗。同时要重视ER表达阳性者的内分泌治疗。     

Role of aromatase inhibitors in the treatment of breast cancer

BACKGROUND: Estrogens play a pivotal role in the development of breast cancer. Endocrine therapy based on estrogen blockade is a well-established treatment in hormone-dependent breast cancer. Tamoxifen citrate has long been considered the "gold standard" due to its relative safety and efficacy. Aromatase inhibitors are anti-estrogen agents that target specifically the aromatase enzyme, which is the final step in the estrogen production. The first use of aromatase inhibitors in breast cancer was associated with adverse effects such as rash, drowsiness, and adrenal-gland suppression. Newer third-generation agents are emerging as potential alternatives to tamoxifen, associating clinical efficacy with a more favorable safety profile. OBJECTIVES: The aim of this article is to review the mechanisms of actions pharmacology, adverse effects, and clinical applications of the aromatase inhibitors available in the United States. METHODS: The terms breast cancer or neoplasia, aromatase, aromatase inhibitors, third-generation, endocrine therapy, and antiestrogens were used to search MEDLINE for English-language studies published between 1966 and April 2004. A parallel search was performed at the corresponding Web site of each of the aromatase inhibitors available in the United States. Identified publications relevant to the article objectives were selected. RESULTS: Anastrozole, letrozole, and exemestane are the 3 commercially available aromatase inhibitors approved by the US Food and Drug Administration for the treatment of hormone receptor-positive breast cancer in postmenopausal women. They have been used in several clinical scenarios, including advanced and early disease and chemoprevention, and in the neoadjuvant setting. There is evidence that aromatase inhibitors are more effective and tolerable than tamoxifen in advanced breast cancer and in the neoadjuvant setting. Based on the results of a large, randomized trial, their use in early disease and in chemoprevention is also promising. Aromatase inhibitors appear safe; however, the long-term safety profile is still unknown, especially concerning bone metabolism. CONCLUSION: Third-generation aromatase inhibitors are a new treatment modality in estrogen and/or progesterone-receptor positive breast cancer. Although they are replacing the "classic" antiestrogen agents used in metastatic breast cancer, their benefit in early disease and as chemopreventive agents is not completely clear. Ongoing clinical studies should become available within the next few years and will provide additional recommendations for their use in patients with breast cancer.     

Estrogen replacement and migraine aura

OBJECTIVE: To assess the association between estrogen replacement therapy and migraine aura. BACKGROUND: Estrogen replacement therapy is increasingly used by perimenopausal and postmenopausal women for management of menopausal symptoms and for long-term protection against osteoporosis and arterial disease. There are few reports about the effects of estrogen replacement therapy on migraine. METHOD: Case reports were collected from women developing migraine aura related to use of estrogen replacement therapy. RESULTS: Four patients who developed migraine aura associated with the use of estrogen replacement therapy are described. In all cases, reducing the dose of estrogen or changing the route of delivery was associated with loss of aura. CONCLUSION: These findings suggest that high levels of estrogen in women using replacement therapy can trigger migraine aura.     

Existing and emerging endocrine therapies for breast cancer

Endocrine therapy is first-line therapy for patients with estrogen receptor-positive or progesterone receptor-positive metastatic breast cancer. Commonly used endocrine therapies are tamoxifen, megestrol acetate, and aromatase inhibitors. Although tamoxifen and megestrol acetate have a favorable therapeutic profile, there are risks associated with these agents. With tamoxifen, the partial agonist property can lead to thromboembolic events. An important adverse event of megestrol acetate is weight gain and fluid retention in some patients. The aromatase inhibitors are currently used as second-line therapy after tamoxifen failure. A recent study showed that anastrozole, an aromatase inhibitor, is as effective or even superior to tamoxifen when used as a first-line therapy. However, not all patients will respond to currently available therapies. A new class of drug, the estrogen receptor downregulators, has been developed. Fulvestrant, the first agent in this new class, not only induces the degradation of the estrogen receptor but also is an estrogen antagonist; further, its lack of agonist activity provides a better safety profile. Two phase III trials have proven that fulvestrant is at least as effective as anastrozole in postmenopausal women with advanced breast cancer. Fulvestrant is an effective and safe endocrine therapy for postmenopausal women who have failed prior endocrine therapy.     

Diagnosis and Treatment of Genitourinary Syndrome of Menopause

Genitourinary syndrome of menopause (GSM), formerly referred to as vulvovaginal atrophy or atrophic vaginitis, is a common chronic condition that requires a collaborative treatment plan between a health care provider and a woman to relieve symptoms and improve quality of life. Many women are not aware that symptoms can be controlled with treatment. Current treatment options approved for GSM include vaginal moisturizers, lubricants, and hormones. For women with GSM symptoms that are unresponsive to nonhormonal therapy, low-dose vaginal estrogen therapy is the preferred pharmacologic treatment. Clinicians should be trained to routinely ask appropriate questions during the history to elicit sufficient information to assess for GSM. Physical examination findings may further confirm suspicion of GSM.     

Hormonal Changes Throughout Life in Women

The changes in hormonal milieu associated with menarche, pregnancy, lactation, and menopause are frequently accompanied by changes in the patterns and frequency of migraine. Migraine headache is more common in females and, for many women, the onset of this condition occurs at menarche. As many as 60% of women migraineurs report an association between migraine and menstruation, and evidence suggests that estrogen withdrawal may be a trigger for menstrual migraine in susceptible women. Moreover, in the majority of women, migraine frequency increases during the pill-free interval with oral contraceptive use and during the postpartum period, which are other times of decreasing estrogen levels. Migraine frequency tends to decrease during periods of increasing or stable estrogen levels. For these reasons, the numerous neuroendocrine effects elicited by estrogen have been evaluated to explain its role in migraine. Overall, estrogen appears to be a key factor in menstrual migraine, but it is likely to be only one of several factors that act in concert to trigger migraine in susceptible women. Understanding the relationship of the different hormonal milieus through the natural course of women's lives can guide diagnosis and treatment.     

Estrogen in Cardiovascular Disease during Systemic Lupus Erythematosus

PurposeSystemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease that disproportionately affects women during their childbearing years. Cardiovascular disease is the leading cause of mortality in this patient population at an age when women often have low cardiovascular risk. Hypertension is a major cardiovascular disease risk factor, and its prevalence is markedly increased in women with SLE. Estrogen has traditionally been implicated in SLE disease progression because of the prevalence of the disease in women; however, its role in cardiovascular risk factors such as hypertension is unclear. The objective of this review is to discuss evidence for the role of estrogen in both human and murine SLE with emphasis on the effect of estrogen on cardiovascular risk factors, including hypertension.MethodsPubMed was used to search for articles with terms related to estradiol and SLE. The references of retrieved publications were also reviewed.FindingsThe potential permissive role of estrogen in SLE development is supported by studies from experimental animal models of lupus in which early removal of estrogen or its effects leads to attenuation of SLE disease parameters, including autoantibody production and renal injury. However, data about the role of estrogens in human SLE are much less clear, with most studies not reaching firm conclusions about positive or negative outcomes after hormonal manipulations involving estrogen during SLE (ie, oral contraceptives, hormone therapy). Significant gaps in knowledge remain about the effect of estrogen on cardiovascular risk factors during SLE. Studies in women with SLE were not designed to determine the effect of estrogen or hormone therapy on blood pressure even though hypertension is highly prevalent, and risk of premature ovarian failure could necessitate use of hormone therapy in women with SLE. Recent evidence from an experimental animal model of lupus found that estrogen may protect against cardiovascular risk factors in adulthood. In addition, increasing evidence suggests that estrogen may have distinct temporal effects on cardiovascular risk factors during SLE.ImplicationsData from experimental models of lupus suggest that estrogens may have an important permissive role for developing SLE early in life. However, their role in adulthood remains unclear, particularly for the effect on cardiovascular disease and its risk factors. Additional work is needed to understand the effect of estrogens in human SLE, and preclinical studies in experimental models of SLE may contribute important mechanistic insight to further advance the field.     

Managing menopause

Many women will spend one third of their lifetime after menopause. A growing number of options are available for the treatment of menopausal symptoms like vasomotor instability and vaginal atrophy, as well as the long-term health risks such as cardiovascular disease and osteoporosis that are associated with menopause. Currently, hormone replacement therapy (estrogen with or without progestin) is the primary treatment for the symptoms and long-term risks associated with menopause. However, recent evidence calls into question the protective effect of estrogen on cardiovascular disease risk. The association of risk for breast cancer with estrogen replacement therapy also has not been fully clarified. In addition, many women cannot or choose not to take hormones. For treatment of osteoporosis and heart disease, pharmacologic choices include antiresorptive agents such as bisphosphonates and calcitonin, and estrogens or selective estrogen receptor modulators such as raloxifene. In addition, complementary options that include vitamins, herbal treatments, exercise and other lifestyle adaptations are gaining increased interest. The growing number of choices and questions in this area emphasizes the need to individualize a treatment plan for each woman to meet her specific needs.     

低剂量雌激素替代疗法对围绝经期症状及激素水平的影响

目的探讨低剂量雌激素替代疗法对围绝经期症状及激素水平的影响。方法将120例围绝经期综合征患者随机分为2组,每组60例。治疗组给予低剂量雌激素治疗,对照组给予安宫黄体酮,观察2组患者雌二醇(E)、促卵泡素(FSH)、黄体生成素(LH)、骨密度值、更年期症评分、阴道评分、子宫内膜厚度以及并发症等指标。结果 2组患者治疗后E、FSH、LH、骨密度值、更年期症状评分、阴道评分均较治疗前显著改善,但2组之间无显著差异。治疗组不良反应发生率显著低于对照组。结论低剂量雌激素替代疗法治疗围绝经期症状具有显著疗效,能有效改善患者的更年期症状,不良反应少,适于临床推广应用。     

Postmenopausal estrogen therapy and serum estradiol fatty acid esters in women with and without previous intrahepatic cholestasis of pregnancy

BACKGROUND. Fatty acid esters of 17β‐estradiol (E2) are estrogen metabolites associated with lipoproteins in blood.

AIM. To study the effects of estrogen therapy on concentrations of serum E2 fatty acid esters in postmenopausal women with a history of an estrogen‐related liver disorder, intrahepatic cholestasis of pregnancy (ICP), and in healthy women in a double‐blind, crossover fashion.

METHOD. ICP (n?=?10) and control women (n?=?10) received increasing doses of E2 valerate orally 2–4?mg/day, or transdermal E2 50–100?μg/day for 6 weeks. After a 4‐week wash‐out period, the subjects crossed over to the alternate E2 treatment. Concentrations of serum E2 fatty acid esters were quantified after saponification by fluoroimmunoassay.

RESULTS. Oral E2 administration increased median serum E2 fatty acid ester concentrations from 57 to 73?pmol/L in the ICP and from 56 to 74?pmol/L in the control group, in association with elevations in serum E2, estrone and sex hormone‐binding globulin levels. Transdermal E2 treatment did not increase serum E2 ester levels.

CONCLUSIONS. The increase in serum E2 fatty acid esters during oral E2 administration may be attributed, at least partly, to the higher estrogen dose during oral compared with transdermal therapy. A history of ICP did not affect esterification of E2 during estrogen therapy.     

Effect of Estrogen Depletion on Pain Sensitivity in Aromatase Inhibitor–Treated Women With Early-Stage Breast Cancer

Aromatase inhibitors (AIs), which are used to treat breast cancer, inhibit estrogen production in postmenopausal women. AI-associated musculoskeletal symptoms occur in approximately half of treated women and lead to treatment discontinuation in 20 to 30%. The etiology may be due in part to estrogen deprivation. In premenopausal women, lower estrogen levels have been associated with increased pain as well as with impairment of descending pain inhibitory pathways, which may be a risk factor for developing chronic pain. We prospectively tested whether AI-induced estrogen deprivation alters pain sensitivity, thereby increasing the risk of developing AI-associated musculoskeletal symptoms. Fifty postmenopausal breast cancer patients underwent pressure pain testing and conditioned pain modulation (CPM) assessment prior to AI initiation and after 3 and 6 months. At baseline, 26 of 40 (65%) assessed patients demonstrated impaired CPM, which was greater in those who had previously received chemotherapy (P = .006). No statistically significant change in pressure pain threshold or CPM was identified following estrogen deprivation. In addition, there was no association with either measure of pain sensitivity and change in patient-reported pain with AI therapy. AI-associated musculoskeletal symptoms are not likely due to decreased pain threshold or impaired CPM prior to treatment initiation, or to effects of estrogen depletion on pain sensitivity.PerspectiveThis article presents our findings of the effect of estrogen deprivation on objective measures of pain sensitivity. In postmenopausal women, medication-induced estrogen depletion did not result in an identifiable change in pressure pain threshold or CPM. Impaired CPM may be associated with chemotherapy.     

Management of the adverse effects of lenalidomide in multiple myeloma

The introduction of new agents in the treatment of multiple myeloma, such as thalidomide, bortezomib, or lenalidomide, has represented an important step forward in the management of this disease, with improvement in both treatment response and patient survival. On the other hand, when new drugs are used it is very important to know their associated toxicity, since adequate management of the adverse effects can help to avoid unnecessary treatment interruptions - thereby undoubtedly contributing to improvement in the efficacy of therapy. The present study reviews the main hematological and nonhematological adverse effects potentially associated with the use of lenalidomide in its most common combinations used for the treatment of multiple myeloma, and the recommendations for dealing with such effects.     

结合雌激素治疗儿童造血干细胞移植后出血性膀胱炎

目的:观察结合雌激素对异基因造血干细胞移植受者术后出血性膀胱炎的临床疗效和不良反应.方法:8例异基因造血干细胞移植受者,在移植后并发出血性膀胱炎,给予结合雌激素治疗,10岁以下患儿1.25 mg/次,2次/天,口服;10岁以上患儿2.5 mg/次,2次/天,口服.在临床显效和有效后逐步减量至停药,平均疗程1～2周.结果:显效5例,有效1例,2例无效死亡,死于出血性膀胱炎和严重感染各1例;出现恶心、呕吐2例,男性乳房增大2例,停药后恢复正常.结论:结合雌激素治疗异基因造血干细胞移植术后受者出血性膀胱炎具较好疗效,不良反应轻微,可作为一种有效的辅助治疗方法.     

Effects of reciprocal treatment with estrogen and estrogen plus parathyroid hormone on bone structure and strength in ovariectomized rats.

Intermittent administration of PTH has been found to be an effective anabolic agent in cancellous bone. We have reported previously that combined treatment with PTH and estrogen in estrogen-deficient rats was beneficial in correcting established osteopenia. To determine if the beneficial effects of PTH therapy can be preserved by estrogen alone and whether PTH therapy can be effective in treating osteopenic subjects stabilized with estrogen, we have undertaken a "crossover" study in the rat model of estrogen-deficiency induced osteopenia. Six-month-old female rats were ovariectomized and after 5 wk treated for 8 wk with vehicle, 30 micrograms/kg per day of rPTH(1-34) plus 15 micrograms/kg per day of 17 beta-estradiol or 17 beta-estradiol alone. One group from each treatment regimen was then sacrificed and for an additional 8 weeks the remaining rats were (a) maintained on their previous treatment; (b) "crossed over" to their reciprocal treatment; or (c) administered vehicle only. At the end of this second 8-wk treatment period all rats were sacrificed. Bone mineral density of the distal femur, histomorphometric measurements of the proximal tibia and mechanical testing of the distal femur and selected vertebral bodies were performed. Our results demonstrated that (a) the gains in bone mass, trabecular connectivity and mechanical strength induced by PTH can be maintained by estrogen alone, but are reversed when both agents are withdrawn; and (b) rats with established osteopenia, maintained on estrogen treatment alone, can derive the full beneficial effects from the addition of PTH to the treatment at a later date. These data indicate that combined and/or sequential use of antiresorptive and anabolic agents may be a promising approach to the treatment of osteoporosis.     

Bone Health in Metastatic Cancer

ObjectiveThis article reviews the epidemiology and treatment of bone metastases. Also, it revisits the mechanism of action, indications, benefits, and complications of antiresorptive agents; discusses the adverse event profile of these agents; and addresses the prevention and management of these side effects.Data SourcesFor this review, peer-reviewed articles, research publications, and relevant clinical guidelines identified from PubMed were used.ConclusionBone metastases are common in advanced cancer and much more frequently than in primary bone cancer, especially in adults. Bisphosphonates and Denosumab are potent antiresorptives and significantly reduce the risk of skeletal-related events. These complications are related to poor quality of life, bone pain, functional disability, and decreased survival. Prolonged therapy with these antiresorptive agents in patients with advanced malignancy is generally well tolerated, but some side effects are potentially serious and require periodic monitoring. Furthermore, some of them can be avoided.Implications for Nursing PracticeThe role of health care providers and specially nurses on identifying patients at risk of complications from these antiresorptive agents, and providing information on how to prevent them, is essential for health and quality of life maintenance in these patients.