Changes in endocrine therapy: anastrozole and advanced breast cancer in postmenopausal women

Emerging data on endocrine therapies necessitates a re-evaluation of treatment strategies for advanced breast cancer. In this review, we present data from recent studies of the third-generation, nonsteroidal aromatase inhibitor (AI) anastrozole that illustrate its changing role in the treatment of postmenopausal women with advanced breast cancer. These studies demonstrate that anastrozole is now a treatment of choice as first-line therapy for patients presenting with advanced breast cancer and for patients who have progressed to advanced disease after adjuvant therapy with tamoxifen. A further trial has also shown that anastrozole is an effective and well-tolerated alternative to tamoxifen as adjuvant treatment for postmenopausal women with early breast cancer.     

Management of Advanced Breast Cancer

Breast cancer is the most common malignancy affecting women and imposes a substantial economic burden on society. Estrogen is thought to play a major role in both the initiation and promotion of hormone dependent breast cancer, and a number of well recognized risk factors for breast cancer reflect increased cumulative estrogen exposure (e.g. early menarche, late menopause).Metastatic breast cancer is an incurable condition and the goals of treatment are to relieve symptoms, improve health-related quality of life and prolong life. Women with hormone receptor-positive disease are candidates for hormonal treatment. In contrast, chemotherapy is traditionally the treatment of choice in those with hormone receptor-negative disease or symptomatic visceral disease.Anastrozole is a highly selective nonsteroidal type II aromatase inhibitor that suppresses plasma and intratumoral estrogen levels. The results of 2 multicenter, randomized, double-blind trials have shown anastrozole to be at least as effective as tamoxifen in the first-line treatment of postmenopausal women with advanced breast cancer, although survival data are lacking. In the smaller of these trials, the median time to disease progression was significantly prolonged (p = 0.005) in anastrozole, compared with tamoxifen, recipients (11.1 vs 5.6 months), although combined analysis of the 2 trials revealed no significant difference between an-astrozole and tamoxifen in terms of this end-point.Similarly, anastrozole has been shown to be at least as effective as megestrol in the second-line treatment of postmenopausal women with advanced breast cancer in 2 multicenter randomized studies. Combined analysis of the studies revealed a significant survival advantage (p < 0.025) for anastrozole 1 mg/day, compared with megestrol 40mg 4 times daily, recipients (estimated hazard ratio 0.78; 97.5% confidence interval 0.6 to <1).Tolerability is an important consideration in women with advanced breast cancer. The most common adverse events associated with anastrozole therapy were gastrointestinal disturbance, hot flushes, asthenia and pain. Anastrozole is associated with less vaginal bleeding and thromboembolic disease than tamoxifen and less bodyweight gain than megestrol. Anastrozole also appears to be a cost-effective option in the first- and second-line treatment of advanced breast cancer, although data are limited. Conclusion: Current treatment guidelines support the use of anastrozole in the second-line treatment of postmenopausal women with advanced breast cancer. Although current treatment guidelines do not yet reflect this, data from recent, well designed studies demonstrate that anastrozole is likely to be a viable alternative to tamoxifen in the first-line treatment of postmenopausal women with advanced breast cancer.     

Cost utility analysis of early adjuvant letrozole or anastrozole versus tamoxifen in postmenopausal women with early invasive breast cancer: the UK perspective

Five years with the aromatase inhibitors letrozole or anastrozole is clinically superior to 5 years tamoxifen in postmenopausal women with early breast cancer. This paper analyses the cost-effectiveness of the aromatase inhibitors compared to tamoxifen using the same health economic model. A Markov model describes lifetime incidence of breast cancer events and treatment-related adverse events. Probabilities of disease progression, adverse events, and utility values were estimated using secondary sources; costs of breast-cancer care were obtained from a primary costing study. The incremental cost per QALY gained of letrozole vs. tamoxifen is ￡10,379 (95% CI ￡6,705–23,574), and of anastrozole versus tamoxifen is ￡11,428 (95% CI ￡6,211–48,795). If a 5-year carry over effect for the reduction in breast cancer events is assumed, the incremental costs per QALY gained compared to tamoxifen are ￡6,253 (95% CI ￡3,675–14,766) for letrozole and ￡7,015 (95% CI ￡3,316–31,997) for anastrozole. Five years of letrozole or anastrozole therapy is cost-effective in postmenopausal women with early breast cancer. Though the respective confidence intervals show significant overlap, letrozole has a 95% probability of being more cost-effective than tamoxifen at a ￡20,000 QALY value, whilst anastrozole has an 85% probability.     

Optimal adjuvant hormone therapy in postmenopausal women with hormone-sensitive mammary carcinoma: tamoxifen and the aromatase inhibitors anastrozole, exemestane and letrozole

Postmenopausal patients with hormone-sensitive breast cancer may be eligible for adjuvant hormone therapy. - For years, tamoxifen was the treatment of choice. - However, the side effects associated with tamoxifen, such as endometrial cancer and thromboembolic disorders, and the search for more effective agents have led to the introduction of new hormonal therapies. - The results of randomised trials with the third-generation aromatase inhibitors anastrozole, exemestane and letrozole demonstrate improved efficacy compared to tamoxifen. - Using aromatase inhibitors, the disease-free survival is prolonged and recent data from some studies also show a benefit in overall survival. - Aromatase inhibitors are associated with specific side effects consisting of osteoporosis/increased incidence of fractures and myalgia/arthralgia.     

第三代芳香化酶抑制剂在绝经后乳腺癌新辅助内分泌治疗中的应用

乳腺癌新辅助内分泌治疗是指对非转移性的乳腺癌患者在应用局部治疗前进行的系统性的内分泌治疗.研究证实,第三代芳香化酶抑制剂（Aromatase inhibitors,AIs）应用于绝经后乳腺癌患者的新辅助内分泌治疗效果显著优于他莫西芬（Tamoxifen,TAM）,并且能够明显提高局部进展期乳腺癌（Locally advanced breast cancer,LABC）的手术切除率,改善巨大肿瘤和不可手术切除乳腺癌的外科治疗效果.     

The effect of hormone therapy on cognitive function in patients with breast cancer

Preclinical and clinical studies suggest that oestrogens have an important role in brain functioning and cognitive ability. Given that hormone therapies for breast cancer reduce oestrogen levels or block oestrogen receptors, it is conceivable that these agents also influence cognitive function. Several small studies have been conducted to address this issue, but many of them are methodologically insufficient. The negative effects of oophorectomy and luteinising hormone-releasing hormone (LHRH) analogues on verbal memory and working memory have been demonstrated the most consistently, albeit only in small studies. Anastrozole and tamoxifen also appear to exert some negative effect on cognition, but well-designed studies are lacking. No data are available on the influence of the aromatase inhibitors exemestane and letrozole on cognitive function. Raloxifene, a drug that has no obvious advantages over tamoxifen and will likely not be developed further for breast cancer treatment, has no negative influence on cognitive functioning. It remains unclear whether the observed effects are transient or permanent, and to what extent age, menopausal status and duration of therapy influence the severity of cognitive effects.     

Three men with breast cancer

In three men, aged 81, 66 and 58 years, breast cancer was diagnosed. All three were treated by modified radical mastectomy and axillary-node dissection. They received tamoxifen and the first and the third patient also received radiotherapy. Presentation of these patients is usually delayed, because of the rarity of and unfamiliarity with the disease. Consequently, the disease is often in a more advanced stage at presentation and overall mortality is higher in comparison with women with breast cancer. However, survival of male patients is similar to survival of female patients when matched for age and stage. This stresses the importance of a timely diagnosis. As in women, of the known risk factors for male breast cancer, a positive family history is one of the most important ones. Modified radical mastectomy, combined with sentinel-node biopsy by experienced teams, is the standard treatment. Criteria for adjuvant systemic treatment are identical for men and women, although hormonal therapy (tamoxifen) has a more prominent place in the adjuvant setting because of the high percentage of positive hormone receptors in men.     

Tamoxifen therapy in breast cancer control worldwide.

In most developed and many developing countries, breast cancer is the most frequent cancer and the leading cause of cancer death among women. At least 50% of all breast cancer patients worldwide would survive longer, however, if public awareness about and early detection of the condition were increased and greater use were made of efficient treatment of proven value. With early-stage, localized breast cancer, local treatment combined with adjuvant hormonal therapy with tamoxifen, a synthetic estrogen, could save the lives of 6 women out of 100 compared with local treatment alone. Tamoxifen has anti-estrogenic effects not only on breast cancer cells but also on liver metabolism and bone, with concomitant decreases in risk factors for chronic skeletal and vascular system diseases. Long-term tamoxifen treatment causes major adverse clinical effects in < 5% of women; menopausal and vasomotor symptoms occur in the majority of treated women, but their severity lessens over time. Tamoxifen is being considered as a standard therapy and is included in the WHO list of essential drugs for the treatment of breast cancer patients in both developing and developed countries. For the control of breast cancer more successfully worldwide, one challenge is to make tamoxifen therapy available to greater numbers of women.     

Current trends in pharmacotherapy of breast cancer

INTRODUCTION: Breast cancer is a systemic disease, unfortunately clinically undetectable micrometastases are present in many women even in early stages of the disease. Many of these patients can be cured with combined modality treatment of surgery, radiation and chemo- or hormone therapy. AIM: To survey the treatment of breast cancer. METHOD: The author presents an overview of the treatment of breast cancer based on the relevant literature and experience. RESULTS: Systemic adjuvant treatments include cytotoxic and hormone therapy. The most commonly used cytotoxic agents are cyclophosphamide, methotrexate, 5-fluorouracil, doxorubicin and epirubicin. The anthracycline-containing regimens are slightly superior, and the addition of taxane to an anthracycline-containing regimen may further increase the efficacy of adjuvant chemotherapy. Patients with metastatic disease cannot be cured, the goal of the treatment is to improve quality of life, and prolong survival. Up to 60-80% of these patients may experience objective tumor response to first-line combination chemotherapy. The taxanes (paclitaxel or docetaxel) with anthracyclines are the most active chemotherapy drugs against breast cancer. The best results are achieved with second-, third-line chemotherapy drugs: capecitabine, vinorelbine, gemcitabine, 5-fluorouracil and a variety of its oral pro-drugs. The most recent developments are represented by the biologically-targeted drugs, the first agent developed trastuzumab, has already been introduced in the clinic. The combination of chemotherapy with various response modifiers is a rapidly developing field of clinical cancer research. Several other new agents including growth factor receptor antagonists, tumor vaccines, antiangiogenic agents are tested in clinical trials alone and in combination with chemotherapy. CONCLUSIONS: The combination of chemotherapy with the new generation of drugs is a rapidly advancing and important field of clinical oncology.     

Hormone receptors and breast cancer--an occasional survey

Hormone receptors are proteins, localised in the membrane, cytosol, mitochondrion or nucleus of target cells; binding of hormone to the receptor leads to alterations in intracellular activity or growth. The development of antagonists which competitively bind to receptor sites has been used clinically to block, for example, the action of androgen, histamine, adrenaline and oestrogen. In patients with breast cancer, measurements of hormone receptor activity are valuable (1) in predicting which patients with advanced disease will respond to endocrine therapy, (2) as an additional independent guide to the patients' prognosis. The anti-oestrogen, tamoxifen has few side-effects and is therefore particularly useful in the treatment of advanced disease. In addition, two trials, performed in the USA, suggest that this receptor-blocker may be valuable in the adjuvant treatment of early disease. In the UK, further trials are underway to confirm this and to assess the relationship of hormone receptor status in the primary tumour to benefit from treatment.     

Breast cancer in patients, 70 years or older

Over 30% of breast cancers are diagnosed after age 70. The incidence of breast cancer in the elderly has increased since 1960. Risk factors for breast cancer are a medical history without pregnancy, a first pregnancy after age 30 and the use of hormonal replacement therapy. The biology of breast cancer at advanced age indicates a relative slow, less aggressive and hormone dependent tumour growth. In spite of these favourable characteristics, the prognosis is not better than at middle age. Over 20% of older patients die from co-existing other diseases within 5 years after the diagnosis of breast cancer. This comorbidity, mostly cardiovascular or pulmonary, affects the possibilities and the outcome of treatment. Treatment of the primary tumour is performed according to the same guidelines as in younger patients. Indication exists for hormonal adjuvant treatment with tamoxifen in patients with oestrogen receptor positive tumours. Hormonal treatment is the treatment of choice in metastatic disease. Chemotherapy is given in patients with oestrogen receptor negative tumours and in patients with progressive hepatic or pulmonary metastases.     

Prospects for the primary prevention of breast cancer.

In this paper, the rationale, stage of development, and known or potential adverse effects of three potential strategies for the prevention of breast cancer are reviewed. Two methods--the use of tamoxifen in postmenopausal women and the use of luteinizing hormone (LH)-releasing hormone agonists in premenopausal women--involve hormonal manipulation. In the premenopausal period, the goal is to reduce the number of ovulatory menstrual cycles a woman experiences in order to reduce her exposure to estrogen and progesterone. Physical activity during adolescence is proposed as a nonhormonal method of accomplishing this. The use of LH-releasing hormone agonists to produce a reversible menopause can also reduce a woman's cumulative exposure to ovarian steroid hormones. Tamoxifen, which is effective in breast cancer therapy, provides endocrine control of estrogen-regulated breast tumor growth. Breast cancer chemoprevention trials using tamoxifen among postmenopausal women have been proposed, and pilot studies are under way.     

Treatment of epithelial ovarian cancer

Epithelial ovarian cancer is the most lethal gynecological cancer among women. The median age at diagnosis is 63 years. The vast majority of patients present with advanced disease and require a combination of cytoreductive surgery and adjuvant chemotherapy. Important features that determine the outcome of treatment include the stage of disease, hystological type, grade and the size of the residual tumour after initial surgery. Current guidelines recommend that standard first-line chemotherapy should include a platinum-based regimen with paclitaxel. Despite the combined therapy, over 50% of all the patients has relapse. Relapsed ovarian cancer is incurable, however chemotherapy can improve quality of life and survival. Currently, there is no worldwide accepted standard treatment for patients with platinum-refractory ovarian cancer. Docetaxel, topotecan, gemcitabine, pegylated liposomal doxorubicin, etoposide and tamoxifen can be used in this group. However response duration rarely exceeds 12 months. Intraperitoneal chemotherapy, gene therapy, immunotherapy, signal transduction inhibitors (trastuzumab) and angiogenesis inhibitors (bevacizumab) are all potential future therapies, and are being investigated in ongoing clinical research. In this publication authors review the literature of current treatment options in epithelial ovarian carcinoma.     

Survival impact of tamoxifen use for breast cancer risk reduction: projections from a patient-specific Markov model.

The authors estimate tamoxifen's impact on life expectancy among healthy women. A Markov model compared the effects of 5 years of tamoxifen on survival among 50-year-old postmenopausal women. Scenarios were explored using alternative assumptions with regard to tamoxifen's long-term effects on breast and endometrial cancer. Postmenopausal women without a uterus had substantial life expectancy gains from tamoxifen (1 to 4 months), whereas women with a uterus had such gains only if they were at a very high breast cancer risk. If tamoxifen's impact on endometrial cancer persists after treatment is discontinued, women at high risk for endometrial cancer have life expectancy losses from tamoxifen unless they are at a very high risk for breast cancer. The authors conclude that tamoxifen use among postmenopausal women is associated with substantial life expectancy gains. However, this benefit is modulated in women at increased endometrial cancer risk and depends on assumptions concerning tamoxifen's lingering effects on breast and endometrial cancer.     

Comparison of adjuvant therapies using quality-of-life considerations.

The benefit for patients with operable breast cancer treated with adjuvant systemic therapy is small, if reduction of early mortality within the context of randomized control trials is used for treatment comparison. One might consider that the 75%-85% of patients who die despite treatment are overtreated, as are patients who remain alive even without therapy within a given time frame. Larger treatment benefits in terms of avoided or delayed breast cancer relapse have been demonstrated even at early phases of follow-up in the vast majority of adjuvant trials. Exposure of all patients to adjuvant therapy at a time at which no symptoms of disease are present is detrimental in terms of quality of life. Based on our assumption that the quality of life of the patient is typically altered both by subjective toxic effects of adjuvant treatment and by the appearance of relapse, we developed a method of comparing treatment effects in terms of time without symptoms of disease and toxicity of treatment (TWiST). Because the impact of treatment on relapse rates appears earlier than survival effects in all adjuvant therapy trials, and because the value of time without relapse in terms of the quality of life of the patients is as yet poorly defined, we have generalized our method of comparing treatment attitudes to include individual qualitative judgment values. The experience gained from integrating quality-of-life issues into clinical trials for breast cancer might also be applied to other diseases characterized by a chronic course, toxic treatments, and gains in periods of relative or absolute freedom from toxic effects and progressive disease.     

The status of hormone therapy in breast cancer in 2001?

Cancer of the breast represents in Tunisia and the most frequent female cancer in the world. Hormonotherapy is one of the main weapons of the medical treatment based on the blockage of hormonal action on the cellular growth. Endocrine therapy remains an essential part of treatment in both adjuvant and metastatic settings and is guided by the presence and degree of expression of estrogen receptor (ER) and progesterone receptor (PgR). Adjuvant 5-years tamoxifen (TAM) is still the standard therapy for postmenopausal ER and/or PgR positive women. In premenopausal women and in adjuvant setting, medical castration by LH-RH analogues plus Tamoxifen in addition to chemotherapy improve the prognosis. All these data arose from the successive meta-analyses done showing a benefit from hormonotherapy for patients with positive HR in term of survival, disease-free survival, loco-regional and distant relapse rate. In metastatic disease, the position of tamoxifen is presently in competition with the third generation antiaromatases that seems to be equally active as tamoxifen opening the way for its use for the future in adjuvant situations.     

孕激素与他莫西芬合用降低子宫内膜癌的风险

他莫西芬由于其本身的优势仍是激素依赖型转移性乳腺癌的一线治疗用药,也是雌激素受体阳性、原发性早期乳腺癌术后辅助内分泌治疗的首选药物。乳腺癌患者在长时间服用他莫西芬后,可增加发生子宫内膜癌的危险性。孕激素不仅可以治疗乳腺癌,而且在口服避孕药、雌孕激素替代疗法中,孕激素有保护子宫内膜的作用。该文意在探讨长期口服他莫西芬治疗的乳腺癌患者加服小剂量孕激素降低子宫内膜异常的风险。     

Cost-Effectiveness of Switching to Exemestane after 2 to 3 Years of Therapy with Tamoxifen in Postmenopausal Women with Early-Stage Breast Cancer

OBJECTIVES: Data from the Intergroup Exemestane Study (IES) suggest that switching to the aromatase inhibitor, exemestane, after 2 to 3 years of tamoxifen therapy prolongs disease-free survival versus continuing on tamoxifen therapy. We sought to evaluate the cost-effectiveness of this management strategy. METHODS: A Markov model was developed to predict patients' transitions across various health states based on treatment strategy (continuing tamoxifen vs. switching to exemestane), breast cancer status (no recurrence, local or distant recurrence, contralateral breast cancer), and other related health events (osteoporosis, endometrial cancer, death). Rates of disease-related events (recurrence and contralateral breast cancer) were estimated using data from the IES. Survival and lifetime medical-care costs by type of disease-related event were estimated using SEER-Medicare data. The model was used to estimate direct costs (in 2004 US dollars), life expectancy, quality-adjusted life-years (QALYs), and incremental cost-effectiveness. RESULTS: Switching to exemestane versus continuing tamoxifen therapy was associated with increased disease-free survival (181 vs. 172 months), QALYs (12.21 vs. 11.89), and net discounted lifetime costs of cancer care ($12,124 vs. $7724 per patient). The incremental cost-effectiveness ratio of exemestane was $20,100 per QALY gained (95% confidence interval: $12,100, $59,000). Sensitivity analyses showed that results were robust to plausible variations in recurrence rates, costs, and utilities. CONCLUSIONS: Switching postmenopausal early-stage breast cancer patients to exemestane after 2 to 3 years of tamoxifen appears to be a cost-effective treatment strategy versus completing a 5-year course of tamoxifen.     

Adjuvant therapy for breast cancer

Adjuvant therapy for breast cancer, a rapidly changing area of management, has made the difference to the breast cancer mortality figures over the last ten years. Initial treatments used hormonal manipulation such as ovarian ablation. This was followed by the development of tamoxifen, an oestrogen receptor antagonist. This has been followed by other hormonal regimes such as aromatase inhibitors, which have been used initially in the metastatic setting but are now being transferred to the adjuvant setting for post-menopausal women. Chemotherapy is used routinely for many breast cancers and is now well tolerated. Newer treatments include the use of taxanes and an antibody against HER-2 receptors; both of these are currently being evaluated in the adjuvant setting. Radiotherapy is a local adjuvant treatment that is given after breast conservation treatment surgery and in some cases is required after a mastectomy to decrease the risk of local recurrence.     

Dietary Supplement Use and Interactions with Tamoxifen and Aromatase Inhibitors in Breast Cancer Survivors Enrolled in Lifestyle Interventions

The use of dietary supplements is common in the general population and even more prevalent among cancer survivors. The World Cancer Research Fund/American Institute for Cancer Research specifies that dietary supplements should not be used for cancer prevention. Several dietary supplements have potential pharmacokinetic and pharmacodynamic interactions that may change their clinical efficacy or potentiate adverse effects of the adjuvant endocrine therapy prescribed for breast cancer treatment. This analysis examined the prevalence of self-reported dietary supplement use and the potential interactions with tamoxifen and aromatase inhibitors (AIs) among breast cancer survivors enrolled in three randomized controlled trials of lifestyle interventions conducted between 2010 and 2017. The potential interactions with tamoxifen and AIs were identified using the Natural Medicine Database. Among 475 breast cancer survivors (2.9 (mean) or 2.5 (standard deviation) years from diagnosis), 393 (83%) reported using dietary supplements. A total of 108 different types of dietary supplements were reported and 36 potential adverse interactions with tamoxifen or AIs were identified. Among the 353 women taking tamoxifen or AIs, 38% were taking dietary supplements with a potential risk of interactions. We observed a high prevalence of dietary supplement use among breast cancer survivors and the potential for adverse interactions between the prescribed endocrine therapy and dietary supplements was common.